U.S. patent application number 14/748065 was filed with the patent office on 2017-10-05 for conformationally-stabilized intraluminal device for medical applications.
The applicant listed for this patent is Kenneth F. BINMOELLER, James T. McKINLEY, Fiona M. SANDER, Matthew YUREK. Invention is credited to Kenneth F. BINMOELLER, James T. McKINLEY, Fiona M. SANDER, Matthew YUREK.
Application Number | 20170281383 14/748065 |
Document ID | / |
Family ID | 40877055 |
Filed Date | 2017-10-05 |
United States Patent
Application |
20170281383 |
Kind Code |
A1 |
BINMOELLER; Kenneth F. ; et
al. |
October 5, 2017 |
CONFORMATIONALLY-STABILIZED INTRALUMINAL DEVICE FOR MEDICAL
APPLICATIONS
Abstract
The invention relates to devices that are stabilized at an
intraluminal residence site in the gastrointestinal tract by their
conformation, including dimensions of length and curvature. The
device as a whole corresponds to the conformation of the residence
site; more particularly, the curved or angled portions correspond
to the curved or angled portions of the residence site and do not
conform to an immediately proximal or distal site. In some
embodiments, the conformationally stabilized device may effect a
change in the residence site shape that contributes to stability of
the device. Some embodiments are directed toward curbing appetite
and/or reducing food intake, other embodiments may be directed
toward other therapeutic ends. Some embodiments of the device are
designed to reside wholly in the duodenum; others reside
principally within the duodenum but extend proximally into the
gastric antrum, while other embodiments are designed to reside
elsewhere within the gastrointestinal tract.
Inventors: |
BINMOELLER; Kenneth F.;
(Rancho Santa Fe, CA) ; McKINLEY; James T.;
(Redwood City, CA) ; YUREK; Matthew; (San Diego,
CA) ; SANDER; Fiona M.; (Los Altos Hills,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BINMOELLER; Kenneth F.
McKINLEY; James T.
YUREK; Matthew
SANDER; Fiona M. |
Rancho Santa Fe
Redwood City
San Diego
Los Altos Hills |
CA
CA
CA
CA |
US
US
US
US |
|
|
Family ID: |
40877055 |
Appl. No.: |
14/748065 |
Filed: |
June 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12174337 |
Jul 16, 2008 |
9060835 |
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14748065 |
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11807107 |
May 25, 2007 |
8585771 |
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12174337 |
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60950071 |
Jul 16, 2007 |
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60808820 |
May 26, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 5/0076 20130101;
A61F 2210/0019 20130101; A61F 2002/044 20130101; A61F 5/0036
20130101; A61F 2002/045 20130101; A61F 5/003 20130101; A61F 5/0013
20130101; A61F 2210/009 20130101; A61F 2210/0014 20130101 |
International
Class: |
A61F 5/00 20060101
A61F005/00 |
Claims
1. (canceled)
2. A method of providing therapy in a gastrointestinal tract
comprising: positioning the distal end of a device into a first
portion of a gastrointestinal tract residence site; conforming a
portion of the device proximal to the distal end of the device to a
second portion of the gastrointestinal tract residence site; and
positioning the proximal end of the device into a third portion of
the gastrointestinal tract residence site.
3. The method of claim 2, the second portion of the
gastrointestinal tract residence site comprising at least one of:
the transition from the duodenal bulb to the vertical duodenum; the
transition from the vertical duodenum to the horizontal duodenum;
the transition from the horizontal duodenum to the jejunum; the
duodenojejunal flexture; and the portion of the duodenum adjacent
to the Ligament of Trietz.
4. The method of claim 2, the positioning the distal end of a
device step further comprising: deploying an atraumatic feature
into contact with the first portion of a gastrointestinal tract
residence site.
5. The method of claim 2, the positioning the proximal end of a
device step further comprising: deploying an atraumatic feature
into contact with the third portion of a gastrointestinal tract
residence site.
6. The method of claim 2, further comprising: aligning the
atraumatic feature on the proximal end of the device with the
atraumatic feature on the distal end of the device.
7. The method of claim 2 wherein the first portion of a
gastrointestinal tract residence site is distal to the vertical
duodenum.
8. The method of claim 2, wherein the first portion of a
gastrointestinal tract residence site is within to the horizontal
duodenum.
9. The method of claim 2, wherein the first portion of a
gastrointestinal tract residence site is within or distal to the
horizontal duodenum and adjacent to the third portion of the
gastrointestinal tract residence site.
10. The method of claim 2, wherein the first portion of a
gastrointestinal tract residence site is within or near the
duodenojejunal fexture.
11. The method of claim 2, wherein the first portion of a
gastrointestinal tract residence site is within or near the portion
of the duodenum adjacent to the Ligament of Trietz.
12. The method of claim 2, wherein the third portion of a
gastrointestinal tract residence site is proximal to the
pylorus.
13. The method of claim 2, wherein the third portion of a
gastrointestinal tract residence site is within the antrum of the
stomach.
14. The method of claim 13, wherein after the deploying step, the
atraumatic feature is in contact with the stomach wall in the
antrum.
15. The method of claim 2, further comprising: maintaining the
postion of the device within the gastrointestinal residence site
without imparing pyloric function or gastric emptying.
16. The method of claim 2, further comprising: maintaining the
position of the device within the gastrointestinal residence site
while atraumatically withstanding peristaltic action.
17. The method of claim 2, wherein after performing the steps of
claim 2, the proximal end of the device is within 1 to 7 cm of the
distal end of the device.
18. The method of claim 2, wherein after performing the steps of
claim 2, the proximal end of the device is separated from the
distal end of the device by a portion of the stomach wall and a
portion of duodenal wall.
19. The method of claim 2, wherein after performing the delivery
step the proximal end of the device is separated from the
atraumatic feature by a portion of the stomach wall and a portion
of duodenal wall.
20. The method of claim 2, wherein after performing the delivery
step the distal end of the device is separated from the atraumatic
feature by a portion of the stomach wall and a portion of duodenal
wall.
21. The method of claim 2, the conforming step further comprising:
moving the device relative to the gastrointestinal residence site
to assume a portion of a preformed device shape.
22. The method of claim 2, the conforming step further comprising:
moving the device relative to the gastrointestinal residence site
to obtain a preselected alignment of the proximal end and the
distal end of the device.
23. The method of claim 2, further comprising deploying at least
one flow reduction element from the device to reduce the flow of
chyme past the device.
24. The method of claim 2, further comprising positioning the
device to provide slowing of chyme flow through the duodenum.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of U.S. patent
application Ser. No. 12/174,337, titled
"CONFORMATIONALLY-STABILIZED INTRALUMINAL DEVICE FOR MEDICAL
APPLICATIONS," filed Jul. 16, 2008, now U.S. Pat. No. 9,060,835,
which claims the benefit of U.S. Provisional Patent Application No.
60/950,071 titled "CONFORMATIONALLY-STABILIZED INTRALUMINAL DEVICE
FOR MEDICAL APPLICATIONS," filed on Jul. 16, 2007. Ser. No.
12/174,337 is also a continuation-in-part of U.S. patent
application Ser. No. 11/807,107 titled "METHODS AND DEVICES TO CURB
APPETITE AND/OR REDUCE FOOD INTAKE," filed on May 25, 2007, now
U.S. Pat. No. 8,585,771, and claims priority under 35 U.S.C.
.sctn.119 to U.S. Provisional Patent Application No. 60/808,820,
titled "IMPROVEMENTS IN METHODS AND DEVICES TO CURB APPETITE AND/OR
REDUCE FOOD INTAKE," and filed on May 26, 2006.
INCORPORATION BY REFERENCE
[0002] All publications, patents and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent or patent
application was specifically and individually indicated to be
incorporated by reference.
FIELD OF THE INVENTION
[0003] The invention is in the field of medical devices that reside
within a lumen of the gastrointestinal tract and provide a platform
for medical applications. More particularly, embodiments of the
invention stabilize at a luminal residence site by virtue of their
physical conformation.
BACKGROUND OF THE INVENTION
[0004] Obesity, defined as a body mass index (BMI) of greater than
30, is a major health concern in the United States and other
countries; it has been estimated that one in three Americans and
more than 300 million people world-wide are obese. Complications of
obesity include many serious and life-threatening diseases
including hypertension, diabetes, coronary artery disease, stroke,
congestive heart failure, pulmonary insufficiency, multiple
orthopedic problems, various cancers and a markedly decreased life
expectancy. Intentional weight loss, however, can improve many of
these medical complications associated with obesity.
[0005] While weight loss can improve many of the medical
complications associated with obesity, its management as a health
concern has proven troublesome. A variety of approaches including
dietary methods, psychotherapy, behavior modification, and
pharmacotherapy have each met with some success but as a whole
failed to effectively control the rapid growth in the incidence and
severity of obesity seen in the United States. The severity of
problems associated with obesity also has led to the development of
several drastic surgical procedures. One such procedure physically
reduces the size of the stomach so that a person cannot consume as
much food as was previously possible. These stomach reduction
surgeries had limited early success, but now it is known that the
stomach can stretch back to a larger volume over time, limiting the
achievement of sustained weight loss in many individuals. Another
drastic surgical procedure induces the malabsorption of food by
reducing the absorptive surface of the gastrointestinal (GI) tract,
generally via by-passing portions of the small intestine. This
gastric by-pass procedure further has been combined with stomach
reduction surgery. While these described surgical procedures can be
effective to induce a reduction in food intake and/or overall
weight loss in some, the surgical procedures are highly invasive
and cause undue pain and discomfort. Further, the described
procedures may result in numerous life-threatening postoperative
complications. These surgical procedures are also expensive,
difficult to reverse, and place a large burden on the national
health care system.
[0006] Non-surgical approaches for the treatment of obesity also
have been developed. For example, one non-surgical endoscopic
approach to treating obesity includes the placement of a gastric
balloon within the stomach. The gastric balloon fills a portion of
the stomach, providing the patient with a feeling of fullness,
thereby reducing food intake. This approach has yet to be
convincingly shown to be successful, and a number of problems are
associated with the gastric balloon device, however, including poor
patient tolerance and complications due to rupture and/or migration
of the balloon. Other non-surgical devices designed to induce
weight loss limit the absorption of nutrients in the small
intestine by funneling food from the stomach into a tube found
within the small intestine so that the food is not fully digested
or absorbed within the small intestine. While this type of device
may be somewhat effective at limiting the absorption of consumed
food, there is still room for a variety of improvements in
non-surgical devices designed to induce weight loss and/or a
reduction in food intake.
[0007] An understanding of biological events that contribute to the
creation of satiety signals provides an opportunity to develop
"smart" nonsurgical devices that can trigger such events. The
amount of food that individuals consume is largely dependent on
biological signals between the gut and the brain. Specifically,
hormonal signals from the gut to the brain are correlated with both
the onset and cessation of food intake. While increased levels of
hormones such as ghrelin, motilin and agouti-related peptide are
involved in the promotion of appetite and the onset of food intake,
increased levels of a number of other hormones are involved in the
cessation of food intake.
[0008] Various biologic events contribute to the physiologic
cessation of food intake. Generally, as a meal is consumed, the
ingested food and by-products of digestion interact with an array
of receptors along the GI tract to create satiety signals. Satiety
signals communicate to the brain that an adequate amount of food
has been consumed and that an organism should stop eating.
Specifically, GI tract chemoreceptors respond to products of
digestion (such as sugars, fatty acids, amino acids and peptides)
while stretch receptors in the stomach and proximal small intestine
respond to the physical presence of consumed foods. Chemoreceptors
respond to the products of digestion by causing the release of
hormones or other molecular signals. These released hormones and/or
other molecular signals can stimulate nerve fibers to send satiety
signals to the brain. The arrival of these signals in the brain can
trigger a variety of neural pathways that can reduce food intake.
The released hormones and/or other molecular signals can also
travel to the brain themselves to help create signals of satiety.
Mechanoreceptors generally send satiety signals to the brain
through stimulation of nerve fibers in the periphery that signal
the brain. The present invention provides methods and devices that
help to reduce food intake by providing non-surgical devices and
methods that trigger the aforementioned biological events that
contribute to the creation of satiety signals.
SUMMARY OF THE INVENTION
[0009] In one embodiment of the present invention, there is
provided a duodenal device having a solid elongate body having a
proximal end, a distal end and a central curved portion between the
proximal end and the distal end. The length of the elongated body
is selected such that, in use within the gastrointestinal tract,
the proximal end is within the stomach proximal to the pylorus and
the distal end is within the distal duodenum and in proximity to
the proximal end. In one aspect, the length of the elongate body is
selected to place the distal end adjacent to the duodenojejunal
junction. In another aspect, at least the proximal end is sized for
atraumatic passage through the pylorus. In another aspect, the
device is configured to remain in position within the
gastrointestinal tract without connecting to a wall of the
gastrointestinal tract. In still another aspect, at least a portion
of the central curved portion is configured to conform to the shape
of the duodenum. In other aspects, the length of the elongate body
is selected to position the proximal end in the stomach, near the
distal end when the device is in use or the length of the elongate
body is selected to position the proximal end in or against the
stomach antrum when the device is in use. In still other
alternatives, the elongate body comprises a tapered end portion
near the proximal end or the distal end, or, alternatively the
elongate body comprises at least one diameter reducing area and at
least one diameter increasing area.
[0010] In still other alternative embodiments, the device includes
an atraumatic feature on the proximal end or the distal end. The
atraumatic feature is a coil, or includes a pad or a mesh or
braided structure. In still other alternatives, an atraumatic
feature on the proximal end with a tissue contact surface and an
atraumatic feature on the distal end with a surface shaped to at
least partially conform to the shape of the tissue contact surface.
In one aspect, the atraumatic feature on the proximal end comprises
a pad and the atraumatic feature on the distal end comprises a mesh
structure. In one aspect, the pad is spoon shaped, or includes a
convex surface or includes a concave surface.
[0011] In other aspects, the elongate body includes a bulbous tip
on the proximal end or a bulbous tip on the distal end. In one
alternative, the bulbous tip is formed from the elongate body. In
another aspect, the elongated body comprises a shape memory
material, and the material may be Nitinol or other suitable shape
memory material metal or shape memory polymer. In still another
aspect, the elongate body, the proximal end, the distal end and the
central curved portion are formed from a single piece of shape
memory material. There may also be a coating around the elongate
body and the coating may be a tube formed from a biocompatible
polymer.
[0012] In still another additional aspect, the device may also
include at least one flow reduction element positioned on the
elongate body central curved portion. In one embodiment, the at
least one flow reduction element comprises a braided structure. In
one aspect, the braided structure ranges from 8 picks per inch to
16 picks per inch. In another aspect, the portion of the braided
structure is secured to the elongate body and a portion of the
braided structure is freely slideable relative to the elongate
body. In still another aspect, the braided structure assumes a
preformed shape when the portion of the braided structure that is
freely slideable moves towards the portion of the braided structure
that is secured to the elongate body. In still another aspect, the
preformed shape comprises a plurality of flow reduction forms. In
another aspect, the braided structure comprises polymer filaments.
In other aspects, the at least one flow reduction element is
arranged around the elongate body. In another alternative, the at
least one flow reduction element includes one or more radially
expandable segments. In still another aspect, a portion of the flow
reduction element is attached to the elongate body. In another
aspect, a portion of the flow reduction element is freely slideable
over the elongate body. In another aspect, the device includes a
feature on the elongate body distal to the proximal end configured
to engage a deployment device. In another alternative, the device
includes a stopping feature on the elongate body adapted to prevent
movement of the freely slideable portion of the at least one flow
reduction element. In one aspect, the stopping feature is
positioned on the elongate body proximal to the portion of the flow
reduction element that is attached to the elongate body.
[0013] In another embodiment, there is a method of providing
therapy in a gastrointestinal tract including the step of
positioning the distal end of a device into a first portion of a
gastrointestinal tract residence site. Next, there is the step of
conforming a portion of the device proximal to the distal end of
the device to a second portion of the gastrointestinal tract
residence site. Next, there is the step of positioning the proximal
end of the device into a third portion of the gastrointestinal
tract residence site. In one aspect, the second portion of the
gastrointestinal tract residence site includes at least one of: the
transition from the duodenal bulb to the vertical duodenum; the
transition from the vertical duodenum to the horizontal duodenum;
the transition from the horizontal duodenum to the jejunum; the
duodenojejunal flexure; and the portion of the duodenum adjacent to
the Ligament of Treitz. In another aspect, the positioning the
distal end of a device step includes deploying an atraumatic
feature into contact with the first portion of a gastrointestinal
tract residence site. In another aspect, the positioning the
proximal end of a device step includes deploying an atraumatic
feature into contact with the third portion of a gastrointestinal
tract residence site. The method may also include aligning the
atraumatic feature on the proximal end of the device with the
atraumatic feature on the distal end of the device.
[0014] In other aspects, the first portion of a gastrointestinal
tract residence site is distal to the vertical duodenum or the
first portion of a gastrointestinal tract residence site is within
to the horizontal duodenum. In another aspect, the first portion of
a gastrointestinal tract residence site is within or distal to the
horizontal duodenum and adjacent to the third portion of the
gastrointestinal tract residence site. In still another aspect, the
first portion of a gastrointestinal tract residence site is within
or near the duodenojejunal flexure. In another aspect, the first
portion of a gastrointestinal tract residence site is within or
near the portion of the duodenum adjacent to the Ligament of
Treitz. In another aspect, the third portion of a gastrointestinal
tract residence site is proximal to the pylorus. In another aspect,
the third portion of a gastrointestinal tract residence site is
within the antrum of the stomach. In another alternative, after the
deploying step, the atraumatic feature is in contact with the
stomach wall in the antrum.
[0015] In another alternative, the method includes the step of
maintaining the position of the device within the gastrointestinal
residence site without impairing pyloric function or gastric
emptying. In another aspect, the method includes the step of
maintaining the position of the device within the gastrointestinal
residence site while atraumatically withstanding peristaltic
action. In still another aspect, after performing the steps of the
method, the proximal end of the device is within 1 to 7 cm of the
distal end of the device. In another aspect, the proximal end of
the device is separated from the distal end of the device by a
portion of the stomach wall and a portion of duodenal wall. In
still another aspect, after performing the delivery step, the
proximal end of the device is separated from the atraumatic feature
by a portion of the stomach wall and a portion of duodenal wall. In
still another aspect, after performing the delivery step, the
distal end of the device is separated from the atraumatic feature
by a portion of the stomach wall and a portion of duodenal
wall.
[0016] In other embodiments, the conforming step also includes
moving the device relative to the gastrointestinal residence site
to assume a portion of a preformed device shape. Additionally, the
conforming step may include moving the device relative to the
gastrointestinal residence site to obtain a preselected alignment
of the proximal end and the distal end of the device. In some
embodiments, the force to accomplish a moving step is provided by a
shape memory component of the device.
[0017] In still other aspects of the method, there is the
additional step of providing therapy from the device. In one
alternative, the step of providing therapy includes deploying at
least one flow reduction element from the device to reduce the flow
of chyme past the device. In another aspect, the providing therapy
step includes providing electrical stimulation from the device to a
portion of the gastrointestinal residence site. In one aspect, the
electrical stimulation in the providing step produces a sensation
of satiety in the patient. In still other aspects, the providing
therapy step includes providing mechanical stimulation from the
device to a portion of the gastrointestinal site. In one
alternative, the mechanical stimulation in the providing step
produces a sensation of satiety in the patient. In still another
alternative, the providing therapy step includes providing a
bioactive agent from the device to a portion of the
gastrointestinal site. In one aspect, the step of providing a
bioactive agent produces a sensation of satiety in the patient. In
one aspect, the providing therapy step is selected to cause loss of
excess weight in a patient. In still other aspects, the providing
therapy step includes positioning the device to provide slowing of
chyme flow through the duodenum.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a general drawing of the stomach and duodenum of
the small intestine.
[0019] FIG. 2 depicts several exemplary mechanisms through which
satiety signals may be generated.
[0020] FIG. 3 is a perspective view of one embodiment of a
duodenal/small intestinal insert in accordance with the present
invention positioned inside the stomach and small intestine.
[0021] FIG. 4 is a partial section view of a central tube
illustrating attached flow reduction elements and a central
lumen.
[0022] FIG. 5 is a partial section view of a central tube
illustrating eccentrically attached flow reduction elements and a
central lumen.
[0023] FIG. 6 is a perspective view of an alternative embodiment
showing an elongated member and illustrating attached flow
reduction elements.
[0024] FIG. 7 is a perspective section view of a central tube and
an anchoring member.
[0025] FIG. 8 is a perspective view of an alternative embodiment of
a central tube and an anchoring member.
[0026] FIG. 9 is a section view of a central tube of the present
invention that may lodge in the small intestine for a period of
time without any anchoring to the stomach or pylorus.
[0027] FIG. 10 illustrates a central tube attached to an expandable
sleeve, the expandable sleeve allowing expansion of particular
segments of the central tube to form flow reduction elements.
[0028] FIG. 11 illustrates an expandable sleeve in a collapsed
configuration for insertion into the small intestine.
[0029] FIG. 12 illustrates one mechanism for keeping flow reduction
elements formed with an expandable sleeve in a desired expanded
configuration.
[0030] FIG. 13 is a flow diagram depicting the intestinal insert's
role in contributing to the generation of one or more signals of
satiety.
[0031] FIG. 14 is perspective view of the duodenum.
[0032] FIG. 15 depicts a side view of the duodenum, showing the
folds of rugae that form the periphery of the inner space within
which embodiments of the insert device are positioned.
