U.S. patent application number 17/404798 was filed with the patent office on 2021-12-02 for intestinal devices and methods for facilitating weight loss.
This patent application is currently assigned to 3DT Holdings, LLC. The applicant listed for this patent is 3DT Holdings, LLC. Invention is credited to Ghassan S. Kassab, Xiao Lu.
Application Number | 20210369479 17/404798 |
Document ID | / |
Family ID | 1000005782852 |
Filed Date | 2021-12-02 |
United States Patent
Application |
20210369479 |
Kind Code |
A1 |
Kassab; Ghassan S. ; et
al. |
December 2, 2021 |
INTESTINAL DEVICES AND METHODS FOR FACILITATING WEIGHT LOSS
Abstract
An intestinal device, or a non-constrictive cuff, is configured
for placement around an intestine. In the closed position the
non-constrictive cuff is configured to be around at least part or
all of an intestine, wherein the non-constrictive cuff does not
constrict the portion of the intestine when deployed. A first
intestinal device can be deployed for placement around a portion of
an intestine, wherein a proximal end of the first intestinal device
is configured to longitudinally overlap a distal end of a second
intestinal device when disposed around an intestine. A method of
use for a first intestinal device or non-constrictive cuff is also
disclosed.
Inventors: |
Kassab; Ghassan S.; (La
Jolla, CA) ; Lu; Xiao; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
3DT Holdings, LLC |
San Diego |
CA |
US |
|
|
Assignee: |
3DT Holdings, LLC
San Diego
CA
|
Family ID: |
1000005782852 |
Appl. No.: |
17/404798 |
Filed: |
August 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15819657 |
Nov 21, 2017 |
11090180 |
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17404798 |
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14368988 |
Jun 26, 2014 |
9820879 |
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PCT/US2012/071560 |
Dec 23, 2012 |
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15819657 |
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61580293 |
Dec 26, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 5/0079 20130101;
A61F 5/005 20130101; A61F 5/0076 20130101 |
International
Class: |
A61F 5/00 20060101
A61F005/00 |
Claims
1. A device for placement around an intestine, comprising: a
non-constrictive cuff, wherein the non-constrictive cuff is
configured for placement around a portion of an intestine of a
patient and further configured to reduce or limit localized
intestinal distension and to facilitate weight loss of the patient
without constriction of the intestine upon deployment.
2. The device of claim 1, wherein the non-constrictive cuff
comprises an effective inner diameter greater than an outer
diameter of the portion of an intestine at a location of the
placement of the device thereon.
3. The device of claim 1, wherein an inner diameter of the
non-constrictive cuff is no less than an outer diameter of the
portion of an intestine at a location of the placement of the
device thereon.
4. The device of claim 1, wherein the non-constrictive cuff defines
an axial gap which defines a 30-45 degree arc of an outer
circumference of the non-constrictive cuff when measured from an
opposite side of the non-constrictive cuff.
5. The device of claim 1, wherein the device is configured to
transform from a compressed, first configuration during device
delivery into the patient using a delivery device to an
uncompressed, second configuration when the device is within the
patient and outside of the delivery device.
6. The device of claim 2, wherein the effective inner diameter is
greater than 5.0 cm.
7. The device of claim 1, wherein the non-constrictive cuff has a
first, open configuration that can transform to a second, closed or
partially closed configuration.
8. A device for placement around an intestine, comprising: a first
intestinal device having a longitudinal axis defined along its
length, the first intestinal device configured for placement around
a portion of an intestine of a patient and configured to reduce or
limit localized intestinal distension; and wherein a proximal end
of the first intestinal device is further configured to
longitudinally overlap a distal end of a second intestinal device
when disposed around an intestine.
9. The device of claim 8, wherein when the first intestinal device
is positioned around the portion of the intestine, the first
intestinal device does not constrict the intestine.
10. The device of claim 8, wherein the first intestinal device is
configured for placement around at least half of a perimeter of the
intestine.
11. The device of claim 8, wherein the first intestinal device is
configured for placement completely around the intestine.
12. The device of claim 8, further comprising: a hinged arm coupled
to the first intestinal device at a hinge location; wherein when a
hinged arm end engages a relative end of the first intestinal
device, the first intestinal device is in a closed configuration;
and wherein the device is in an open position when the hinged arm
extends radially outward.
13. The device of claim 8, further comprising: a post and a post
aperture defined within the first intestinal device, the post
configured to engage the post aperture to close the device.
14. The device of claim 9, further comprising: one or more tabs
positioned at or near a first end of the first intestinal device;
and a tab receiver positioned at or near a second end of the first
intestinal device, the tab receiver configured to receive the one
or more tabs to close the first intestinal device; wherein the one
or more tabs allows a user of the first intestinal device to adjust
an overall closed configuration size of the first intestinal
device.
15. A method of treating a patient, comprising: positioning a first
non-constrictive cuff around a portion of an intestine of a
patient; and closing the first non-constrictive cuff around the
portion of the intestine such that the first non-constrictive cuff
does not constrict the portion of the intestine upon closing.
16. The method of treating a patient as in claim 15, further
comprising the step of securing the first non-constrictive cuff in
place on the portion of the intestine.
17. The method of treating a patient as in claim 15, further
comprising the step of limiting expansion of the portion of the
intestine after closing the first non-constrictive cuff without
constricting the intestine.
18. The method of treating a patient as in claim 15, further
comprising the step of positioning a second non-constrictive cuff
on a second portion of the intestine such that there is a gap on
the intestine between the first non-constrictive cuff and the
second non-constrictive cuff.
19. The method of treating a patient as in claim 15, further
comprising the step of positioning a second non-constrictive cuff
on a second portion of the intestine such that the first
non-constrictive cuff is immediately adjacent the second
non-constrictive cuff.
20. The method of treating a patient as in claim 19, further
comprising the step of securing the second non-constrictive cuff in
place on the second portion of the intestine such that the second
non-constrictive cuff does not constrict the second portion of the
intestine upon closing.
Description
PRIORITY
[0001] The present patent application is related to, and claims the
priority benefit of, and is a U.S. continuation application of,
U.S. patent application Ser. No. 15/819,657, filed Nov. 21, 2017
and issued as U.S. Pat. No. 11,090,180 on Aug. 17, 2021, which is
related to, claims the priority benefit of, and is a U.S.
continuation application of, U.S. patent application Ser. No.
14/368,988, filed Jun. 26, 2014 and issued as U.S. Pat. No.
9,820,879 on Nov. 21, 2017, which is related to, claims the
priority benefit of, and is a U.S. .sctn. 371 National Stage
Application of, PCT Patent Application Serial No.
PCT/US2012/071560, filed Dec. 23, 2012, which is related to, and
claims the priority benefit of, U.S. Provisional Patent Application
Ser. No. 61/580,293 filed Dec. 26, 2011. The contents of each of
the aforementioned patent applications are hereby incorporated by
reference in their entirety into this disclosure.
BACKGROUND
[0002] Physical forces act on the intestinal wall when the
intestine propels chime. The intestinal tract is abundantly
innervated with mechanosensors to sense the physical forces in
intestinal wall when a meal transits through the gut. The
excitation of extrinsic sensory afferents provides clear evidence
of the intestinal mechanosensory endings in response to distension.
These sensory afferents respond to mechanical stimulation arising
during intestinal distension and contraction. The level of
mesenteric afferent firing increases in proportion to the increase
in intraintestinal pressure.
[0003] Brain-gut interactions are recognized as major players in
physiological and pathpophysiological regulation of the intestinal
tract. The intestinal tract is dominated by enteric nervous system
together with the myogenic pacemakers known as interstitial cells
of Cajal that allows the intestine to have a considerable degree of
independent control from the central nervous system.
[0004] Although the mechanical sensory and afferent excitations in
response to mechanical stimulation have been extensively studied,
the role of mechanical stimulation on intestinal contractility is
poorly understood. Intestinal contractility consists of intricate
interplay between intestinal sensors to afferent nerves to central
nervous system and back to efferent nerves and intestinal smooth
muscles.
[0005] Unfortunately, there is currently no quantitative method to
study the intact (in vitro or in situ) intestinal contractility. To
understand the relation between distension (intestinal sensors) and
contractility (intestinal smooth muscles), a novel quantitative
assay was used, namely an in situ and in vitro isovolumic myograph,
to determine the role of extrinsic nervous system and intrinsic
nervous regulation on the contractility. An external restraint was
used to inhibit the distension and hence determine the role of
distension or stretch. Depending on the outcomes of the study, use
of such a restraint may be useful to, depending on configuration
and placement, operate as a safe and effective weight loss
device.
