U.S. patent application number 17/378719 was filed with the patent office on 2021-11-04 for devices for gastrointestinal stimulation and uses thereof.
The applicant listed for this patent is OBERON SCIENCES ILAN LTD.. Invention is credited to Yaron Ilan.
Application Number | 20210338479 17/378719 |
Document ID | / |
Family ID | 1000005725226 |
Filed Date | 2021-11-04 |
United States Patent
Application |
20210338479 |
Kind Code |
A1 |
Ilan; Yaron |
November 4, 2021 |
DEVICES FOR GASTROINTESTINAL STIMULATION AND USES THEREOF
Abstract
A gastrointestinal stimulation devices including a random
stimulation delivery mechanism(s), configured to provide stimuli to
a bodily tissue in a vicinity of the stimulation capsule, the
provided random stimuli being characterized by a stimulation
parameter, and a control circuitry in communication with said
physical stimulation delivery mechanism, and configured to set and
alter the stimulation parameter non-systematically, thereby
altering the characterization of the stimuli provided to the bodily
tissue. The algorithm may be patient tailored, and may have a
learning machinery which responds to data being received from the
patient.
Inventors: |
Ilan; Yaron; (Kefar Tavor,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OBERON SCIENCES ILAN LTD. |
Kfar Tavor |
|
IL |
|
|
Family ID: |
1000005725226 |
Appl. No.: |
17/378719 |
Filed: |
July 18, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15738344 |
Dec 20, 2017 |
11116658 |
|
|
PCT/IL2016/050666 |
Jun 22, 2016 |
|
|
|
17378719 |
|
|
|
|
62185628 |
Jun 28, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61H 9/0078 20130101;
A61F 2007/0022 20130101; A61F 2007/0094 20130101; A61N 1/36002
20170801; A61H 2205/083 20130101; A61N 1/0509 20130101; A61H
2023/0209 20130101; A61H 2201/5007 20130101; A61H 2230/70 20130101;
A61H 2201/1207 20130101; A61H 2205/04 20130101; A61H 2201/5035
20130101; A61H 2201/0228 20130101; A61F 2007/0093 20130101; A61H
2205/02 20130101; A61H 2201/1685 20130101; A61H 2230/08 20130101;
A61H 2201/165 20130101; A61H 2230/705 20130101; A61F 2007/0095
20130101; A61H 2230/805 20130101; A61H 2201/0207 20130101; A61H
2201/5012 20130101; A61H 2201/501 20130101; A61H 23/02 20130101;
A61H 11/00 20130101; A61N 1/36034 20170801; A61N 1/36139 20130101;
A61H 2205/06 20130101; A61H 2011/005 20130101; A61F 7/00 20130101;
A61H 2201/5082 20130101; A61H 15/00 20130101; A61H 23/004 20130101;
A61H 2015/0042 20130101; A61H 2230/80 20130101; A61N 1/3756
20130101; A61N 2/006 20130101; A61F 7/12 20130101; A61F 2007/0228
20130101; A61H 23/0218 20130101; A61N 1/36007 20130101; A61N
1/36053 20130101; A61H 2201/0103 20130101; A61H 2201/0214
20130101 |
International
Class: |
A61F 7/12 20060101
A61F007/12; A61N 1/36 20060101 A61N001/36; A61H 23/00 20060101
A61H023/00; A61H 11/00 20060101 A61H011/00; A61H 9/00 20060101
A61H009/00; A61N 1/375 20060101 A61N001/375; A61N 1/05 20060101
A61N001/05; A61H 23/02 20060101 A61H023/02 |
Claims
1. A system for closed loop abdominal stimulation, comprising: an
update module, computationally configured to receive a plurality of
feature values, and provide stimulation parameters based thereon, a
sensor, configured to measure a physiological property, and provide
a signal indicative thereof, a stimulation device, comprising: a
stimulation inducer, configured to generate a stimulation action
based on stimulation parameters to affect a physiological change in
a target organ or organs; and a communication unit, configured to
allow transfer of data to the stimulation device for modifying one
or more stimulation parameters, and wherein the update module
comprises a processing circuitry, configured to: obtain a signal
from said sensor; determine stimulation parameters based on the
signal obtained from said sensor; and provide said stimulation
device with the determined stimulation parameters via said
communication unit, wherein said processing circuitry of said
update module is utilizing deep learning system, in which the
learning on some features is guided learning, while learning on
other features is unguided learning.
2. The system of claim 1, wherein the stimulation is provided for
achieving a desired physiological change.
3. The system of claim 1, wherein the desired physiological change
is a lowering of bodyweight, managing glucose levels, and/or
lowering blood pressure.
4. The system of claim 1, wherein the feature values are selected
from a list comprising: age, weight, periodic caloric intake and
output, gender, ethnicity, geography, pathological history/state,
temperature, metabolic rate, glucose levels, blood tests and any
physiological or pathological parameters that can be measured
whether directly or indirectly associated with the physiological
target.
5. The system of claim 1, wherein said stimulation inducer is
configured to affect a stimulation by providing a magnetic signal
to a target body part, using various types of rate and rhythms of
stimuli with various frequencies, amplitudes, durations, and
interval, in structured or random manner.
6. The system of claim 1, wherein said stimulation inducer is
configured to affect a stimulation by physical movement, using
various types of rate and rhythms of stimuli with various
frequencies, amplitudes, durations, and interval, in structured or
random manner.
7. The system of claim 1, wherein said stimulation inducer is
configured to affect a stimulation by electromagnetic signal
emission, using various types of rate and rhythms of stimuli with
various frequencies, amplitudes, durations, and interval, in
structured or random manner.
8. The system of claim 1, wherein said stimulation inducer is
configured to affect a stimulation by temperature alteration, using
various types of rate and rhythms of stimuli with various
frequencies, amplitudes, durations, and interval, in structured or
random manner.
9. The system of claim 1, wherein said stimulation inducer is
configured to affect a stimulation by including pressure, or using
various types of rate and rhythms of stimuli with various
frequencies, amplitudes, durations, and interval, in structured or
random manner.
10. The system of claim 1, wherein the sensor is configured to
measure temperature, oxygen levels, blood pressure, and/or blood
tests.
11. A stimulation device for abdominal stimulation, comprising: a
stimulation inducer, configured to generate a stimulation action
based on stimulation parameters to affect a physiological change in
a target region; and a communication unit, configured to allow
transfer of data between the stimulation device and an update
module; wherein the update module comprises a processing circuitry,
configured to: obtain a signal from a sensor indicative of a
physiological property; determine stimulation parameters based on
the signal obtain from said sensor; and provide said stimulation
device with the determined stimulation parameters via said
communication unit, wherein said processing circuitry of said
update module is utilizing deep learning system, in which the
learning on some features is guided learning, while learning on
other features is unguided learning.
12. The stimulation device of claim 11, having a form of a pill,
configured to be swallowed or transplantable and reach a target
body region within the digestive track.
13. The stimulation device of claim 11, having a form of a wearable
device, configured to be placed/held on/near a target body
region.
14. The stimulation device of claim 11, wherein said stimulation
inducer is configured to affect a stimulation by providing a
magnetic signal to a target body part, by physical movement, by
electromagnetic signal emission, by temperature alteration, and/or
by including pressure, or by any combination thereof.
15. The stimulation device of claim 11, wherein the sensor is
configured to measure, temperature, oxygen levels, pressure and/or
body weight.
16. A method for a continuous, semi-continuous, conditional, or
non-continuous closed loop abdominal stimulation, comprising:
providing/placing in a proximity of a target body part the
stimulation device of claim 11; providing initial stimulation
parameters to the stimulation device based on initial acquired
information and a desired physiological change; providing
stimulation via the stimulation inducer based on the initial
stimulation parameters; and obtain information from the user and/or
device or other sources, and update the stimulation parameters
based on the obtained information.
17. The method of claim 16, wherein the stimulation device is an
implantable device.
18. The method of claim 16, wherein the stimulation device is
configured to be swallowed by a user.
19. The method of claim 16, wherein the stimulation device is
configured to be placed on the body of the user.
20. The method claim 16, wherein the physiological change is a
reduction of weight and/or maintaining a weight loss and wherein
the method is for treatment of obesity, or any metabolic,
inflammatory, infectious malignant condition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/738,344 filed Dec. 20, 20217, which is a National Phase of PCT
Patent Application No. PCT/IL2016/050666 having International
filing date of Jun. 22, 2016, which claims the benefit of priority
of U.S. Provisional Application No. 62/185,628 filed on Jun. 28,
2015 entitled DEVICES FOR GASTROINTESTINAL STIMULATION AND USES
THEREOF. The contents of the above applications are all
incorporated by reference as if fully set forth herein in their
entirety.
FIELD
[0002] The present disclosure relates to medical devices configured
to stimulate the gastrointestinal tract and optionally other organs
through various stimuli including mechanical and electrical stimuli
for prevention of the adaptation of the human body to regular
stimuli.
BACKGROUND
[0003] The gut-brain axis is a bidirectional neuro-humoral
communication system that integrates brain and gastrointestinal
(GI) functions. The gut-brain axis is involved in a multitude of
physiological processes including, for example, satiety, food
intake, regulation of glucose and fat metabolism, and insulin
secretion. In addition, a growing body of research shows that a
gut-body communication axis also exists, where the gut affects
various bodily functions through neuro- and hormonal pathways.
[0004] The vagus nerve, through its afferents and efferents, is
thought to be one of the major conduits in these communication
systems. For example, it has been shown that the vagus nerve is
involved in anti-inflammatory responses. Studies have demonstrated
that stimulation of the left cervical vagus nerve trunk (in the
neck) using an electrode in various experimental models of
inflammation results in anti-inflammatory. These effects are
thought to be mediated via peripheral release of acetylcholine from
the vagus and subsequent activation of macrophages.
[0005] With respect to appetite and satiety, the alimentary canal
and its content are known to play a key role in mediating signals
involved in appetite and satiety control. For example, intrinsic
and extrinsic sensory neurons in the alimentary canal provide
information about visceral distension (which generally corresponds
to the volume of luminal contents), the chemical composition and
temperature of ingested material and its movement along the mucosal
surface of the gut. This input generates signals that regulate
intestinal motility, blood flow, secretion and absorption, and is
critical for normal digestion. In addition, hormones secreted from
the gut or other organs, such as the pancreas, in response to the
nutritional status of the body are involved in appetite and satiety
control.
[0006] Manipulation of the gut-brain axis was previously suggested
as a mean to control appetite and food absorption. Manipulation of
the gut-brain axis was also suggested as a mean to control
gastrointestinal (GI) motility. It was shown that mechanical
stimulation applied to the walls of the GI tract or a segment
thereof, for example, to the walls of the stomach, can affect
processes regulated in the digestive system and can be used to
induce such manipulations.