[0033] FIG. 16A depicts an embodiment of the insert with flow
reduction elements in the form of a simple coil. FIG. 16B depicts
an end of the device as it emerges from a deployment tube.
[0034] FIG. 17A depicts an embodiment of the insert with flow
reduction elements in the form of a spine with ribs. FIG. 17B
depicts an end of the device as it emerges from a deployment
tube.
[0035] FIG. 18 depicts an embodiment of the insert with flow
reduction elements in the form of a spine with nets.
[0036] FIG. 19A depicts an embodiment of the insert with flow
reduction elements in the form of closed mesh baskets, and further
showing coil proximal and distal ends. FIG. 19B depicts an end of
the device as it emerges from a deployment tube.
[0037] FIG. 20 depicts an embodiment of the insert with flow
reduction elements in the form of centrally-mounted
outwardly-extending baffles, and further showing coil proximal and
distal ends.
[0038] FIG. 21 depicts an embodiment of the insert with flow
reduction elements in the form of a foam-like bodies, and further
showing coil proximal and distal ends.
[0039] FIG. 22 depicts an embodiment of the insert with flow
reduction elements in the form of a centrally-mounted fans, and
further showing coil proximal and distal ends.
[0040] FIG. 23 depicts an embodiment of the insert with bioactive
material in reservoirs that passively elute.
[0041] FIG. 24 depicts an embodiment of the insert with a bioactive
material-loaded osmotic pump.
[0042] FIG. 25 depicts an embodiment of the insert with a bioactive
material loaded reservoir coupled to an electrically driven pump,
energy storage unit, and an external control.
[0043] FIG. 26 depicts an embodiment of the insert with electrodes
for local neurostimulation, an energy storage unit, and an external
control.
[0044] FIGS. 27A-B depict an embodiment of the central member of an
insert that includes biodegradable elements and shape memory
elements. FIG. 27A shows the central member in an intact
configuration; FIG. 27B shows the central member after
biodegradation.
[0045] FIGS. 28A-B depict an embodiment of the central member of an
insert that includes a biodegradable shape memory polymeric
material. FIG. 28A shows the central member in an intact
configuration; FIG. 28B shows the central member after
biodegradation.
[0046] FIG. 29 provides a perspective schematic view of device with
three substantially straight central portions of an elongate body,
focusing on angles alpha, beta, and delta that determine the
relative conformation of the three portions with respect to each
other.
[0047] FIG. 30 provides an axial facing view of the device shown in
FIG. 29.
[0048] FIG. 31 provides a view of a device with structural feature
projecting from a central spine that contributes to
conformationally stabilizing the device.
[0049] FIGS. 32A-32C show alternative embodiments of
conformationally-stabilizing devices, each with substantially
straight major segments of an elongate body that vary in length,
angles between each segment, and residence site within the
duodenum.
[0050] FIG. 33 provides a view of a conformationally-stabilizing
device with four curvilinear segments comprising the elongate
body.
[0051] FIG. 34 provides a view of a conformationally-stabilizing
device with a single curvilinear portion comprising the elongate
body.
[0052] FIG. 35 provides a view of a conformationally-stabilizing
device that may alter the shape of the duodenum, the proximal
segment resides in the superior duodenum and the distal segment
resides near the duodenojejunal flexure, the proximal and distal
ends of the device configured to be in close apposition.
[0053] FIG. 36 provides a view of a device with a proximal portion
extending upstream from the duodenum, through the pylorus, and into
the gastric antrum, and with the distal end extending to the
duodenojejunal junction. This device does not necessarily alter the
shape of the duodenum or gastrointestinal tract in any substantial
way. The proximal and distal ends of the device are in close
apposition because the anatomical points where they reside are
actually in such close apposition. This particular embodiment does
not have flow reduction elements, but is otherwise similar in
length and placement to the embodiment depicted in FIG. 44, and as
shown in a residence site in FIG. 47.
[0054] FIG. 37 provides a view of conformationally-stabilizing
device with a relatively long central portion, a proximal portion
that reaches through the pylorus, a distal portion that terminates
near the duodenojejunal junction, and an outwardly deflecting bias
that alters the shape of the duodenum by distending it along a
cephalad-caudal axis.
[0055] FIG. 38 provides a view of conformationally-stabilizing
device similar to that of FIG. 37, with a relatively long central
portion, but with proximal and distal portions that terminate well
within the duodenum, and an outwardly deflecting bias that alters
the shape of the duodenum by distending it along a cephalad-caudal
axis.
[0056] FIG. 39 provides a view of conformationally-stabilizing
device comprising a curvilinear elongate body with an acute central
angle, and a proximal end terminating just distal to the pylorus
and a distal end terminating just proximal to the duodenojejunal
junction.
[0057] FIG. 40 provides a view of a conformationally-stabilizing
device at non-duodenal residence site, within the inferior
esophagus and conforming to its curvature.
[0058] FIG. 41 provides a view of a conformationally-stabilizing
device in residence at the site of the duodenojejunal flexure, the
device being curvilinear with an acute central angle that conforms
to the flexure.
[0059] FIG. 42 provides a view of a conformationally-stabilizing
device at non-duodenal residence site, the device being curvilinear
and residing at site at the junction of the colon and the terminal
ileum, the central portion of the device extending through the
ileal orifice, the device as a whole conforming to the curvature of
the residence site.
[0060] FIG. 43 provides a view of a conformationally-stabilizing
device in residence at the site in the sigmoid colon, the device
being curvilinear with an oblique central angle and overall length
that conforms to the residence site.
[0061] FIG. 44 shows an embodiment of a
conformationally-stabilizing device that has a similar flow
reduction element as that of the device shown in FIG. 19A, and with
a residence site similar to that of the device shown in FIG. 36,
with a proximal portion that terminates in the gastric antrum; and
the distal portion terminates near the duodenojejunal junction.
[0062] FIG. 45A provides a detail view of a tapered end portion,
with a coil feature and a terminal bulbous feature. FIG. 45B is the
view of FIG. 45A straightened to more clearly show the diameter
transitioning regions and the bulbous feature.
[0063] FIGS. 46A and 46B show two devices with a varying amount of
end-end crossover: FIG. 46A depicts a device with a relatively long
separation between ends and a relatively large end-end cross over
dimension. FIG. 46B depicts a device with a relatively short
separation between ends and a relatively small end-end cross over
dimension.
[0064] FIG. 47 shows the device depicted in FIG. 44 in a
gastrointestinal residence site, with the proximal portion
terminating in the gastric antrum, and the distal portion
terminating near the duodenojejunal junction.
[0065] FIG. 48 shows an alternative embodiment of a device similar
to that shown in FIG. 44, with a large single flow reduction
element.
[0066] FIGS. 49A-49D show alternative atraumatic end features. FIG.
49A shows an end piece formed by shape memory material that
radially expands in a lantern like fashion when released from
linear constraint. FIG. 49B shows an end view of the end piece of
FIG. 48A 49A. FIG. 49C shows an end piece in the form of an
expandable braided sphere with a blunt distal end. FIG. 49D shows
an end piece in the form of an expandable braided sphere with an
invaginated distal end.
[0067] FIGS. 50A-50D shows spoon or paddle shaped atraumatic end
features of a conformationally-stabilizing device. FIG. 50A shows a
top view. FIG. 50B shows a side view. FIG. 50C shows an end view,
depicting a curvature that reflects a rollable bias. FIG. 50D shows
an end view of the spoon feature rolled into a stowable
configuration for inclusion in an endoscope working channel or
delivery sheath.
[0068] FIG. 51 shows a conformationally-stabilizing device such as
depicted in FIG. 50A-50E, the device situated in a gastrointestinal
tract residence site, with the proximal end and spoon-shaped end
feature pressed against the wall of the gastric antrum, and the
spoon-shaped end feature of the distal end pressed against the wall
near the duodenojejunal junction.
[0069] FIG. 52 shows a conformationally-stabilizing device such as
depicted in FIG. 51, the device situated in a gastrointestinal
tract residence site, with the proximal end and spoon-shaped end
feature pressed against the wall of the gastric antrum, as in FIG.
51, and a bulb shaped end feature of the distal end as in FIGS. 49C
or 49D pressed against the wall near the duodenojejunal junction in
a complementary position relative to the proximal end feature.
[0070] FIG. 53 shows a device similar to that depicted in FIG. 47
in a gastrointestinal residence site, with the proximal portion
terminating in the gastric antrum and the distal portion
terminating near the duodenojejunal junction with an atraumatic
features as in FIGS. 49C or 49D an in complementary relation to the
proximal end feature.
DETAILED DESCRIPTION
Embodiments of the Device In Situ
[0071] FIG. 1 provides a view of the human gastrointestinal tract,
including the stomach 4 and duodenum of the small intestine 10.
Important features are the esophagus 2, stomach 4, antrum 7,
pylorus 8, pyloric valve 11, duodenum 10, jejunum 12 and ampulla of
Vater (or hepatopancreatic ampulla) 13, which is formed by the
union of the pancreatic duct and the common bile duct.
Functionally, the esophagus 2 begins at the nose or mouth at its
superior end and ends at the stomach 4 at its inferior end. The
stomach 4 encloses a chamber which is characterized, in part, by
the esophageal-gastric juncture 6 (an opening for the esophagus 2)
and the antrum-pyloric juncture 5 (a passageway between the antrum
7 through the pylorus 8 to the duodenum 10 of the small intestine).
The pylorus 8 controls the discharge of contents of the stomach 4
through a sphincter muscle, the pyloric valve 11, which allows the
pylorus 8 to open wide enough to pass sufficiently-digested stomach
contents (i.e., objects of about one cubic centimeter or less).
These gastric contents, after passing into the duodenum 10,
continue into the jejunum 12 and on into the ileum (not shown). The
duodenum 10, jejunum 12 and ileum make up what is known as the
small intestine. However these individual portions of the
alimentary canal are sometimes individually referred to as the
small intestine. In the context of this invention the small
intestine can refer to all or part of the duodenum, jejunum and/or
ileum. The ampulla of Vater 13, which provides bile and pancreatic
fluids that aid in digestion, is shown as a small protrusion on the
medial wall of the duodenum 10.
[0072] Embodiments of the inventive device include various forms
that provide stability in a residence site in the gastrointestinal
tract, particularly the duodenum. Some embodiments of the device,
which may be synonymously referred to as an intestinal insert, are
stabilized in the intestine by way of an anchoring member that
resides in the stomach and is too large to be swept through the
pylorus. Other embodiments reside stably in the intestine not by
virtue of a separate anchoring member in the stomach, but rather by
virtue of the device as a whole fitting into the small intestine
with angled portions that fit or correspond with angled portions of
the intestine, and the device further having a sufficient
structural integrity that it resists being moved distally because
the distal location does not physically accommodate the shape of
the device. Embodiments that are further described in a following
section, rather than having angled sections per se, have instead, a
curvilinear central portion. Aspects of the device that are adapted
to provide anchorless stabilization at a target site in the
intestine include physical dimensions of length and width, as well
as angles of the device, all of which complement the target portion
of intestine. In other embodiments, stabilizing features in the
intestine may include expanded portions of the device in the
duodenal bulb, which is larger than the more distal portion of the
duodenum, and which thereby effectively prevents distal movement
(as in FIG. 18, for example).
[0073] Some embodiments of the device and associated methods of
using the device are directed toward reducing the rate of food
transit through the intestine by physical mechanisms of intervening
in the rate of food transit. In other aspects, embodiments of the
invention act by eliciting satiety signals by way of physiological
mechanisms, or, alternatively, by directly providing satiety
signals through bioactive materials or agents, or by neuronal
stimulation, thereby reducing food intake behaviorally. Some
embodiments of the device are directed toward medical purposes
broader than satiety and digestive physiology alone, although the
satiety and food consumption functionalities of embodiments of the
device and method will be described herein in greater detail. As an
example of non-obesity or satiety-inducing medical use, some
embodiments of the devise may be used as an eluting source for
bioactive agents (described in greater detail below, and depicted
in FIG. 25), and as such any medically appropriate drug could be
delivered by such a device. In some aspects, embodiments of the
device may contribute to slowing food transit and/or reducing food
intake by the satiety signals generated by the intestine in direct
response to the mere physical presence of the device. Such signals
could, for example, be mediated by stretch-responsive neurons or
mechanoreceptors in the intestinal wall. In other embodiments,
satiety signals could be mediated by hormones that are responsive
to physical presence of material in the intestine, or which are
secondarily responsive to mechano-receptors. In other embodiments,
the slowing of food or the increased residency time, and the
consequent change in the chemical environment of the intestine, may
elicit responses from chemoreceptors residing in the intestine to
signal either neurally or hormonally in such a way that has a net
effect of signaling satiety.
[0074] In still other embodiments of the invention, the device may
convey bioactive material or agents that are released over time
within the intestine, the bioactive agents conveying a net signal
of satiety. In some embodiments, the bioactive agents with a net
satiety signaling effect are passively released from sites such as
coatings, depots, or reservoirs within the device. Bioactive
materials or agents have been described in detail above, but
briefly and in broad aspect may include any of hormones, drugs, or
cells. In some embodiments, bioactive agents may be held in osmotic
pumps and released by osmotic drive. Release mechanisms such as
osmotic pumps provide a level of control and predictability to
bioactive agent release, but the mechanism remains relatively
passive and without means of intervention. Other embodiments of the
invention, however, may include more active mechanisms for
bioactive agents release or delivery, as could be provided by
electrically driven pumps, or by piezoelectric elements that allow
or promote the release stored bioactive agents in response to
applied current. Such devices may include power storage elements,
or may be provided power by external sources by wired or wireless
approaches.
[0075] In still other embodiments of the invention, the device may
include electrodes or conductive elements that provide electrical
stimulation to nerves in the intestine, such resulting neural
activity contributing to a net effect of signaling satiety to the
brain. In some embodiments, satiety-related neuronal activity may
further be mediated by endocrine mechanisms. As in embodiments of
the invention with powered mechanisms for bioactive agent release,
embodiments with electrical capability may include power storage
devices, or be enabled to receive energy conveyed from external
sources.
[0076] In other aspects of the invention, embodiments of the
inserted device, with or without an anchor, may provide a platform
for bioactive agent delivery, neural stimulus delivery, or
radiation therapy delivery, for medical purposes more broad than
inducing satiety, or intervening in food transit. For the delivery
of some bioactive agents, there may be considerable advantage
associated with local delivery of an agent to an intestinal site.
Such advantages may include localization of dosing, lack of
exposure to stomach acid as occurs in oral delivery or diminished
exposure to the metabolic machinery of the liver and kidney that i.
v. drug delivery, or any form of systemic delivery faces. Further,
embodiments of the device may accommodate multiple drugs; in some
embodiments the release of such multiple drugs may be independently
controlled.
Digestive System Context of Invention
[0077] The description now addresses the digestive system, the
digestive process, and aspects of the endocrinology and
neurophysiology of satiety as they relate to embodiments of the
invention. The adult duodenum is about 20-25 cm long and is the
shortest, widest, and most predictably placed part of the small
intestine. The duodenum forms an elongated C-shaped configuration
that lies between the level of the first and third lumbar vertebrae
in the supine position. Susan Standring (ed.), Gray's Anatomy,
39.sup.th Ed., 1163-64 (2005), provides a standard reference.
Returning to FIG. 1 for reference and further detail of aspects of
the digestive system, the first part of the duodenum, often
referred to as the duodenal bulb 10a, is about 5 cm long and starts
as a continuation of the duodenal end of the pylorus 8. This first
part of the duodenum passes superiorly, posteriorly and laterally
for 5 cm before curving sharply inferiorly into the superior
duodenal flexure 465, which marks the end of the first part of the
duodenum. The second part of the duodenum, often called the
vertical duodenum 10b, is about 8-10 cm long. It starts at the
superior duodenal flexure 465 and runs inferiorly in a gentle curve
towards the third lumbar vertebral body. Here, it turns sharply
medially into the inferior duodenal flexure 475 which marks its
junction with the third part of the duodenum. The third part of the
duodenum, often called the horizontal duodenum 10c, starts at the
inferior duodenal flexure and is about 10 cm long. It runs from the
right side of the lower border of the third lumbar vertebra, angled
slightly superiorly, across to the left and ends in continuity with
the fourth part of the duodenum in front of the abdominal aorta.
The fourth part of the duodenum is about 2.5 cm in length; it
starts just to the left of the aorta and runs superiorly and
laterally to the level of the upper border of the second lumbar
vertebra. It then turns antero-inferiorly at the duodenojejunal
flexure and is continuous with the jejunum. Some embodiments of the
present invention take advantage of this predictable configuration
of the small intestine to provide duodenal/small intestinal
implants that do not require anchoring within the pylorus or
stomach, as described more fully below.
[0078] The digestive process starts when consumed foods are mixed
with saliva and enzymes in the mouth. Once food is swallowed,
digestion continues in the esophagus and in the stomach, where the
food is combined with acids and additional enzymes to liquefy it.
The food resides in the stomach for a time and then passes into the
duodenum of the small intestine to be intermixed with bile and
pancreatic juice. Mixture of the consumed food with bile and
pancreatic juice makes the nutrients contained therein available
for absorption by the villi and microvilli of the small intestine
and by other absorptive organs of the body.
[0079] Robert C. Ritter, author of "Gastrointestinal mechanisms of
satiation for food", published by Physiology & Behavior 81
(2004) 249-273, summarizes our understanding of the various means
the gastrointestinal tract uses to control appetite. He states that
the role of the stomach in satiation is to sense the volume of
ingesta arriving from a meal and to produce a variety of signaling
substances that may be involved in satiation. It is, however, the
small intestine specifically that receives these signals. Further,
it is the intestine that responds to the energy density of ingesta,
limiting further gastric emptying and signally satiety when
adequate calories have passed. Through analysis of the location of
afferent nerves (p.255), Ritter shows that vagal nerve afferents
are most concentrated in the duodenum and least concentrated more
distally in the ileum. This early concentration of afferents will
moderate appetite early in the eating process. The timeliness of
the response to nutrient intake has been further demonstrated by
others in a variety of mammals including monkeys, rats and humans.
It is clear that the reduction in food intake begins within minutes
of the start of intake and that this reduction is not therefore a
response to postabsorptive or systematic metabolic effects. These
passages of Ritter are specifically incorporated herein by
reference as relates to the positioning of the devices described
herein or for the placement and size of flow reduction elements of
embodiments of the present invention.
[0080] The presence of partially digested food within the stomach
and small intestine initiates a cascade of biological signals that
create satiety signals principally emanating from the proximal
small intestine that contribute to the cessation of food intake.
One such satiety signal is initiated by the release of
cholecystokinin (CCK). Cells of the small intestine release CCK in
response to the presence of digested foods, and in particular, in
response to dietary fat, fatty acids, small peptides, and amino
acids. Elevated levels of CCK reduce meal size and duration and may
do so through a number of different mechanisms. For example, CCK
may act on CCK-A receptors in the liver and within the central
nervous system to induce satiety signals. CCK stimulates vagal
afferent fibers in both the liver and the pylorus that project to
the nucleus tractus solitarius, an area of the brain that
communicates with the hypothalamus to centrally regulate food
intake and feeding behavior. CCK also stimulates the release of
enzymes from the pancreas and gall bladder and inhibits gastric
emptying. Because CCK is a potent inhibitor of gastric emptying,
some of its effects on limiting food intake may be mediated by the
retention of food in the stomach.
[0081] Cells of the small intestine (particularly L cells) also
release glucagon-like peptide 1 (GLP-1) and oxyntomodulin (OXM) in
response to nutrient signals of digestion. Elevated levels of GLP-1
and OXM are associated with satiety signals and the cessation of
food intake. These hormones may signal satiety by activating
receptors on afferent vagal nerves in the liver and/or the GI tract
and/or by inhibiting gastric emptying.
[0082] Pancreatic peptide (PP) is released in proportion to the
number of calories ingested, and in response to gastric distension.
Elevated levels of PP have been shown to reduce food intake and
body weight. PP may exert some of its anorectic effects via vagal
afferent pathways to the brainstem, as well as through more local
effects, such as by suppression of gastric ghrelin production.
[0083] Peptide YY.sub.3-36 (PYY.sub.3-36) is another biological
signal whose peripheral release may be correlated with reduced food
intake and/or the cessation of eating. Specifically, low levels of
PYY.sub.3-36 have been correlated with obesity while its
administration decreases caloric intake and subjective hunger
scores. Intravenous administration of PYY.sub.3-36 may reduce food
intake through its effects of suppressing ghrelin expression,
delaying gastric emptying, delaying various secretion from the
pancreas and stomach and increasing the absorption of fluids and
electrolytes from the ileum after a meal.
[0084] Insulin and leptin are two additional biological signals
that regulate satiety and eating behavior. Through parasympathetic
innervation, beta cells of the endocrine pancreas release insulin
in response to circulating nutrients such as glucose and amino
acids, and in response to the presence of GLP-1 and gastric
inhibitory peptide (GIP). Insulin stimulates leptin production from
adipose tissue via increased glucose metabolism. Increased insulin
levels in the brain leads to a reduction in food intake. Elevated
leptin levels also decrease food intake and induce weight loss.
Insulin and leptin have also been implicated in the regulation of
energy expenditure since their administration induces greater
weight loss than can be explained by reduction in food intake
alone. Both insulin and leptin act within the central nervous
system to inhibit food intake and to increase energy expenditure,
most likely by activating the sympathetic nervous system. Insulin's
effects to decrease food intake also involve interactions with
several hypothalamic neuropeptides that are also involved in the
regulation of feeding behavior such as, by way of example, NPY and
melanocortin ligands.