[0006] In view of the foregoing, a novel intestinal device and
method for using the same to facilitate weight loss, for example,
would be well accepted in the marketplace.
BRIEF SUMMARY
[0007] In an exemplary method of patient treatment of the present
disclosure, the method comprises the step of positioning a device
that is configured to reduce or limit localized intestinal
distension, around a portion of an intestine of a patient. In
another exemplary method of patient treatment of the present
disclosure, the method comprises the step of positioning a device
around a portion of an intestine of a patient. In another
embodiment, the method is performed to facilitate weight loss of
the patient. In yet another embodiment, the method is performed to
facilitate a reduction in food intake by the patient. In an
additional embodiment, the method is performed to treat
obesity.
[0008] In an exemplary method of patient treatment of the present
disclosure, the method is performed to treat a diabetic condition
of the patient. In an additional embodiment, the positioning step
is performed to reduce or limit localized distension of the
intestine, slowing overall digestive and/or excretory processes of
the patient. In yet an additional embodiment, the positioning step
is performed to facilitate satiety of the patient. In another
embodiment, the positioning step is performed to slow overall
digestive and/or excretory processes of the patient.
[0009] In an exemplary method of patient treatment of the present
disclosure, the method further comprises the step of introducing
the device into the patient prior to the step of positioning the
device. In another embodiment, the introducing step is performed
using a procedure selected from the group consisting of a
laparoscopic procedure and an open surgical procedure. In yet
another embodiment, the method further comprises the step of
securing the device to the patient using one or more sutures. In an
additional embodiment, the method is performed to treat a blood
glucose level condition of the patient.
[0010] In an exemplary method of patient treatment of the present
disclosure, the positioning step is performed to position the
device around at least half of a perimeter of the intestine. In
another embodiment, the positioning step is performed to position
the device around at least three quarters of a perimeter of the
intestine. In yet another embodiment, the positioning step is
performed to position the device completely around the intestine.
In an additional embodiment, the weight loss of the patient is
facilitated by the patient eating less food. In yet an additional
embodiment, the weight loss of the patient is facilitated by the
patient eating less food due to slower overall digesting and/or
excretory processes of the patient.
[0011] In an exemplary method of patient treatment of the present
disclosure, the device remains within the patient for a desired
amount of time. In an additional embodiment, the desired amount of
time is selected from the group consisting of at least two weeks,
between two weeks and one month, between one month and three
months, between three months and six months, between six months and
one year, between one year and two years, and at least two years.
In yet an additional embodiment, the method further comprises the
step of removing the device from the patient after the desired
amount of time has elapsed. In another embodiment, the positioning
step is performed to position the device around a portion of the
intestine at a first location. In yet another embodiment, the
method further comprises the step of positioning a second device
configured to reduce or limit localized intestinal distension
around a portion of the intestine at a second location.
[0012] In an exemplary method of patient treatment of the present
disclosure, the device is positioned adjacent to the second device.
In another embodiment, the device touches the second device. In yet
another embodiment, the second device overlaps at least a portion
of the device. In an additional embodiment, the device does not
touch the second device.
[0013] In an exemplary method of patient treatment of the present
disclosure, the method further comprises the step of positioning a
third device configured to reduce or limit localized intestinal
distension around a portion of the intestine at a third location.
In an additional embodiment, the device touches at least one of the
second device and the third device. In yet an additional
embodiment, the second device overlaps at least a portion of the
device, and wherein the third device overlaps at least a portion of
the second device. In another embodiment, the device, the second
device, and the third device do not touch one another.
[0014] In an exemplary method of patient treatment of the present
disclosure, the device comprises a temperature-sensitive material.
In an additional embodiment, the device changes from a first
configuration to a second configuration after introducing the
device into the patient and prior to the step of positioning the
device. In yet an additional embodiment, the first configuration is
compressed, and wherein the second configuration is uncompressed.
In another embodiment, the introducing step is performed by
introducing at least part of a delivery device into the patient,
wherein at least a portion of the device is positioned within the
delivery device.
[0015] In an exemplary method of patient treatment of the present
disclosure, the introducing step further comprises the step of
removing the device from the delivery device. In another
embodiment, the device is in a first, compressed configuration when
at least a portion of the device is positioned within the delivery
device, and wherein the device is in a second, uncompressed
configuration after the device is removed from the delivery device.
In yet another embodiment, the step of securing is performed by
placing the one or more sutures within one or more suture apertures
defined within the device. In an additional embodiment, the device
comprises a flexible or pliable material.
[0016] In an exemplary device of the present disclosure, the device
comprises a body configured for placement around a portion of an
intestine of a patient and further configured to reduce or limit
localized intestinal distension. In another embodiment, the device
comprises a temperature-sensitive material so that the device can
change from a first configuration to a second configuration after
placement of the device within the patient. In yet another
embodiment, one or more suture apertures are defined within the
body. In an additional embodiment, the device is configured to
transform from a compressed, first configuration during device
delivery into the patient using a delivery device to an
uncompressed, second configuration when the device is within the
patient and outside of the delivery device.
[0017] In an exemplary device of the present disclosure, when the
device is positioned around the intestine, the device facilitates
weight loss of the patient. In an additional embodiment, the weight
loss of the patient is facilitated by the reduction or limitation
of localized intestinal distension, which slows overall digestive
and/or excretory processes of the patient. In yet an additional
embodiment, the weight loss of the patient is facilitated by the
patient eating less food due to a slowing of overall digestive
and/or excretory processes of the patient. In another embodiment,
when the device is positioned around the intestine, the device
treats a diabetic or other blood glucose level condition of the
patient.
[0018] In an exemplary device of the present disclosure, the body
comprises a flexible or pliable material. In another embodiment,
the body comprises a biologically compatible polymer material. In
yet another embodiment, the body further comprises a biologically
compatible metal material. In an additional embodiment, the body
comprises a biologically compatible metal material. In yet an
additional embodiment, the body has a first, open configuration
that can transform to a second, closed or partially closed
configuration.
[0019] In an exemplary device of the present disclosure, the body
defines a first end and a second end. In an additional embodiment,
engagement of the first end and the second end effectively closes
the device. In yet an additional embodiment, the body is configured
for placement around at least half of a perimeter of the intestine.
In another embodiment, the body is configured for placement around
at least three quarters of a perimeter of the intestine. In yet
another embodiment, the body is configured for placement completely
around the intestine.
[0020] In an exemplary device of the present disclosure, the device
has an inner diameter and an outer diameter when in a closed or
partially closed configuration. In another embodiment, the device
further comprises a hinged arm coupled to the body at a hinge
location. In yet another embodiment, wherein when a hinged arm end
engages a relative body end, the device is in a closed
configuration. In an additional embodiment, the device further
comprises a post and a post aperture defined within the body, the
post configured to engage the post aperture to close the device. In
yet an additional embodiment, the post is located at or near a
first end of the body, and the post aperture is located at or near
a second end of the body.
[0021] In an exemplary device of the present disclosure, a
plurality of suture apertures are defined within the body. In an
additional embodiment, when a suture is positioned within suture
apertures located at relative opposing ends of the body, the device
is in a closed configuration. In yet an additional embodiment, the
plurality of suture apertures allows a user of the device to adjust
an overall closed configuration size of the device.
[0022] In an exemplary device of the present disclosure, the device
further comprises one or more tabs positioned at or near a first
end of the body, and a tab receiver positioned at or near a second
end of the body, the tab receiver configured to receive the one or
more tabs to close the device. In another embodiment, the one or
more tabs allow a user of the device to adjust an overall closed
configuration size of the device. In yet another embodiment, the
device further comprises a second body configured for placement
around a portion of the intestine of the patient and further
configured to reduce or limit localized intestinal distension.
[0023] In an exemplary system of the present disclosure, the system
comprises a first intestinal device, comprising a body configured
for placement around a portion of an intestine of a patient and
further configured to reduce or limit localized intestinal
distension, and a delivery device configured to receive at least a
portion of the first intestinal device therein and further
configured for at least partial placement into the patient to
deliver the first intestinal device into the patient. In another
embodiment, the system further comprises a second intestinal
device, comprising a second body configured for placement around a
portion of the intestine of the patient and further configured to
reduce or limit localized intestinal distension. In yet another
embodiment, the delivery device is further configured to receive at
least a portion of the second intestinal device therein and to
deliver the second intestinal device into the patient.