[0007] For example, gastric and intestinal electrical stimulation
has been suggested for treating obesity and gastrointestinal
dysmotility disorders, using implantable gastric pacemakers. The
electrical stimulation is typically delivered by means of
electrodes, implanted for example in the musculature of the gastric
wall, which are connected to a stimulator device placed
subcutaneously in the abdomen. For the treatment of gastric
dysmotility, the device is typically set to deliver electrical
pulses to the gastric and/or intestinal muscles with the objective
of stimulating gastrointestinal myoelectric activity, and thereby
alter the motility of the gastrointestinal tract. In the treatment
for obesity, the goal of gastric stimulation is usually to cause
early satiety and reduce appetite through electrical stimulation of
the gastric wall, intestines or vagal nerve. It has been suggested
that the pacemaker induces alterations in the secretion of hormones
associated with hunger or satiety.
[0008] Another example is intragastric balloons, which are
liquid-filled or air-filled balloons placed endoscopically in the
stomach of patients and left inflated for six months.
[0009] There is thus a need for more effective means to stimulate
different parts of the GI tract and optionally other body organs.
For example, it would be highly beneficial to have an external
device or an ingestible device having an optimized combination of
stimulation capabilities together with means of control, that may
be utilized to achieve long term, durable effects in various
clinical applications relating to the digestive system, as well as
in clinical conditions involving body parts outside the digestive
system.
SUMMARY
[0010] 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, not limiting in
scope. In various embodiments, one or more of the above-described
problems have been reduced or eliminated, while other embodiments
are directed to other advantages or improvements.
[0011] For some symptoms, it has been found that applying/providing
stimulation to target regions in the human body may be utilized for
affecting a treatment or for managing the symptom. Such
stimulations may be mechanical, electrical and/or thermal, and can
be provided by certain stimulation pattern such as pulses,
alternating waves or other patterns.
[0012] The human body and other organisms have mechanisms of
habituation, which is a form of learning in which the organism
decreases or ceases to respond to the stimulus after repeated
presentations. Essentially, the organism learns to decrease the
response, or even stop responding to the stimulus, which renders
the stimulation biologically irrelevant or less relevant.
[0013] As a result, applying stimuli utilizing repetitive patterns
may result in having the target organ be less responsive to the
stimulation treatment, thereby reducing the treatment efficacy.
[0014] The present disclosure provides, according to some aspects,
medical devices capable of stimulating a target organ, such as the
gastrointestinal tract, and their use for the treatment of various
clinical conditions for overcoming the adaptation of human organs
to procedures. Advantageously, the devices disclosed herein are
configured to alter parameters of the stimulation during their
operation, according to some embodiments; the disclosed herein are
configured to randomly alter parameters of the stimulation during
their operation. Moreover, most organs in the human body work
according to a regular pattern. Regular pattern, such as regular
electrical, endocrinological, cytokine patterns, or any other type
of pattern, are associated with the habituation of the body organs.
Irregular chaotic pattern is suggested to affect this
habituation.
[0015] Without wishing to be bound by any particular theory of a
mechanism of action, it is contemplated that the random (chaotic)
dynamics of the stimulation applied by the devices of the present
disclosure are configured such that to avoid/mitigate adaptation
and/or accommodation of the body/target organ to the delivered
stimuli, which may prevent their effect and/or reduce
responsiveness over time. The random dynamics of the stimulation
enables a sustained, prolonged effect on the target organ, and
according to some embodiments, aid in preventing weight regain, or
providing other treatment effects.
[0016] Advantageously, altering the stimuli parameters may reduce
and/or prevent the habituation from occurring in the target organ,
thereby increase the efficacy of the provided treatment. According
to some embodiments, altering the stimuli parameters may be done
randomly, or pseudo-randomly in a chaotic way.
[0017] According to some embodiments, the stimulation parameters
may include frequencies, intermittencies, amplitude, alteration,
shape of the stimuli signal, rise slope, fall slope and the like. A
random chaotic combination of several types of stimulations, such
as electrical, thermal, and like that, may further prevent the
adaptation of the target organ to stimuli.
[0018] In some embodiments, gastrointestinal (GI) stimulation
capsules or external wearable devices such as belts are provided,
such as swallowable capsules that propel along the GI tract of a
subject after they are swallowed and apply stimuli, e.g. mechanical
and/or electrical stimuli, or any other type of stimuli, to the
walls of the gastrointestinal tract. In other embodiments, external
devices are provided, such as belts, which induce various stimuli
from the outside.
[0019] In some embodiments, the present disclosure provides methods
for treating diseases, including for example inflammatory and
infectious diseases, using the devices disclosed herein. The
present disclosure discloses that systemic beneficial effects
induced by such devices can be utilized for the treatment of
various diseases, including diseases affecting organs and body
parts outside the digestive system. In some exemplary embodiments,
the present disclosure discloses the use of gastrointestinal
capsules in the treatment of inflammatory, infectious, autoimmune
and malignant diseases or disorders.
[0020] According to some embodiments, the present disclosure
discloses the use of gastrointestinal capsules for enhancing a
function and/or condition in the body of the user, even if the user
is not diseased.
[0021] The present disclosure provides, according to some
embodiments, gastrointestinal stimulation capsules or belts which
may be particularly useful for efficient treatment of
gastrointestinal motility disorders and/or obesity, and may also be
used for the treatment of other diseases or disorders. The improved
gastrointestinal capsules and belts disclosed herein are configured
to apply various stimuli on the GI tract of a subject, including
mechanical and/or electrical stimuli, and/or induction of
temperature alteration within the GI tract or any type of random
combination of any of these stimuli. The improved gastrointestinal
capsules or belts are further configured for dynamic alterations of
the parameters of the stimuli during their operation in order to
reduce/avoid habituation, thereby obtaining responsiveness for
prolonged periods of time, to achieve, for example, effective long
term weight loss, or long term proper GI motility. The present
disclosure discloses for the first time the use of temperature
alteration in a random way within the GI tract for the treatment of
GI disorders and obesity.
[0022] As used herein, and throughout the application, the term
"belt" may be replaceable with any wearable device.
[0023] According to one aspect, the present disclosure provides a
gastrointestinal capsule or outside wearable belt configured to
apply at least one physical stimulation selected from the group
consisting of mechanical stimulation and electrical stimulation to
a gastrointestinal tract wall (or a segment thereof) of a subject
when activated inside the gastrointestinal tract of the subject.
According to some embodiments, said capsule or belt comprises a
controller configured to alter at least one parameter of said at
least one physical stimulation during operation of the capsule
inside the gastrointestinal tract of the subject. According to some
embodiments, the controller is configured to dynamically alter at
least one parameter of the stimuli. According to some embodiments,
the controller is configured to randomly/pseudo-randomly alter at
least one parameter of the stimuli. According to some embodiments,
the controller is configured to randomly/pseudo-randomly alter a
random combinations of several parameters of several types of
stimuli.
[0024] As used herein, "configured to randomly alter at least one
parameter", when referring to the controller, means that the
controller is configured to alter parameter(s) of a stimulation
between randomly or pseudo-randomly selected values. For example,
the controller can be configured to alter the frequency of a
vibration stimulation between a first frequency and a second
frequency, wherein the second frequency is randomly selected by the
controller according to an algorithm. In some embodiments, the
first frequency is also randomly selected by the controller.
Alternatively, or additionally, the term means that the controller
is configured to alter parameter(s) of a stimulation at random time
points during the operation of the capsule inside a
gastrointestinal tract of a subject. For example, the controller
can be configured to alter the frequency of a vibration stimulation
between a first and second frequencies, e.g. about 0.1 to 60
minutes after activation of the capsule (after the beginning of
stimulation application by the capsule), wherein the time is
randomly selected by the controller. Similarly, the proprietary
algorithm of the controller can also select any combination of
different types of stimuli, and each of these types of stimuli by
itself is being controlled randomly. Thus, according to some
embodiments, the algorithm may provide random chaotic pattern of
combination of stimuli for which the parameters of each of the
types of stimuli is being randomly determined from the first beat
to the following one. In some embodiments, the capsule or the belt
are configured to apply a mechanical stimulation through vibration
of the capsule or the belt, and the at least one parameter is
vibration frequency.
[0025] Vibration frequency in the range of a few dozens of Hz
corresponds to the normal frequency of peristaltic activity of the
stomach and/or intestine. In some embodiments, the controller is
configured to randomly alter the vibration frequency between values
within the physiological range. In other embodiments, the
controller is configured to randomly alter the vibration frequency
between values below and above physiological values. In some
embodiments, the controller is configured to randomly alter the
vibration frequency between values ranging from about 0.01 to about
10,000 Hz or higher. In some embodiments, the controller is
configured to randomly alter the vibration frequency between values
ranging from about 0.01 to about 5,000 Hz, for example between
about 0.1-1000 Hz. Each possibility represents a separate
embodiment of the disclosure. In some embodiments, the controller
is configured to randomly alter the vibration frequency between
values ranging from about 1 to about 500 Hz. In some embodiments,
the controller is configured to randomly alter the vibration
frequency between values ranging from about 1 to about 50 Hz.
[0026] As used herein, the term "about", when referring to a
measurable value, is meant to encompass variations of +/-10% more
preferably +1-5%, even more preferably +/-1%, and still more
preferably +/-0.1% from the specified value, as such variations are
appropriate to achieve the intended purpose.
[0027] In some embodiments, the capsule or the belt are configured
to apply a mechanical stimulation through rotation of the capsule
or the belt, and the at least one parameter is rotation frequency.
In some embodiments, the controller is configured to randomly alter
the rotation frequency between values ranging from about 10,000
cycles/second to 1 cycle/minute. In some embodiments, the
controller is configured to randomly alter the rotation frequency
between values higher than about 10,000 cycles/second and values
lower than about 1 cycle/minute.
[0028] According to some embodiments, the capsule or the belt are
configured to apply a mechanical stimulation through a mechanical
movement of or within the capsule or the belt, for example through
rotation or vibration of the capsule or of the belt. According to
some embodiments, the pattern of the mechanical movement may be
altered, for example vibration direction, rotation axis or
others.
[0029] In some embodiments, the capsule or the belt are configured
to apply a mechanical stimulation through an inflatable-deflatable
balloon. In some embodiments, such capsule or the belt comprise a
capsule or belt body comprising the controller, and a balloon
functionally attached to said capsule body, said balloon is
operative to inflate or deflate in response to a command from the
controller, to thereby apply a mechanical stimulation to the
gastrointestinal wall of a subject. According to these embodiments,
the at least one parameter is a volume of the balloon, meaning that
the volume of the balloon does not remain constant throughout the
operation of the capsule or the belt. In some embodiments, the
balloon is configured to be in contact with the gastric wall or
intestinal wall (or portions thereof) upon its inflation. In some
embodiments, the volume of the balloon is randomly altered between
values ranging from about 10 ml to about 2000 ml, for example from
about 300 ml to about 800 ml, for example between about 400-700 ml.