[0085] Other hormones or biological signals that are involved in
the suppression or inhibition of food intake include, by way of
example, GIP (secreted from intestinal endocrine K cells after
glucose administration or ingestion of high carbohydrate meals;
enterostatin (produced in response to dietary fat; amylin
(co-secreted with insulin from pancreatic beta cells); glucagon,
gastrin-releasing peptide (GRP), somatostatin, neurotensin,
bombesin, calcitonin, calcitonin gene-related peptide, neuromedin U
(NMU), and ketones.
[0086] In relation to embodiments of the present invention, when
the passage of partially digested food or chyme is partially
impeded within the duodenum of the small intestine and the flow
rate through this area is reduced (or to express the same
phenomenon in another way, as residency time is increased), the
emptying of the stomach and the duodenum will occur more slowly.
This slowing, by itself, may create extended feelings of satiety
and thus lead to a decrease in food intake (due to the longer
retention time of food in the stomach). The slowing of the passage
of food also provides more time for the partially digested food to
interact with chemoreceptors, stretch receptors, and
mechanoreceptors along the GI tract so that stimulation of satiety
signals may be increased and/or prolonged, which may, in turn, lead
to a reduction in food intake during an eating period and/or longer
periods between food intake.
[0087] In addition to keeping partially-digested food within the
small intestine for an extended period of time, the methods and
devices of the present invention may also enhance and/or prolong
the release of satiety signals by releasing signals into the small
intestine themselves. For example, in some embodiments, the methods
and devices of the present invention may release nutrient products
of digestion to stimulate chemoreceptors to cause the release of
hormones and/or other molecular signals that contribute to the
creation of satiety signals. In another embodiment, the methods and
devices of the present invention may exert a small amount of
pressure on the walls of the GI tract to stimulate stretch
(mechanoreceptors) to generate and send satiety signals to the
brain. In another embodiment, the methods and devices of the
present invention may release signals, such as, by way of example,
nutrient by-products of digestion of food, to stimulate
chemoreceptors as described above and may exert a small amount of
pressure on the walls of the small intestine as described above to
contribute to the generation of satiety signals.
Device with Flow Reduction Elements, and Embodiments with an
Anchoring Member
[0088] FIG. 2 depicts several exemplary non-limiting mechanisms
through which satiety signals may be generated. As shown FIG. 2, a
by-product of digestion, such as a fatty acid or other protein,
stimulates an L-cell of the small intestine to release CCK locally
and into the circulation. CCK released locally may stimulate vagal
afferent nerve fibers in the area to generate satiety signals to
the central nervous system (CNS). CCK that enters the circulation
may travel to the liver to stimulate vagal afferent nerve fibers in
the liver to generate satiety signals to the CNS. CCK in the
circulation may travel to the gall bladder and pancreas to
upregulate the digestion-related activities of these organs. CCK in
the circulation also may travel to the CNS itself to contribute to
the creation of a satiety signal. Once satiety signals are received
and integrated within the CNS, the CNS may trigger physiological
effects that serve to contribute to a feeling of fullness and/or
the cessation, slowing or reduction of food intake.
[0089] Turning now to embodiments of the invention, FIG. 3 shows an
exemplary small intestinal insert 20 made in accordance with the
present invention that may contribute to the creation of satiety
signals. The insert 20 is positioned in the stomach 4 and small
intestine 10. The insert 20 has a proximal portion 30 and a distal
portion 40, and a central tube 50 that extends from the proximal
portion 30 to the distal portion 40. One or more flow reduction
elements 200 that are sized to fit within the small intestine 10
may be attached to the central tube 50. While not required, the
portion of the central tube 50 near the ampulla of Vater 13
generally will not include a flow reduction element 200 so that the
introduction of bile and pancreatic fluid into the small intestine
is not impeded.
[0090] In some embodiments, the central tube 50 has an anchoring
member 100 near its proximal end 52, with the anchoring member 100
securing the proximal end 52 of the central tube 50 in the antrum 7
of the stomach. The anchoring member 100 is sized so that it will
not pass through the pylorus 8. In this way, embodiments of the
present invention including an anchoring member anchor the flow
reduction elements 200 within the small intestine. In some
embodiments, the anchoring member may be established by one or more
inflatable balloons 102 that when inflated are larger than the
pylorus 8. The inflatable balloons 102 may be deflated for delivery
into the stomach and then inflated inside the stomach. The
inflatable balloons 102 may also be deflated for later removal
using endoscopic techniques.
[0091] As will be described in further detail below, embodiments of
flow reduction elements 200 may assume many configurations, and may
vary further with regard to physical features such as composition,
nature of the surface, and porosity of the bulk material. Some
further exemplary embodiments of flow reduction elements 200 are
depicted in FIGS. 16-25. In some embodiments, as depicted in FIGS.
16, the central tube or member, also referred to as an elongated
member, may, itself, be configured into a form that reduces chyme
flow in the duodenum. A functional property that embodiments of
flow reduction elements have in common is that they slow the
transit of digesting food without blocking it, and within
clinically appropriate guidelines. The process of slowing the
transit rate may also have effects on the composition of the
digesting food material, such as varying its biochemical profile
with regard to the nutritional compounds being metabolized.
Chemical receptors and nerves of the duodenum are sensitive to the
biochemical profile of metabolites within the chyme, and
participate in the coordination of physiology of digestion and
satiety and hunger, accordingly. As such, by altering the flow rate
and hence, the biochemical profile of chyme, embodiments of the
inventive small intestinal insert contribute to the generation of
signals associated with satiety. Flow reduction elements may
further effect the composition of the digesting food material by
the mixing action the flow reduction elements may provide.
[0092] FIG. 4 shows an embodiment of the invention with a central
tube 50 that includes an outer wall 54 and an inner wall 56 that
define an interior space 58. The interior space 58 forms an inner
lumen 59 that may be continuous from the proximal end 52 of the
central tube 50 to just short of the distal end 53 of the central
tube 50. The distal end 53 of the central tube 50 is sealed at a
point 55 so that fluid introduced into the central tube 50 does not
leak out distally into the small intestine. In some embodiments a
valve 90 may be located substantially at the proximal end of the
inner lumen 59. The valve 90 may be a self sealing valve that has a
septum 92 that may be accessed by a needle or blunt tip tube for
introduction of fluid into the inner lumen 59. The valve 90 also
may be accessed so that the fluid inside the inner lumen 59 of the
central tube 50 may be aspirated for removal. It is to be
understood that the valve type is not limited to a septum type
valve only, and that other types of mechanical valves may also be
used in place of the septum valve described. Particular embodiments
of the present invention are adapted to accept fluids in this
manner so that the devices of the present invention may be
implanted in a deflated configuration and later expanded into an
inflated configuration.
[0093] As shown in FIG. 4 and as mentioned above, one or more flow
reduction elements 200 may be attached to the central tube 50. In
some embodiments the diameter of each flow reduction element 200
may be concentric with the axis of the central tube 50. In the
embodiment depicted in FIG. 4, each flow reduction element 200 has
an outer wall 210, an inner wall 212, and an inner space 214. At or
near its proximally-oriented surface 220 and also at or near its
distally-oriented surface 222, each flow reduction element 200 may
be attached to the central tube 50 with the inner space 214 of the
flow reduction element 200 in fluid communication with the lumen 59
of the central tube 50, such that the inner space 214 surrounds the
outer wall 54 of the central tube 50. Each flow reduction element
200 may be attached to the central tube 50 by, for example,
adhesives, heat bonding, mechanical restraint or other suitable
methods.
[0094] As also depicted in FIG. 4, the central tube 50 may be
formed with plural inlet/exit ports 216 that are located inside
respective flow reduction elements 200. More specifically, each
port 216 is formed completely through the central tube wall 51 to
establish a pathway for fluid communication between the inner lumen
59 of the central tube 50 and the inner space 214 of the respective
flow reduction elements 200. Consequently, the inner lumen 59 of
the central tube 50 may be used to introduce fluid into the inner
spaces 214 of the flow reduction elements 200 and to inflate the
flow reduction elements 200 from a collapsed configuration, in
which insertion and removal of the flow reduction elements 200 is
facilitated, to an inflated configuration shown in FIG. 4, in which
resistance to food passage is increased to induce satiety. Thus, as
suggested earlier, the flow reduction element or elements 200 in
this embodiment act as balloons that may be deflated and collapsed
around the central tube 50 for introduction into the small
intestine and then inflated to the desired diameter once in
position.
[0095] Embodiments of the flow reduction elements may assume other
forms, such as coils, ribs, fans, baffles, either
peripherally-mounted or centrally-mounted, as well as sleeves, mesh
cages or baskets. Embodiments such as these are described further,
below, in the section entitled "Further exemplary embodiments of
the invention", which also includes description of embodiments with
biodegradable components, active biomaterial release mechanisms,
and nerve stimulation features, and as depicted in FIGS. 15-31.
[0096] In some embodiments, individual flow reduction elements 200
of the present invention may be elastic balloons or inelastic
balloons. When an elastic balloon material is used to establish a
flow reduction element 200, the flow reduction element 200 inflates
to a diameter that is dependent on the volume of fluid introduced
into the inner space of the flow reduction element. This embodiment
permits adjustment of the balloon size as determined by the
physician. If the balloon is too small, for instance, additional
fluid could be introduced to enlarge the balloon diameter.
Alternatively, if the balloon is too large, additional fluid could
be removed to shrink the balloon diameter. It is understood that an
alternate embodiment consisting of an inelastic balloon that
inflates to a diameter that is independent of a volume of fluid
introduced into its inner space is also included within the present
invention. The diameter of this type of balloon is fixed when
manufactured and does not permit in situ adjustment of the balloon
size. However, this type of balloon prevents possible over
inflation and rupture if too much fluid is introduced into the
balloon.
[0097] The flow reduction elements 200 shown in FIG. 4 have the
shape of a round sphere. However, other shapes are contemplated and
any shape that effectively functions to inhibit the passage of
partially digested food in the small intestine is acceptable in
accordance with the present invention. It is understood that the
ability of the small intestinal insert to remain within the small
intestine may be affected by the shape, orientation and tautness of
the flow reduction elements 200. For example alternate shapes such
as ovoid, elliptical, elongated ellipse and even irregular
non-geometrical shapes could be used in accordance with the present
invention.
[0098] FIG. 5 illustrates an alternative embodiment of the present
invention in which one or more flow reduction elements 300 are
eccentrically attached to a central tube 350. In this embodiment
the axis or diameter of the flow reduction element or elements 300
is not concentric with the axis of the central tube. The outer wall
302 of the flow reduction element is attached to the side of an
outer wall 354 of the central tube 350. An inner space 314 of each
flow reduction element 300 is eccentric relative to the axis of the
central tube 350 and is in fluid communication with an inner lumen
359 of the central tube 350 through a respective opening 316. As
was the case with the embodiment shown in FIG. 4, in the embodiment
shown in FIG. 5 the inner lumen 359 may be used to introduce and
remove fluid into the inner space 314 of the flow reduction element
300 to move the flow reduction element 300 between inflated and
deflated configurations.
[0099] In some embodiments of the present invention, the flow
reduction elements 300 may be inflated with a fluid, including a
liquid and/or a gas. In some embodiments, the gas may be, for
example, air, nitrogen or carbon dioxide. In another embodiment a
liquid may be, for example, water or water mixed with other
solutions. Any appropriate inflation medium may be modified to
deliver bioactive materials or other signals that may diffuse from
the insert of the present invention into the small intestine to
trigger biological signals of satiety. When bioactive materials are
delivered through an inflation medium, the central tube and/or flow
reduction elements should be permeable to the bioactive materials.
Porosity may be adjusted to control the diffusion rate of the
bioactive materials.
[0100] When inflating the flow reduction elements of the present
invention, it may be important for the physician to monitor the
flow reduction element 300 location in the small intestine and the
diameter of the flow reduction element relative to the diameter of
the small intestine. For this purpose, the flow reduction element
may be inflated with a radio opaque fluid that is visible on X-ray.
When the flow reduction element contains radio opaque fluid, a
physician may non-invasively visualize the size and placement of
the flow reduction element(s) from outside the patient's body. This
knowledge enables the physician to adjust the size and/or placement
of the flow reduction element(s). Likewise radio opaque marker
bands 218 as shown in FIG. 5 may be placed around the central tube
to facilitate visualization of the central tube's location in the
small intestine. The radio opaque marker bands 218 may be placed at
predetermined intervals so that the distance inside the small
intestine may be used as depth markers and may be measured from
outside of the body.
[0101] The central tube and flow reduction elements of the present
invention may be flexible. In some embodiments, they may be
constructed of a polymeric material that may be easily formed or
extruded and delivered with the aid of an endoscope by known
techniques. A central tube 50 that is soft and flexible will
contour to the anatomy of the gastrointestinal tract and provide
less irritation of the stomach and intestinal lining.
[0102] FIG. 6 shows an alternative embodiment of the invention with
flow reduction elements that are generally self-expanding, and do
not necessarily include a central lumen. These embodiments include
a central shaft 450 around which flow reduction elements are
concentrically attached 400 and/or are eccentrically attached 410.
The elements 400 and 410 may be attached to the central shaft 450
by, for example, heat fusing, adhesives or other suitable methods
as known in the art. These flow reduction elements 400 may be made
from material that may be folded or collapsed to a first volume
suitable for insertion with the aid of an endoscope and then may
self expand to a second volume suitable for restricting the flow of
partially digested food according to the present invention. These
flow reduction elements may be made from materials, or materials
may be configured so as to take the form of such as, by way of
example, a sponge, a foam, a hydrogel, or springs that may be
compacted into a small volume and then self expand to a
pre-determined shape and volume when unrestricted. Gel- or
sponge-based embodiments may include open cell or closed cell
forms. In addition to having features that allow such gel- or
sponge-based embodiments to be collapsible and expandable for
deployment, such embodiments typically have a high surface area
which is beneficial in embodiments that may include bioactive
agents, and may further be conducive for purposes of
biodegradability. Another foam-related embodiment is described
below in the section entitled "Further embodiments of the
invention", and depicted in FIG. 21. Because the flow reduction
elements self expand, the need for an inflation system is
eliminated and this embodiment represents a simple mechanical
design. These flow reduction elements may also be impregnated with
bioactive materials or other signals that may trigger biological
signals of satiety.
[0103] The central shaft 450 of an embodiment such as that depicted
in FIG. 6 may be solid and without an inner lumen or inner space.
In another embodiment the central shaft 450 may include a
passageway for consumed food so that the food may pass through the
small intestine without being fully absorbed.
[0104] Turning now to various anchoring members that may be used in
accordance with the present invention, FIG. 7 depicts one such
member. In FIG. 7, the central tube 50 has an anchoring member 100
near its proximal end 52. As stated earlier, the anchoring member
100 may be established by one or more inflatable balloons 102.
These balloons 102 may be eccentrically attached to the central
tube at point 104 near the proximal end 52 of the central tube 50.
These balloons may be formed in many shapes and are not limited to
the spherical shape shown. The central tube may be formed with an
opening 116 for each respective balloon 102 so that a pathway for
fluid communication is established between the inner lumen 59 of
the central tube 50 and the inner space of each balloon 106. The
inner lumen 59 is used to introduce fluid into the inner space of
the balloon 106 and inflate the balloon 102 from a first volume in
a collapsed state to a second volume or inflated state.
[0105] When the one or more balloons 102 of the anchoring member
100 are fully inflated, they secure the proximal end of the central
tube 52 within the antrum of the stomach. The one or more
inflatable balloons 102 have a combined cross sectional diameter
greater than the diameter of the pyloric valve to prevent migration
across the pylorus. The inflatable balloons 102 may be inflated and
deflated by adding or removing fluid from the central tube inner
lumen 59. The inflatable balloons 102 may be connected to the same
central tube inner lumen 59 as the one or more flow reduction
elements attached to the central tube and may be inflated
simultaneously with the flow reduction elements. The central tube
50 may also have more than one inner lumen so that the inflatable
balloons 102 and individual one or more flow reduction elements may
be inflated and deflated independently as well.
[0106] FIG. 8 illustrates another embodiment of the invention,
wherein an anchoring member 100 of the present invention is
deployed in the antrum 7. In this embodiment, a central tube 50 is
attached to an inverted umbrella skeleton 160. This skeleton 160
has a ring 162 that surrounds the central tube 50 and is supported
by struts. In the depicted embodiment the ring 162 is supported by
three struts 164, 165, and 166, however more or fewer struts may be
successfully employed. In the embodiment depicted in FIG. 8, the
struts are joined together at the central tube 50 at point 167 and
attached to the ring 162 at points 170, 171 and 172. The ring 162
of this anchor configuration may be made from, by way of example,
flexible plastic material or flexible wire and has a diameter
significantly larger than the diameter of the pyloric valve. This
umbrella skeleton 160 may be collapsed around the central tube 50
for insertion into the stomach with the aid of an endoscope. As the
device is released from the endoscope, the umbrella skeleton 160
may spring out and assume a configuration similar to that shown in
FIG. 8. The struts 164, 165 and 166 may be made from, by way of
example, plastic, metal or from plastic covered metal. The edge of
the ring which is in contact with the antrum walls 163, may be
constructed to assist in securing the umbrella ring 162 to the
walls of the antrum.
Device Embodiments Without an Anchoring member
[0107] FIG. 9 shows a central tube or elongated member 50 of the
present invention that may lodge and remain in the small intestine
for a period of time without any anchoring to the stomach or
pylorus. Embodiments of the present invention that can lodge and
remain within the small intestine for a period of time without any
anchoring to the stomach or pylorus do so by (i) adopting a central
tube with appropriately placed angles or curvilinear portions that
mimic the contours of the small intestine; and (ii) flow reduction
elements of an appropriate diameter that help to hold the
intestinal insert in place. This particular section of the
description focuses on angled sections, as exemplified by FIG. 9.
Details and particulars of angles are described further below, in
the context of illustrative example depicted in FIGS. 29 and
30.
[0108] In FIG. 9, the first three parts of the duodenum, including
the duodenal bulb 10A, the vertical duodenum 10B, and the
horizontal duodenum 10C are depicted. The flow reduction elements
of the depicted embodiment have been removed for clarity. Distal to
the pylorus 8 and immediately after entering the duodenum 10, the
central tube 50 may assume a sharp bend of radius .beta. between
the duodenal bulb 10A and the vertical duodenum 10B, and a sharp
bend of radius a between the vertical duodenum 10B and horizontal
duodenum 10C. In some embodiments the radius .beta. and the radius
.alpha. may be between about 45 degrees and about 110 degrees. In
another embodiment the radius .beta. and the radius a may be
between about 60 degrees and about 100 degrees such that the
central tube 50 bends to follow or correspond to the inner lumen of
the duodenum 10 at these locations that contain predictably
configured bends. In another embodiment the radius .beta. and the
radius a may be about 80 degrees. While most embodiments of the
present invention will include lengths that require adoption of
angle .beta. and angle .alpha., shorter devices adopting one or the
other are also included within the scope of the present invention.
In these described embodiments of the present invention, it may be
advantageous that the central tube 50 be flexible enough to conform
to the sharp angulations of the small intestine to avoid kinking.
One or more flow reduction elements with a diameter about equal to
that of the small intestine are also included along the length of
the central tube 50. In some embodiments, this diameter is about 3
cm; in other embodiments this diameter is about 4 cm.
[0109] To stabilize an intestinal insert in situ without the need
for an anchoring element, the central tube or elongated member 50
may be pre-formed with a configuration that conforms to the
duodenal angulations prior to insertion in the body. This
embodiment of the present invention may be constrained in a
straight configuration by a stiffening rod 110 placed down the
inner lumen 59 of the central tube 50 as shown. This stiffening rod
110 may be placed into a separate lumen designed to house this
stiffening rod or may be imbedded in the wall of the central tube
50. Upon insertion into the patient with the aid of an endoscope,
when the central tube 50 reaches the location of the sharp bends in
the duodenum 10, the stiffening rod 110 may be withdrawn, thereby
allowing the central tube 50 to assume a pre-formed shape.
[0110] In another embodiment that stabilizes in situ without an
anchoring member, the central tube or elongated member 50 may have
a shape memory alloy wire embedded inside the central tube wall 51
or residing in the inner lumen 59. This shape memory alloy wire has
a pre-set bend configuration with a radius .beta. and .alpha.
radius a that matches or corresponds to the bend configuration of
the duodenum and is positioned in the central tube 50 at the
corresponding location. Upon insertion into the patient with the
aid of an endoscope, when the central tube 50 reaches the location
of the sharp bend in the duodenum 10 and the shape memory alloy
wire reaches a pre-set transition temperature equal to body
temperature or about 37.degree. C., the wire assumes the programmed
shape and forces the central tube 50 and the central tube wall 51
to assume the same shape.
[0111] In another embodiment, the central tube or elongate member
50 may have a spring embedded inside the central tube wall 51 or
inner lumen 59. This spring could be pre-shaped to the anatomy of
the wall of the small intestine. The spring is held straight during
delivery and conforms to the small intestine anatomy after release,
and such shape enables the device to remain in place. The shape
enables the device to remain in place. In one embodiment, due to
its configuration that matches or corresponds to the predictable
placement and configuration of the small intestine, the device can
remain in place for a period of time within the small intestine
without anchoring to the stomach or pylorus of the stomach.