[0024] In an exemplary system of the present disclosure, the system
comprises a first intestinal device and a second intestinal device,
each comprising a body configured for placement around a portion of
an intestine of a patient and further configured to reduce or limit
localized intestinal distension. In another embodiment, the system
further comprises a delivery device configured to receive at least
a portion of the first intestinal device and the second intestinal
device therein and further configured for at least partial
placement into the patient to deliver the first intestinal device
and the second intestinal device into the patient.
[0025] In an exemplary method of the present disclosure, the step
of positioning the device is performed to position the device
around the portion of the intestine selected from the group
consisting of a duodenum, a jejunum, an ilium, and a large
intestine. In another embodiment, the step of positioning the
device is performed to position the device around a portion of a
duodenum, and wherein the one or more sutures are attached to a
stomach at or near a pyloric region. In yet another embodiment,
when the device is positioned around the portion of the intestine,
the device does not constrict the intestine. In an additional
embodiment, when the device is positioned around the portion of the
intestine, the intestine, when expanded due to digesting content
therein, exerts a pressure against the device.
[0026] In an exemplary device of the present disclosure, the body
is sized and shaped so not to invoke any stenosis of the intestine
when placed around a portion of the intestine. In an additional
embodiment, the body is sized and shaped so when the device is
positioned around the portion of the intestine, the device does not
constrict the intestine. In yet an additional embodiment, the body,
when in the second, closed or partially closed configuration,
defines an inner diameter that corresponds to an outer diameter of
the intestine. In another embodiment, the body, when in the second,
closed or partially closed configuration, defines an inner diameter
that is larger than an outer diameter of the intestine.
[0027] In an exemplary device of the present disclosure, the device
comprises a non-constrictive cuff, wherein the non-constrictive
cuff is configured for placement around a portion of an intestine
of a patient and further configured to reduce or limit localized
intestinal distension and to facilitate weight loss of the patient
without constriction of the intestine upon deployment. In an
exemplary embodiment, the non-constrictive cuff comprises an
effective inner diameter greater than an outer diameter of the
portion of an intestine at a location of the placement of the
device thereon. In another embodiment, an inner diameter of the
non-constrictive cuff is no less than an outer diameter of the
portion of an intestine at a location of the placement of the
device thereon. In one example, the effective inner diameter is
greater than 5.0 cm.
[0028] The non-constrictive cuff may also define an axial gap which
defines a 30-45 degree arc of an outer circumference of the
non-constrictive cuff when measured from an opposite side of the
non-constrictive cuff.
[0029] In an exemplary embodiment, the device is configured to
transform from a compressed, first configuration during device
delivery into the patient using a delivery device to an
uncompressed, second configuration when the device is within the
patient and outside of the delivery device. The non-constrictive
cuff can have a first, open configuration that can transform to a
second, closed or partially closed configuration.
[0030] In an exemplary embodiment, a first intestinal device has a
longitudinal axis defined along its length, and the first
intestinal device is configured for placement around a portion of
an intestine of a patient and configured to reduce or limit
localized intestinal distension; and a proximal end of the first
intestinal device is further configured to longitudinally overlap a
distal end of a second intestinal device when disposed around an
intestine.
[0031] In a further embodiment, the first intestinal device is
positioned around the portion of the intestine, the first
intestinal device does not constrict the intestine. The first
intestinal device may be configured for placement around at least
half of a perimeter of the intestine. Alternatively, the first
intestinal device is configured for placement completely around the
intestine.
[0032] The device may comprise a variety of closure features. In an
embodiment, the device comprises a hinged arm coupled to the first
intestinal device at a hinge location; wherein when a hinged arm
end engages a relative end of the first intestinal device, the
first intestinal device is in a closed configuration; and wherein
the device is in an open position when the hinged arm extends
radially outward. In another embodiment, the device comprises a
post and a post aperture defined within the first intestinal
device, the post configured to engage the post aperture to close
the device. In another embodiment, the device comprises one or more
tabs positioned at or near a first end of the first intestinal
device; and a tab receiver positioned at or near a second end of
the first intestinal device, the tab receiver configured to receive
the one or more tabs to close the first intestinal device; wherein
the one or more tabs allows a user of the first intestinal device
to adjust an overall closed configuration size of the first
intestinal device.
[0033] An exemplary embodiment of a method of treating a patient
comprises: positioning a first non-constrictive cuff around a
portion of an intestine of a patient; and closing the first
non-constrictive cuff around the portion of the intestine such that
the first non-constrictive cuff does not constrict the portion of
the intestine upon closing.
[0034] In a further embodiment the method of treating a patient
further comprises the step of securing the first non-constrictive
cuff in place on the portion of the intestine. In another
embodiment, the method of treating a patient further comprises the
step of limiting expansion of the portion of the intestine after
closing the first non-constrictive cuff.
[0035] The method of treating a patient as in claim 15 further
comprising the step of positioning a second non-constrictive cuff
on a second portion of the intestine such that there is a gap on
the intestine between the first non-constrictive cuff and the
second non-constrictive cuff. The second non-constrictive cuff can
also be placed on a second portion of the intestine such that the
first non-constrictive cuff is immediately adjacent the second
non-constrictive cuff. The second non-constrictive cuff should be
secured in place on the second portion of the intestine such that
the second non-constrictive cuff does not constrict the second
portion of the intestine upon closing.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] The disclosed embodiments and other features, advantages,
and disclosures contained herein, and the matter of attaining them,
will become apparent and the present disclosure will be better
understood by reference to the following description of various
exemplary embodiments of the present disclosure taken in
conjunction with the accompanying drawings, wherein:
[0037] FIGS. 1A and 1B show a device of the present disclosure in
an open or partially closed configuration, according to an
exemplary embodiment of the present disclosure;
[0038] FIGS. 1C and 1D show a device of the present disclosure in a
fully closed configuration, according to an exemplary embodiment of
the present disclosure;
[0039] FIGS. 1E and 1F show a device of the present disclosure
having a hinged portion, according to an exemplary embodiment of
the present disclosure;
[0040] FIG. 1G shows a device of the present disclosure having a
post and defining a post aperture, according to an exemplary
embodiment of the present disclosure;
[0041] FIG. 1H shows a device of the present disclosure having a
series of apertures defined therein in an open configuration,
according to an exemplary embodiment of the present disclosure;
[0042] FIG. 1I shows a device of the present disclosure having a
series of apertures defined therein in a closed configuration,
according to an exemplary embodiment of the present disclosure;
[0043] FIG. 1J shows a device of the present disclosure having a
plurality of tabs and a tab receiver, according to an exemplary
embodiment of the present disclosure;
[0044] FIG. 1K shows a device of the present disclosure positioned
around at least part of an intestine, according to an exemplary
embodiment of the present disclosure;
[0045] FIG. 2 shows an exemplary myograph used to test an exemplary
intestinal device, according to at least one embodiment of the
present disclosure;
[0046] FIGS. 3A and 3B show data indicative of an increase in
injection volume during pressurization of duodenum and colon,
respectively, according to the present disclosure;
[0047] FIGS. 3C and 3D show data indicative of an increase in
diameter during pressurization of duodenum and colon, respectively,
according to the present disclosure;
[0048] FIGS. 3E and 3F show data indicative of an increase in
compensation volume rate during pressurization of duodenum and
colon, respectively, according to the present disclosure;
[0049] FIGS. 4A and 4B show data indicative of temporal contractile
waves of the duodenum and colon, according to the present
disclosure;
[0050] FIGS. 5A and 5B show data indicative of the contractility of
duodenum and colon vs. pressure relationship, respectively,
according to the present disclosure;
[0051] FIGS. 5C and 5D show data indicative of the contractile
tension of duodenum and colon vs. diameter relationship,
respectively, according to the present disclosure;
[0052] FIGS. 6A-6D show data indicative of the relationship of
duodenal and colonic contractility (amplitude) and incremental
stretch ratio during pressurization, according to the present
disclosure;
[0053] FIG. 7 shows use of a device around an intestine, according
to an exemplary embodiment of the present disclosure;
[0054] FIGS. 8A-8C show data indicative of weight loss, food
intake, and glucose levels, respectively, with and without use of a
device in Wistar rats, according to the present disclosure;
[0055] FIGS. 9A-9C show data indicative of weight loss, food
intake, and glucose levels, respectively, with and without use of a
device in Zucker diabetic fatty rats, according to the present
disclosure;
[0056] FIGS. 10A and 10B show block diagrams of systems, according
to exemplary embodiments of the present disclosure; and
[0057] FIG. 10C shows use of a device around a duodenum, according
to an exemplary embodiment of the present disclosure.