Each possibility represents a separate embodiment of the present
disclosure.
[0030] In some embodiments, the capsule is configured to apply a
mechanical stimulation through vibration, rotation or a combination
thereof, optionally through vibration, rotation,
inflatable/deflatable balloon or a combination thereof.
[0031] In some embodiments, the capsule is configured to apply an
electrical stimulation and the at least one parameter is selected
from the group consisting of electric pulse frequency and electric
pulse intensity or the combination thereof. Each possibility
represents a separate embodiment of the disclosure.
[0032] The normal gastrointestinal myoelectric frequency is 3
cycles/minute (corresponds to 0.05 Hz). In some embodiments, the
controller is configured to randomly alter the parameter(s) of the
electrical stimulation between values within the physiological
range. In other embodiments, the controller is configured to
randomly alter the parameters(s) of the electrical stimulation
between values below and above physiological values.
[0033] In some embodiments, the electric pulse frequency is altered
between values ranging from about 0.01 to about 4000 Hz or even to
about 10000 Hz. In other embodiments, the electric pulse frequency
is altered between values in the range of about 0.00001-10000
Hz.
[0034] In some embodiments, the electric pulse intensity is altered
between values ranging from about 0.01 to about 10000 mA, for
example, from about 0.01 to about 500 mA.
[0035] In some embodiments, the frequency of the electric pulse is
altered between values ranging from once every 0.0001 seconds to
once every few hours.
[0036] In some embodiments, the capsule or the belt are further
configured to generate a local temperature alteration in the
immediate surroundings of the gastrointestinal capsule when the
capsule is activated inside a gastrointestinal tract of a
subject.
[0037] The capsule or the belt according to these embodiments may
create a hypothermic effect or a hyperthermic effect. In some
embodiments, the temperature ranges from about 4.degree. C. to
about 96.degree. C. In some embodiments, the temperature alteration
is induced for short periods of time, for example, several seconds
or shorter.
[0038] According to another aspect, the present disclosure provides
a gastrointestinal capsule or the belt configured to apply at least
one physical stimulation selected from the group consisting of
mechanical stimulation and electrical stimulation to a
gastrointestinal tract wall (or a segment thereof) of a subject
when activated inside the gastrointestinal tract of the subject,
said capsule comprises a controller configured to alter at least
one parameter of said at least one physical stimulation between
above and below physiological values during operation of the
capsule inside the gastrointestinal tract of the subject.
[0039] In some embodiments, the capsule is configured to apply a
mechanical stimulation through vibration of the capsule, and the at
least one parameter is vibration frequency.
[0040] In some embodiments, the controller is configured to alter
the vibration frequency between values lower than about 10 Hz to
values higher than about 100 Hz, for example, between values
ranging between about 0.01-10 Hz to values ranging between about
100-10,000 Hz.
[0041] In some embodiments, the capsule is configured to apply an
electrical stimulation and the at least one parameter is selected
from the group consisting of electric pulse frequency and electric
pulse intensity. According to some embodiments, electric
stimulation may include electric-field stimulation, magnetic-field
stimulation electromagnetic stimulation or any combination thereof.
Each possibility represents a separate embodiment of the present
disclosure.
[0042] In some embodiments, the controller is configured to alter
the electric pulse frequency between values lower than about 0.05
Hz to values higher than about 1 Hz, for example, between values
ranging between about 0.00001-0.05 Hz to values ranging between
about 1-10,000 Hz.
[0043] In some embodiments, the controller is configured to alter
the electric pulse frequency between values ranging from about 0.01
mA to about 10000 mA.
[0044] In some embodiments, the capsule or the belt are further
configured to generate a local temperature alteration in the
immediate surroundings of the gastrointestinal capsule when the
capsule or the belt are activated inside a gastrointestinal tract
of a subject. In some embodiments, the controller is configured to
generate a local temperature alteration between values ranging from
about 4.degree. C. to about 96.degree. C.
[0045] In some embodiments, the controller is configured to be
pre-programmed to alter the at least one parameter or any type of
combination of several parameters in a random chaotic way. In some
embodiments, the controller is configured to be pre-programmed to
alter the at least one parameter for each of the types of stimuli
in a random chaotic way.
[0046] In other embodiments, the controller is configured to
receive commands from an external source to alter the at least one
parameter.
[0047] According to another aspect, the present disclosure provides
a gastrointestinal capsule or belt configured to generate a local
temperature alteration in the surroundings of the gastrointestinal
capsule or belt when activated inside a gastrointestinal tract of a
subject.
[0048] In some embodiments, the temperature ranges from about
4.degree. C. to about 96.degree. C. In some embodiments, the
capsule or the belt are configured to induce the temperature
alteration for short periods of time, for example about several
seconds or less.
[0049] In some embodiments, the controller is configured to be
pre-programmed to generate the local temperature alteration.
[0050] In other embodiments, the controller is configured to
receive commands from an external source to generate the local
temperature alteration.
[0051] In some embodiments, the controller is configured to be
pre-programmed according to the subject physiological parameters
including body weight, metabolic and cardiovascular status, and any
other physiological parameter. The controller provides an algorithm
which is based on these parameters and is thus
patient-tailored.
[0052] In some embodiments, the controller is configured to receive
data from the target organ, for example by sensing of biological
indications.
[0053] In some embodiments, the controller is configured to have a
learning machinery such that the stimuli generated are altered
based on the data being received from different organs in the
body.
[0054] In some embodiments, the capsule or the belt are further
configured to apply at least one physical stimulation selected from
the group consisting of mechanical stimulation and electrical
stimulation to a gastrointestinal wall (or a segment thereof) of a
subject.
[0055] In some embodiments, the capsules or the belts are of the
present disclosure further comprise one or more arms configured to
extend and anchor the capsules at a selected location within the GI
tract.
[0056] In some embodiments, the position of the arms relative to
the capsule body can be changed during the operation of the capsule
between open and closed positions. In some typical embodiments, the
extent to which the arms can be opened up ranges from 0% (arms
closed, placed along the capsule body) to 100% (arms extend
outwards, perpendicular to the capsule body). In some embodiments,
the extent to which the arms are opened up is determined according
to the diameter of a specific target area within the GI tract.
[0057] In some embodiments, operation or activation of the capsules
disclosed herein is set to commence after a defined time-period
following ingestion thereof, such that the capsule is activated as
it reaches a target segment within the GI tract. The delay can
range from a few seconds to a few hours. For example, for
activation in the stomach, the capsule may be programmed to
activate automatically within 1-10 seconds, or 15 minutes after
ingestion.
[0058] According to yet another aspect, the present disclosure
provides a stimulation device comprising an attachment element
configured to be externally affixed to a subject's abdomen or any
other area of the human body including the head, neck, arms, and
legs, a stimulation module configured to apply a stimulation, e.g.,
mechanical and/or electrical stimulation, to at least a segment of
the subject's abdomen or any other organ; and a controller
configured to randomly alter at least one parameter, or any random
combinations of parameters, of said mechanical and/or electrical
stimulation during operation of the device. According to some
embodiments, randomly altering the at least one parameter, or any
random combinations of parameters, of mechanical and/or electrical
stimulation comprises altering between above and below a
physiological value. According to some embodiments, the attachment
element is in the form of a belt, a strap, a sticker or any
combination thereof.
[0059] According to yet another aspect, the present disclosure
provides an external device configured to be affixed to a subject's
abdomen or any other organ of the body, and apply at least one
physical stimulation selected from the group consisting of
mechanical stimulation and electrical or any other type of
stimulation to a segment of the subject's body, said device
comprises a controller configured to randomly alter at least one
parameter of said at least one physical stimulation during
operation of the device.
[0060] According to yet another aspect, the present disclosure
provides an external device configured to be affixed to a subject's
abdomen or any other organ, and apply at least one physical
stimulation selected from the group consisting of mechanical
stimulation and electrical stimulation, or any random combinations
of these stimuli, to a segment of the subject's abdomen or any
other organ, said device comprises a controller configured to alter
at least one parameter of said at least one physical stimulation
between above and below physiological values during operation of
the device.
[0061] In some embodiments, the external device configured to be
affixed to a subject's abdomen, or to any organ, is in the form of
a belt.
[0062] In some embodiments, the devices disclosed herein are
configured to induce a continuous stimulation. In other
embodiments, the devices are configured to induce an intermittent
stimulation. As used herein, "an intermittent stimulation"
indicates a stimulation characterized by active periods ("on"
periods) interleaved by pauses ("off" periods). According to these
embodiments, the at least one altered parameter may comprise the
"on" and "off" time periods. For mechanical stimulation applied by
vibration and/or rotation, the "on" period is the period in which
the capsule or the belt vibrates and/or rotates. When mechanical
stimulation is applied through a balloon, the "on" period refers to
the period in which the balloon is inflated. For electrical
stimulation, the "on" period refers to the period in which
electrical pulses are delivered.
[0063] The active period may range from a few parts of a second to
a few dozens of minutes. The pauses may also range from a few parts
of a second to a few dozens of minutes or hours.
[0064] In some embodiments, the controller is configured to be
pre-programmed to randomly alter the at least one parameter.
[0065] In some embodiments, the controller is configured to be
pre-programmed to randomly alter a combination of parameters for
which each is being altered in a random chaotic way every part of a
second to every few minutes or hours.
[0066] In other embodiments, the controller is configured to
receive commands from an external source to alter at least one
parameter to a random value.
[0067] In some embodiments, the devices described herein are
configured to stimulate at least one part of the gastrointestinal
tract selected from the group consisting of the mouth, esophagus,
stomach, duodenum, small intestine, large intestine colon and
rectum. Each possibility represents a separate embodiment of the
disclosure.
[0068] In some embodiments, the devices described herein are
configured to receive data from the target organs, by utilizing
sensor(s) for obtaining measurements related to the activity of the
target organ.
[0069] In some embodiments, the devices described herein are
configured to change the algorithm based on the data being received
from the target organ.
[0070] In some embodiments, the devices are used for the treatment
of obesity or overweight.
[0071] In additional embodiments, the capsules or belts devices are
used in the treatment of a gastrointestinal disease or disorder
selected from the group consisting of gastroparesis, constipation,
and intestinal pseudo-obstruction. Each possibility represents a
separate embodiment of the disclosure.