[0112] While the present embodiments of the present invention can
remain in the small intestine for a period of time without
anchoring to the stomach or pylorus, they are not intended to
remain indefinitely. In some embodiments, the inserts are
endoscopically removed after a predetermined period of time. In
other embodiments, the inserts may be formed of one or more
biodegradable materials that are eventually degraded and eliminated
from the body. The rate of biodegradability of any embodiment of
the inventive device may be adjusted by varying the biodegradable
aspects of the embodiment, thus allowing for a manufacturing route
to control the residency time in the intestinal tract to a
clinically appropriate level. Biodegradable composition may be
varied in qualitative terms, by varying the composition of the
materials. Biodegradability of devices may also be varied in
quantitative terms, for example by varying the quantity of material
at a location vulnerable to biodegradation. For example, varying
the thickness of a junction designed for biodegradable
vulnerability may be varied in thickness.
[0113] Biodegradable aspects of embodiments of the invention are
described further below; all embodiments described herein, and all
embodiments as depicted in FIGS. 3-12, and 16-31 may have portions
that include biodegradable materials, both within the central tube
or member, also referred to synonymously as elongate member 50
and/or any of the various embodiments of the chyme flow reduction
elements 200. Exemplary processes of biodegradation are depicted,
for example in FIGS. 27A-28B. In the description that ensues, some
embodiments are used as specifically illustrative examples that are
formed wholly or in part from biodegradable materials, but, as
stated, all embodiments may include biodegradable materials, even
when not specifically identified as such, including embodiments
with and without an anchoring member.
Deployment of Inserts and Flow Reduction Elements
[0114] The description now turns to considerations related to
deployment of the inventive insert, some embodiments of which
include flow reduction elements. Flow reduction elements are
referenced in a generic sense with the label 200, but some
exemplary embodiments make use of different label numbers, for
their particular features. FIG. 10 illustrates an embodiment of the
present invention where flow reduction elements may be created
through the expansion of portions of an expandable sleeve; this
embodiment will be used in the context of describing an example of
how to deploy a device with flow reduction elements. In the
embodiment depicted in FIG. 10, a central tube 50 is attached to an
expandable sleeve 508 at the expandable sleeve's distal end 510
near the distal portion of a duodenal/small intestinal insert of
the present invention. In a delivery configuration of the depicted
embodiment, the opposite proximal end of the central tube 50 is
attached to a detachable extension tube 520 that may lock onto a
proximal portion of the central tube 50 when the flow reduction
elements 530 are expanded (post delivery). One non-limiting method
of detachable attachment is the use of one or more screws 504,
whereby the extension tube 520 screws into the central tube 50. The
central tube 50 may be pre-formed to have a configuration that
conforms to the anatomy of the duodenum 10 shown in FIG. 1. A
central tube 50 so described would force the expandable sleeve 508
to assume the configuration of the central tube 50. The central
tube 50 may be constructed, merely by way of example, of wire,
spring, superelastic or shape memory alloys, hollow steel tubing or
plastic polymers. In some embodiments a stiffening rod or guide
wire 110 may also be inserted through the lumen of central tube
50.
[0115] The expandable sleeve 508 herein described is designed to
expand at predefined segments to allow the formation of flow
reduction elements 530. In some embodiments, the non-expanded
segments 532 of expandable sleeve 508 may be coated with a polymer
to prevent their expansion. In another embodiment, the flow
reduction elements 530 may be covered with a flexible polymer to
prevent partially digested food from entering the flow reduction
elements 530. In another embodiment, a stiffening rod or guide wire
110 may be inserted through the lumen of central tube 50 to
straighten the central tube 50 when the device is delivered into
the duodenum.
[0116] The expandable sleeve 508 may, merely by way of example be
configured as any one or more of a knit, a weave, a mesh or a braid
that may be formed, merely by way of example from any one or more
of a metal, a wire, a ribbon, a plastic polymer or a biodegradable
material.
[0117] FIG. 11 illustrates the expandable sleeve 508 consisting of
flow reduction elements 530 in a collapsed configuration for
insertion into the small intestine. In this configuration a force A
is applied to the expandable sleeve 508 to collapse the flow
reduction elements 530. The collapsed form may be restrained by a
constraining mechanism such as, merely by way of example, a sheath
or a tightly wound string, or by applying sustained traction on the
proximal end of the expandable sleeve 508. FIG. 11 also shows
portions of the central tube that will remain unexpanded 532, a
detachable extension tube 520 and a guidewire 110.
[0118] The expansion of the flow reduction elements 530 in the
embodiments depicted in FIGS. 10 and 11 may occur passively or
actively. One example of passive expansion may be the removal of a
constraining mechanism to allow the flow reduction elements 530 to
expand to an original expanded state. Another non-limiting
mechanism can be to release traction on the proximal end of an
expandable sleeve 508 to allow the flow reduction elements 530 to
expand to an original expanded state.
[0119] The flow reduction elements 530 of the embodiments depicted
in FIGS. 10 and 11 can expand in a distal to proximal fashion, a
proximal to distal fashion or in a central fashion depending on
their relative position in relation to, in some embodiments, motion
of the expandable sleeve 508 and the central tube 50 to one
another. For example, if the proximal end of the flow reduction
element lumen is held in the duodenal bulb and the central tube 50
is pulled back, the distal end of the flow reduction element lumen
may expand first. Expansion in this direction may be advantageous
because the position of the proximal end of the flow reduction
element lumen remains in the duodenal bulb.
[0120] FIG. 12 illustrates some embodiments of the present
invention that may lock the proximal end of the expandable sleeve
508 to the central tube 50 at a position to keep the flow reduction
elements in a desired expanded configuration. Traction on the
extension tube 520 retracts central tube 50 until wedge 52 engages
the proximal end of the expandable sleeve 508. The central tube 50
may have multiple ratchet-like wedges that may lock the expandable
sleeve 508 at different degrees of expansion. The extension tube
may be unscrewed from the central tube 50 after deployment of the
device and expansion of the expandable sleeve 508.
Biodegradable Features
[0121] While the present embodiments of the present invention may
remain in the small intestine for a period of time, they are not
intended to remain indefinitely. In some embodiments, the inserts
are endoscopically removed after a predetermined period of time. In
other embodiments, the inserts may be formed or partially-formed of
one or more biodegradable materials that are eventually degraded
and eliminated from the body. In some embodiments, the device may
include some material that is biodegradable and some material that
is not biodegradable. In some embodiments that include
non-biodegradable materials, the degradation of the biodegradable
portions of the device may facilitate the breakdown and eventual
elimination of the non biodegradable portions.
[0122] Biodegradable is used in a broad sense, so as to include the
any type of material breakdown or disintegration of any type that
may occur in a biological environment, such environment being
defined primarily by the biological host, but also by any
microorganisms within the host. Other terms that biodegradability
broadly embraces include bioabsorbability and bioerodibility.
Biodegradation, per embodiments of the invention, may occur, for
example, by dissolution, by effects of pH, such as action of acids,
by hydrolytic mechanisms, by hydration, by digestive or
enzyme-catalyzed effects such as cleavage, or by physical effects
of bodily or muscular movement. An example of biodegradation is
provided by the hydrolysis, dissolution, or reaction to pH, or
enzymatic lysis that results in a scission of the polymer backbone
of an inserted device. Microorganisms such as those that reside in
the intestine, may eat or digest polymers, and also initiate a
mechanical, chemical, or enzymatic aging. The biodegradable
materials of embodiments of the invention are also biologically
compatible, as well as are breakdown products of biodegradable
materials, as included in embodiments of the present invention.
Biodegradable materials may include organic and inorganic
compounds. Some representative inorganic compounds are described
below in the section related to "device features to accommodate
bioactive agents"; in this section, a description of biodegradable
polymers is provided for inclusion as embodiments of the present
invention.
[0123] As mentioned above, some embodiments of the invention may
include a resilient shape holding portion, and in some embodiments,
a shape memory portion that supports the maintenance of an
advantageous configuration of the device, particularly with regard
to maintenance of angles alpha and beta of the inventive C-shaped
duodenal insert device. Metals as well as some polymers are capable
of resiliently holding a shape. Shape memory materials include
metal alloys as well as biodegradable polymers. Shape memory alloy
elements of the device are not biodegradable, but these alloy
structural elements may be combined or joined with polymeric
elements that are biodegradable, and upon such degradation, the
alloy elements are released in a form that allows their
elimination. Such embodiments are depicted in FIGS. 27A and 27B, as
described below. Other embodiments or the invention may include
biodegradable shape memory polymeric elements. Biodegradable shape
memory polymers have been described in various publications,
including U.S. Pat. No. 6,160,084, 6,281,262, 6,388,043, 6,720,402,
and US Published Applications US 20050075405A1, US 20030055198A1,
US 20040015187A1, US 20040110285A1, US 20050245719A1, and US
20060142794A1. Embodiments of the invention may include any one or
more of such shape memory materials, and further, such materials
may be joined together in various ways as depicted in FIGS. 28A and
28B.
[0124] A variety of natural, synthetic, and biosynthetic polymers
are biologically degradable and may be included as materials that
comprise embodiments of the intestinal insert device. A polymer
based on the C-C backbone tends to be nonbiodegradable, whereas
heteroatom-containing polymer backbones confer biodegradability.
Biodegradability may be engineered into polymers by the judicious
addition of chemical linkages such as anhydride, ester, or amide
bonds, among others. The mechanism for degradation is by hydrolysis
or enzymatic cleavage resulting in a scission of the polymer
backbone. Microorganisms, such as those that reside in the
intestine, may eat or digest polymers, and also initiate a
mechanical, chemical, or enzymatic aging.
[0125] Biodegradable polymers with hydrolyzable chemical bonds are
appropriate as materials for a biodegradable intestinal insert. In
addition to being biocompatible, the material should meet other
criteria, for example, being processable, sterilizable, and capable
of controlled stability or degradation in response to biological
conditions. The degradation products often define the
biocompatibility of a polymer, not necessarily the polymer itself.
Poly(esters) based on polylactide (PLA), polyglycolide (PGA),
polycaprolactone (PCL), and their copolymers have been extensively
employed as biomaterials. Degradation of these materials yields the
corresponding hydroxy acids, making them safe for in vivo use.
[0126] Other biodegradable polymers include poly(hydroxyalkanoate)s
of the PHB-PHV class, additional poly(ester)s, and natural
polymers, particularly, modified poly(saccharide)s, e.g., starch,
cellulose, and chitosan. Chitosan is derived from chitin, and is
the second most abundant natural polymer in the world after
cellulose. Upon deacetylation, it yields the novel biomaterial
Chitosan, which upon further hydrolysis yields an extremely low
molecular weight oligosaccharide. Chitosan is biocompatible,
antibacterial and environmentally friendly polyelectrolyte, thus
appropriate for medical devices and as material for controlled
release in drug delivery.
[0127] Poly(ethylene oxide), PEO, a polymer with the repeat
structural unit --CH.sub.2CH.sub.2O--, has applications in drug
delivery. The material known as poly(ethylene glycol), PEG, is in
fact PEO but has in addition hydroxyl groups at each end of the
molecule. In contrast to high molecular weight PEO, in which the
degree of polymerization, n, might range from 10.sup.3 to 10.sup.5,
the range used most frequently for biomaterials is generally from
12 to 200, that is PEG 600 to PEG 9000, though grades up to 20,000
are commercially available. Key properties that make poly(ethylene
oxide) attractive as a biomaterial are biocompatibility,
hydrophilicity, and versatility. The simple, water-soluble, linear
polymer may be modified by chemical interaction to form
water-insoluble but water-swellable hydrogels retaining the
desirable properties associated with the ethylene oxide part of the
structure.
[0128] Multiblock copolymers of poly(ethylene oxide) (PEO) and
poly(butylene terephthalate) (PBT) may also be appropriate for
intestinally inserted devices. These materials are subject to both
hydrolysis (via ester bonds) and oxidation (via ether bonds).
Degradation rate is influenced by PEO molecular weight and content.
Additionally, the copolymer with the highest water uptake degrades
most rapidly.
[0129] A widely used nondegradable polymer is ethylene-vinyl
acetate copolymer. This copolymer has excellent biocompatibility,
physical stability, biological inertness, and processability. In
drug delivery application these copolymers usually contain 30-50
weight percent vinyl acetate. Ethylene-vinyl acetate copolymer
membrane acts as the rate-limiting barrier for the diffusion of the
drug. In the Type II class of degradable polymers, the conversion
of the hydrophobic substituents to hydrophilic side groups is a
first step in the degradation process. The tyrosine-derived
polycarbonate poly(DTE-co-DT carbonate), may, for example, be an
appropriate material for a biodegradable intestinal insert. The
material may be made with the pendant group via the tyrosine as
either an ethyl ester (DTE) or free carboxylate (DT). Through
alteration of the ratio of DTE to DT, the material's
hydrophobic/hydrophilic balance and rate of in vivo degradation may
be manipulated.
[0130] Water-swellable polymer networks may function as hydrogels
at one end or as superabsorbers at the other extreme. Hydrogels are
characterized by the pronounced affinity of their chemical
structures for aqueous solutions in which they swell rather than
dissolve. Such polymeric networks may range from being mildly
absorbing, typically retaining 30 wt. % of water within their
structure, to superabsorbing, where they retain many times their
weight of aqueous fluids. Several synthetic strategies have been
proposed to prepare absorbent polymers including:
polyelectrolyte(s) subjected to covalent cross-linking, associative
polymers consisting of hydrophilic and hydrophobic components
("effective" cross-links through hydrogen bonding), and physically
interpenetrating polymer networks yielding absorbent polymers of
high mechanical strength. These approaches are not mutually
exclusive, and materials may include composite gels that are
critically reliant on the balance between polymer-polymer and
polymer-solvent interactions under various stimuli including
changes in temperature, pH, ionic strength, solvent, concentration,
pressure, stress, light intensity, and electric or magnetic
fields.
Bioactive Materials Deliverable by Embodiments of the Device
[0131] As previously stated, in some embodiments, the central tube
and/or flow reduction elements of the invention may be adapted to
release bioactive materials or bioactive agents that trigger
biological satiety signals. In some embodiments, the one or more of
the flow reduction elements and/or central tube may be a porous and
malleable solid designed to release a signal into the
gastrointestinal (GI) tract over time. In some embodiments,
nutrient products of digestion are released from the one or more
flow reduction elements 200 and/or central tube or elongate member
50 to trigger chemoreceptors within the GI tract to release
molecular signals involved in transmitting and/or creating satiety
signals.
[0132] The description now turns to a consideration of release of
bioactive materials from the device in furtherance of reducing
appetite or slowing food absorption or intake. The term "bioactive
material(s)" refers to any organic, inorganic, or living agent that
is biologically active or relevant; the term has been extensively
described in U.S. application Ser. No. 11/300,283, and will
described here only briefly. For example, a bioactive material may
be a protein, a polypeptide, a polysaccharide (e.g. heparin), an
oligosaccharide, a mono- or disaccharide, a lipid, an organ
metallic compound, or an inorganic compound, an antimicrobial agent
(including antibacterial and anti-fungal agents), an anti-viral
agent, anti-tumor agent, immunogenic agent. It may include a living
or senescent cell, a stem cell, a bacterium, a virus, or any part
thereof. It may include a biologically active molecule such as a
hormone, a growth factor, a growth factor-producing virus, a growth
factor inhibitor, a growth factor receptor, an anti-inflammatory
agent, an ant metabolite, or a complete or partial functional
insense or antisense gene. It may also include a man-made particle
or material that carries a biologically relevant or active
material. A bioactive material also may be a by-product of
digestion or an agent that alters the pH of its surrounding
environment.
[0133] Bioactive materials also may include drugs such as chemical
or biological compounds that can have a therapeutic effect on a
biological organism. Bioactive materials also may include precursor
materials that exhibit the relevant biological activity after being
metabolized, broken-down (e.g. cleaving molecular components), or
otherwise processed and modified within the body. Combinations,
blends, or other preparations of any of the foregoing examples may
be made and still be considered bioactive materials within the
intended meaning herein. Aspects of the present invention directed
toward bioactive materials may include any or all of the foregoing
examples.
[0134] Examples of bioactive materials included with the present
invention include hormones and other compounds that convey satiety
promoting signals. Bioactive materials of the present invention may
also include other naturally-occurring or synthesized peptide,
protein, and steroid hormones. Bioactive agents further may include
anti-tumor agents, antimicrobial agents, such as antibiotics:
cephalosporins: aminoglycosides:; macrolides: tetracyclines,
chemotherapeutic agents, sulfonamides, urinary tract antiseptics,
anaerobic infection antibiotics, drugs for tuberculosis, drugs for
leprosy, antifungal agents, antiviral agents, chemotherapeutic
agents for amebiasis, anti-helminthiasis agents, anti-inflammatory
agents, anti-gout agents, centrally acting analgesics, thyroid
drugs, including those used in adjunctive therapy, and those used
as anti-thyroid agents, viral surface antigens or parts of viruses,
bacterial surface antigens or parts of bacteria, surface antigens
of parasites causing disease or portions of parasites,
immunoglobulins, antitoxins, and antigens that elicit an immune
response, such as disease-associated antigens, or bioactive agents
such as hormones, enzymes or clotting factors:
Device Features to Accommodate Bioactive Agents for Delivery
[0135] The central tube 20 and/or flow reduction elements 200 of
the present invention may have bioactive materials adhered to their
surface (through dip-coating, spray-coating, sputter-coating and a
variety of other techniques known to those of skill in the art) or
included in reservoirs or depots accessible to the surface, or may
be manufactured so that the materials making up the intestinal
insert include and diffuse such bioactive materials. The central
tube and/or flow reduction elements of the present invention that
diffuse bioactive materials, may be created by a number of
different procedures that are referenced in U.S. application Serial
No. 11/300,283 of Binmoeller, filed on Dec. 15, 2005 and published
as U.S. Publication 2006/0178691 on Aug. 10, 2006, including
references to U.S. Pat. No. 5,019,400 to Gombotz et al. U.S. Pat.
No. 6,685,957 to Bezemer et al. and U.S. Pat. No. 6,685,957.
[0136] When a hydrophobic bioactive material, such as a steroid
hormone is incorporated by the above-described method, at least one
hydrophobic antioxidant may be present. Hydrophobic antioxidants
which may be employed include, tocopherols (such as
.alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol,
.delta.-tocopherol, epsilon-tocopherol, zeta.sub.s-tocopherol,
zeta.sub.2-tocopherol, and eta-tocopherol) and 1-ascorbic acid
6-palmitate. Such hydrophobic antioxidants may retard the
degradation of the copolymer and retard the release of the
bioactive material.
[0137] When a loaded polymer made according to the above-referenced
technique includes a hydrophilic bioactive material, the loaded
polymer may also include, in addition to a hydrophobic antioxidant,
a hydrophobic molecule such as, by way of example, cholesterol,
ergosterol, lithocholic acid, cholic acid, dinosterol, betuline, or
oleanolic acid, which may serve to retard the release rate of the
agent from the copolymer. Such hydrophobic molecules prevent water
penetration into the loaded polymer, but do not compromise the
degradability of the polymer matrix. Further, such molecules may
decrease the polymer matrix diffusion coefficient for the bioactive
material to be released and thereby provide for a more sustained
release of a bioactive material from the polymer matrix.
[0138] Methods of dispersing bioactive materials into polymers and
the role of lyophilization to include thermoprotectants have been
provided in U.S. application Ser. No. 11/300,283 of Binmoeller,
filed on Dec. 15, 2005, which has been incorporated by
reference.
[0139] Non-limiting examples of polymers that may be used in
accordance with the present invention, particularly with regard to
accommodating and releasing bioactive agents, include
polyurethanes, polyesterurethanes, silicone, fluoropolymers,
ethylene vinyl acetate, polyethylene, polypropylene,
polycarbonates, trimethylenecarbonate, polyphosphazene,
polyhydroxybutyrate, polyhydroxyvalerate, polydioxanone,
polyiminocarbonates, polyorthoesters, ethylene vinyl alcohol
copolymer, L-polylactide, D,L-polylactide, polyglycolide,
polycaprolactone, copolymers of lactide and glycolide,
polymethylmethacrylate, poly(n-butyl)methacrylate, polyacrylates,
polymethacrylates, elastomers, and mixtures thereof. Representative
elastomers that may also be used include, by way of example, a
thermoplastic elastomer material available under the trade name
"C-FLEX" from Concept Polymer Technologies of Largo, Fla.,
polyether-amide thermoplastic elastomer, fluoroelastomers,
fluorosilicone elastomer, sytrene-butadiene rubber,
butadiene-styrene rubber, polyisoprene, neoprene (polychloroprene),
ethylene-propylene elastomer, chloro-sulfonated polyethylene
elastomer, butyl rubber, polysulfide elastomer, polyacrylate
elastomer, nitrile, rubber, polyester, styrene, ethylene,
propylene, butadiene and isoprene, polyester thermoplastic
elastomer, and mixtures thereof.
[0140] One of skill in the art can determine the amount or
concentration of bioactive material(s) to include on the surface or
within the material of the intestinal inserts of the present
invention depending on particular treatment objectives and desired
release profiles, as described in U.S. application Ser. No.
11/300,283 of Binmoeller, filed on Dec. 15, 2005, which has been
incorporated by reference.
[0141] In some embodiments, the intestinal inserts of the present
invention, or portions thereof, may include a topcoat or barrier to
slow the diffusion or release of bioactive materials. Typically,
the barrier should be biocompatible (i.e., its presence does not
elicit an adverse response from the body), and may have a thickness
ranging from about 50 angstroms to about 20,000 angstroms. In some
embodiments the barrier may include a polymer provided over the
polymer that diffuses bioactive materials.