[0058] An overview of the features, functions and/or configurations
of the components depicted in the various figures will now be
presented. It should be appreciated that not all of the features of
the components of the figures are necessarily described. Some of
these non-discussed features, such as various couplers, etc., as
well as discussed features are inherent from the figures
themselves. Other non-discussed features may be inherent in
component geometry and/or configuration.
DETAILED DESCRIPTION
[0059] For the purposes of promoting an understanding of the
principles of the present disclosure, reference will now be made to
the embodiments illustrated in the drawings, and specific language
will be used to describe the same. It will nevertheless be
understood that no limitation of the scope of this disclosure is
thereby intended.
[0060] An exemplary device for placement around a portion of an
intestine to facilitate weight loss, to facilitate a reduction in
food intake, to treat obesity, to treat a diabetic condition, to
facilitate satiety, and/or to slow the overall digestive and/or
excretory processes of a patient using the device of the present
disclosure is shown in FIGS. 1A and 1B. As shown in FIGS. 1A and
1B, an exemplary device 100 comprises a body 102 configured for
placement around a portion of (at least part of) an intestine 208,
as shown in FIG. 1K, for example. The overall dimensions of an
exemplary device 100 of the present disclosure are such to
reduce/limit a localized intestinal expansion within a mammalian
body where device 100 is positioned.
[0061] Device 100, in at least one embodiment, comprises a
flexible/pliable material (such as any number of biologically
compatible polymers and/or metals) that, when configured as a
device 100 of the present disclosure, can fit around part of an
intestine 208 and limit intestinal distension. As shown in FIGS. 1A
and 1B, device 100 is in an open configuration, and as shown in
FIGS. 1C and 1D, device 100 is in a fully closed configuration.
Other embodiments of devices 100 of the present disclosure may have
a partially closed configuration resembling to configurations shown
in FIGS. 1A and 1B. However, and in various embodiments of devices
100 of the present disclosure, devices 100 may remain in an open
configuration, and may never form a fully closed configuration,
when positioned around at least part of an intestine 208, such as
around most or a majority of a perimeter of an intestine 208. A
device first end 104 and a device second end 106, as shown in FIGS.
1A and 1B, may engage one another upon closure of device 100, as
shown in FIGS. 1C and 1D, or may be in close proximity to one
another when device 100 is positioned around an intestine 208. One
or more suture apertures 108, as shown in FIGS. 1A and 1C, may be
defined within body 102 so that when device 100 is positioned
around an intestine 208, sutures 144 (shown in FIG. 1I, such as
silk sutures) may be used to secure device 100 around the intestine
208 to prevent device migration. In lieu of suture apertures 108,
for example, one or more sutures 144 could be used and placed
directly through and/or around portions of device 100.
[0062] An exemplary device 100 of the present disclosure has a
length 110 (as shown in FIG. 1C) and an inner diameter 112 and an
outer diameter 114 (as shown in FIG. 1D) when positioned around at
least a portion of an intestine 208. In an open configuration, as
shown in FIGS. 1A and 1B, the inner diameter 112 and outer diameter
114 (assuming a full circle) would be relatively larger than the
inner diameter 112 and the outer diameter 114 of the same device in
a closed or partially closed configuration. Other embodiments, as
referenced in detail herein, may not have a relative inner diameter
112 or outer diameter 114 when not positioned around an intestine
208, but would have said diameters when positioned around at least
a portion of an intestine 208. In addition, and as shown in FIG.
1D, device 100 has at least one inherent thickness 116, which may
vary from embodiment to embodiment. Various device 100 embodiments
can be configured as bands, sleeves, or cuffs, for example.
[0063] An additional embodiment of a device 100 of the present
disclosure is shown in FIGS. 1E and 1F. As shown therein, device
100 comprises a hinged arm 118 connecting to part of body 102 at a
hinge location 120. Hinged arm 118 is shown as being relatively
open in FIGS. 1E and 1F, and would, in at least one embodiment,
fully close so that a hinged arm end 122 would contact second end
106 of body 102. In other embodiments (not shown), hinged arm 118
would close but the entirety of device 100 may not actually close
(such that first end 104 does not contact and/or overlap second end
106).
[0064] Additional device embodiments are shown in FIGS. 1G-1J. As
shown in FIG. 1G, an exemplary device 100 may comprise a post 140
and define one or more post apertures 142, wherein when post 140 is
positioned within post aperture 142, device 100 is secured in a
closed configuration, around an intestine 208 if desired. In at
least one embodiment, post 140 is at or near a first end 104 of the
device, and post aperture 142 is located at or near a second end
106 of the device 100. FIGS. 1H and 1I show device 100 embodiments
where two apertures 108 defined therein may be used to secure the
device together using one or more sutures 144 as shown in FIG. 1I.
FIG. 1H shows an exemplary device 100 in an open configuration,
while FIG. 1I shows the same device 100 in a closed configuration
with a suture 144 positioned through one or more suture apertures
108. Such an embodiment, having a plurality of apertures 108
defined therein, would allow a user positioning such a device 100
to be able to adjust the overall inner diameter 112 of the device
100 when positioning the same around an intestine 208.
[0065] An additional embodiment of a device 100 of the present
disclosure is shown in FIG. 1J, whereby device 100 comprises one or
more tabs 146 configured to fit within an aperture 147 of tab
receiver 148, so that when a tab 146 is positioned within aperture
147 of tab receiver 148, tab receiver 148 holds that part of device
100 in place by way of tab 146. In at least one embodiment, the
tabs 146 are at or near a first end 104 of the device, and the tab
receiver 148 is located at or near a second end 106 of the device
100. Such an embodiment, having a plurality of tabs 146, would
allow a user positioning such a device 100 to be able to adjust the
overall inner diameter 112 of the device 100 when positioning the
same around an intestine 208.
[0066] FIG. 1K shows an exemplary device 100 of the present
disclosure positioned around at least part of an intestine 208. As
shown therein, device 100 may be secured in place using one or more
sutures 144 through apertures 108 and through part of a wall of
intestine 208 to prevent device 100 migration. Removal of an
exemplary device 100, in various embodiments, may be by way of
removing sutures 144, disengaging post 140 from post aperture 142,
removing tab 146 from tab receiver 148, etc., or by generally
opening the device from a fully closed or partially closed
configuration to a relatively open configuration. As noted in
further detail below and shown in FIG. 7, two or more devices 100
can be placed in parallel (adjacent to one another (with or without
spaces in between) or at least partially overlapping one another)
to cover a larger portion of an intestine 208.
[0067] Placement of various device 100 embodiments of the present
disclosure around an intestine 208 may occur at various intestinal
locations. The human small intestine, for example, extends from the
pyloric region of the stomach and forms, from proximal end to the
distal end, the duodenum, the jejunum, and the ilium, the latter of
which is immediately adjacent to the proximal end of the large
intestine. In at least one method of using a device 100 of the
present disclosure, and as discussed in further detail herein,
device 100 can be placed around the duodenum. FIG. 10C shows a
portion of a mammalian digestive system 150, including the stomach
152, the pyloric region 154 of the stomach 152, and various
intestine 208 portions, including the duodenum 156, the jejunum
158, the ilium 160, as well as the large intestine 162. As shown
therein, an exemplary device 100 of the present disclosure is
positioned around at least a portion of intestine 208, namely at
duodenum 156, and is secured to stomach 152 at or near pyloric
region 154 using one or more sutures 144. Placement of various
device 100 embodiments may be made at one or more of the other
above-referenced portions of intestine 208. As shown in FIG. 7, for
example, three devices 100 can be used and positioned relative to
one another at the duodenum 156.
[0068] Various device 100 embodiments of the present disclosure,
which may also be referred to as non-constrictive cuffs (NCCs), may
be made of polytetrafluoroethylene (PTFE), silicone rubber, or a
bioabsorbable permeable or non-permeable material, for example.
Such materials, and other biologically-compatible materials, would
be sufficiently hard as to bear the forces generated from duodenal
motility and distension but flexible enough to be configured to
wrap around the duodenum 156 so that device 100 would be generally
cylindrical.