[0072] In some embodiments, there is provided herein a method for
treating a clinical condition selected from the group consisting of
obesity and a GI motility disorder in a subject in need thereof,
the method comprising introducing a gastrointestinal capsule as
described herein into a gastrointestinal tract of the subject, and
activating the gastrointestinal capsule.
[0073] In additional embodiments, a method is provided for treating
a clinical condition selected from the group consisting of an
inflammatory disease, an infectious disease, an autoimmune disease,
a metabolic disease and a malignant disease, the method comprising
introducing a gastrointestinal capsule into a gastrointestinal
tract of a subject in need thereof, said capsule or belt are
configured to apply at least one physical stimulation to a
gastrointestinal tract wall when activated inside the
gastrointestinal tract, the at least one physical stimulation is
selected from the group consisting of mechanical stimulation,
electrical stimulation and local temperature alteration; and
activating said gastrointestinal capsule or belt.
[0074] In some embodiments, a method is provided for treating a
clinical condition selected from the group consisting of an
inflammatory disease, an infectious disease, an autoimmune disease,
a metabolic disease, including for example diabetes type 1 and type
2, atherosclerosis, and any type of heart disease, and a malignant
disease, the method comprising affixing an external device to a
subject's abdomen, said external device is configured to apply at
least one physical stimulation selected from the group consisting
of mechanical stimulation and electrical stimulation to a segment
of the subject's abdomen when affixed to said segment and
activated; and activating said external device.
[0075] In some embodiments, the clinical condition is an
inflammatory disease. In some embodiments, the inflammatory disease
is an inflammatory bowel disease. In some embodiments, the
inflammatory disease is a TNF-mediated inflammatory disease.
[0076] In some embodiments, the clinical condition is an infectious
disease. The infectious diseases that can be treated include
bacterial, viral, fungal and parasitic infections. Each possibility
represents a separate embodiment of the disclosure. In some
embodiments, the infectious disease is an infection of the
gastrointestinal tract (chronic or acute). In other embodiments,
the infectious disease is an infection outside the gastrointestinal
tract. In some embodiments, the infectious disease is a systemic
infection.
[0077] In some embodiments, the clinical condition is an autoimmune
disease.
[0078] In some embodiments, the clinical condition is a metabolic
disease. In some embodiments, the metabolic disease is
diabetes.
[0079] In some embodiments, the clinical condition is a malignant
disease. In some embodiments, the malignant disease is a malignancy
of the gastrointestinal tract, such as malignancy of the gut. In
some embodiments, the malignancy of the gut is selected from the
group consisting of a precancerous condition, polyp, primary tumor
and secondary tumor. Each possibility represents a separate
embodiment of the present disclosure.
[0080] In other embodiments, the malignant disease is a malignancy
outside the gastrointestinal tract, of body parts other than the
gastrointestinal tract.
[0081] In some embodiments, the malignant disease is a malignancy
of the gallbladder. In additional embodiments, the malignant
disease is a malignancy of the pancreas.
[0082] In some embodiments, the capsule is configured to apply a
mechanical stimulation through vibration, rotation or a combination
thereof.
[0083] In some embodiments, the capsule or the belt are configured
to apply a mechanical stimulation through vibration of the capsule.
In some embodiments, the vibration frequency is the range of about
0.01 to about 10,000 Hz, for example between about 0.1-1000 Hz. In
some embodiments, the vibration frequency is the range of about
10-100 Hz. In some embodiments, the capsule is configured to change
the vibration frequency during its operation.
[0084] In some embodiments, the capsule or the belt are configured
to apply a mechanical stimulation through rotation of the capsule.
In some embodiments, the rotation frequency is in the range of
about 10,000 cycles/second to about 1 cycle/minute. In some
embodiments, the capsule is configured to change the rotation
frequency during its operation.
[0085] In some embodiments, the capsule or the belt are configured
to apply an electrical stimulation. In some embodiments, the
electrical stimulation is characterized by a frequency in the range
of about 0.01 to 4000 Hz, for example between about 0.01-1000 Hz.
In some embodiments, the electrical stimulation is characterized by
an intensity in the range of about 0.01 to 500 mA. In some
embodiments, the capsule or the belt are configured to change the
frequency and/or intensity of the electrical stimulation during its
operation. Each possibility represents a separate embodiment of the
disclosure.
[0086] In some embodiments, the capsule or the belt are configured
to generate local temperature alterations in the immediate
surroundings of the capsule within the GI tract. In some
embodiments, the local temperature alterations are in the range of
about 4.degree. C. to about 96.degree. C. In some embodiments, the
temperature alterations are induced for short periods of time, for
example, for several seconds or shorter.
[0087] In some embodiments, the capsule or the belt are configured
to apply a continuous stimulation. In other embodiments, the
capsule is configured to apply an intermittent stimulation.
[0088] In some embodiments, activation of the capsule or the belt
are set to commence after a defined time-period following ingestion
thereof, such that the capsule is activated as it reaches a target
segment within the GI tract.
[0089] In some embodiments, the physical stimulation generated by
the devices disclosed herein induce at least one physiological
effect selected from the group consisting of decreased appetite,
reduced absorption throughout the GI tract, increased GI motility,
decreased GI motility, secretion of incretins and/or insulin, or
any other type of a hormone, alteration of local or brain connected
neuronal pathways and suppression of bacterial overgrowth. Each
possibility represents a separate embodiment of the disclosure.
[0090] In some embodiments, there is provided herein a method for
increasing GI motility in a subject in need thereof, the method
comprising inserting and activating a gastrointestinal capsule as
described herein to the GI tract of the subject.
[0091] In additional embodiments, there is provided herein a method
for inducing malabsorption throughout the GI tract of a subject in
need thereof, the method comprising inserting and activating a
gastrointestinal capsule as described herein to the GI tract of the
subject.
[0092] In additional embodiments, there is provided herein a method
for treating bacterial overgrowth in the GI tract of a subject in
need thereof, the method comprising inserting and activating a
gastrointestinal capsule as described herein to the GI tract of the
subject.
[0093] In some exemplary embodiments, the method is applied for the
treatment of a Clostridium difficile infection. Without being bound
by any particular theory or mechanism of action, it is contemplated
that Clostridium difficile infection, whether chronic or acute, is
inhibited by altering the motility of the gut directly or via the
induction of hormones or any other type of mediators released
locally or systemically.
[0094] In yet additional embodiments, there is provided herein a
method for treating a disease or disorder associated with
alteration of the gut microbiome in a subject in need thereof, the
method comprising inserting and activating a gastrointestinal
capsule or the belt are described herein to the GI tract of the
subject.
[0095] In yet additional embodiments, there is provided herein a
method for diagnosing a GI motility disorder in a subject, the
method comprising inserting and activating a gastrointestinal
capsule as described herein to the GI tract of the subject, and
monitoring the motion of the gastrointestinal capsule within said
GI tract of the subject.
[0096] Without being bound by any particular theory or mechanism of
action, it is contemplated that beneficial effects generated by the
devices described herein are induced, inter alia, by altering GI
motility per se, and/or via induction of hormones and/or other
mediators released locally or systemically. Thus, both local and
systemic effects can be achieved. It is further contemplated that
the stimuli generated by the devices described herein can affect
the vagal nerve, and/or any type of sympathetic or parasympathetic
innervations of the gastrointestinal tract, to thereby generate
beneficial effects within the GI tract, as well as in other parts
of the body. It is further contemplated that the stimuli generated
by the devices described herein can affect the immune system, e.g.,
to alter chemokine and cytokine secretion from immune cells, to
thereby generate beneficial effects within the GI tract, as well as
in other parts of the body.
[0097] For each of the above type of signals delivered by the
device, the random dynamics of the stimulation applied by the
devices provides a way for overcoming the ability of the target
organ or the brain, or the brain-gut axis, to accommodate to the
delivered signal and thus preventing its effect. It also provides a
way to prevent adaptation of the brain or any part of the
gastrointestinal tract to the stimuli, thereby enabling a prolonged
effect. According to some embodiments, the disclosed treatment
methods and devices may be used for preventing weight regain
following a weight-loss process, such as a diet or procedure or
device used for weight reduction.
[0098] The randomization of the stimuli may include randomization
of both the rate and magnitude of the stimuli.
[0099] These and further aspects and features of the present
disclosure will become apparent from the figures, detailed
description and claims which follow.
BRIEF DESCRIPTION OF THE FIGURES
[0100] FIG. 1 schematically illustrates a stimulation capsule
according to some embodiments;
[0101] FIG. 2 schematically illustrates an external stimulation
device, according to some embodiments;
[0102] FIG. 3 schematically illustrates a setting of an external
controller and a stimulation device, according to some
embodiments;
[0103] FIG. 4a schematically illustrates a stimulation capsule with
a balloon at a first state, according to some embodiments;
[0104] FIG. 4b schematically illustrates a stimulation capsule with
a balloon at a second state, according to some embodiments;
[0105] FIG. 5 schematically illustrates a magnetically actuated
vibrating stimulation capsule, according to some embodiments;
[0106] FIG. 6 schematically illustrates a stimulation capsule with
electrodes, according to some embodiments;
[0107] FIG. 7 illustrates a block diagram of a stimulation device,
according to some embodiments;
[0108] FIG. 8 illustrates a flow chart of a stimulation method,
according to some embodiments;
[0109] FIG. 9 depicts a first experiment result, according to some
embodiments;
[0110] FIG. 10 depicts a second experiment result, according to
some embodiments, and
[0111] FIG. 11 depicts a third experiment result, according to some
embodiments.
DETAILED DESCRIPTION
[0112] Most organs in the human body function in a regular constant
rhythm. Providing a regular stimuli to human organs is associated
with adaptation of the organ within a certain period of time. A
similar mechanism is leading to weight regain following dietary
procedures.
[0113] Both-diets and endoscopic and surgical procedures, fail to
maintain long term weight loss. Sustained weight loss and
prevention of weight regain are therefore major problems. Most
dietary procedures are effective only for short term.
[0114] Dieting is defined as an intentional effort to create a
negative energy balance for the purpose of losing weight, at least
in part through the restriction of energy intake. Dieting via a
metabolic route (attempts to control weight using pills)-loss of
lean tissue and reduced metabolic rate per kilogram of lean body
mass. Biologically, the human body experiences the dieting process
as a form of starvation. Therefore, the body shifts into primal
survival mode, where the metabolism slows down and food cravings
escalate. With each diet, the body learns and adapts, resulting in
rebound weight gain. Dieting through a behavioral route (controlled
eating habits)--increased hunger and reward value of food. This
method disconnects the innate hunger and satiety cues, and it
becomes easier to eat in the absence of hunger and develop a
mistrust of the biological eating cues. Very-low-energy diets
(VLEDs) which provides 800 kcal a day with high levels of protein
and minimal carbohydrate to encourage weight loss with minimal loss
of lean tissue, supplemented with vitamins, minerals, electrolytes
and fatty acids to ensure adequate nutrition are used. However, all
are associated with body adaptation and weight regain in a large
proportion of the patients. For many dietary procedures, 90% of all
dieters' regained weight over the course of 3 years. Endoscopic or
surgical procedures to reduce the size of the stomach, intragastric
balloon, to fill the stomach, and bariatric surgeries, such
as-sleeve gastrectomy, biliopancreatic diversion, gastric bypass
surgery, while achieving weight loss, are not successful for
long-term weight management.