[0142] In some embodiments, a barrier of the present invention
comprises inorganic materials, which have been detailed in U.S.
application Ser. No. 11/300,283 of Binmoeller, filed on Dec. 15,
2005, which has been incorporated by reference. Further detailed in
that application are several methods that may be used to deposit a
barrier over the inserts of the present invention. Nitride barrier
coatings, such as, by way of example, titanium nitride, titanium
carbonitride, chromium nitride, titanium aluminum nitride, and
zirconium nitride may be deposited on the inserts of the present
invention at relatively low temperatures by cathodic arc vacuum
deposition. Such a method may be chosen where bioactive materials
included within an insert of the present invention are
temperature-sensitive. Further detailed in that application are
methods for producing films of pure metals and alloys.
[0143] In some embodiments, it is contemplated that the barrier
will contain mostly inorganic material. However, other embodiments
may include barriers with a mixture of organic and inorganic
materials or barriers of all organic materials. Some organic
compounds that may be used in accordance with the present invention
include, by way of example, polyacrylonitrile, polyvinylidene
chloride, nylon 6-6, perfluoropolymers, polyethylene terephthalate,
polyethylene 2,6-napthalene dicarboxylate, and polycarbonate.
Generally, the solubility of the drug in the material of the
barrier is less than the solubility of the drug in its polymer
carrier. Also, generally, the diffusivity of the drug in the
material of the barrier is lower than the diffusivity of the drug
in its polymer carrier. The some embodiments, the barrier may be
biodegradable. Appropriate biodegradable materials that may be used
to create a barrier include, by way of example, calcium phosphates
such as, by way of example, hydroxyapatite, carbonated
hydroxyapatite, tricalcium phosphate, .beta. -tricalcium phosphate,
octacalcium phosphate, amorphous calcium phosphate, and calcium
orthophosphate. Certain calcium salts such as calcium phosphate
(plaster of Paris) may also be used. The biodegradability of the
barrier may act as an additional mechanism for controlling drug
release from the underlying first layer.
Active Control of Bioactive Material Release
[0144] Some embodiments of the device and methods provide a more
active, i.e., a more controlled, or metered method of delivering
bioactive agents, in contrast to the more passive diffusion of drug
from surfaces or depots. These approaches are also more amenable to
handling the delivery of multiple-drug release. Embodiments of the
inventive devise may include a pump to dispense one or more
bioactive agents from a reservoir or depot. Pumps may include
electrically-driven pumps 72 mechanical pumps, piezo-electric
devices that control pores, for example, or pumps may be
osmotically-driven pumps 71. The osmotic pump delivery is
relatively passive in that it does not require energy input, but it
is controllable, predictable, and calibratable. Osmotic pumps
typically are driven or urged via pH difference or concentration
gradients. Release of bioactive materials may be controlled by
external control devices, such as by an electronic signaling device
either user-controlled or a programmable pacing/signaling device.
Examples of devices that embody these active approaches to the
delivery of bioactive materials or agents are described further
below, and are depicted in FIGS. 23-25.
[0145] There are advantages to a drug delivery site within the
intestinal lumen that may, for example advantageously be applied to
the delivery of bioactive agents in a broader array than just drugs
specific to modulating digestion or appetite. Such other agents may
include chemotherapeutic agents, or radioactive particles for
anti-cancer therapy. Another type of bioactive material that may
benefit from local delivery may include cells, such as stem cells
or activated immune cells, for cellular therapy of the intestine.
Advantages of the intra-duodenal site of release may include
proximity to target sites, taking advantage of specific chemical
recovery receptors in the intestine, and minimizing systemic
metabolism of drugs that occurs during the passage of the drug
through such organs as the liver and kidney that occurs when drugs
are delivered intravenously or orally.
[0146] In addition to delivering bioactive materials to the small
intestine that may reduce food intake, the methods and devices of
the present invention may be used to deliver other bioactive
materials normally taken orally as well. The release of bioactive
materials directly into the small intestine may be advantageous
because many bioactive materials, including many drugs that are
generally taken orally, are degraded by the harsh conditions of the
stomach before they may reach the small intestine to be absorbed.
For this reason, many bioactive materials are coated with layers of
protective materials. By releasing bioactive materials, including
drugs, directly into the small intestine, coatings to protect the
bioactive materials may not be required. This lack of required
protective coatings may be beneficial for patients because less
unnecessary substances are introduced into their systems, and it is
further beneficial as a process step reduction and cost reduction
measure.
[0147] In another aspect of the invention which takes a more active
interventional role, embodiments of the device may include an
electronic emitter configured to apply an electrical potential to
tissue in the stomach or duodenum. This electrical potential will
trigger neuron-receptors and/or mechano-receptors, and/or
osmo-receptors, and/or chemo receptors to send satiety signals to
the brain. Exemplary embodiments of the device such as these are
described further below, and depicted in FIG. 26. The role of
embodiments of the intestinal insert and methods associated with
its use are more generally considered in the context of FIG. 13, as
detailed in the following section.
Further Exemplary Embodiments of the Invention
[0148] FIG. 13 is a schematic flow diagram of various embodiments
of a method by which embodiments of the device engage the
physiology of the host subject, and intervene in ways to generate a
sense of satiety that ultimately reduces food intake. Embodiments
of the inventive device intervene in the physiology of digestion
and satiation by two broad approaches, each of which mimic or
exploit the natural mechanisms of satiety. Embodiments may engage
the physiology of the host subject by (1) their mere physical
presence having effects, and/or (2) they may intervene more
directly or actively by the direct provision of bioactive agents or
direct neural stimulation. FIG. 13 and this associated description
are provided as a simplified theoretical framework for
understanding the invention; it is not intended to be complete in
all detail; various interactions, dotted lines, and blurring of
distinctions are omitted for sake of simplicity.
[0149] First, the mere physical presence of a device has two main
effects, it has distensional effects and, if it has distinct flow
reduction elements, it impedes the flow of chyme. Each of these two
broad effects is dependent on the dimensions of the device and its
flow reduction system, if the latter is present. First, then, the
presence of the device distends the duodenum, and such distension
may be neurally-sensed or detected, as for example, by
stretch-sensitive neurons in the duodenum. Accordingly, any
physical dimension, aspect, or feature, such as, by way of example,
any of length, width, total volume, overall conformation or
topography, density, weight, or surface properties may affect
distension, or may be neurally detected in some way. Secondly, with
regard to physically impeding the flow of chyme, this impeding
process may alter the biochemical profile of digesting chyme, and
chemoreceptors in the duodenum sense that profile as being more
fully digested. It may also be that there is neural recognition
more specifically of longer chyme residency time, as information
separate from the altered biochemical profile per se; an effect
such as that also then may be related to neural detection of
distension. Neuronal pathways are indeed stimulated by distension,
and neuroelectric signals and/or neuropeptides and
neurotransmitters may be released for local or more distant sites
of action. Joining neural feedback are chemical signals, both from
the metabolite profile per se, and by the secretion of hormones
such as CCK. Neural and chemical responses emanate to the central
nervous system and other organs which, in sum, indicate that enough
has been eaten, and satiation is achieved. In further response, the
central nervous system supports a cessation of eating and digestive
processes slow.
[0150] Second, with further reference to FIG. 13, embodiments of
the device may intervene in a more active manner, beyond that which
is provoked by mere physical presence. Embodiments of the device
may assertively provide (1) bioactive agents and/or (2) provide
electrical stimulation of nerves which then engage the physiology
of satiety and digestion in the much the same manner, or through
the same physiological pathways described above. In sum, a variety
of effects of the presence of the device in the duodenum result in
biochemical effects or signals (such as hormonal responses, and/or
biochemical profile of metabolites both within the intestine and in
the blood stream) and neural activity involving electrical signals,
all of which converge physiologically to result in "satiety", with
its complement of sensed satiety, sensed or perceived appetite,
psychological correlates, and behavioral and habitual responses. As
such, the action of the device or the presence of the device could
be part of a method of providing therapy. The therapy may include
providing a bioactive agent from the device to a portion of the
gastrointestinal site. Moreover, this step of providing may produce
a sensation of satiety in the patient.
[0151] Embodiments of the invention, a small intestinal insert,
typically include an elongated member including at least one angled
portion and at least one flow reduction element, for slowing the
passage of chyme (or, stated in other terms, increasing the
residency time of chyme) in the duodenum, although some embodiments
of the device do not necessarily include a flow reduction element
(as illustrated in FIGS. 23 -26), and in some embodiments, the
central or elongated member itself may be configured to reduce flow
(FIGS. 16, for example). These embodiments typically do have one or
two angled portions that correspond to angled target portions of
the duodenum. The configuration of the angled portions of the
insert, including the flow reduction elements, is such that the
device resides stably in the duodenum for a period of time.
Embodiments of the insert may include adaptations that contribute
to the generation of one or more physiological signals of satiety.
Embodiments of the insert may include other features, such as the
inclusion of biodegradable portions, a neurological stimulator, and
one or more releasable reservoirs of bioactive materials that can
be actively released by a bioactive material release mechanism.
[0152] Residency time of embodiments of the insert within the
targeted angled site within the duodenum will vary according to the
configuration of the embodiment and according to the particulars of
the biodegradable materials that comprise portions of the device.
Degradation of the device by biological processes is typically what
causes release or unseating, or disengagement of the device from
the target site, and elimination of the device through the
intestinal tract. It may be understood therefore, that the device
may be configured initially to sit or be seated in the targeted
angled portion of the small intestine, and then, following a period
of residency and through the effects of biodegradation, then
configured to be unseated from the target site, and eliminated from
the body by way of defecation. Biodegradability is feature of some
polymers, and may be included in polymeric portions of any
embodiment described herein and/or as illustrated in exemplary
devices of FIGS. 3-12, or any device described herein.
Biodegradation is a feature explicitly depicted in the embodiments
shown in FIGS. 27 and 28.
[0153] Embodiments of the device elicit physiological signals of
satiety typically through hormonal or neurological pathways. In
some embodiments, the pathways are stimulated by the physical
presence of the device, including a portion of or the sum total of
a central member and flow reduction elements, whose collective or
individual dimensions, either length, width, or total volume, or
surface properties, are such that neuronal elements of the
intestine, such as mechanoreceptors or stretch receptors, sense the
presence of material which is interpreted as the presence of
partially digested food, and therefore stimulate neuronal messages
to the central nervous system that are interpreted as food
satiation. In some embodiments, the central member, elongated body
or spine may primarily provide the trigger for signaling. In some
other embodiments, one or more flow reduction elements may
primarily provide the trigger for signaling. In still other
embodiments, a combination of the flow reduction element or
elements and the elongated body provide the trigger for
signaling.
[0154] In other embodiments, the satiety signal may be hormonal.
Flow reduction elements slow the passage of chyme being processed
in the duodenum, the biochemical profile of the food breakdown
products is altered, and chemoreceptors in the duodenum respond to
the altered biochemical profile in a manner that conveys satiety to
the central nervous system and other portions of the digestive
system.
[0155] In still other embodiments, the device includes reservoirs
of bioactive materials that may be released, either by passive or
active mechanisms. In the embodiments, the satiety signals are
provided directly by the device, not by the endocrine pathways of
the insert's host. Embodiments of the device may include material
reservoirs of any type, including, for example, drug coatings that
elute passively, or in concert with degradation of a host coating
material, and some embodiments include reservoirs that are coupled
with pumps. Such pumps may be mechanical, harnessing for example,
biological energy conveyed by peristalsis, or electrical energy, or
mechanical energy. Some embodiments may include osmotic pumps,
which do not require input of electrical energy, but instead tap
into the stored energy of osmotic gradients. Embodiments that are
dependent on electrical energy for release by a pump typically
include an energy storage device, such as a battery or a capacitor.
Some of the powered embodiments include, as part of a larger
system, a remote stimulator that can control the action of the
pump. In some embodiments, the device may provide direct neural
stimulation, through electrodes that stimulate local nerves in the
duodenum, which convey a sensation of satiety to the central
nervous system. As with pumps, devices that include neural
stimulation features, may also include energy storage devices and
external on/off or variable power control devices that communicate
either by direct wired connection or wirelessly, as for example
through radiofrequency signals.
[0156] FIG. 14 provides a perspective view of a portion of the
human gastrointestinal tract that focuses on the duodenum of the
small intestine 10, starting at the antrum-pyloric juncture 5, and
extending to the entrance of the jejunum 12. Shown are the ampulla
of Vater 13, the site of the entrance of the hepatopancreatic duct
15, which is formed by the union of the pancreatic duct (from the
pancreas 9) and the common bile duct from the liver. The pylorus 8
controls the discharge of contents of the stomach through a
sphincter muscle, the pyloric valve 11, which allows the pylorus 8
to open wide enough to pass sufficiently-digested stomach contents.
These gastric contents, after passing into the duodenum 10,
continue into the jejunum 12 and on into the ileum. The duodenum
10, jejunum 12 and ileum make up what is known as the small
intestine; however the individual portions of the alimentary canal
are also commonly referred to as the small intestine. In the
context of this invention the small intestine can refer to all or
part of the duodenum, jejunum and/or ileum. FIG. 15 provides a
flattened planar view of the duodenum 10, including the rugae 19,
or inner-folding lining portion of the duodenum that form the
periphery of the inner space within which embodiments of the insert
device are positioned. Also depicted are the pylorus 8, the pyloric
valve 11, the duodenal bulb 10A, the vertical duodenum 10B, and the
horizontal duodenum 10C, the ampulla of Vater 13, and the initial
portion of the jejunum 12. This figure provides a visual background
for many of the figures that follow, each of which depicts an
embodiment of the inventive inserted device seated within the
targeted site of the duodenum.
[0157] FIG. 16A depicts an embodiment of the insert 20 with a
central tube or member 50 in the form of a simple coil like a
telephone cord; in this embodiment the flow reduction elements 200A
may be understood as the individual coiled elements or segments of
the extended central member 50. FIG. 16B shows a detail of a
proximal or distal end portion of the device that takes the form of
a coil 61, as it would emerge from a device deployment tube 620.
Coil end portion embodiments may provide utility and advantage
during deployment, as well as a stabilizing and non-irritating
end-point when the insert is seated in the target site.
[0158] FIG. 17A depicts an embodiment of the insert 20 with a
central tube or member 50 in the form of a C-shaped spine, similar
to the embodiment depicted in FIGS. 3 and 9, with flow reduction
elements 200 in the form of ribs attached to the spine. FIG. 17B
shows the central member 50 and tips of ribs 200 emerging from a
deployment tube 620. Some embodiments of the rib-formed flow
reduction elements 200 may be spring-like and outwardly biased, the
elements reducing flow by their presence, but also, and
advantageously, stimulating the wall of the duodenum 10, thereby
contributing to the generation of a satiety signal, and further,
contributing to stabilization of the insert as it resides within
the targeted and angled site of the duodenum. In the latter regard,
the duodenal bulb portion 10A bulges out to a wider radius than the
more distal portion of the duodenum, and thus, an expansive element
in this site provides a particularly effective stabilization
site.
[0159] FIG. 18 depicts an embodiment of the insert 20 with flow
reduction elements in the form of a spine with nets. This
embodiment may be considered similar to that shown in FIGS. 17, but
with a net, filter, or mesh deployed between expandable ribs. The
expandable ribs provide benefits as described above; the netting
provides leverage in terms of reducing the flow of chyme being
processed through the duodenum 10. By use of mesh of varying pore
size in the flow reduction elements 200, the device may be provided
in variations that slow the flow rate to varying degree. Further,
the mesh elements may be formed of materials of varying properties,
such as varied hydrophilicity or hydrophobicity, which may have
effects on chyme flow rate. Further still, the mesh may provide a
site advantageous by virtue of its high surface area for the
adsorption of bioactive materials, which may then passively elute
or desorb during the period that the insert 20 resides in the
duodenum.
[0160] FIG. 19A depicts an embodiment of the insert 20 with flow
reduction elements 200 in the form of closed mesh baskets along a
central member 50 and contiguous with it, and further showing coil
proximal and distal ends 61. FIG. 19B shows the device emerging
from a deployment tube 620, and expanding on emergence. Embodiments
of the mesh baskets are flexible and expandable; the mesh may be of
varying dimension and composition. Typically, the basket portions
themselves do not form angles, but the interconnecting central
portion 50 may form and resiliently hold predetermined angles. The
composition of the baskets and the central portion may be identical
and continuous, or the compositions may vary from each other. The
interconnecting central portion 50, in particular, may further have
shape-memory features, as provided either by shape memory alloys or
shape memory polymers. The polymeric materials comprising the
baskets 200 and/or the central member 50, whether resiliently
shape-holding, or shape-memory capable, may further be
biodegradable. An embodiment of a device similar to that depicted
in FIG. 19A, particularly with regard to the mesh or braid
comprising embodiments of flow reduction elements, are described
further below, and depicted in FIG. 44.
[0161] FIG. 20 depicts an embodiment of the insert 20 with flow
reduction elements 200 in the form of centrally-mounted
outwardly-extending baffles, and further showing coil proximal and
distal ends 61. The baffles are mounted at spatial intervals on a
central member 50 that may include angled portions that are
maintained by resiliently-shaped or memory-shaped materials, as
described in the context of the embodiment shown in FIG. 20.
[0162] FIG. 21 depicts an embodiment of the insert 20 with flow
reduction elements 200 in the form of foam-like bodies, and further
showing coil proximal and distal ends 61. This embodiment, in broad
aspect, is similar to the embodiment shown in FIG. 6. Foam-like
flow reduction elements 200 are compressible and expandable, and
are thereby amenable to deployment into a target zone through
narrow tubes or scopes. The foam-like materials may be of a
closed-cell form or an open-cell form, or they may be hydrogels.
Such foam-like materials serve the flow reduction function well
because they are bulky, compliant, and tend to be space-filling.
They also provide a high amount of surface area, which is
advantageous for adsorption of bioactive agents, as provided by
embodiments of the invention, which may then be passively desorbed
during the residency period within the duodenum. Such foam or
sponge-like materials may also be wholly or partially
biodegradable. The biodegradability generally serves the purpose of
providing for a limited residency time, as well as being a way in
which to disperse bioactive agents incorporated or adsorbed onto
the material.
[0163] FIG. 22 depicts an embodiment of the insert 20 with flow
reduction elements 200 in the form of a centrally-mounted fans or
blades, mounted at spatial intervals on a central member 50, and
further showing coil proximal and distal ends 61. Such fan blades
200 may be rotatable, with variable degrees of resistance to
rotation, including minimal resistance. To the extent that such
flow reduction embodiments 200 do rotate in accordance with the
flow of processing chyme, such movement may be beneficial in that
mixing of chyme may be a useful process as an adjunct to reducing
flow rate.
[0164] FIG. 23 depicts an embodiment of the insert 20 with
bioactive material in reservoirs or depots, or layered, or
adsorbed, or incorporated on the central- or elongated member 50,
from which the bioactive agent may passively elute into the
duodenum 10. This embodiment emphasizes the bioactive material or
agent delivery aspect of the devise, and it is shown without any
particularly formed flow reduction element other than its own
physical dimension, however, it should be understood that a drug
eluting central member 50 such as this may be combined with any of
the various flow reduction elements 200 depicted in other
figures.
[0165] FIG. 24 depicts an embodiment of the insert 20 with a
bioactive material-loaded osmotic pump 71, as supported by central
or elongate member 50. Osmotic pumps are well known in the art, as
provided, for example, by Alza Corporation (Cupertino, Calif.). The
actuation of an osmotic pump may occur in various ways; for
example, water driven by a chemical potential crosses an osmotic
membrane and enters a salt chamber. The increased volume in the
salt chamber forces an expansion membrane to deflect into a drug
reservoir. As the expansion membrane pushes into the reservoir, the
drug is dispensed via one or more outlet ports.
[0166] FIG. 25 depicts an embodiment of the insert 20 with a
bioactive material loaded reservoir 73 coupled to an electrically
driven pump 72, energy storage and dispensing unit 75, all such
components being supported by central or elongate member 50, as
well as external control 77. As in FIGS. 23 and 24, the presently
depicted embodiment emphasizes the delivery of a bioactive agent or
material to the targeted duodenal site. Any of these embodiments
could include more than one drug. The difference between this
bioactive agent dispensing embodiment and those of FIGS. 23 and 24
is that they are relatively passive, running on a predetermined
time course as determined by the particulars of bioactive agent
release mechanism. In the embodiment depicted in FIG. 25, however,
the release of the bioactive material is under active control of a
pump, and the pump may be further under the control of an external
control that communicates to the pump either by an implanted wire,
or, as depicted here, by wireless communication, as for example by
radiofrequency transmission. A device may include more than one
such unit, or a single unit may include more than one reservoir and
pump, thus more than one bioactive agent may be delivered
independently from a single device 20.
[0167] FIG. 26 depicts an embodiment of the inventive insert 20
with electrodes 78 for local neurostimulation, an energy storage
and delivery unit 75, such as a battery or capacitor, and an
external controller 77, all such components being supported either
directly or indirectly by the central or elongate member 50. This
embodiment is illustrated in such a way so as to focus on neuronal
stimulation, but as explained above in reference to drug-eluting
devices, the neural stimulatory features of the device may be
combined with any of the various flow reduction elements 200. In
the present embodiment, the electrodes may be advantageously
positioned at sites where nerves are known to reside. Electrodes
may target more than one nerve to stimulate, or may target a nerve
at more than one point.