[0069] FIG. 7 shows an exemplary embodiment of a device 100 of the
present disclosure being delivered and positioned about an
intestine 208. As shown in FIG. 7, an exemplary delivery device
700, which may be a general catheter, a delivery catheter, trocar,
another type of tube, or a component having a lumen 702 defined
therein, can be delivered laparoscopically, for example, into the
patient so that a device 100 positioned therein can ultimately be
delivered into the patient. In various embodiments, device 100 can
have a first configuration 704, such as a folded, curled, or other
configuration that is intended to facilitate delivery, and can have
a second configuration 706, also as shown in FIG. 7, that is
suitable for positioned about an intestine 208. First configuration
704, in various device 100 embodiments, may be the relatively open
configuration, and second configuration 706 may be the partially or
fully closed configuration. As shown in FIG. 7, an exemplary device
100 of the present disclosure has a relatively curled first
configuration 704 that can open to an intermediate configuration
705 at a first temperature, and can ultimately change to a second
configuration 706 at or near a second temperature. In at least one
embodiment, the first temperature would be at or near room
temperature (less than body temperature), and the second
temperature would be at or near body temperature. To facilitate the
change in configuration, temperature-sensitive materials such as
nitinol can be used to comprise at least part of device 100, and
devices 100 can be generally configured to have a first
configuration 704 and a second configuration 706 suitable for
delivery and placement, respectively. Materials comprising device
100, in such an embodiment, give device 100 a "memory"
characteristic, such as changing from a first configuration 704 to
a second configuration 706, whereby the second configuration 706 is
a natural configuration at or near body temperature based upon the
memory characteristic. Aside from temperature-sensitive materials,
other materials that would allow device 100 to have a memory
characteristic, such as a native partially or fully closed
configuration, but also pliable/flexible enough to open, fold, or
curl, for example, to facilitate delivery, may be used as well.
[0070] In various embodiments, the cross-section of device 100,
such as shown in FIGS. 1B, 1D, and 7, may be generally circular or
elliptical to fit the duodenal contour, whereby the longitudinal
configuration of device 100 mimics the duodenal axial contour. In
various embodiments, the inner diameter 114 of device 100, as shown
in FIG. 1D, may be 105% to 150% of the duodenal external diameter.
Furthermore, and in various embodiments, the length 110 of device
100, as shown in FIG. 1C, may vary from 10% to 80% of the entire
length of duodenum 156, or may be even smaller (less than 10%), as
shown in the general ring embodiment shown in FIG. 1C.
[0071] As shown in FIG. 7, and in various embodiments of devices
100 of the present disclosure, device 100 can be first collapsed
(in a first configuration 704) to fit through standard trocar (an
exemplary delivery device 100), and once in the abdomen, device 100
can be opened to sector for implantation and then folded back for
wrapping the duodenum 156. When implanted, and in at least one
embodiment of a method of using a device 100 of the present
disclosure, device 100 will be first opened to sector and slipped
half underneath the duodenum 156 from non-mesenteric side and then
folded to wrap the duodenum 156. An axial gap 708 (0.6 to 2 mm, for
example), in at least some device 100 embodiments, is made on
device 100 to prevent disturbances to the mesentery 710 circulation
of the bowel. Gap 708, also referred to as a lateral opening, on
device 100 allows mesentery 710 access the duodenum 156 without
compression to prevent ischemia. In at least some embodiments, and
as shown in FIG. 7, an angle (.theta.) of our about 30.degree. to
45.degree. can be formed within device 100 to create gap 708,
noting that smaller or larger gaps 708 may be used as well.
[0072] One or more sutures 144, such as shown in FIGS. 1K and 7 and
as referenced above, may be used to secure an end of the device 100
(such as a proximal end) or another portion of device 100 on the
stomach 152 at or near the pyloric sphincter to prevent device 100
migration. Additional sutures 144 may be made be placed axially
along device 100 at the two edges of the sector with care to not
close the sector to further reinforce the stiffness of device 100
during distension. Sutures 144, when placed as such, will penetrate
the mesentery and stabilize device 100 in place during
motility.
[0073] As shown in FIG. 7, more than one device 100 can be
positioned about/upon intestine 208, either immediately adjacent to
each other, with gaps in between, or overlapping one another. Based
on the dimensions of intestine 208 at a particular location, said
multiple devices 100 can be of different sizes (having different
lengths 110 and/or diameters 112). Regarding device 100 sizes,
preferred embodiments of the present disclosure are sized and
shaped so not to invoke any intestine 208 stenosis. For example,
and in various device 100 embodiments of the present disclosure,
when devices 100 are in a fully or partially closed configuration
around part or all of an intestine 208, device 100 does not
constrict intestine 208, as the dimensions of device 100 exceed the
native dimensions (perimeter, diameter, circumference, etc.) of
intestine 208. For example, if a portion of a small intestine (such
as duodenum 156) has an outer diameter of 5.0 cm, and it is desired
to position an exemplary device 100 at that portion of duodenum
156, the dimensions of device 100 would be such that when device
100 is positioned around some or all of duodenum 156 at that
portion/location, the effective inner diameter 112 of device 100 is
greater than 5.0 cm. Devices 100 of the present disclosure, also
referred to as non-constrictive cuffs as referenced above, are
configured to avoid constricting intestine 208, but are configured,
as noted above, to provide a restriction of intestine 208 beyond
the normal non-distended intestional dimensions. Accordingly, and
in various device 100 embodiments of the present disclosure, inner
diameter 112 of device 100, when in a partially or fully closed
configuration, is greater than an outer diameter of intestine 208
at the location of placement of device 100 thereon. In at least
various other device 100 embodiments, inner diameter 112 of device
100, when in a partially or fully closed configuration, is no less
than the outer diameter of intestine 208 at the location of
placement of device 100 thereon.
[0074] Various devices 100 of the present disclosure may be used to
facilitate weight loss, or for other purposes as referenced herein,
as follows. In at least one embodiment of a method of using such a
device 100, the method comprises the step of delivering a device
100 laparoscopically (for example) into a patient relative to the
patient's intestine 208. The device 100 may then be positioned
around a patient's intestine 208 and secured in place using one or
more closure mechanisms described herein and one or more sutures
144 if desired. Additional devices 100 may be delivered in a
similar fashion if desired. In at least one embodiment of a method
of the present disclosure, the device 100 may be delivered through
an open surgical procedure. The device 100 may then be left in
place for a desired amount of time, and ultimately removed by
reversing the procedure (entering the patient, removing the device
100, and withdrawing the device 100 from the patient).
[0075] As described in detail below, use of such a device 100 can
significantly attenuate the intestinal contractility in response to
an increase in intraluminal pressure. Such a decrease in
contractility has the effect of slowing the movement of food
through a patient's gut during the digestion and excretion
processes. Such a slowing of said processes, by way of
contractility attenuation using a device of the present disclosure,
would cause a patient to ultimately ingest less food, and therefore
lose weight while the device 100 is positioned at least partially
around the patient's intestine 208.
[0076] An exemplary device 100 of the present disclosure was tested
using mouse intestine with an exemplary myograph as shown in FIG. 2
and referenced in further detail below. Other myograph embodiments,
such as those disclosed within U.S. Patent Application Publication
No. 2010/0022265 of Kassab and Lu, may also be used to perform the
tests described below.
[0077] FIG. 2 shows an exemplary system (myograph) 200, such as the
myograph used in the present study, and the in situlin vitro
experimental setup, used in the present study. As shown in FIG. 2,
system 200 comprises a chamber 202 with a catheter 204 on one side
wall of the chamber 202 which bridges the lumen 206 of an intestine
208 to an inflation flask 210 and pressure transducer 212. A 50 ml
inflation flask 210 with PSS 214 (connected to a pressure regulator
216) inflated the intestine 208 to the desired pressure. The
catheter 204, a solid state pressure transducer 212 (SPR-524,
Microtip catherter transducer, Millar Inc, Tex.), a tube 218 to the
inflation flask 210, and a compensatory microsyringe 220 were
assembled using a connector 222. The clamping of tube 218 between
inflation flask 210 and intestine 208, by way of clamp 224,
achieved isovolumic conditions, i.e., the intestinal lumen volume
was constant.
[0078] The compensatory microsyringe 220 (50 .mu.l gastight
microsyringe, UltraMicroPump III, and Micro 4TM microsyringe
controll, World Precision Instruments, USA) was used to stablize
(maintain) the baseline pressure since water transport across the
intestinal wall changes the intraluminal pressure. The criteria for
compensation was to mantain the contour of periodic pressure at
baseline. The rate of compensation generally changed with inflation
pressure. A CCD camera on a microscope and an image proccessing
system tracked the intestinal diameter. As the intestine was
inflated to a desired pressure (e.g., 5 mmHg, 10 mmHg, etc.), the
clamp 224 was closed, and the intestinal contraction or relaxation
was quantified by the variation of intraluminal pressure under a
constant rate of compensation. The isovolumic system 200 recorded
the periodic contractions of intestine in response to changes of
inflation pressure. The isovolumic measurements usually lasted 5 to
10 minutes and the intestine 208 was reversed to proximal and
distal open as in physiological state.