[0115] Appetite regulation involves a number of orexigenic and
anorexigenic peptide hormones. Ghrelin-producing cells are
identified throughout the gastrointestinal tract but
enteroendocrine cells of the gastric fundus are the main source of
its production. Ghrelin is the only circulating gut orexigenic
hormone. It regulates energy metabolism and act as a signal of
hunger. Ghrelin administration increases energy intake and induces
weight gain. In the acute setting, its levels are elevated by
fasting and suppressed following a meal or after an oral glucose
tolerance test. At the chronic state, its levels increase in obese
and are low in lean subjects. Ghrelin levels are enhanced under
physiological stress. The ghrelin axis plays a role in energy
homeostasis, adipogenesis, insulin regulation, reward associated
with food stress-induced food intake.
[0116] Ghrelin is a dynamically regulated peripheral hunger signal.
The vagal afferent pathway is the neural path by which information
about ingested nutrients reaches the central nervous system (CNS)
to influence feeding behavior. Ghrelin signals gut nutrients to the
CNS and up-regulates food intake while lowering energy expenditure.
In the CNS, ghrelin acts on hypothalamus and limbic system, known
areas of regulation of appetite and energy expenditure. Its effects
in the hypothalamus are mediated by homeostatic pathways to signal
hunger, increase food intake and adiposity, promoting weight gain.
AMP-activated protein kinase (AMPK) in the hypothalamus modulates
energy balance. Ghrelin exerts its effect through a network of
neuroendocrine links, including the melanocortin and
endocannabinoid systems. Hypothalamic nuclei, the hippocampus, the
amygdala, the caudal brain stem, and midbrain dopaminergic neurons
play roles in the orexigenic actions of ghrelin. The only known
ghrelin receptor is the growth hormone secretagogue receptor (GHSR)
located in several distinct regions of the CNS.
[0117] Ghrelin acts centrally and by affecting the GI tract,
increasing skeletal muscle growth and lipolysis, decreasing protein
breakdown, and body fat utilization. Ghrelin administration causes
hyperglycemia in both rodents and in humans. It inhibits insulin
release from the pancreas, increases hepatic glucose production,
and prevents glucose disposal in muscle and adipose tissues, which
leads to hyperglycemia and impaired glucose tolerance. Ghrelin
stimulates neuropeptide Y (NPY) neurons, but not
pro-opiomelanocortin neurons, to regulate food intake.
[0118] As ghrelin is the only peripheral hormone to transmit
satiety signal, inhibiting its signaling is being evaluated as a
target for anti-obesity therapies. Efficacy of ghrelin was tested
in diseases involving anorexia, negative energy balance, systemic
inflammation, and gastroparesis, cancer, cachexia, cardiovascular
disorders, chronic heart failure, chronic renal failure,
chemotherapy, arthritis, and inflammatory bowel disease. Ghrelin
agonists have been developed for the treatment of hypomotility
disorders and the peptidomimetic TZP-102 is in phase 2 clinical
trials for diabetic gastroparesis.
[0119] Weight loss causes changes in appetite and energy
expenditure that promote weight regain. It is unclear whether the
increases in ghrelin during weight loss are associated with regain.
If circulating ghrelin participates in the adaptive response to
weight loss, its levels should change with dieting. Although
dietary restriction often results in initial weight loss, majority
of obese dieters fail to maintain their reduced weight.
Diet-induced weight loss results in a compensatory increase of
hunger, decreased ghrelin suppression that encourage weight regain.
Compensatory metabolic changes that accompany weight loss,
including increased ghrelin levels, contribute to weight regain and
difficulty in long-term weight loss maintenance. A recent review
showed changes in ghrelin, leptin, and insulin during intentional
weight loss with a follow-up period to promote weight regain.
[0120] Twelve weeks of high-fat diet feeding causes ghrelin
resistance in arcuate neuropeptide Y (NPY)/agouti-related protein
(AgRP) neurons. Diet-induced obese ghrelin-knockout mice exhibit
less weight regain after calorie-restricted weight loss compared
with wild-type mice, further supporting the notion that ghrelin
mediates rebound weight gain after calorie-restricted weight
loss.
[0121] Ghrelin levels are increased by fasting in lean rodents and
are elevated before meals in humans, suggesting an important role
for ghrelin in meal initiation. However, in obese human,
circulating ghrelin levels were found to be significantly reduced
as compared to lean individuals. Obesity-induces central ghrelin
resistance regulates behavior and impaired ghrelin secretion from
the stomach. Weight loss restores ghrelin secretion and function.
It was suggested that ghrelin resistance is a mechanism that keep a
higher body weight set-point during times of food availability.
Ghrelin secretion was reduced in obese mice but its diurnal
regulation was lost. No change in ghrelin secretion upon fasting
and refeeding was noted. The sensitivity to the orexigenic effects
of exogenous ghrelin was reduced in obese mice when compared to
lean mice fed a chow or a lean fat diet. The insensitivity of obese
mice to ghrelin was improved upon weight loss.
[0122] In a one year randomized controlled trial greater weight
loss, achieved through a reduced calorie diet or exercise, was
associated with increased ghrelin levels in overweight or obese
postmenopausal women. The change in total ghrelin was inversely
associated with changes in leptin, insulin and insulin resistance,
and positively associated with change in adiponectin. In a
randomized clinical trial, with a 12-month follow-up period, obese
Mexican-American women following interventions including diet,
exercise, and orlistat, ghrelin levels increased at 6 months but
returned to baseline at 12 months in the weight loss group.
Baseline ghrelin concentrations were directly related to the degree
of weight loss achieved after 12 months. The data suggested that
ghrelin rises in response to weight loss as a counterregulatory
mechanism. In a study of 193 obese adult men and women who were
randomized to a low carbohydrate breakfast or an isocaloric diet
with high carbohydrate and protein breakfast, a high carbohydrate
and protein breakfast prevented weight regain by reducing
diet-induced compensatory changes in hunger, cravings and ghrelin
suppression.
[0123] Population-based studies suggest that repetitive cycling of
weight loss and regain may be associated with future weight gain. A
cross-sectional study evaluated the relationship between a history
of frequent weight loss and biomarkers, including serum ghrelin in
one hundred fifty-nine weight stable overweight postmenopausal
women. A higher degree of weight cycling, characterized by the
frequency of intentionally losing more than 10 lb, was associated
with an appetite-stimulating hormonal profile, including higher
concentrations of ghrelin. In another study, of 88 overweight/obese
patients who received an 8-week hypocaloric diet program and were
categorized as regainers (>/=10% weight-lost regain) and
non-regainers (<10% weight-lost regain) 6 months after finishing
the dietary treatment, regainers showed a higher baseline and after
treatment leptin/ghrelin ratio (L/G) than non-regainers. Subjects
with higher plasma leptin and lower ghrelin levels at baseline were
more prone to regain lost weight.
[0124] In a prospective study of 43 patients treated with
BioEnterics intragastric balloon, ghrelin hyper-response in non
morbid obese patients was characterized with greater short-term
treatment efficiency and leaning to weight regain of obesity. In a
five years follow up study after sleeve gastrectomy (SG),
significant weight regain and severe reflux were described in some
patients. Ghrelin levels remained low postoperatively. Ghrelin
levels were reduced after gastrectomy and did not recover by 12
months postoperatively. In this trial, the appetite score increased
significantly by 12 months. A diet-induced weight loss after
gastric bypass of 17% of initial body weight was associated with a
24% increase in the area under the curve for the 24-hour ghrelin
profile. Gastric bypass was associated with markedly suppressed
ghrelin levels, contributing to the weight-reducing effect of the
procedure.
[0125] Weight regain is a major concern following Roux-en-Y gastric
bypass (RYGB). In a study of 24 patients, secretion of gut hormones
in patients with weight regain after RYGB was different from that
in patients with satisfactory weight outcome. After meal
stimulation, reduced levels of GIP and GLP-1 may indicate the
influence of gut hormones in the process of weight regain. There
was no difference in the ghrelin secretion. In a follow up of 45
patients, higher preoperative ghrelin levels might identify
patients that are more susceptible to weight regain after RYGB. In
another study, measurement of ghrelin, insulin, and leptin before
surgery is not useful as predictors of weight loss or regain at
long term after RYGBP.
[0126] The SHAPE (Screened Health Assessment and Pacer Evaluation)
trial was a 24 month randomized multicenter placebo-controlled
study to determine the efficacy of an implantable gastric
stimulator (IGS) for weight loss. At 24 months the control group
exhibited weight gain from baseline that was significantly
different from the weight loss in the treatment group. At 12
months, fasting ghrelin was significantly increased in the
treatment group but not in the control. No significant change was
observed in postprandial suppression of plasma ghrelin or in
fasting and postprandial PYY levels. The data suggested that IGS
does not prevent the increase in fasting plasma ghrelin levels
associated with weight loss.
[0127] The present disclosure provides, in accordance with some
embodiments, devices for stimulating a target organ, such as the
gastrointestinal tract or any other organ in the human body. In
some embodiments, a gastrointestinal capsule is provided, capable
of applying a physical stimulation to the walls of different parts
of the GI tract.
[0128] In other embodiments, an external device is provided, such
as a belt configured to be worn by a subject, and when worn, to
apply a physical stimulation to a target organ, such as a portion
of the GI tract.
[0129] According to some embodiments, the devices disclosed herein
are characterized by chaotic dynamics (chaotic rhythm) of the
stimulation, meaning that they are configured to randomly alter the
parameters of the stimulation during their operation. According to
some embodiments, the terms "chaotic" and "random"/"randomly" can
be used interchangeably. According to some embodiments, the
chaotic/random type of the stimuli may be induced by different
patterns, different magnitude or different rhythms of the stimuli,
each of them by itself, or all together. According to some
embodiments, the devices disclosed herein are characterized by
chaotic dynamics (chaotic rhythm) of the stimulation, meaning that
they may be configured to randomly select different combinations of
various types of stimuli each being altered in a random way.
According to some embodiments, the chaotic/random type of
combination of stimuli may be induced by different patterns,
different magnitude or different rhythms of the stimuli, each of
them by itself, or all together.