[0168] FIGS. 27A and 27B depict an embodiment of the central member
50 of an insert 20 that includes biodegradable elements and shape
memory elements. FIG. 27A shows the central member in an intact
configuration with angles .alpha. and .beta. apparent; FIG. 27B
shows the central member after biodegradation has begun. At a later
point, the central member will deteriorate further, lose its
integrity and conformation, and the angles .alpha. and .beta. will
disappear as the defining arms of the C-shape device disappear. As
such, this represents an embodiments of device that is configured
first to sit within a targeted site in the intestine, and then
following residency and a period of biodegradation, the device is
configured to become unseated from the target site, such unseating
due to the loss of the initial conforming correspondence to the
target site. In the exemplary embodiment depicted here, an insert
device 20 is formed from a combination of curved shape-memory alloy
portions 22 and relatively straight biodegradable polymer portions.
The metal portions 22 and polymer portions 24 are joined together
segmentally to create an insert of full dimension and with a
complete an angle or curve as desired, such as angles of radius
.alpha. and radius .beta. depicted in FIG. 9. The metal portions
have expanded portions at either end to provide a more substantial
joining surface, and to protect the host subject from injury or
irritation from sharps, as the metal elements are loosed upon
biological degradation of the member 20 as a whole. Metal and
polymer portions may be joined together in other ways to complete
an angled device, as would be familiar to those skilled in the
art.
[0169] FIGS. 28A and 28B depict an embodiment of the central member
50 of an insert that includes a biodegradable polymeric material;
biodegradable polymers have been described extensively, above. FIG.
28A shows the central member in an intact configuration; FIG. 28B
shows the central member after biodegradation has begun. At a later
point, the central member 50 will further disintegrate, and angles
of radius a and radius .beta. will no longer hold their form. In
some embodiments, the polymeric material may be capable of
resiliently holding an angle, such as angles of radius a and radius
.beta. depicted in FIG. 9, and in other embodiments, the polymer
may be of a type capable of holding a shape memory, as described
above.
Conformationally-Stabilized Devices in a Residence Site: General
Considerations
[0170] Embodiments of the invention include devices or intestinal
inserts with an elongated member with a proximal end and a distal
end and an angled or curved portion between the proximal end and
the distal end. The curved portion typically corresponds to a
curved aspect of a residence site in a lumen of the body, for
example, a portion of the gastrointestinal tract, and more
particularly, the duodenum. The device is stabilized against distal
or proximal movement relative to the residence site by a
conformation that corresponds to the residence site, and more
particularly, such conformation does not correspond to a site
immediately distal and/or proximal to the residence site. Depending
on the particulars of device design and location of a residence
site, the device conformation may stabilize the device against
proximal device movement, distal device movement, rotational device
movement or a combination of any of these movements. Typically in
luminal sites within the gastrointestinal tract there is a greater
accumulation of forces that tend to move a device situated therein
in a distal direction than in a proximal direction, as the general
flow of contents, and the direction of peristalsis are both
distally-directed. Accordingly, it is of particular importance that
the device be stabilized against a distal-ward drift. Additionally,
devices described herein are also suited to resisting proximal
directed forces such as regurgitation. Accordingly, some
embodiments of devices described herein are configured to resist
gastrointestinal forces that may dislodge the device from a
residence site whether the forces are proximally directed or
distally directed.
[0171] Some embodiments of conformationally-stabilized devices, as
described herein, do not rely on a hard or specific attachment or
tethering anchor to stabilize at a target residence site, nor do
they rely on an anchoring mechanism that resists downward drift by
being blocked at a site of radial dimension limitation, such as the
pylorus. Instead, embodiments of the device stabilize at a
residence site by virtue of the conformation of the device in part
or as a whole fitting into the residence site. Moreover, the device
has sufficient structural integrity that it resists being moved
relative to the residence site because an immediately distal and/or
proximal location does not conformationally accommodate the
device.
[0172] The conformation of a device that provides its stability in
a residence site refers to the physical totality of the device,
including the dimensions in units of measure such as length, width,
and volume, as well as shape, which relates to the distribution of
the dimensions in space. While not desiring to be bound by theory,
it is believed that a device self-stabilizes at a residence site
because that position within the residence site represents the
state of least free energy in a system that includes the device and
the residence site. In other aspects, ends proximal and distal to
the corresponding curved portion are in proximity to one another
for further stability.
[0173] Aspects of the device that are adapted to provide
conformational stabilization at a target site in a lumen of the
body include physical dimensions of length and width, as well as
angles or curvature assumed by the lumen. Conformationally
stabilized (or conformationally-stabilizable devices) may vary with
respect to the degree to which their physical aspects of size and
shape correspond to the size and shape of the intraluminal
residence site to which they are targeted; their characteristic
feature is that it is their conformation that stabilizes them
against movement from the target site, once situated therein. More
particularly, it is typical that such stabilization involves at
least one curved or angled portion of the device that is
accommodated by a corresponding at least one curved angled portion
of the residence site, and the angled portion of the device
characteristically provides a curvilinear retaining force within
that site.
[0174] Some conformationally stabilizable embodiments may further
stabilize in a residence site by providing radially outward force
that meets the surrounding wall of the lumen. Conformationally
stabilizing devices further may vary with regard to their stiffness
or compliance in response to forces exerted upon them by the
luminal residence site. A device with a high degree of stiffness
bends or changes its own shape relatively little in response to
forces exerted by the residence site, while a highly compliant
device offers little resistance and complies with forces exerted on
it by bending or changing shape. A conformationally stabilized
device thus must have a sufficient degree of stiffness and overall
structural integrity in order for its conformation to maintain its
stability.
[0175] Some embodiments of a conformationally stabilizing device
have a high degree of size and angular correspondence to their
target site, in which case the residence site substantially retains
its native configuration when occupied by the device. In some of
these embodiments with a high degree of correspondence to the
target site, the angles and the placement of angles along the
length of a device substantially match the shape and linear
dimensions of the residence site. In other embodiments, the device,
in spite of having a conformation that as a whole stabilizes it at
a residence site, the device, or more specifically, the preferred
or unconstrained conformation of the device may nevertheless vary
in terms of size and shape with respect to the target site. In some
embodiments, a device with a preferred configuration that varies
with respect to the residence site does not substantially change
the shape of the residence site, as the device may be more
compliant than the residence site. In some embodiments of devices
that vary in conformation from that of the residence site, the
device, if provided with sufficient stiffness and conformational
integrity, may impart a change of shape to the luminal residence
site. Typically, the configuration of devices that changes the
shape of residence site is a feature that contributes to the
stability of the device in that target site.
[0176] Some embodiments of the conformationally-stabilizing device
are configured such that the conformation of the structure as a
whole, including substantially the totality of physical features,
is substantially directed toward providing conformational
stability. With other embodiments, however, some aspects of the
conformation of various physical features may not be directed
specifically toward providing conformational stability, but rather
may be directed toward another functional or therapeutic end, such
as reducing the flow of chyme (as detailed in U.S. patent
applications Ser. No. 11/300,283 and 11/807,107), or toward other
therapeutic purposes or modalities, as described further herein
below. In other embodiments, physical features may not be designed
singularly to support conformational stability, but, rather such
features may be designed such that they serve one or more
functional purposes. A physical feature may, for example,
contribute both to providing conformational stability and toward
another functional or therapeutic purpose. In any of these
aforementioned embodiments that include physical features that are
not specifically-focused or singularly-focused on contributing to
the stability of the device within the residence site, these
embodiments nevertheless have a sufficient total level or amount of
conformational features that are directed toward supporting
conformational stability that the device is capable of stabilizing
in a residence site by virtue of such totality of conformation,
particularly in gastrointestinal luminal sites that include one or
more curvilinear or angled aspects.
[0177] Some embodiments are targeted to the duodenum and described
in detail, but other embodiments are targeted to residence sites
elsewhere in the gastrointestinal tract. Further, as mentioned
above, some devices are configured to align with a high degree of
correspondence with their designated residence site, while other
vary in correspondence, and by such variance may alter the shape of
the residence site. Further, some devices, though stabilized
substantially by the conformation of the device which precludes
movement that displaces it from the residence site, may further
derive site-stabilizing benefit from a balance of materials-based
and construction-based features such as structural integrity,
elasticity, stiffness, and ability to counter lumen-generated
radially-inward force with a radially-outward counterforce.
[0178] Conformation refers to the physical totality of the device,
including the dimensions in units of measure such as length, width,
and volume, as well as shape, which relates to the distribution of
the dimensions in space. While the claims to this invention are not
bound by theory, to understand the invention it can theorized that
a device self-stabilizes at a duodenal residence site because its
residence there represents the state of least free energy in a
system that includes the device within the gastrointestinal
tract.
[0179] Some embodiments of the duodenal device are configured to
reside within gastrointestinal tract residence sites completely
within the duodenum. The duodenum is anatomically situated distal
to the pylorus and stomach and proximal to the jejunum, as
illustrated in FIG. 14. Some other embodiments, however, may
include portions that extend proximally in a minimal manner, into
the pylorus, and some may extend further proximally into the antrum
of the stomach. Some embodiments may extend further distally, past
the site of the ligament of Treitz, and into the jejunum. However,
even these embodiments that include portions extending proximally
or distally from the duodenum still rely on conformational
stabilization within the duodenum to preclude dislodgment from the
residence site and consequent movement of the device as a whole. As
a result, such embodiments do not rely, for example, on being
constrained from distal or downstream movement by the radial
constraint of the pylorus.
[0180] The duodenal residence site of embodiments of the device
includes at least one angled portion, and the device, accordingly
has at least one angled portion that corresponds to that angled
portion within the residence site. Other embodiments of the device
may include two, three, four, or more angled portions between the
proximal and distal end of the device, these angles corresponding
to angles in a residence site. The duodenal residence site can also
be understood as a continuous curvilinear form, and accordingly,
some embodiments of the device are configured as a curvilinear
foini, without particular angled regions.
[0181] FIG. 29 illustrates an embodiment of a conformationally
stabilized insert 2900 with at least two angled portions. The
insert 2900 may be described as a central segment 2905 with two
peripheral segments, a distal segment 2910 and a proximal segment
2920. As described in U.S. patent application Ser. No. 11/807,107,
the two angles defined by the junction between the central segment
2905 and the two peripheral segments 2910, 2920 may be understood
as angle alpha and an angle beta, respectively. Additionally, a
third angle delta may be used to describe the relationship and
orientation of the components of an insert. A central segment of
the device is disposed between the two angled portions, wherein
each angled portion joins the central segment with a first
peripheral segment and with a second peripheral segment. The axes
of the central segment and the first segment define a first plane
and the axes of the central segment and the second segment define a
second plane. The lines representing the intersection of each of
these two planes on a third plane perpendicular to the axis of the
central segment form an angle delta.
[0182] As best seen in the perspective view of FIG. 29 the angle
delta is formed by the projection of the proximal segment 2920 and
distal segment 2910 onto a plane 2930 substantially perpendicular
to the central segment 2905. The angle delta is also shown in the
top down view of FIG. 30. The angle delta ranges between 0.degree.
and 90.degree. in some embodiments. The angle delta range and
selected value will vary depending upon the specific anatomy of the
targeted residence site or the desired modification of a targeted
residence site.
[0183] This general description of angle delta as it applies to a
device with two angled portions and a central segment situated
between two peripheral segments may be generalized to describe a
device with more than two angles, indeed any multiple number of
angles, and with a segment between each angle. In these
embodiments, it can be understood that an angle delta is associated
with each individual segment (with the exception of the most
peripheral and most distal segments). Thus, each segment is
associated with an angle delta that describes the relationship
between the two planes defined by the segment and each peripheral
segment. The shape of the device may be described based in part on
the totality of the angles describing the relationship between
adjoining segments along the main axis of the device, and the delta
angles associated with the segments.
[0184] The totality of the conformation of the device depends not
only on the angles, but also on the dimensions of each segment in
absolute terms, such as, for example, in units of length, width,
and volume. Additional aspects of the total device conformation are
described in the embodiments that follow.
Conformationally-Stabilizing Device Examples
[0185] Some embodiments of the conformationally stabilized device
are structurally based on a central spine that may vary in form,
and provide a support base for other structural elements. Such
elements may have specific functions, such elements that reduce the
rate of chyme flow and increase the residency time or transit time
through the duodenum, while other elements attached to the spine
may contribute to the overall ability of the device to correspond
with the residence site, and contribute to the conformational
stability of the device. Attached elements in some embodiments may
serve still other functions, such as stimulating neural receptors,
such as mechano-receptors within the luminal wall, that are
responsive to movement, stretch, or pressure. Other embodied
features may serve an atraumatic function. FIGS. 16A and 16B, 19A
and 19B, 20, 21, and 22 for example, show coils on the ends of
devices, such coils preventing trauma to the luminal wall that
could occur from contact with device ends that have stiffer,
sharper, or otherwise less forgiving device ends. For purposes of
illustration, in some of the figures that follow, the spine is used
as a representative embodiment and may be depicted in a size
smaller that which would typically be suitable for the targeted
residence site so as not to distract the anatomical detail of the
targeted residence site.
[0186] FIG. 31 illustrates a device where a structural feature
projecting from a central spine contributes to conformationally
stabilizing a device. FIG. 31 includes a cross section view of the
duodenum 10 with an insert 20 conformationally stabilized therein.
Insert 20 includes structural features 201 distributed at positions
along the spine 20 that are shaped to conform to a portion of the
duodenal residence site. Structural features may be of any suitable
shape and size to conform to the desired location. For example,
structural features may be spherical, elliptical, ovoid, circular,
rectangular, polygonal, curvilinear or any other compound or simple
shape that corresponds to the targeted residence site for that
structural feature. As shown in FIG. 31, the structural features
201 have a generally elliptical shape that is bulged or warped to
conform to the residence site. It can be further understood that
structural features such as these advantageously distribute force
that the device is exerting on the wall of the duodenum at contact
or pressure points over a wider surface area, reducing the force
impinging per unit area at such points, and thereby providing such
pressure points a level of protection. These structural features
may contribute to flow reduction, but that is not their designated
function, which is, instead, to contribute to the stability of the
device, and to distribute pressure the device may bring to bear on
the gastrointestinal wall over a broad surface area. The same
principle of force distribution is seen later in the form of spoon-
or paddle-shaped atraumatic ends, as seen in FIGS. 50A-51.
[0187] The spine of a spine-based device, in some embodiments may
be configured for a radially-central position within the duodenum
as shown and described in FIGS. 19, 20, 21, and 22. In other
embodiments, the spine is configured for a radially off center
position in the duodenum as shown and described in FIGS. 17 and
18.
[0188] In some other embodiments the spine is segmented into
substantially straight segments, as shown and described in FIGS.
17, 18, and 21. Some embodiments include a spine with three
segments such as, for example, the embodiment illustrated in FIGS.
4, 9, and 28. Still other embodiments include a spine with more
than three segments such as, for example, FIGS. 3, 26, 27, and 32A
Still other embodiments include a segment or segments that assume a
more curvilinear form such as, for example, the devices shown in
FIGS. 16A, 20, and 22-25, 44, 46A, 46B, 47, 48, and 51.
[0189] In still other embodiments, the spine may assume an overall
curvilinear form, without discrete segments, as depicted in FIGS.
23, 24, and 25 of U.S. patent application Ser. No. 11/807,107 and
in FIGS. 33, 34, 35, and 36. The curvilinear shape can be described
by a Cartesian coordinate system or a curvilinear coordinate
system. The curvilinear coordinate system is used for a Euclidean
space that is based on a transformation of the standard Cartesian
coordinate system. As the spine may be described as spherical in
shape, a polar coordinate system can specifically be used.
[0190] In some embodiments, the spine may assume a convoluted form
and the convolutions are used to provide conformational stability,
in addition to other functions they may have, such as slowing the
flow of chyme. Convolutions in an insert are illustrated and
described in FIGS. 16A and 17A.
[0191] Some embodied configurations may advantageously include
extensions or portions of the device that extend beyond the
duodenum, as into the pylorus, or as in further to the antrum of
the stomach, or, alternatively, extending distally beyond the
duodenum, and into the jejunum. An example of an embodiment that
extends beyond the duodenum is provided by FIG. 36, where the
proximal portion 20P of the conformationally stabilized device
projects through the pylorus and into the antrum of the stomach;
and the distal portion 20D extends into the duodenal-jejunal
flexure. While this configuration may provide advantageous leverage
in embodiments configured to change the shape of the duodenum,
these embodiments may also be configured to allow the duodenum to
substantially retain its native shape, in which case the portions
that extend beyond the duodenum may provide for an increased
curvilinear retaining force in general. With regard to a larger
view of the gastrointestinal tract, it can be understood that the
proximal and distal ends of the device are in close apposition
because the anatomical points where they reside (the gastric antrum
and the duodenojejunal junction or, externally, the ligament of
Treitz) actually are in such close apposition. This particular
embodiment (FIG. 36) does not have flow reduction elements, but is
otherwise similar in length and placement to the embodiment
depicted in FIG. 44, and as shown in a residence site in FIG.
47.
Conformationally-Stabilized Devices That Alter Residence Site
Shape
[0192] In some embodiments, a device of the present invention
corresponds to a residence site in a target location, particularly
with regard to an angled site, and the segments or lengths of the
device on either side of the angle within the residence site.
However, the device may vary in terms of the exactness of the
matching of the respective angles of the device to those angles of
a residence site at a target location within the body, and it may
further or alternatively vary in segment lengths or curvilinear
portions between angles. In some embodiments, the device has a
resilient bias in an angled portion that is angularly larger than
the angled portion of a residence site. In still other embodiments,
the angled portion of the device may have a resilient bias that is
inward, or angularly smaller than the angled portion of a residence
site. Still other embodiments may have a resilient bias that is
nearly congruent with the native residence site configuration.
[0193] Additionally or alternatively, in devices with angles that
correspond to one or more angles in a residence site, some device
angles may be more obtuse and some angles may be more acute than
the angle to which they correspond. In any of these embodiments
where the angles of the device vary with respect to the native
angles of the residence or target site, the device may effect a
change on the shape of the residence site occupied by the device.
Typically, the net effect with regard to the conformational
stability of the device is to enhance the stability. However, in
some embodiments where the shape of the residence site is changed,
the effect of the change is to serve a therapeutic purpose, as
elaborated on in a following section, in an organ or system
associated with the residence site. While the foregoing examples
have used the variation of angled portions of a device, the
invention is not so limited. On other embodiments, portions of the
device other than or in addition to an angled portion may be
modified to produce a shape altering result of a portion of a
residence site. It is to be appreciated that shape changing
conformational inserts may also pinch, clamp or crimp a portion of
a residence site.
Conformationally-Stabilized Devices That Alter the Shape of the
Duodenum
[0194] In some embodiments, device corresponds to the intestinal
target location, particularly with regard to an angled site, and
the segments or lengths of the device on either side of the angle
within the residence site, but may vary in terms of the exactness
of the matching of the respective angles of the device to that of
the target site. For example, some embodiments have a resilient
bias that is outward, or angularly more expansive than the native
intestinal site configuration as illustrated in FIG. 37. Other
embodiments may cause localized distention of the duodenum as
illustrated in FIG. 38. Other embodiments may have a resilient bias
that is inward, or angularly more acute than the native intestinal
configuration. Still other embodiments may have a resilient bias
that is nearly congruent with the native intestinal site
configuration. And in devices with angles that correspond to one or
more angles in a duodenal residence site, some device angles may be
more obtuse and some angles may be more acute than the angle to
which they correspond. In another aspect, changes in the shape of
devices as affected by changes in angles can also be understood, in
some cases, as varying the lengths of segments or varying the
lengths of particular curvilinear portions. The length of the
central segment or portion of the device shown in FIG. 38 is
lengthened in comparison to the analogous portion of the device
shown in FIG. 37, and such lengthening changes the shape of the
duodenum in which the respective devices reside.
[0195] In any of these embodiments where the angles or segments (or
portions of a curvilinear section) of the device vary with respect
to the native angles or segment linear dimensions of the duodenal
target site, the device may effect a change on the shape of the
duodenum occupied by the device. In typical embodiments that change
the shape of the duodenum, the net effect with regard to the
conformational stability of the device is to enhance the stability.
In some embodiments where the shape of the duodenum is changed by
the intraluminal presence of a device, the effect of the change is
to serve a therapeutic purpose, such as, merely by way of example,
altering the flow rate of chyme through the duodenum. In other
embodiments, changing the shape of the duodenum my benefit the
duodenal wall by either the compression or the distension of local
regions of the wall that may be associated with an overall shape
change. In one example, the device may provide localized distention
sufficient to trigger a response from the duodenum, such as
activation of stretch receptors and the associated triggering
response.
[0196] In still another example, an extension, distension, or mild
stretching of a luminal wall may benefit the vascularity of a
particular region, or generally serve to protect or promote the
healing of a region that has been injured or compromised. In
another example, altering the shape of the small intestine may
facilitate the emptying of the afferent loop in a patient with
afferent loop syndrome. In another example, a conformationally
stabilizable stent could facilitate the anastamosis process for the
roux limb in a Roux-en-Y gastric bypass procedure.
[0197] Other embodiments of the invention produce a duodenal
shape-change by pinching, clamping, or otherwise applying device
end-to-end appositionally-directed force on a residence site or
portion of a residence site in the duodenum. In addition to such
changes being directed toward a therapeutic end, as mentioned
above, duodenal shape-changing embodiments of the device also may
advantageously contribute to the conformational stability of the
device in the target site. In one shape-altering embodiment of the
conformationally-stabilizing inventive device described by FIG. 35,
the proximal segment of the spine is configured to reside in the
superior duodenum, while the distal segment resides near the
duodenojejunal flexure. The spine has sufficient force, more so
than the shape-corresponding designs already described, such that
the duodenum is altered in shape. This particular embodiment does
not have flow reduction elements, but is otherwise similar in
length and placement to the embodiment depicted in FIG. 44, and as
shown in a residence site in FIG. 47.