[0079] The animal experiments were performed as follows. Twelve
C57BL/6J mice at 24 weeks of age, having 31.2.+-.5.8 grams of body
weight, were obtained from Jackson Laboratory. The animals were
acclimated to the facility for approximately one (1) week prior to
the start of the study. The animals were anesthetized with xylazine
(1 mg/kg, i.p.) and ketamine (9 mg/kg, i.p.) and maintained with
xylazine (0.5 mg/kg) and ketamine (4.5 mg/kg) every half hour. The
animal experiments were performed in accordance with the guidelines
of Institute of Laboratory Animal Research Guide, Public Health
Service Policy, Animal Welfare Act, and an approved IACUC
protocol.
[0080] In situ intestinal contractility. Under anesthesia, the
abdominal skin and muscle layers of the animal were opened to
expose either the duodenum or the distal colon. The intestine was
moistened with warm (37.degree. C.) HEPES physiological saline
solution (HEPES-PSS in mmole/L: 119 NaCl, 4.7 KCl, 3 HEPES acid,
2.3 HEPES sodium salt, 1.17 MgSO.sub.4, 1.6 CaCl, 5.5 Dextrose).
The applied PSS was aerated with 95% O.sub.2 and 5% CO.sub.2. The
intestine was cannulated with a HEPES-PSS prefilled catheter (ID: 1
mm, OD: 2 mm) which connected to the isovolumic system 200 as shown
in FIG. 2. A 2 mm incision was cut at the oral intestine where the
catheter 204 (having an outer diameter of 2 mm) was inserted into
the intestinal lumen. The incision was tied on the catheter 204
with 6-0 silk suture twice to ensure no leakage. Two milliliters of
PSS was gently injected into the intestine through the catheter 204
to wash away the content. Another 6-0 silk suture was tied 11 mm
away towards the anal intestine from the cannulation. The
intestinal mesentery was untouched to allow the intestine to work
in a physiological environment maintaining normal circulation and
vagal responses.
[0081] In vitro intestinal contractility. The animals were
euthanized by overanesthesia. Deudenum or distal colon was excised
quickly and placed in ice cold (4.degree. C.) PSS to slow down
cellular metabolism and preserve cell vitality during preparation.
The adjacent tissue was dissected with the aid of a stereo
microscope. The intestine was allowed to warm up to room
temperature (22.degree. C.) slowly over approximately 10-15 minutes
and was transferred to a chamber 202 of the isovolumic myograph 200
with HEPES-PSS (22.degree. C.). The two ends of the intestine were
cannulated to connectors 226, 228 (having an inner diameter of 1 mm
and an outer diameter of 2 mm) in the chamber 202 of the isovolumic
myograph 200 and the length of the intestine considered was 11 mm.
The content in the intestine was gently rinsed with HEPES-PSS. The
intestine in the chamber 202 was slowly warmed to 37.degree. C.
over approximately 15-20 minutes and equilibrated for 30 minutes at
a basal pressure of about 1 mmHg before distension.
[0082] Intestinal contractility and inflation pressure. The
mechanical stimulation of intestine was induced by random sequence
of intraluminal inflation pressures. The intestinal contraction was
quantified by the intraluminal pressure under isovolumic condition
and the contractility was characterized with the amplitude and
period of the pressure waveforms. The intestine was inflated to a
desired pressure by a pressure regulator 216 connected to flask 210
as referenced above. The clamping of the tube 222 between the
inflation flask 210 and the intestine 208 maintained a constant
volume of solution in the intestinal lumen (an isovolumic
condition). The compensatory microsyringe 220 maintains isovolumic
conditions at, for example, an infusion rate of 0.6-2.3 .mu.l/min.
he data was discarded if the rate was larger than 50/min since this
implied damage (leakage) of the intestinal wall. At isovolumic
conditions, the variations of intraluminal pressure were recorded
with a data acquisition system (Biopac, MP100, Houston, Tex.). The
amplitude, frequency, and contractile duration of pressure
waveforms were analyzed to characterize the intestinal
contractility.
[0083] Intestinal restraint: A loosely fitting restraint (an
exemplary device 100 of the present disclosure) made of plastic
tube (body 102) was used to determine the role of stretch. A
portion of body 102 was removed (semi-cylinder) to allow the
intestinal mesentery to pass through freely. The dimensions of body
102 used in the study were 12.5 mm in length, 6 mm in internal
diameter, and 2 mm in wall thickness, noting that bodies 102 of
different dimensions may also be used in similar studies. The width
of the semi-cylinder was about 0.3 mm. The semi-cylinder was
axially opened up to a sector with the aid of a forceps. The
semi-cylinder was passed through the intestine. The forceps was
released to allow the semi-cylinder to fully wrap the intestine.
The semi-cylinder was circumferentially tied with a 6-0 silk suture
to restrain the intestine into the lumen of the semi-cylinder when
the intesine was inflated. Device 100 covered the cylindrical area
and limited the stretch of intestinal circumference despite an
increase in intraluminal pressure in the intestine. The noncovered
intestinal wall on the two ends was distended during the increase
in intraluminal pressure. To verify that the duodenal nerves were
not damaged while mounting the restraint, the contractility was
measured again after removal of device 100.
[0084] Protocol of mechanical stimulation. The intraluminal
pressure was increased stepwise to 2, 5, 10, 15, 20, 30, 40, and 50
(colon only) mmHg by injection of HEPES PSS into the intestine at
rate of 0.05 ml/min, respectively. The intestinal contraction at
isovolumic condition was recorded by the changes of pressure at
each inflation or distension pressure. This protocol was applied to
both in situ and in vitro intestine with or without intestinal
restraint. In the experiment of in vitro intestine, acetylcholine
(10.sup.-6 mole/l) was used to elicit non-neuroactive contraction
of intestinal smooth muscle at intraluminal pressure of 40 mmHg
(duodenum) or 50 mmHg (colon) to evalute contractility of
intestinal smooth muscle.
[0085] Data Analysis and Statistics. The intestinal contractile
amplitude was represented by the amplitude of pressure variation.
The incremental stretch ratios of intestinal circumference during
the stepwise inflation were computed with and without device 100.
The contractile tension was calculated by the amplitude of pressure
multiplied by the intestinal diameter. The linear regression of
intestinal contractility and incremental stretch was then analyzed.
The data were presented as mean.+-.SD and significant differences
between groups were determined by student t-test. Significant
differences between the in situ, in vitro, and restraint groups
were determined by use of Analysis Of Variance (ANOVA) between
groups. A probability of p<0.05 was considered indicative of a
statistically significant difference.
[0086] Results. The injection volumes into duodenum and colon for
both in situ and in vitro inflation were summarized in FIGS. 3A and
3B, respectively, which increased rapidly during low pressure and
slowed down during high pressure. Changes of injection volume,
diameter, and compensation rate during pressurization of duodenum
(left column) and colon (right column) are generally shown in FIGS.
3A-3F. FIGS. 3A and 3B show an increase in injection volume during
pressurization of duodenum and colon, respectively. Inflation
volume was significantly smaller when restraint applied. FIGS. 3C
and 3D show an increase in diameter during pressurization of
duodenum and colon, respectively. Diameter did not change when
restraint was applied. FIGS. 3E and 3F show an increase in
compensation volume rate during pressurization of duodenum and
colon, respectively. Compensation rate was suppressed by restraint.
There were no difference between in situ and in vitro states
(p>0.05), and the restraint significantly reduced the injection
volume, diameters, and compensation rate at in situ and in vitro
states (p<0.05). As shown within the figures, .diamond.
indicated an in situ state, .diamond-solid. indicates an in situ
state with a restraint, .DELTA. indicates an in vitro state, and
.tangle-solidup. indicates an in vitro state with a restraint.
[0087] As shown in the figures, the diameters had a similar trend
to the injection volume (FIGS. 3C and 3D), which reflect the
circumferential distensibility of the duodenum and colon during
pressurization. The compensatory rates of duodenum and colon at
isovolumic condition increased rapidly during low pressure and
slowed down during high pressure (FIGS. 3E and 3F, respectively).
The compensatory rates, diameters, and compensatory rates were not
significantly different between in situ and in vitro inflation
(p>0.05). The application of the restraint (an exemplary device
100 of the present disclosure) on the duodenum or colon limited the
increase of in situ and in vitro injection volume, diameters, and
compensatory rates during pressurization, as shown in FIGS.