[0130] As used herein, a "gastrointestinal capsule" refers to a
capsule that propels and operates in the gastrointestinal tract. As
used herein, the term "gastrointestinal" refers to the mouth,
esophagus, stomach, duodenum, small intestine, large intestine and
colon and rectum. The gastrointestinal capsule applies direct
stimulation to different parts of the gastrointestinal tract. It is
to be understood though that the effects resulting from the direct,
local stimulation are not limited to the gastrointestinal tract or
the digestive system. Systemic effects may result, affecting body
parts within and outside the digestive system.
[0131] As used herein, the term "belt" refers to any type of
external device that can deliver the stimuli. These include any
type of wearable devices, such as neck chain, a watch, a patch that
can be put anywhere on the skin, a rectal device, a bracelet, any
type of an undershirt of underwear, any type of a shirt, pants, or
socks, or shoes, heats, or any other wearable device.
[0132] As used herein, and throughout the disclosure, the terms
"random", "pseudo-random" and "dynamic" and "chaotic" may be
interchangeable, and refer to changes, in the stimuli parameter(s),
that are arbitrary or unsystematic, at least to the extent of
preventing or reducing a habituation effect for the stimuli in the
target organ/region.
[0133] According to some embodiments, the changes, being
random/pseudo-random, may apply to parts of the stimuli and not
necessarily to others. For example, the stimuli signal may include
multiple frequencies, and the random/pseudo-random changes may be
applied to some of the frequencies, and not apply to the other
frequencies.
[0134] According to some embodiments, the stimuli may include
different sections/intervals being applied at different times.
According to some embodiments, the stimuli parameter(s) in some
sections/intervals may be changed/altered randomly, while not so in
other section/intervals.
[0135] For example, in some embodiments, the capsule or the belt of
the present disclosure induces indirect effects on organs
associated directly or indirectly with the GI tract, including, for
example, the gallbladder, liver, and pancreas, meaning that the
capsule is not operated within these organs but may induce systemic
effects affecting these organs. These devices can also exert an
effect on other organs in the body which are not part of the
gastrointestinal tract.
[0136] The devices according to some embodiments of the present
disclosure includes means for optimized control over parameters
such as the length, intensity and frequency of the stimulation, as
well as novel means to induce the stimulation comprising
temperature alteration. The devices may operate at low and/or high
frequencies, that can be selected and varied according to specific
needs. The devices according to some embodiments of the present
disclosure generate local physical stimulation that may affect
various processes regulated in the digestive system or any other
organ system in the body. It is contemplated that the local
physical stimulation activates reflex arcs and regulation pathways
involving the digestive system. The present disclosure further
provides methods and uses of such devices in various clinical and
diagnostic applications.
[0137] The Gastrointestinal Stimulation Capsule
[0138] The capsule according to embodiments of the present
disclosure is preferably swallowable and ingested by a subject in
need. After ingestion, the capsule is propelled through the GI
tract by the normal peristaltic motion of the GI tract, and.
expelled naturally.
[0139] Alternatively, the capsule may be arranged to be inserted
into the GI tract using an invasive procedure, an endoscopic
procedure, a laparoscopic surgery procedure and/or a surgical
laparotomy procedure.
[0140] The capsule is configured to induce a mechanical
stimulation, electrical stimulation, temperature/thermal
alteration, or a combination thereof.
[0141] In some embodiments, the mechanical stimulation is applied
by the capsule through vibration, rotation or a combination
thereof. Mechanical vibrations and/or rotations may be excited in
the chyme contained within a segment of the GI tract and/or
directly applied to the walls of the GI tract by the
vibrating/rotating capsule. Thus, direct contact of the capsule
with the GI tract inner surface may not be required in order to
induce mechanical stimulation. Movement of the capsule to induce a
mechanical stimulation is accomplished by elements embedded in the
capsule, as is known in the art.
[0142] The elements that constitute the capsule are typically
biocompatible and a-traumatic. They may comprise any suitable
material, such as metal or plastic, or a combination thereof.
[0143] The capsule according to embodiments of the present
disclosure typically comprises a power source, such as a battery,
to provide power to all electrical elements of the capsule.
According to some embodiments, the power source may be rechargeable
and/or replaceable.
[0144] The capsule may be rounded or oval. Typically, the diameter
of the capsule body ranges from about 8-15 mm. Typical length of
the capsule body ranges from about 10-20 mm. If arms are included,
their length is typically up to about 50 mm.
[0145] Reference is now made to FIG. 1, which shows a schematic
illustration of a capsule according to some embodiments of the
present disclosure. The capsule 100 comprises a capsule body 104
capable of inducing a mechanical stimulation and/or an electrical
stimulation and/or temperature/thermal alteration, utilizing a
stimuli delivery mechanism such as one or more arms 112 and 114,
and a controller, such as control circuitry 150 for instructing the
operation of an actuator 110 to move one or more of arms 112 or 114
relative to capsule body 104. According to some embodiments, the
position of arms 112 or 114 relatively to capsule body 104 can be
controlled and changed from open to closed and vice versa.
According to some embodiments, capsule 100 further comprises an
inflatable/deflatable balloon 116 functionally and mechanically
connected to capsule body 104, wherein the inflating/deflating
thereof is controlled via a pump 118 that is configured to pump gas
and/or fluid in and from balloon 116. According to some
embodiments, pump 118 and balloon 116 may be connected to a gas
container within capsule body 104 for providing gas to and from
balloon 116.
[0146] The External Device
[0147] The external device according to embodiments of the present
disclosure is preferably affixed onto the subject's body. In some
embodiments, the external device is in the form of a belt
configured to be worn by a subject around the subject's waists or
torso. In some embodiments, the external device is in the form of a
patch or a watch or a bracelet or any type of a wearable object
including hats, socks, shoes. Following attachment, the external
device is operated to induce at least one physical stimulation,
such as a mechanical stimulation. In some embodiments, the
mechanical stimulation is applied through vibration, induction of
pressure or other mechanical stimulations. In some embodiments, the
stimulation is applied through change in temperature, or any other
type of physiological signal that can be generated by the device,
including light, or any other type of energy transfer.
[0148] Reference is now made to FIG. 2 which shows a schematic
illustration of an external device 200 according to some
embodiments of the present disclosure in the form of a belt
configured to be affixed around a subject's waists or torso. Device
200 further comprises a stimulation unit 210 capable of inducing a
mechanical stimulation. Stimulation unit 210 comprises an internal
controller (not shown) configured to control the parameters of the
stimulation. Device 200 further comprises means for affixing
thereof to the body of the subject such as strap 270.
[0149] According to some embodiments, the controller can be
integrated within the device (capsule or wearable), or
alternatively, the controller may include an external processing
circuitry with communication with the stimulation providing
unit(s). such a controller may include a mobile device such as a
cellphone or a tablet, a desktop, a laptop, a server or the like.
According to some embodiments, the external controller may be in
communication with the gastrointestinal capsule or the belt.
[0150] Reference is now made for FIG. 3, which schematically
illustrates a setting 300 of an external controller, such as a
mobile device 380, and a stimulation device 310, according to some
embodiments. According to some embodiments, mobile device 380 is
configured to be in communication with stimulation device 310 via
wireless communication link 390. According to some embodiments,
wireless communication link 390 may be Wi-Fi, Bluetooth, IR, NFC,
or the like.
[0151] According to some embodiments, the randomization/alteration
technique/algorithm may be configurable based on user
characteristics and/or previous learnings. According to some
embodiments, the technique(s) may be based on the metabolic rate of
the user, age, health state of others.
[0152] According to some embodiments the controller will have an
embedded algorithm that will generate the random combination of
stimuli.
[0153] According to some embodiments the controller is also a
receiver of data generated in the target organ.
[0154] According to some embodiments the controller has a
self-learning algorithm that can change the type of stimuli it
delivers based on the data it receives from the target organs.
[0155] According to some embodiments these changes can be made
instantly thus that the immediately followed stimuli is already
changed according to the internal learning machinery.
[0156] Induction of Stimuli to Other Organs
[0157] In some embodiments, stimulatory devices characterized by
chaotic dynamics of stimulation may be used to induce stimuli to
organs other than the GI tract.
[0158] In some embodiments, the stimulatory devices are configured
to be inserted into the target organ using an invasive procedure,
including an endoscopic procedure, a radiological procedure or a
surgical procedure, including a laparoscopic surgical
procedure.
[0159] In some embodiments, the stimulatory devices may induce at
least one physical stimulation selected from the group consisting
of mechanical stimulation, electrical stimulation and temperature
alteration. Each possibility represents a separate embodiment of
the present disclosure.
[0160] Reference is now made to FIG. 4a, which schematically
illustrates a stimulation capsule 400 with a balloon 412 at a first
state, according to some embodiments. According to some
embodiments, stimulation capsule 400 is configured to provide
stimuli by means of applying pressure and/or filling of a volume
space, by means of inflating and deflating of a balloon 412.
According to some embodiments, the inflation and deflation is
performed utilizing a pump 410 controlled by a control circuitry
450, which is configured to apply a stimulation pattern by means of
inflation and deflation in a dynamic randomized/nonsystematic
manner. As illustrated, balloon 412 is in a deflated state.
[0161] Reference is now made to FIG. 4b, which schematically
illustrates a stimulation capsule 401, essentially as disclosed in
FIG. 4a stimulation capsule 400, with a balloon 413 at a second
state, according to some embodiments. As illustrated, balloon 413
is in an inflated state, wherein pressure may be applied to a
surrounding tissue of stimulation capsule 401.
[0162] According to some embodiments, the capsule or the external
devices may be configured to apply/deliver stimuli by means of
physical movement thereof. For example, the physical movement may
include vibration, rotation of the like.
[0163] Reference is now made to FIG. 5, which schematically
illustrates a magnetically actuated vibrating stimulation capsule
500, according to some embodiments. According to some embodiments,
stimulation capsule 500 is configured to provide stimulation by
vibration, achieved via movement of a magnetic element, for example
a magnetic elongated element/member, such as a magnetic shaft 518
in an enclosure 510 within capsule body 504, thereby affecting a
movement of capsule body 504 at a controlled pace.
[0164] According to some embodiments, the movement of magnetic
shaft 518 may be achieved by changes in the magnetic field
surrounding it, for example by activation of magnetic field
modifying elements, such as electromagnets 514 and 512, which are
controlled by a controller 550 applying an altering operation
signal. According to some embodiments, capsule 500 and components
therein may be operated by electric power supplied via a battery
554 within capsule body 504.
[0165] According to some embodiments, other mechanisms may be
utilized for achieving physical movement of the capsule, for
example, an actuator (electric motor) configured to mechanically
rotate an elongated shaft. According to some embodiments, the
rotation of the elongated shaft may be done on a rotation axis that
does not pass through the center of mass of the elongated
shaft.