[0198] Another such duodenal shape-changing embodiment includes a
clamping duodenal insert. If the duodenum is depicted simply as a
C-shaped organ, the effect produced by a clamping duodenal insert
is the general movement of the duodenum into a partially closed
C-shape dictated by the shape of the insert as illustrated in FIG.
39. Magnets may be used to maintain the position of the clamped
insert. As shown in FIG. 35, magnets M1 and M2 are positioned in
the ends of the device. The magnetic field between M1 and M2, or
between a magnet and magnetic material may be adjusted to produce
the desired degree of alteration in the duodenal shape. Adjustment
of the magnetic field can be used to vary the distance between the
ends of the device and shape altering characteristics of the
device. Depending upon the anatomical features in a residence site,
the device ends or other magnet locations remain in proximity but
are not in contact as a result of the strength of the magnetic
field. In some cases, it may be desirable to have the magnets pull
together completely so that only the tissue of the residence site
separates the magnets as shown in FIG. 35. Optionally, the magnets
may not be needed, and the device alone may be used to alter
duodenal shape as shown, for example, in FIG. 39.
[0199] Clamping may also be localized such as where the duodenal
angle produced by an angled portion of an insert grasps or secures
the duodenum within the clamping angle. Pinching refers to the
effect caused on a residence site by when the ends of a partially
closed C-shaped insert are moved towards each other. The result
exerts an overall pinching effect on the duodenal C-shape and
results in a portion of the duodenum or the residence site
positioned between the ends of the insert. In some embodiments, a
pinching insert moves the ends of the general C-shape toward a
nearly O-shaped configuration. Pinching embodiments include: ends
of insert come towards one another; ends of insert contact through
a portion of the residence site; ends of the insert draw a wall of
the stomach into contact with a wall of the duodenum; one end in
stomach and the other end in the third or fourth portion of the
duodenum; one end in the duodenal bulb and the other in the third
or fourth portion of the duodenum. In some embodiments, the ends or
portions of the insert could be joined magnetically through the
walls of the residence site to other portions or the end of the
insert. In one embodiment, the ends of the insert are on opposite
sides of the stomach/duodenal wall.
[0200] Some of these embodiments may advantageously include
extensions or portions of the device that extend either proximally
from the duodenum, as into the pylorus, or as in further to the
antrum of the stomach, or, alternatively, extending distally beyond
the duodenum, and into the jejunum. An example of an embodiment
that extends beyond the duodenum is provided by FIG. 36, where the
proximal portion of the conformationally stabilized device projects
through the pylorus and into the antrum of the stomach, and the
distal portion extends into the duodenal-jejunal flexure. An
advantage that may be associated with the inclusion of device
portions that extend beyond the duodenum (in either the distal or
proximal direction) is that such portions may create an overall
shape that allows for an increased curvilinear retaining force in
general, and greater leverage, if the device is configured to
change the shape of the resident site.
Conformationally-Stabilized Devices Targeted to Other
Gastrointestinal Residence Sites
[0201] Embodiments of the present invention have been shown and
described with relation to the duodenum. Conformationally
stabilized inserts of the invention are not so limited and have
application into other residence sites within the body. Moreover,
embodiments of the conformationally-stabilized intraduodenal device
as described herein may be understood as an example of devices that
are configured to conformationally stabilize at other sites in the
gastrointestinal tract. In typical embodiments, residence sites
include a portion with at least one curved aspect. In one
alternative, the curved aspect is provided by the native anatomical
curvature of the mammal anatomy. In general, the shape of a portion
of the device will conform to at least one anatomic curvature
within at least one resident site. Embodiments of the devices
described herein may be configured, designed and shaped to conform
to more than one residence site. Devices as described herein may be
used for providing therapy of any kind, not necessarily directed
toward obesity or metabolic disease.
[0202] Examples of various sites in the gastro-intestinal tract
that have a particular configuration that provides an appropriate
residence site for use with a conformationally stabilized device
include, but are not limited to: 1) the esophago-gastric junction,
2) the first to second duodenal transition, 3) the duodenal "C", as
described in this patent application in detail, 4) the
duodenojejunal flexure point, 5) the terminal ileum, 6) the right
colic hepatic and left colic splenic flexures, and 7) the sigmoid
colon.
[0203] The unique shape of an esophageal-gastric junction or
esophageal residence site is formed when the distal esophagus meets
the proximal stomach as it goes posterior to anterior in an almost
horizontal component of the cardia while transitioning through the
diaphragm. The general direction of the esophagus is vertical, but
it presents two or three slight curves in its course. At its
commencement it is placed in the median line, but it inclines to
the left side as far as the root of the neck, gradually passes to
the middle line again, and finally again deviates to the left as it
passes forward to the esophageal opening of the diaphragm. The
esophagus also presents an antero-posterior flexure, corresponding
to the curvature of the cervical and thoracic portions of the
spine. It is the narrowest part of the alimentary canal, being most
contracted at its commencement and at the point where it passes
through the diaphragm. The curvatures of the esophagus provide
residence sites for placement of a conformationally stabilized
device
[0204] FIG. 40 illustrates the placement of a conformationally
stabilized device within or in proximity to an esophageal-gastric
junction resident site, to which it conformationally corresponds.
The device 20 can be seen placed in the curved inferior portion of
the esophagus 2, the portion prior to gastrointestinal tract
opening into the stomach 4. The device is configured in a
stent-like manner, pressing radially outward against the wall of
the esophagus. The combination of curvature and the
radially-outward force prevents distal or proximal movement.
[0205] FIG. 41 shows an anterior view of a conformationally
stabilized device consisting only of an unadorned spine 50. The
device is conformationally stabilized within a resident site
located at the duodenojejunal flexure 14 region of the duodenum 10.
This unique inverted `U` shape of the duodenum and flexure is held
in place mainly by the Ligament of Treitz 850 and the dropping
jejunum 12 that distally follows the duodenum. The Ligament of
Treitz 850 is generally supported by the diaphragm 830 and the
right crura of the diaphragm 840R and the left crura of the
diaphragm 840L.
[0206] FIG. 42 shows an anterior view of conformationally
stabilized device having a spine 50. The device is conformationally
stabilized within a terminal ileum 854 resident site, penetrating
the ileal orifice 852, entering into the ascending colon 850 in the
general vicinity of the cecum 856. The unique residence site shape
here is formed by the distal ileum just before the junction of the
colon, and terminates in the ileocecal valve.
[0207] FIG. 43 shows an anterior view of a conformationally
stabilized device having an unadorned spine 50. The device is
conformationally stabilized within a sigmoid colon resident site
868, centered around the sigmoid mesocolon 860. This unique
resident site is formed by the distal colon as it approaches the
rectum, just proximal to the rectosigmoid junction 862. The
resident site is held in place primarily by the surrounding
structures, such as the sigmoid mesocolon 860. Although there are
variations in patient anatomy with respect to the shape of this
anatomical site, it is typically sigmoid in shape.
[0208] The preceding series of illustrated residence sites for
conformationally-stabilized embodiments of the device in the
gastrointestinal tract is not intended to be limiting. Other sites,
including, for example, the transition portion of the first to
second duodenum, as it courses retro-peritoneal from anterior to
posterior, and the hook-like shape it takes on as through the
peritoneum, and/or the right colic hepatic and left colic splenic
flexures, which include curved portions that typify suitable
residence sites, as described above. Additionally, residence sites
may be located in various ducts that empty into the
gastrointestinal tract. Exemplary but not limiting examples of such
ductal sites include the bile duct and the pancreatic duct.
An Intraduodenal Conformationally-Stabilized Device with a Proximal
End Terminating in the Gastric Antrum and a Distal End Terminating
Near the Duodenojejunal Junction
[0209] Some embodiments of the devices described and depicted
herein generally match, correspond, or conform to the anatomy of
the duodenum, and gain a positional stability within the duodenum
from that relationship. Positional stability of the device provides
resistance to movement relative to the gastrointestinal tract. The
device is stable against nutrient flow and peristalsis (both in the
downstream direction) and regurgitation (upstream direction). Some
embodiments (FIGS. 3, 7, and 8) additionally rely on an anchoring
mechanism, a portion adjunct to the major duodenally-residing
portion of the device which extends upstream from the duodenum,
proximally through the pylorus. The anchoring portion is of a size
and configuration that prevents its movement through the pylorus,
and thus it anchors the device as a whole. Other embodiments, in
addition to the enjoying the stability provided by generally
conforming to the duodenal residence site, derive further
positional stability from a clamping or distending of the device
within the duodenal residence site (FIGS. 32A-35, 37-39). In some
instances, this contributes to positional stability because the
shape of the device makes the device less amenable to being passed
downstream. In some these instances (FIGS. 38 and 39, in
particular), the device may alter the shape of the duodenum, thus
making the device less likely to being passed downstream in that
way as well.
[0210] The device embodiments illustrated in FIGS. 36 and 44-51 not
only conform to the duodenal residence site, but engage the
gastrointestinal tract in a manner that particularly contributes to
positional stability in the duodenally-centered residence site.
Embodiments of devices described in this section may generally be
characterized as having a proximal end that terminates in the
gastric antrum, and a distal end that terminates in the region of
the duodenojejunal junction, where the Ligament of Treitz is a
landmark external to the duodenum. Embodiments in this section
(FIGS. 44-51) may also be generally characterized as having a
central curved portion that is configured to conform to a duodenal
lumen between the proximal and distal ends. The device further may
be characterized as being stabilized in its residence site
substantially by the fact that its conformation accords with the
conformation of the residence site. Embodiments of the device
typically do not have any piercing elements that attach to the
gastrointestinal wall for securing the device within the site.
Further, embodiments of the device, and particularly embodiments of
the portion of the device that resides proximal to the pylorus are
typically able to freely pass through the pylorus, such that the
device does not have an anchoring mechanism that depends on the
pylorus as a pass-through restraint.
[0211] It is to be appreciated that other earlier described devices
may be modified to include one or more aspects of conformal
stabilization. Embodiments of the devices described herein are
modified to configure a specific embodiment of a device to have the
curved central portion that at least partially conforms to a
portion of or all of a residence site along with proximal and
distal ends that, in use, are near or in proximity to one another.
Those of ordinary skill will appreciate that the devices may be
modified by lengthening or adding a curved central portion of
desired geometry, modifying or adding proximal end or distal ends
or other changes according to the specific characteristics of the
device and the targeted residence site.
[0212] Conformationally-stabilizing devices, as particularly
illustrated in FIGS. 44-51 provided herein include features that
are particularly configured so as to be advantageous toward an
objective of providing safety, conformational stability, and
performance to a device as it resides in the duodenum. Other
features relate to the ability of the device to have two
configurations and the ability to easily transition from one to the
other. The two basic configurations are: (1) a stowable
configuration for accommodation in the working channel of an
endoscope, or within a sheath that can be delivered endoscopically,
and (2), a deployed configuration for functioning once the device
is situated in a residence site within the gastrointestinal tract.
These features relate to numerous aspects of the device, as, for
example: the elongated member of spine of the device as a whole,
end portions and end features of the spine, a unitary construction,
a shape memory alloy composition, an end-end crossover design, the
length of the device, a thermoplastic polymeric coating, and the
composition and configuration of the braid of a flow reduction
element. These features and the particular benefits derived there
from are described in detail, below, and then followed by a
description of exemplary embodiments as shown in FIGS. 44-51.
[0213] The end portions of the spine of embodiments of the device
are generally tapered prior to a terminal expansion into bulbous
features, as described below. This tapered aspect of the spine of
the device allows for a relatively thick central portion that
provides for sufficient stiffness to hold an angle that stabilizes
the device in the duodenum. The diameter of the central curved
portion of embodiments of the device typically ranges between about
0.025 inch and 0.055 inch; the diameter of some embodiments range
between about 0.036 inch and 0.046 inch, and the diameter of
particular embodiments is about 0.042 inch. The stiffness allows
the device to have a tight central radial aspect, while the device
as a whole nevertheless has an elasticity from the material
properties of its alloy composition (described below) that allows
it to straighten out for accommodation in an endoscope. The smaller
diameter end portions that taper from the thicker central portion
are advantageously more flexible. Each of the tapered end portions
transition into a coil end, and ultimately culminate in a bulbous
feature, both as described further below. The relative flexibility
associated with the narrow diameter end portions, the coils, and
the bulbous end features all contribute, advantageously, to a safe
and atraumatic end to the device.
[0214] The end-portion tapering of embodiments of the device is
preferably accomplished by uniform radial reduction in dimension,
rather than by chamfering. The uniform radial reduction precludes
the formation of a discontinuous transition point, in specific
contrast to a chamfered tapering, which could create a point of
weakness or bending vulnerability. The smaller diameter of the
tapered ends permits a high degree of flexibility that allows the
tight-radius coil ends to straighten out for accommodation in the
working channel of an endoscope.
[0215] The shape of each of the two ends of device embodiments has
features that contribute to an atraumatic configuration that
precludes irritation or injury to the lining of the
gastrointestinal tract. Coils formed from or on the terminal end
portions of the spine or elongated body are used as atraumatic
features. Coils may refer to the shape of the distal end of the
device or to the type of wire formed added to or taken by the
elongate body. An end-point of the diameter of the tapered
end-portion of the device, even if on a coiled end, that is merely
blunted could still too sharp for atraumatic contact with a
gastrointestinal wall. An exemplary form of a soft or atraumatic
end feature is a bulbous tip, although other features that present
only smooth surfaces and oblique angles to a tissue surface may
serve the same purpose, and are included as embodiments of the
invention. Thus, the diameter of the end point of the device may be
increased from the tapered diameter of the end portions to assume a
generally bulbous, ovular, ball-shaped, or spherical form, with a
diameter in the same range as that of the central curved portion of
the device. The bulbous form also provides a stop-surface or
shoulder against which the Hytrel.RTM. coat (see further detail
below) abuts from its central portion. This center-biased
confinement advantageously serves to stabilize that Hytrel.RTM. in
place, preventing slippage of the coating from the center toward
either of the end points of the spine of the device.
[0216] Other types of atraumatic ends, alternatives to coiled ends,
are depicted in the Figures and described in greater detail below.
Briefly, however, these atraumatic end features may include
polymeric shape memory components that can assume a linear form for
deployment, but expand in a lantern-like manner upon release from
the linear constraint of an endoscope working channel. In other
embodiments, a braided mesh bumper, similar to the flow reduction
element is bonded to the ends of the device, and can assume a
linear form for deployment and assume radially-expanded form once
released from being stowed in the endoscope. In another embodiment,
the atraumatic end features are paddle- or spoon-shaped. These end
features offer the advantage of presenting a substantially flat or
shallow convex surface that distributes force over a wide area
against the wall of the gastrointestinal tract. The substantially
spoon-shaped end features, being composed of a resilient or
shape-memory material, have a rollable bias that allows them to be
compressed into a substantially linear stowable configuration that
unrolls into the spoon shape as the device is released from the
constraint of an endoscopic working channel or a holding sheath. In
some embodiments, the composition may include Nitinol or an alloy
with similar properties, or alternatively a resilient polymer, or a
combination such a metal core with as a polymer-coat. Some of these
embodiments may be mounted on a swivel mechanism, which facilitates
orientation of the flat or convex surface against the luminal
wall.
[0217] The spine of a typical embodiment of the device is formed
from a single piece of alloy, and in some embodiments, the unitary
construction can include the atraumatic bulbous ends, as described
above. Single-piece construction is advantageous over multi-piece
construction for absence of points of bonding that can fail or be
points vulnerable to bending.
[0218] The relatively proximal portion of the device residing in
the pylorus is typically a portion of the spine of the device that
does not include any flow reduction elements; and it is of a
sufficiently narrow diameter that the pylorus does not react to its
presence. Accordingly, the device is effectively invisible to the
pylorus. The invisibility of the device is further supported by the
smooth surface presented by a Hytrel.RTM. coating (see below). The
blindness of the pylorus to the spine of the device advantageously
allows normal and desirable functioning of the pylorus.
[0219] Embodiments of the device are typically encased in
thermoplastic polyester elastomer, such as Hytrel.RTM. (Du Pont
Engineering Polymers, Wilmington, Del.). The Hytrel.RTM. material
is applied to the device as a tube fitted over the spine, thus
forming a single unitary outer layer, without bonding sites that
could be vulnerable to failure. The Hytrel.RTM. tubing covers the
entirety of the Nitinol spine, even over-lapping the ends. In the
process of manufacture, the tubing, once fitted over the Nitinol
core, is heated to sufficiently melt, shrink and seal it as a skin
around the metal. Other methods of applying the Hytrel.RTM. to the
metal core (included as embodiments of a method of making the
device) include dipping the metal core into molten Hytrel, or
spraying Hytrel.RTM. on the metal through a deposition process.
This application of Hytrel.RTM. creates a sealed environment for
the Nitinol, which protects it from the corrosive environment of
the stomach. The Hytrel.RTM. covers the tapered Nitinol sections as
well, further contributing to device safety as it protects the
thinner Nitinol from being over stressed by providing a flexible
and resilient buffering layer that distributes any point-specific
strains over a broader region, similar to a strain relief.
[0220] Embodiments of the device include a shape memory alloy such
as Nitinol as a primary component of the composition, which
provides the device a flexibility that allows easy and atraumatic
accommodation in the gastrointestinal tract. The flexibility or
superelastic feature of Nitinol further supports the ability of the
device to assume the straight configuration required for placement
in the working channel of an endoscope, and to assume the curved
deployed configuration when released from the constraint of the
working channel. When the Nitinol surface has been appropriately
finished, its surface has exceptional corrosion resistance. The
Nitinol surface is substantially covered by the Hytrel.RTM.
coating, but the properties of the Nitinol surface provide a fall
back layer of corrosion resistance in the event of any compromise
of the Hytrel.RTM. coating.
[0221] Each of the two ends of embodiments of the device forms a
lever arm with respect to the center of main section, and thus with
increasing lever arm length, less force is required to displace the
end of the device with respect to the center. As there are
constraints on device diameter, the formed shape or preferred shape
of the device can be varied to accommodate a variable length of the
device. From the perspective of the effect of the device on the
gastrointestinal tract, approximately the same amount of
appositional force from the ends of the device is desirably applied
to the two ends of the resident site, regardless of the length of
the lever arm. Thus, for example, one embodiment of a device with a
relatively long length (e.g., greater than about 35 cm) is one in
which the end-end crossover dimension is relatively large (FIG.
46A), in contrast to shorter devices (e.g., less than about 25 cm),
in which the end-end crossover dimension is relatively small (FIG.
46B). The relative amount of crossover (in addition to the overall
length of device) is a feature that can be varied, either in terms
of a range of product options, or as a patient-specific custom
fitting. Thus, by way of example, a patient with a ligament of
Treitz that is located a relatively short distance from the gastric
pylorus might be provided a device with a preferred configuration
that has a relatively small amount of or even no end crossover.
Devices that vary with regard to their preferred configuration or
the amount of end-end crossover can be characterized in terms of
"separation force" or "native resiliency", as these are the metrics
that interact with tissue.
[0222] Embodiments of the device have an appropriate length that to
a considerable degree corresponds to the minimal length required to
prevent its distal migration into the colon. Such appropriate
length may range between about 32 cm and 52 cm; some embodiments
have a length that ranges between about 35 cm to 43 cm; and
particular embodiments have a length of about 39 cm. These lengths
may be considered broadly appropriate for human patients, however,
embodiments of the invention include custom fitting of devices to
individual patients, and accordingly, the appropriate length of the
device, as determined by anatomical landmarks (as described below),
can vary according the gastrointestinal anatomy of the individual
patient. This length is measured from the distal and proximal
points of the device where the tapered portion begins, prior to the
transition into coiled end features. This length corresponds to the
designated residence site of the device in the gastrointestinal
tract, a site spanning the duodenum and having the proximal
anatomical landmark at the gastric antrum and the distal landmark
of ligament of Treitz, in the region of the duodenojejunal
junction.
[0223] The reason the device stabilizes in the duodenum is that
this resident site spans two points where the anatomical position
is fixed, thereby holding the duodenum in a particular shape,
unlike the rest of the small intestine which has a general freedom
of conformational movement. These fixed points are, respectively,
in the proximal duodenum, where the duodenum goes retroperitoneal,
and in the locale of the duodenojejunal junction, just distal to
the fourth portion at the suspensory Ligament of Treitz. Once the
device is situated in the residence site, the proximal and distal
coiled ends are in substantial apposition with each other in spite
of the curvilinear intraduodenal distance that separates them. The
gastric antrum and the duodenojejunal junction, though at some
distance from each other along the length of the gastrointestinal
tract, are close together because of the overall configuration of
the gastrointestinal tract (see, for example FIGS. 36, 47, and
51).
[0224] The values for the appropriate and minimal length of the
device were a consensus result of a number pieces of data,
including standard anatomical references, published studies, a
computer tomography scan data of 12 patients that was compiled into
a three-dimensional model, fluoroscopy measurements of a single
patient with a wire placed in the Ligament of Treitz to a nearby
point in the gastric body, autopsy data of a patient unrelated to
study of the invention, resected duodenum measurements of a patient
(unrelated to study of the invention) who had undergone a
pancreaticoduodenectomy, and X-ray images of 12 patients showing a
25 cm embodiment of a device of the present invention that had been
placed in the resident site.