3A-3F.
[0088] The typical intraluminal pressure waveforms produced by
contraction of duodenum and colon are shown in FIGS. 4A-4F in which
the amplitude of intraluminal pressure was affected by changes in
inflation pressure. FIGS. 4A-4F generally show typical in situ and
in vitro temporal contractile pressure waves of duodenum (left
column) and colon (right column) at various inflation pressures. As
shown in FIGS. 4A and 4B, and without restraint, the in situ
contractile pressure waves of duodenum and colon were significant.
As shown in FIGS. 4C and 4D, also without restraint, the in vitro
contractile pressure waves of duodenum and colon were significantly
attenuated in comparison with in situ state. When a restraint was
applied, as shown in FIGS. 4E and 4F, the in situ contractile
pressure waves of duodenum and colon were significantly attenuated.
The amplitude reached a maximum under all conditions at 5 mmHg of
inflation pressure and decreased monotonically with further
increase of inflation pressure. The in vitro contraction of colon
was significantly attenuated as shown in FIG. 4D.
[0089] As generally shown in FIGS. 5A-5D, the contractility of
duodenum (left column) and colon (right column) as a function of
pressure or diameter. FIGS. 5A and 5B show the contractility of
duodenum and colon vs. pressure relationship, respectively, whereby
the restraint significantly reduced the contractility of duodenum
and colon at in situ and in vitro states (p<0.05). FIGS. 5C and
5D show the contractile tension of duodenum and colon vs. diameter
relationship, respectively, whereby the restraint significantly
reduced the contractile tension of duodenum and colon at in situ
and in vitro states (p<0.05). As shown within the figures,
.diamond. indicated an in situ state, .diamond-solid. indicates an
in situ state with a restraint, .DELTA. indicates an in vitro
state, and .tangle-solidup. indicates an in vitro state with a
restraint.
[0090] The contractility of duodenum and colon are shown as a
function of inflation pressure in FIGS. 5A and 5B, respectively.
The in situ contractility of duodenum increased from 0.97.+-.0.29
to 1.42.+-.0.39 mmHg when the inflation pressure was increased from
1 to 5 mmHg. The duodenal contractility then decreased
significantly down to 0.4.+-.0.28 mmHg when the inflation pressure
was further increased from 5 to 40 mmHg as shown in FIG. 5A. The in
situ contractility of colon increased from 4.15.+-.1.16 to
4.86.+-.1.32 mmHg when the inflation pressure increased from 1 to 5
mmHg. The colonic contractility, then, decreased significantly down
to 1.61.+-.0.98 mmHg when the inflation pressure was further
increased from 5 to 50 mmHg as shown in FIG. 5B. The restraint did
not affect the in situ duodenal contractility at lower inflation
pressures (<5 mmHg), but attenuated the contractility when the
inflation pressures were >10 mmHg as shown in FIG. 5A. However,
the restraint largely attenuated the in situ colonic contractility
in the entire range of inflation pressures as shown in FIG. 5B. The
in vitro contractility of duodenum linearly decreased with increase
in inflation pressure and was significantly attenuated in
comparison with the in situ contractility as shown in FIG. 5A. The
in vitro contractility of colon was significantly attenuated in
comparison with the in situ contractility as shown in FIG. 5B. The
presence of the restraint essentially abolished the in vitro
contractility of duodenum and colon in the entire range of
inflation pressures (shown in FIGS. 5A and 5B, respectively).
[0091] The in vitro smooth muscle contraction of duodenum and colon
stimulated by ACh, however, was still similar to maximum
contractility at the in situ state. The contractility of duodenum
and colon recovered 95-100% when the restraint was removed, which
confirms that the application of in situ restraint did not damage
the nerve fibers or vasculature of duodenum and colon. The
relationship between contractile tension and diameter of duodenum
and colon were analyzed in FIGS. 5C and 5D, respectively. There was
significant peak of contractile tension in both in situ and in
vitro preparations, which implicates duodenal and colonic smooth
muscle appears similar to skeletal and cardiac muscle which
generates the maximal tension at an optimal length. The restraint
was smaller than the optimal length and hence significantly
attenuated the contraction of duodenum and colon.
[0092] FIGS. 6A-6D generally show the relationship of duodenal and
colonic contractility (amplitude) and incremental stretch ratio
during pressurization. FIG. 6A is indicative of the duodenum
inflated without restraint, and in FIG. 6B, the duodenum was
restrained while inflated. Linear regression showed an excellent
linear relationship in FIG. 6A but not in 6B. FIG. 6C is indicative
of the colon inflated without restraint, and in FIG. 6D, the colon
was restrained while inflated. Linear regression showed an
excellent linear relationship in FIG. 6C but not in 6D. A linear
regression of intestinal contractility and incremental strain
suggests a direct correlation of circumferentially incremental
strain and contractility (shown in FIGS. 6A and 6B) of in vitro and
in situ duodenum and colon (shown in Table 1, below, wherein
R.sup.2>0.9).
TABLE-US-00001 TABLE 1 The slope, intercept, and R.sup.2 of linear
regression by least-squares fit Slope Intercept R.sup.2 P value
Duodenum: In vivo 4.62 .+-. 1.03 0.42 .+-. 0.11 0.933 .+-. 0.311
0.047-0.012 Ex vivo 4.55 .+-. 1.16 0.14 .+-. 0.08 0.985 .+-. 0.32*
0.041-0.009 In vivo 3.12 .+-. 1.36 0.41 .+-. 0.29.dagger. 0.523
.+-. 0.28 0.095-0.053 restraint Ex vivo 2.72 .+-. 1.31 0.23 .+-.
0.21.dagger-dbl. 0.376 .+-. 0.22 0.169-0.073 restraint Colon: In
vivo 11.0 .+-. 2.08 1.31 .+-. 0.29 0.953 .+-. 0.33 0.043-0.011 Ex
vivo 6.80 .+-. 1.71 0.89 .+-. 0.15* 0.916 .+-. 0.32* 0.049-0.019 In
vivo 8.16 .+-. 2.96 1.39 .+-. 0.73.dagger. 0.697 .+-. 0.25
0.093-0.049 restraint Ex vivo 4.73 .+-. 2.64 0.41 .+-.
0.39.dagger-dbl. 0.579 .+-. 0.21.dagger-dbl. 0.096-0.049 restraint
Notes: *P < 0.05 indicates statistical difference between "ex
vivo" and "in vivo". .dagger.P < 0.05 indicates statistical
difference between "in vivo restraint" and "in vivo". .dagger-dbl.P
< 0.05 indicates statistical difference between "ex vivo
restraint" and "ex vivo".
[0093] The intercept of linear regression, which reflects the
offset of the contractility response to stretch stimulation,
significantly shifted downward in in vitro duodenum and colon as
shown in Table 1. The slope, which reflects the amplification of
the contractility response to stretch stimulation, significantly
decreased in in vitro colon but did not change among in situ
duodenum. With the restraint (an exemplary device 100), the R.sup.2
of linear regression decreased significantly in both in vitro and
in situ intestines and became statistically non-significant. FIGS.
6C and 6D show that the intestinal contractility response to
incremental strain is blunted by the circumferential restraint. The
slopes decreased due to the restraint in both in situ and in vitro
duodenum and colon, and the intercept decreased due to the
restraint in in vitro colon, as shown in Table 1.
[0094] As referenced herein, an isovolumic myograph (system 200)
was used to assess the role of pressure-induced distension (stretch
or strain and tension) on intestinal contractility for both in situ
and in vitro preparations and an external restraint was used to
separate the effect of distension from pressure. The studies
revealed that the intestine remained normally contractile when
stretch was induced by intraluminal pressures<10 mmHg. When
stretch was induced by the intraluminal pressure of >10 mmHg,
intestinal contractility weakened. There was a different pattern of
contractility from duodenum to colon in response to stretch
stimulation. Furthermore, a linear correlation was found between
intestinal contractility and incremental strain which implicates
the role of stretch in intestinal contractility.
[0095] The isovolumic myograph may be a useful method to evaluate
the intestinal global contractility for understanding the effect of
stimulations of intraluminal pressure on intestinal contraction.
The advantages of isovolumic myograph to wire and pressure
myographs include the utility to make in situ measurements and
application of an external restraint (an exemplary device 100 of
the present disclosure). The restraint blocks the distension
induced by intraluminal pressure and hence separates the effect of
distension from pressure. In fact, the application of a restraint
in this study limited the increase of diameter during inflation as
shown in FIGS. 3C and 3D. The restraint attenuated the in situ and
in vitro intestinal contractility induced by inflation pressure
(shown in FIGS. 5A and 5B), which is consistent with the prior
studies on the pressure-induced contraction of ileum. This result
implicates the role of stretch in intestinal contractility.