[0166] Reference is now made to FIG. 6, which schematically
illustrates a stimulation capsule 600 with electrodes, such as a
first electrode 612 and a second electrode 614, according to some
embodiments. According to some embodiments, first electrode 612 and
second electrode 614 are assembled on a capsule body/housing 604 or
integrally formed therewith, being at least partially exposed for
having electric contact with the environment of stimulation capsule
600. According to some embodiments, first electrode 612 and second
electrode 614 are provided with a stimulation signal by a signal
generator 610 which is configured to produce a stimulation signal
based on parameter configurations received from a controller, such
as processing circuitry 650. According to some embodiments,
processing circuitry 650 is configured to alter the parameters to
generate a semi-random or non-systematic stimuli, for preventing
habituation.
[0167] Reference is now made to FIG. 7, which illustrates a block
diagram of a stimulation device 700, according to some embodiments.
In general, according to some embodiments, stimulation device 700
may include a controller 750 that may have imbedded therein a
signal generator 752 for producing a randomly altering signal to be
delivered to an actuator (optional) 710 which is configured to
operate a stimulation delivery mechanism 712. Optionally, according
to some embodiments, stimulation device 700 may include a sensor
730 for obtaining measurements indicative of the effect of the
stimuli. According to some embodiments, sensor 730 may include a
temperature sensor, or a detector configured to detect certain
molecules, and the measurements may then be sent back to controller
750 for changing the stimulation parameters based thereon.
According to some embodiments the controller also includes a
receiver configured to receive data from the target organs, for
example by means of measuring parameters indicative of an operation
or state of the organ. According to some embodiments, the embedded
algorithm may have an internal learning machinery which can alter
the generated stimuli based on the data being received/measured
from the organ by the controller.
[0168] According to some embodiments the controller can generate a
feedback loop based on the data it receives.
[0169] In some embodiments the gastrointestinal capsule or external
device are configured to induce a stimulation which is based on
pre-programmed patient's tailored algorithm which is based on body
weight, BMI, metabolic, endocrine, and other physiologic parameters
of the subject.
[0170] Reference is now made to FIG. 8, which illustrates a flow
chart of a stimulation method 800, according to some embodiments.
According to some embodiments, Method 800 begins with providing a
stimulation capsule to a user (step 802), then directing the
capsule to a target organ or region (step 804), then stimulation
parameters are set (step 806) and stimulation is delivered to the
target region (step 808). According to some embodiments, if further
stimulation is needed (step 810), the stimulation parameters may be
altered (step 812), and stimulation may be applied based on the
recently altered parameters (step 808) for mitigating or
eliminating a habituation effect. Otherwise, stimulation may be
terminated (step 814) and the capsule may be removed (step
816).
[0171] Therapeutic Utility
[0172] Without being bound by any particular theory or mechanism of
action, it is contemplated that the local stimulation applied by
the devices disclosed herein induces a systemic effect. For
example, it is contemplated that the local stimulation induced by a
gastrointestinal capsule or an external stimulatory device as
disclosed herein induces the release of small peptides, hormones,
cytokines and/or other molecules from the GI tract wall. In
addition, the stimulation may induce release of such molecules from
cells associated with the immune system in the gut. Thus, a
stimulation applied by the capsule may result in both local and
systemic effects. The stimulation may alter the function (inhibit
or activate) of the nervous system of the gut. This can be achieved
via altering the vagus and/or other parts of the sympathetic or
parasympathetic nervous system of the gut.
[0173] Molecules released in the gut, in response to the
stimulation may reach the brain and lead to various effect
including appetite suppression. The secreted molecules may also
work on various parts of the gut wall itself and lead to decreased
absorption. The secreted molecules may also work on various parts
of the gut wall itself to alter their motility either suppressing
or enhancing motility. The secreted molecules may also work on
various parts of the brain to secrete further molecules or to
activate neuronal pathways that will alter the gut motility, either
enhancing, or decreasing, or altering appetite. In addition, the
stimulation mediated by the devices disclosed herein may affect
regulation pathways controlling the GI motility. Increased motility
can be therefore achieved as a result of direct contact of the
capsule with the GI tract wall, as well as a result of systemic
effects. Increased motility mediated by the devices according to
the present disclosure is not limited to the area which is in close
proximity to the capsule.
[0174] The devices according to embodiments of the present
disclosure may be useful in the treatment of various clinical
conditions associated with the digestive system, for example,
obesity and/or GI motility disorders.
[0175] According to an aspect of the present disclosure, there is
provided herein a method for treating obesity in a subject in need
thereof, the method comprising inserting and activating a
gastrointestinal capsule according to embodiments of the present
disclosure to the GI tract of the subject.
[0176] According to another aspect, the present disclosure provides
a method for treating GI motility disorders in a subject in need
thereof, the method comprising inserting and activating a
gastrointestinal capsule according to embodiments of the present
disclosure to the GI tract of the subject.
[0177] Non-limiting examples of GI motility disorders include
diarrhea, constipation, ileus and gastro-paresis.
[0178] According to yet another aspect, the present disclosure
provides a method for increasing GI motility in a subject in need
thereof, the method comprising inserting and activating a
gastrointestinal capsule according to embodiments of the present
disclosure to the GI tract of the subject.
[0179] An increase in GI motility induced by the capsule according
to embodiments of the present disclosure, in particular an
increased small bowel movement, may induce malabsorption due to
increase or decrease in the transition time.
[0180] According to yet another aspect, the present disclosure
provides a method for inducing malabsorption throughout the GI
tract of a subject in need thereof, the method comprising inserting
and activating a gastrointestinal capsule according to embodiments
of the present disclosure to the GI tract of the subject.
[0181] An increase in GI motility induced by the capsule according
to embodiments of the present disclosure, in particular an
increased small bowel movement, may assist in cases of bacterial
overgrowth. This may be achieved by altering the motility of the
gut via the induction of hormones or any other type of mediators
released locally or systemically or by altering neuronal pathways
either local or connected to the brain.
[0182] According to another aspect, the present disclosure provides
a method for treating bacterial overgrowth in the GI tract of a
subject in need thereof, the method comprising inserting and
activating a gastrointestinal capsule according to embodiments of
the present disclosure to the GI tract of the subject.
[0183] According to another aspect, the present disclosure provides
a method for treating an infection in the gastrointestinal tract of
a subject in need thereof, the method comprising inserting and
activating a gastrointestinal capsule according to embodiments of
the present disclosure to the gastrointestinal tract of the
subject.
[0184] According to another aspect, the present disclosure provides
a method for treating an inflammatory disease, including an
inflammatory bowel disease, in the gastrointestinal tract of a
subject in need thereof, the method comprising inserting and
activating a gastrointestinal capsule according to embodiments of
the present disclosure to the gastrointestinal tract of the
subject.
[0185] According to another aspect, the present disclosure provides
a method for treating a disease of the gallbladder, the pancreas,
or other organ directly or indirectly associated with the
gastrointestinal tract in a subject in need thereof, the method
comprising inserting and activating a gastrointestinal capsule
according to embodiments of the present disclosure to the
gastrointestinal tract of the subject.
[0186] According to another aspect, the present disclosure provides
a method for treating a cancerous condition, including a
precancerous condition, polyp, primary or secondary tumor and
metastases, in the gastrointestinal tract of a subject in need
thereof, the method comprising inserting and activating a
gastrointestinal capsule according to embodiments of the present
disclosure to the gastrointestinal tract of the subject.
[0187] In some embodiments, the methods described herein are
applied for the treatment of a disease selected from the group
consisting of pancreatic cancer, acute or chronic pancreatitis, a
premalignant polyp, Barrett's esophagus, a primary or secondary
tumor of any part of the GI tract. Each possibility represents a
separate embodiment of the present disclosure.
[0188] The methods described herein may also be applied for the
treatment of diseases that are associated or augmented by bacterial
translocation or alteration of the gut microbiome and/or gut flora
derangement, diseases in which the immune system plays a role,
including but not limited to chronic liver diseases and Alzheimer
disease, hepatic encephalopathy, ADHD, metabolic syndrome, diabetes
both type 1 and type 2, atherosclerosis or chronic fatigue
syndrome, NASH, obesity, hepatic encephalopathy and potentially
several immune mediated disorders among them Alopecia Areata,
Lupus, Anlcylosing Spondylitis, Meniere's Disease, Antiphospholipid
Syndrome, Mixed Connective Tissue Disease, Autoimmune Addison's
Disease, Multiple Sclerosis, Autoimmune Hemolytic Anemia,
Myasthenia Gravis, Autoimmune Hepatitis, Pemphigus Vulgaris,
Behcet's Disease, Pernicious Anemia, Bullous Pemphigoid,
Polyarthritis Nodosa, Cardiomyopathy, Polychondritis, Celiac
Sprue-Dermatitis, Polyglandular Syndromes, Chronic Fatigue Syndrome
(CFIDS), Polymyalgia Rheumatica, Chronic Inflammatory
Demyelinating, Polymyositis and Dermatomyositis, Chronic
Inflammatory Polyneuropathy, Primary Agammaglobulinemia,
Churg-Strauss Syndrome, Primary Biliary Cirrhosis, Cicatricial
Pemphigoid, Psoriasis, CREST Syndrome, Raynaud's Phenomenon, Cold
Agglutinin Disease, Reiter's Syndrome, Crohn's Disease, Rheumatic
Fever, Discoid Lupus, Rheumatoid Arthritis, Essential Mixed,
Cryoglobulinemia Sarcoidosis, Fibromyalgia, Scleroderma, Grave's
Disease, Sjogren's Syndrome, Guillain-Barre, Stiff-Man Syndrome,
Hashimoto's Thyroiditis, Takayasu Arteritis, Idiopathic Pulmonary
Fibrosis, Temporal Arteritis/Giant Cell Arteritis, Idiopathic
Thrombocytopenia Purpura (ITP), Ulcerative Colitis, IgA
Nephropathy, Uveitis, Insulin Dependent Diabetes (Type I),
Vasculitis, Lichen Planus, and Vitiligo. The methods described
herein may also be applied for the treatment of disorders
associated with an abnormal or unwanted immune response associated
with cell, tissue or organ transplantation, e.g., renal, hepatic,
and cardiac transplantation, e.g., graft versus host disease
(GVHD), or to prevent allograft rejection, by altering various
pathways using the capsule. Each possibility represents a separate
embodiment of the present disclosure.
[0189] For any type of the above-described stimuli that can be
applied by the gastrointestinal capsule of the present disclosure,
durable effect can be achieved by randomness of the parameters of
the stimuli, namely, by randomly-altering the parameters of the
stimuli during operation of the capsule, for example, in terms of
intensity and frequency. Without being bound by any particular
theory or mechanism of action, the randomness of the stimulation
parameters may change the type of mechanism underlying a
physiological effect achieved by the capsule, and may enable
overcoming any type of tolerance to the effect of the capsule on
any of its target organs.
[0190] The capsule may be ingested with a meal, before a meal or
after a meal, to optimize the desired effect. The timing for
ingesting the capsule may be determined, for example, depending on
the condition to be treated.
[0191] In some embodiments, the capsule according to embodiments of
the present disclosure may be used for diagnostic purposes. For
example, the capsule motion within the GI tract may be monitored
and thus assist in locating areas of blockage or reduced motility.
According to these embodiments, the capsule further comprises a
recorder and/or transmitter, which is arranged to transmit the
status of the capsule to an external receiver.
[0192] Thus, according to another aspect, the present disclosure
provides a method for diagnosing a GI motility disorder in a
subject, the method comprising inserting and activating a
gastrointestinal capsule according to embodiments of the present
disclosure to the GI tract of the subject, and monitoring the
motion of the gastrointestinal capsule within the GI tract of said
subject.
[0193] In some embodiments, the capsule according to embodiments of
the present disclosure may be utilized as a delivery system for any
material and substance within the alimentary canal.
[0194] Non-limiting examples of such substances include
chemotherapeutic, cytotoxic anti-inflammatory and antiobiotic
agents. The capsule may include an activation system for release of
the substance in a specific location (controlled release of the
substance). Release of the substance may be remotely
controlled.
[0195] In some embodiments, the stimulatory devices disclosed
herein may be used in the treatment of diseases or disorders
affecting the heart, brain, kidney, muscles, nerves, urinary
system, lungs, liver and/or pancreas.
[0196] In some embodiments, a method is provided, for treating a
clinical condition selected from the group consisting of an
inflammatory disease, an infectious disease, an autoimmune disease,
a metabolic disease and a malignant disease in a subject in need
thereof. In some embodiments, the method comprises introducing an
internal stimulatory device as disclosed herein into a target
organ. In other embodiments, the method comprises affixing an
external device as disclosed herein to the subject's body.
[0197] In some embodiments the capsule or the belt will prevent
weight regain, and can be used as an adjunct therapy to any type of
a diet, or weight loosing procedure, for prevention of the
adaptation of the human body to the procedure and thus preventing
the weight regain following these procedures.
[0198] In some embodiments the capsule or the belt will prevent
weight regain, if being used before, in conjunction, or after the
bariatric surgery, any type of weight loosing procedure including
but not limited to intragastric balloons, use of gastric staples,
gastric evacuation, or any other type of dietary procedures.
[0199] In some embodiments the gastrointestinal capsule or external
device of are configured to induce a stimulation which is based on
the data being received from the subject.
[0200] In some embodiments the gastrointestinal capsule or external
device are configured to induce a stimulation which is based on
pre-programmed patient's tailored algorithm which is based on body
weight, BMI, metabolic, endocrine, and other physiologic parameters
of the subject.
[0201] In some embodiments, the controller is configured to be
pre-programmed to randomly alter a combination of parameters for
which each is being altered in a random chaotic way every part of a
second to every few minutes or hours.
[0202] According to some embodiments, the devices disclosed herein
are characterized by chaotic dynamics (chaotic rhythm) of the
stimulation, meaning that they are configured to randomly select
different combinations of various types of stimuli each being
altered in a random way. According to some embodiments, the
chaotic/random type of combination of stimuli may be induced by
different patterns, different magnitude or different rhythms of the
stimuli, each of them by itself, or all together. In some
embodiments, the devices described herein are configured to receive
data from the target organs.
[0203] In some embodiments, the devices described herein are
configured to change the algorithm based on the data being received
from the target organ.
[0204] According to some embodiments the controller can generate a
feedback loop based on the data it receives.
[0205] In some embodiments the gastrointestinal capsule or external
device are configured to induce a stimulation which is based on
pre-programmed patient's tailored algorithm which is based on body
weight, BMI, metabolic, endocrine, and other physiologic parameters
of the subject.
[0206] In some embodiments the capsule or the belt will prevent
weight regain, and can be used as an adjunct therapy to any type of
a diet, or weight loosing procedure, for prevention of the
adaptation of the human body to the procedure and thus preventing
the weight regain following these procedures.
[0207] In some embodiments the capsule or the belt may be utilized
for preventing weight regain, if being used before, in conjunction,
or after the bariatric surgery, any type of weight loosing
procedure including but not limited to intragastric balloons, use
of gastric staples, gastric evacuation, or any other type of
dietary procedures.
[0208] In some embodiments the gastrointestinal capsule or external
device of are configured to induce a stimulation which is based on
the data being received from the subject.
[0209] In some embodiments the gastrointestinal capsule or external
device are configured to induce a stimulation which is based on
pre-programmed patient's tailored algorithm which is based on body
weight, BMI, metabolic, endocrine, and other physiologic parameters
of the subject.
[0210] As used herein, the statement "receive data from the organ"
may refer to obtaining measurements from a sensor related to a
state or function of the organ.
[0211] According to some embodiments, the device is configured to
provide stimulation based on a set of parameters related to the
user. According to some embodiments, the parameters may include
health state, treatment goals, previous history of treatment,
overall wellbeing, gender, age, weight, height, body fat percentage
and more.
[0212] According to some embodiments, the device may utilize a
machine-learning capability, in which the altering of the
stimulation characteristics may be done for achieving low
habituation based on habituation patterns and behaviors obtained
from previous stimulations.
[0213] The foregoing description of the specific embodiments will
so fully reveal the general nature of the disclosure that others
can, by applying current knowledge, readily modify and/or adapt for
various applications such specific embodiments without undue
experimentation and without departing from the generic concept, and
therefore, such adaptations and modifications should and are
intended to be comprehended within the meaning and range of
equivalents of the disclosed embodiments. It is to be understood
that the phraseology or terminology employed herein is for the
purpose of description and not of limitation. The means, materials,
and steps for carrying out various disclosed chemical structures
and functions may take a variety of alternative forms without
departing from the disclosure.
[0214] According to some embodiments, the randomness of stimulation
altering (chaotic stimulation) may be achieved by
chaotically/randomly altering stimulation characteristics per
stimulation technique, randomly/chaotically altering between
different techniques/mechanisms of stimulation, utilizing multiple
stimulation techniques at a given time or any combination
thereof.
EXAMPLES
Example 1
[0215] Mice: 4 C57BL, Males, 12 Weeks Old
[0216] Following a 12 hours fast, one group of mice was exposed to
5 minutes of external body stimulation or and another group was not
exposed to stimulation to serve as a control group. The stimulation
was delivered using an external rotor attached to their upper
abdomen. The Gherlin levels of the Mice were measured/tracked. The
measurements were done as follows:
TABLE-US-00001 Time Action 0 Draw blood for hormones 5 min rotator
on abdomen Draw blood for hormones
[0217] Preparation of the Samples:
[0218] Blood was drawn into anti-coagulant containing tubes, and
AEBSF was added to stabilize the Ghrelin hormone, to a final
concentration of 1 mg/ml., let clot for 30 min. Centrifuge at
2000-3000 g for 15 min at 4 C. Take the serum to new tubes. Acidify
with HCl to a final concentration of 0.05 N. The samples are ready
for the Ghrelin assay.
[0219] Reference is now made to FIG. 9, which depicts a first
experiment result 900, according to some embodiments. Results 900
show a reduction in ghrelin levels following minutes of external
body stimulation compared with control from 499 to 82 pg/ml
respectively. The data suggests that external gastric stimulation
can reduce ghrelin levels.
Example 2
[0220] Mice: 4 C57BL, Males, 12 Weeks Old
[0221] Following a 12 hours fast, some mice were exposed to 5
minutes of external body stimulation while others were exposed to
no stimulation, forming a control group. The stimulation was
applied using an external rotor attached to the upper abdomen of
the mice, one group thereof was stimulated in in a regular manner,
while the other group was stimulated in an irregular chaotic
way.
[0222] The Gherlin levels of the Mice were measured/tracked. The
measurements were done as follows:
TABLE-US-00002 Time Action 0 Draw blood for hormones 5 min rotator
on abdomen Draw blood for hormones
[0223] Preparation of the Samples:
[0224] Blood was drawn into anti-coagulant containing tubes, and
AEBSF was added to stabilize the Ghrelin hormone, to a final
concentration of 1 mg/ml., let clot for 30 min. Centrifuge at
2000-3000 g for 15 min at 4 C. Take the serum to new tubes. Acidify
with HCl to a final concentration of 0.05 N. The samples are ready
for the Ghrelin assay.
[0225] Reference is now made to FIG. 10, which depicts a second
experiment result 1000, according to some embodiments. Results 1000
show a reduction in ghrelin levels following 5 minutes of external
body stimulation compared with control from 1237 to 800 pg/ml
respectively using regular rhythm. However using an irregular
chaotic rhythm gherlin levels further decreased to 602 pg/ml. The
data suggests that irregular chaotic external gastric stimulation
has a better effect on reducing ghrelin levels.
Example 3
[0226] Mice: 4 C57BL, Males, 12 Weeks Old
[0227] Following a 12 hours fast, some mice were exposed to 5
minutes of external body stimulation, and others were exposed to no
stimulation, forming a control group. The stimulation was applied
using an external rotor attached to the upper abdomen of the mice,
and one group of mice received stimulation in a regular manner,
while another group received stimulation in an irregular chaotic
way.
[0228] The Gherlin levels of the Mice were measured/tracked. The
measurements were done as follows:
TABLE-US-00003 Time Action 0 Draw blood for hormones 5 min rotator
on abdomen Draw blood for hormones
[0229] Preparation of the Samples:
[0230] Blood was drawn into anti-coagulant containing tubes, and
AEBSF was added to stabilize the Ghrelin hormone, to a final
concentration of 1 mg/ml., let clot for 30 min. Centrifuge at
2000-3000 g for 15 min at 4 C. Take the serum to new tubes. Acidify
with HCl to a final concentration of 0.05 N. The samples are ready
for the Ghrelin assay.
[0231] Reference is now made to FIG. 11, which depicts a third
experiment result 1100, according to some embodiments. Results 1100
show a reduction in ghrelin levels following 5 minutes of external
body stimulation compared with control from 340 to 184 pg/ml
respectively using regular rhythm. However, using an irregular
chaotic rhythm gherlin levels further decreased to 134 pg/ml. The
data suggests that irregular chaotic external gastric stimulation
has a better effect on reducing ghrelin levels.
* * * * *