[0096] Further analysis shows that incremental strain plays a
stimulatory role in both in situ and in vitro states through a
dose-response relation, as shown in FIGS. 6A and 6B. The restraint
attenuates incremental strain and weakened the duodenal and colonic
contractility, as shown in FIGS. 6C and 6D. Both the slope and
intercept were changed by the restraint as demonstrated in Table 1
for in situlin vitro states and with/without restraint.
[0097] Additional studies were performed in connection with the
present disclosure to determine the effect in body weight by using
an exemplary device 100 of the present disclosure. A
peri-intestinal cuff (exemplary device 100) was externally
implanted on the proximal duodenum to achieve body weight loss and
metabolic restoration. Device 100 was implanted peri-intestinally
at 107% larger than the external diameter of duodenum in order not
to provide a physical obstruction on the duodenum (so that device
100 was non-constrictive), positioned adjacent to the pyloric
sphincter. As noted above, placement of device 100 about the
intestine 208 decreases the motility of intestine 208. Device 100
reduces the contractility when chyme pass through and therefore
increases the transit time of the chime, whereby an increased
transit time would relate to weight loss and satiety.
[0098] Furthermore, use of devices 100 of the present disclosure
affects epithelial function on the duodenum covered under device
100 and hence affects absorption of nutrients not only at the site
of device 100 but beyond since remodeling (wall thickening) is
observed to extend beyond the site of placement. Intimal thickening
occurs with minimal medial smooth muscle cell damage under an
uninterrupted endothelial cell layer when one or more devices 100
are placed. The increased thickness may also cause nutritional and
glucose absorption changes.
[0099] FIGS. 8A-9C show food intake, weight loss and blood glucose
concentration for normal (Wistar, FIGS. 8A-8C) and diabetic (Zucker
diabetic fatty, FIGS. 9A-9C) rats, respectively. Said figures show
a cause and effect relation between use of device 100 and food
intake/weight loss where placement cause the decreases and removal
cause reversal of the effect. As shown in FIGS. 8A-8C, cuff (device
100) implantation reduced body weight and food intake in Wistar
rats, and body weight and food intake were recovered after removal
of device 100. FIGS. 9A-9C show reductions in weight, food intake,
and plasma glucose levels in Zucker diabetes fatty rats.
Accordingly, use of exemplary devices 100 of the present disclosure
can cause patients to lose weight, decrease food intake/ingestion,
and/or reduce blood glucose levels, the latter being indicative of
a treatment for diabetes or another bodily condition impacted by
levels of blood glucose.
[0100] FIGS. 10A and 10B show block diagrams of components of
exemplary systems of the present disclosure. As shown in FIG. 10A
for example, an exemplary system 1000 (having one or more purposes
referenced herein, such as to facilitate weight loss, to facilitate
a reduction in food intake, to treat a blood glucose level
condition, etc.) may comprise one or more devices 100 of the
present disclosure and an exemplary delivery device 700 of the
present disclosure. A second device 100 is shown as optional in
FIG. 10A. Such a system 1000 may have one, two, or more devices
100. FIG. 10B shows a block diagram of components of another
exemplary system 1000 of the present disclosure, comprising at
least two devices 100 and an optional delivery device 700.
Additional components of the present disclosure may also comprise
one or more exemplary systems 1000 of the present disclosure.
[0101] In general, and as referenced herein, devices 100 and/or
systems 1000 can be considered as solutions to various patient
problems, such as obesity and diabetes. If a patient is attempting
to lose weight, but for whatever reasons cannot, various devices
100 and/or systems 1000 of the present disclosure can solve the
patient's problem of not losing weight or problem of being
overweight. Similarly, should a patient have a problem with
overeating, have a general excess weight problem not rising to the
level of obesity, have a blood glucose problem not rising to the
level of diabetes, etc., one or more of those problems could be
solved using various devices 100 and/or systems 1000 of the present
disclosure.
[0102] Pressure-induced distension has been confirmed as a
stimulator of intestinal afferent sensors. The afferent nerve is
excited significantly in response to inflation, which initiates the
sensory transmission to central nervous system. Intestinal
mechanosensors are located in the intestinal wall, and the increase
of pressure in lumen causes contraction of longitudinal muscle of
intestine and elicits a peristaltic reflex of intestine where
nervous activation is involved. The myogenic response of intestinal
smooth muscle and efferent neurogenic contraction are regulated by
mechanosensors and enteric nerves. The relation between afferent
vagus signals and intestinal distension was identified decades ago.
The mechanosensors in intestinal wall are primary sensors of
mechanical stimulation. In the study referenced herein, the
application of an external restraint terminated the
pressure-induced distension and attenuated the intestinal
contractility, which suggests that stretch or tension but not
inflation pressure is the stimulus for intestinal
mechanosensors.
[0103] The efferent (motor) vagus signals are responses of central
nervous system to the afferent (sensory) vagus stimulation.
Intestinal contractility is regulated by the extrinsic nervous
system (parasympathetic and sympathetic nervous systems) and the
intrinsic nervous system. One of the physiological functions of
efferent signals is to regulate the intestinal contractility. Here,
in situ and in vitro preparations provided the evidence of nervous
regulation. The in vitro preparation implicates the
efferent-independent (local regulatory) contraction, in which the
efferent nervous signals are interrupted and appear to impact
mechanically distension-induced contractility.
[0104] Intestinal contractility disorders can arise from intestinal
obstruction or ileus. Laparotomy and manipulation also interfere
with intestinal movements. The most widely accepted explanation of
postoperative ileus is based on the premise that intestinal
manipulation inhibits motor function through some neurologic reflex
response. Experimental studies have identified central neural
influences that mediate ileus of the gastrointestinal tract. An
interesting observation is that the efferent vagus (motor)
inactivation may occur after abdominal surgery, e.g., postoperative
intestinal ileus. The intestinal ileus (obstruction) may be
mediated by central neural influences, neurologic reflex (sensitive
afferent nerves) response, the disturbances of myoelectrical
activity, humoral responses, and local or regional activation of
immune system function. The contractility pattern in response to
diameter or pressure as referenced herein may mirror the physical
mechanism where surgery or inflammation slows motility of
intestine.
[0105] The present approach has some limitations that warrant
discussion. The isovolumic condition is non-physiological since it
blocks the fluid (or content) movement in intestine from oral to
anal portions and may affect peristaltic reflex of intestine. An
isovolumic myograph only provides the global but not the local
contraction of isolated intestine. To understand the interaction of
intestinal nervous activation and smooth muscle contraction,
isovolumic myography must be combined with measurements of nervous
activation (nervous firing spikes) in additional studies. The
external restraint may result in ischemia or affect the lymphatic
system, albeit it was confirmed that the restraint was reversible
(i.e., function was restored after removal).
[0106] The isovolumic myograph 200 may be a component used in a
powerful method to evaluate the intestinal global contractility
suitable for understanding the effect of stimulations of
intraluminal pressure and on intestinal contraction. The regional
contraction cannot be measured with this method and additional
approaches are needed to assess local contraction. An isovolumic
condition also blocks the fluid (or content) movement in intestine
from oral to anal portions, which may affect peristaltic reflex of
intestine. Since this is a non-physiological condition, isovolumic
conditions were maintained intermittingly and then restored the
physiological state. The advantage of isovolumic myograph to wire
and pressure myographs is the utility to make in situ
measurements
[0107] While various embodiments of intestinal devices for
facilitating weight loss and methods of using the same have been
described in considerable detail herein, the embodiments are merely
offered as non-limiting examples of the disclosure described
herein. It will therefore be understood that various changes and
modifications may be made, and equivalents may be substituted for
elements thereof, without departing from the scope of the present
disclosure. The present disclosure is not intended to be exhaustive
or limiting with respect to the content thereof.
[0108] Further, in describing representative embodiments, the
present disclosure may have presented a method and/or a process as
a particular sequence of steps. However, to the extent that the
method or process does not rely on the particular order of steps
set forth therein, the method or process should not be limited to
the particular sequence of steps described, as other sequences of
steps may be possible. Therefore, the particular order of the steps
disclosed herein should not be construed as limitations of the
present disclosure. In addition, disclosure directed to a method
and/or process should not be limited to the performance of their
steps in the order written. Such sequences may be varied and still
remain within the scope of the present disclosure.
* * * * *