[0225] Some embodiments of the device include chyme flow reduction
elements that may have any of a variety of forms; see FIGS. 44-48,
and 51 (as well as earlier examples, as in FIGS. 16-23) and further
detailed description below. A considerable amount of description
will be devoted to detailing aspects of the flow reduction
elements, because these are important features for the embodiments
that include chyme flow reduction as an objective. Some embodiments
of the invention, however, may not have that as an objective. Some
embodiments, for example, may be directed to providing a platform
for the release of bioactive agents, or for providing a platform
for neuronal stimulation. In such embodiments, flow reduction
elements may not be included, and the profile of the device may be
substantially bare compared to the embodiments that include the
flow reduction elements.
[0226] Returning to description related to particular embodiments
of flow reduction elements, some flow reduction elements include
braided forms that collapse to substantial linearity around the
spine when in a stowed configuration within the working channel of
an endoscope, and open into radially expanded form, their preferred
configuration, when ejected from the working channel and deployed
at the residence site. These flow reduction elements may be formed
by braids of polymeric material, such as polyamides, or nylon, or
any suitable material. The elements may be generically referred to
as spheres, but may assume any of a variety of angled forms. The
number of braided flow reduction elements may vary according to the
length of the device and to other variables related to the
dimension and spacing of the flow reduction elements, but typical
embodiments include a number of elements that ranges between 1 and
10 elements per device, the range in some embodiments is between 2
and 8, and particular embodiments include between 3 and 7 flow
reduction elements per device. Also, however, some embodiments may
include a long single flow reduction element, or an embodiment may
have a plurality of short elements placed closely enough together
so they would functionally act a single flow reduction
elements.
[0227] The flow reduction braid surrounds the portion of the spine
where it resides; it is attached or fused to a site on the distal
portion of the device, near the beginning of the tapered end
portion. The braid is otherwise not attached to spine and can slide
freely, within limits, up and down the spine in a coaxial manner.
The limits of slidability include the overall length of the braid;
using the proximal end of the braid as a reference point, the
proximal end can extend proximally only so far as the length of the
braid permits, whereupon the braid is substantially linearized
around the spine, and there is no longer any lengthening slack from
radially-expanded segments of the braided flow reducing element.
Braid sliding is also limited in the distal direction by a stopper
feature that constitutes a fused radial stop piece located at the
approximate midpoint of the spine, within the space bounded by the
surrounding braid. The force of the downstream flow of chyme can
tend to push the braid, more particularly the expanded segments of
the braid in the downstream or distal direction. The degree to
which the flow reduction element segments are pushed distally is a
result of the sum of the downstream force of the chyme and the
countervailing stiffness of the braid. However, it does not serve
the function of the device for the braid to be pushed to a distal
extreme, and such movement could cause a jamming of the braid and
consequent blockage (rather then impedance) of chyme flow. Thus,
the function of the stopper feature is to prevent distal movement
of the braid beyond a point where the flow reduction function is
served.
[0228] The relative level of stiffness or compliability of the flow
reduction elements is affected by a number of variables. With
stiffer plastics (e.g., polyethylene terephthalate or nylon),
braided radially-expanded forms are more resistant to radial
compression, whereas with softer plastics (e.g., low density
polyethylene or low-durometer Pebax) the flow reduction elements
radially compress more easily. The resistance to compression also
relates to the resistance that the flow reduction elements provide
to the downstream flow of chyme through the duodenum.
[0229] The number of filaments used in the braid also relates to
stiffness of the braided flow reduction elements, as the use of
more filaments increases the overall stiffness of the flow
reduction element, and the resistance to compression or yielding to
chyme flowing downstream. The diameter of the filaments used also
impacts the stiffness of the flow reduction elements: thicker
individual filaments impart greater stiffness to the braided flow
reduction element.
[0230] There are a number of variables in the construction of the
braid used for the flow reduction elements that impart performance
features to the braided flow reduction element. For example,
expansion of the spheres is maximized by choosing a picks-per-inch
value that allows for maximum angular movement of one braid strand
with regard to another. By way of further explanation, a pick in
braiding parlance refers to the point where one fiber crosses
another. Thus, with increasing picks per inch, the braid becomes
denser and stronger. Further, however, as braid becomes more dense,
the radial vector of braid length increases with respect to its
axial vector, and accordingly the braid becomes less able to
radially expand because it already has a radial configuration.
Thus, picks-per-inch becomes a parameter of significance in
determining the radial expandability of the braided flow reduction
elements. Exemplary braid embodiments include a picks-per-inch
value range between 8 and 16 picks-per-inch; some particular
embodiments have about 13 picks-per-inch.
[0231] Sphere expandability is also a function of the size of the
mandrel over which the braid is formed. For example, braiding over
a mandrel of infinitely small diameter ("braiding over air")
maximizes expandability. This approach creates a braid with the
most acute angle of one strand with regard to another when in a
compressed state, thereby allowing maximum angular movement when in
an expanded state. Sphere expansion is one of the variables that
relates to the degree to which the braid effectively prevents or
allows the flow of chime through or around it.
[0232] Filament size, the number of filaments, and the relative
level of filament crossing all also collectively contribute to the
total volume of braid per unit length of braid. This total amount
of braid volume becomes a parameter of significance when the device
as a whole is configured into a collapsed or stowable configuration
as it needs to be to be accommodated in an endoscope working
channel. The collapsed cross-sectional profile can be understood to
have three major components, an inner core of the Nitinol spine, an
intermediate layer of Hytrel.RTM., and an outer layer of braid.
There is relatively little discretion in the diameter of the
Nitinol spine, as that thickness is largely determined to stiffness
considerations as described above, and there is relatively little
variability in the thickness of the Hytrel.RTM. layer, as it is
already preferably of a reasonably minimal thickness. Thus, there
may be a constraint on the thickness of the Hytrel layer as
represented by the diameter of the working channel of the current
standard for therapeutic endoscopes, which is about 3.7 mm.
[0233] The angle by which the flow reduction form rises from the
axial baseline also relates to the relative degree of stiffness or
compliance of flow reduction forms. Typical embodiments of braided
flow reduction elements are linearly symmetrical (i.e., the
distal-facing and proximal-facing angles are the same); although
this is not necessarily the case, and embodiments include flow
reduction elements that are asymmetrical in this aspect. A
relatively steep facing angle such as 45-90 degrees imparts a
resistance to radial compression, whereas a relatively shallow
angle, such as 1-45 degrees, imparts compliance to radial
compression. On the other hand, a relatively steep-facing angle is
more susceptible to inversion, or longitudinally collapse in the
face of pressure from chyme flowing downstream. And, flow reduction
elements that have a shallow facing angle are less susceptible to
longitudinal collapse when encountering downstream flow. In sum,
accounting for the consequences of facing angles being too shallow
or too steep to maintain the integrity of their shape, generally
preferred embodiments of the braided flow reduction elements of the
invention have a face angle, in their preferred or non-constrained
or non-stressed configuration that ranges between about 35 and 50
degrees, more typically ranges between about 40 degrees and 50
degrees, and in some particular embodiments is about 45
degrees.
[0234] Another variable in the overall configuration of a device
that makes use of braided spheres as flow reduction elements
relates to the spacing between the flow reduction forms. Within the
length of the device that is occupied by the plurality of flow
reduction elements, the relative amount of length occupied by the
elements and by the inter-element space can be varied. As relative
amount of inter-element space increases, so may increase the amount
of chyme being held or slowed by the device. Variation in such
holding amount may be reflected by a covarying amount of chyme
residence time, and may, accordingly, have an effect on the
biochemistry of the chyme and the neural or endocrine response of
the duodenum to its content. In other aspects, the amount of neural
stimulation that the flow reduction forms provide to the inner wall
of the duodenum may relate to the total amount of surface contact,
thus, a higher level of surface contact (either flow reduction
forms of greater length, or more forms per unit length of the
device) could provide more stimulation, and a greater source of
input that it perceived as satiety.
[0235] Another variable that relates to braid parameters such as
filament size and count relates to the degree to which the braid
effectively prevents or allows the flow through of chyme. In
general, a higher density of braid material (filament thickness,
count, and picks-per-inch) creates a higher level of resistance to
chyme flow-through, and a lower density of material permits some
degree of flow-through. These variables can be adjusted in
embodiments of the flow reduction form to achieve different levels
of desired flow-permeability. Another feature of the braid material
can relate to surface properties. Non-stick surfaces may be
relatively permissive of flow through, whereas sticky surfaces may
encourage accumulation of chyme that itself tends to clog the pores
within the braid, and create impermeability to chyme. In some
embodiments, the flow reduction elements may be purposely designed
to clog, or the braid may be overlaid with an expandable layer that
prevents chyme from flowing through the interior of the flow
reduction elements.
[0236] During deployment of embodiments of the device, a physician
can see device with the visual capability provided by an endoscope
as the device emerges from the working channel of the endoscope. In
some embodiments of the invention, portions or sites of the
Hytrel.RTM. coating can be color coded in such a way so as to be
informative as to the position on the device that such marking
occurs; this allows the physician to know exactly which portion of
the device has emerged from the working channel.
[0237] Other forms of marking may be included on the device to
facilitate placement and visualization of the device once it has
been placed in the residence site. Radiopaque markers, for example,
may be created by doping certain sections of the Hytrel.RTM. with
barium sulfate or other radio dense materials. These radiopaque
markings may be used to identify particular features of the device
with X-ray imaging, such identification and localization can be
useful in deployment, retrieval, or to visualize the placement of
the device in the gastrointestinal tract.
[0238] Some embodiments of the device include feature molded into
the Hytrel.RTM. coating of the distal end of the device that
specifically mates with the delivery system to facilitate device
delivery into the gastrointestinal tract. This feature is described
further below and shown in FIG. 44.
[0239] Other features of the spine and the flow reduction elements
relate to deployment and maintenance of configuration once
deployed. A pusher feature of the device, for example, provides a
proximal-facing and pushable shoulder edge (see FIG. 44) against
which the delivery system can push the device distal ward for
device delivery from the working channel of an endoscope. The
shoulder is adapted such it provides a proximal-facing surface that
is sufficiently flat and broad to be able to absorbing the pushing
force without allowing an override or slippage, yet configured with
sufficient smoothness that the shoulder does not provoke tissue
irritation. Such a pusher feature can be molded directly into the
Hytrel.RTM. coating.
Examples of Duodenal Conformationally-Stabilized Devices with a
Proximal End Terminating in the Gastric Antrum and a Distal End
Terminating Near the Duodenojejunal Junction
[0240] Turning now to illustrative examples (FIGS. 44-51) of
embodiments of devices and various features, as described above,
which have a proximal end terminating in the gastric antrum, a
distal end terminating in the region of the duodenojejunal
junction, and a central curved portion configured to conform to a
duodenal lumen between its proximal and distal ends. The device is
stabilized in its residence site because its conformation accords
with the conformation of the residence site. Embodiments of the
device do not have any piercing elements that attach to the
gastrointestinal wall for securing the device within the site, and
portions of the device that reside proximal to the pylorus are able
to freely pass through the pylorus, such that the device does not
include an anchoring mechanism that depends on the pylorus as a
pass-through restraint.
[0241] FIG. 44 shows an embodiment of a
conformationally-stabilizing device 20 similar in the form of its
flow reduction element including expandable braided baskets to the
device shown in FIG. 19A, and similar in its residence site
placement to the device shown in FIG. 36, with a proximal portion
20P that terminates in the gastric antrum; and the distal portion
20D that terminates near the duodenojejunal junction. The spine 50
of central curved portion forms a loop, with the proximal 20P and
distal 20D ends coming to be in near apposition with each, and in
some cases crossing each other near their termini. In FIGS. 45A and
45B, and as described above, the ends of the device have a tapered
portion 700, which starts at a transition point 701 where a radial
tapering begins. The end portions include atraumatic features such
as coil ends 61, and bulbous end termini 711. The device is
depicted into its preferred configuration, i.e., the configuration
it assumes at rest. As described above, the devise can be forced
into a linear configuration for inclusion in the working channel of
an endoscope in preparation for deployment. Once implanted in the
residence site in the gastrointestinal tract, the overall
configuration of the device approaches the preferred configuration,
but is generally slightly constrained. For example, the overall
curvature may be made slightly more obtuse, by the counterforce
exerted by the gastrointestinal tract on the device.
[0242] Also depicted in FIG. 44 is a flow reducing element 200
comprising braided filaments that form a plurality of
radially-expanded segments; the braided element is arranged in a
coaxial manner around the Nitinol body of the device. The figure
depicts five segments, but the number may vary, as described above.
The braided flow reduction element 200 is fixed to the device at
its distal end, but freely slideable on its proximal end within
limits. A proximal sliding movement limit is represented simply by
the length the braided element. The slack for sliding comes from
the trade-off between radial expansion of the expandable segments
and the absolute linear length of the braid as the expandable
segments are drawn in. The distal limit on the slideable range of
the braided element is provided by slide stopper feature 730. This
feature is fused to the Nitinol body and has a radial profile over
which the braided element 200, itself, can freely slide, but
sufficiently high that it blocks distal movement of an end ring 740
at the proximal terminus of the braided element 200. The purpose of
this stop feature 730 is to prevent an extreme distal movement or
collapse of the braided element as whole, which could defeat its
function (i.e., to reduce chyme flow, not to block it).
[0243] Also depicted in FIG. 44 is a pushable shoulder 720 on the
proximal portion of the device, the purpose of which is to provide
a surface against which a pushing element can eject the device (in
its linearized configuration) from the working channel of an
endoscope. This description of FIG. 44 in the preceding paragraphs
is also generally applicable to FIGS. 48, 51, 52 and 53, which
provides an embodiment of the device that differs only in that the
flow reduction element 200 is a single large expandable segment
rather than being segmented.
[0244] FIG. 45A provides a detail view of a proximal portion 20P of
a device, and its tapered end portion 700 (internal dotted line
with terminal arrows), which begins at a transition point 701. The
position of the transition point may vary according to the design
choices of a particular design. The transition point may be more
proximal or distal from the locations illustrated in the exemplary
embodiments. The device terminates generally with a coiled end
feature 61 and a terminal bulbous feature 711. Also visible is a
layer of Hytrel 705 which covers the entirety of the Nitinol spine
of the device. FIG. 45B is the detail view of FIG. 45A straightened
to show the detail of the diameter transition regions and the
bulbous end.
[0245] FIGS. 46A and 46B show two devices with a varying amount of
end-end crossover; these devices are schematic representations, not
drawn to scale in order to emphasize differences in end-end
crossover as a function of the length of the device. FIG. 46A
depicts a device with a relatively long separation between ends (a
32 cm device) and a relatively large end-end cross over span (3.75
inches). FIG. 46B depicts a device with a relatively short
separation between ends (a 25 cm device) and a relatively small
end-end cross over span (2 inches). As described above, it is
desirable that the end portions of the device exert approximately
the same amount of end-end appositionally-directed force,
regardless of the length of the lever arm that the distance from
the center of the device to the ends represents. Thus, the longer
device (FIG. 46A) has a greater degree of crossover, the greater
degree of crossover compensating for the greater length of the
lever arm. These end-end crossover spans were determined
empirically in a test where devices that varied only their length
were strained to create a separation force of about 0.04
pounds.
[0246] FIG. 47 shows the device 20 depicted in FIG. 44 in a
gastrointestinal residence site, with the proximal portion 20P of
the device terminating in the gastric antrum, and the distal
portion 20D terminating near the duodenojejunal junction or the
duodenojejunal flexure 14. It can be seen that the portion of
device 20 that transits through the pylorus 8 is a bare portion of
the device, without the flow reduction element 20. The dimension of
the spine 50 alone is sufficiently small that the pylorus does not
feel its presence, an advantageous feature as described above.
[0247] FIG. 48 shows an alternative embodiment of a device 20
similar to that shown in FIG. 44, with a large single flow
reduction element. Other features of the device are substantially
the same as those described above with reference to FIG. 44. This
embodiment may have therapeutic advantages for some particular
applications of the device.
[0248] FIGS. 49A-49D show alternative atraumatic end features 710
of an embodiment of a device such as that shown in FIG. 44. FIG.
49A shows an end piece 710 on a distal or proximal portion 20P, 20D
of a device that is formed from shape memory material that radially
expands in a lantern like fashion when released from linear
constraint. The terminal feature has a blunt aspect 71L FIG. 49B
shows an end view of the end piece 710 of FIG. 49A, with the
radially expanded arms expanding outward from the spine 50 of the
device. FIG. 49C shows an end piece 710 in the form of an
expandable braided sphere with a blunt distal end 711. FIG. 49D
shows an end piece in the form of an expandable braided sphere 710
with an invaginated distal sphere end and a blunted terminal
feature 711. All these variants of atraumatic end features 710 are
designed to distribute force and prevent abrasion or injury that
could arise from the end of a device engaging the surface of
gastrointestinal wall.
[0249] FIGS. 50A-50D shows spoon or paddle shaped atraumatic end
features 715 of a conformationally-stabilizing device, mounted on
an end of a spine 50 of the device. FIG. 50A shows a top view of
the spoon-shaped feature 715. FIG. 50B shows a side view. FIG. 50C
shows an end view of feature 715, depicting a curvature that
reflects a rollable bias. FIG. 50D shows an end view of the spoon
feature 715 rolled into a stowable configuration for inclusion in
an endoscope working channel or delivery sheath. This form of
atraumatic feature differs from others generally in that it has a
particularly expansive surface that is advantageous in distributing
force that may applied against a gastrointestinal wall. By virtue
of properties of a shape-memory superelastic alloy such as Nitinol,
the feature can be rolled for inclusion within the constraints of
the working channel of an endoscope or a delivery sheath, and then
automatically unroll upon being released from constraint for
deployment in a residence site. In broad form, these spoon- or
paddle shaped features 715 are very similar in form and function to
the force distribution features 210 shown in FIG. 31.
[0250] FIG. 51 shows a conformationally-stabilizing device 20 such
as that depicted in FIGS. 50A-50D except that it is depicted only
as a bare spine 50, without flow a reducing element. The device is
situated in a gastrointestinal tract residence site, with the
proximal end of the device 20P and spoon-shaped end feature 715P
pressed against the wall of the gastric antrum, and the
spoon-shaped end feature of the distal end 715D of the device
pressed against the wall near the duodenojejunal junction or the
duodenojejunal flexure 14. Apparent in this figure is the very
close proximity these two anatomical sites are, in spite of the
curvilinear distance separating them within the gastrointestinal
tract. It can also be seen that the spoon-shaped end features 715
align flatly against the gastrointestinal wall at both sites,
ensuring that the engagement between the device end and the wall
surface is without traumatic effect.
[0251] FIG. 52 shows a conformationally-stabilizing device 20 such
as that depicted in FIG. 51 except that it is depicted only as a
bare spine 50, without flow-reducing element(s). The device is
situated in a gastrointestinal tract residence site, with the
proximal end of the device 20P and spoon-shaped end feature 715P
pressed against the wall of the gastric antrum, and the basket
feature (see FIGS. 49C or 49D) of the distal end 20D of the device
715D pressed against the wall near the duodenojejunal junction or
the duodenojejunal flexure 14. Apparent in this figure is the very
close proximity these two anatomical sites are, in spite of the
curvilinear distance separating them within the gastrointestinal
tract. In one aspect, the basket on the distal end may be deformed
by the force applied by the proximal end feature into a shape
complementary to the proximal end feature. In another aspect, the
spoon-shaped end feature 715P and the basket 715D may align flatly
against the gastrointestinal wall at both sites, ensuring that the
engagement between the device end and the wall surface is without
traumatic effect.
[0252] FIG. 53 is a device configured similar to that of FIG. 47.
In the device of FIG. 53, the proximal and distal ends comprise the
mesh or braid baskets of FIGS. 49C and 49D. As before, the device
20 is in a gastrointestinal residence site, with the proximal
portion 20P of the device terminating in the gastric antrum, and
the distal portion 20D terminating near the duodenojejunal junction
or the duodenojejunal flexure 14. It can be seen that the portion
of device 20 that transits through the pylorus 8 is a bare portion
of the device, without the flow reduction element 20. The dimension
of the spine 50 alone is sufficiently small that the pylorus does
not feel its presence, an advantageous feature as described above.
One advantage of the basket structures on both proximal and distal
ends is the ability of the ends to deform into complementary shapes
in order to provide greater stability and resistance to
migration.
[0253] In some embodiments of the inventive device, one or more
flow reduction elements may be positioned on the device so that
when implanted the flow reduction element is within a specific
portion of the anatomy or within a position where the flow element
with produce a desired result. Possible locations for one or more
flow reduction elements include: (a) within the duodenal bulb; (b)
within the proximal duodenum; (c) distal to the duodenal bulb; (d)
distal to the duodenal bulb and within the vertical duodenum; (e)
within 5 cm of the pylorus; (f) one or more positions within the
duodenum selected to increase the probability of rector activation
in the duodenum (for specific location examples see Ritter article
mentioned above and specifically incorporated by reference).
[0254] Numerous alternative embodiments of the atraumatic ends are
described herein. It is to be appreciated that numerous and various
combinations of features and the orientation between them is
possible. For example, a convex surface on a proximal feature may,
in use, be directed towards a convex surface on a distal feature.
Alternatively, a convex surface on a proximal feature may, in use,
be directed towards a concave surface on a distal feature. In still
another alternative, one atraumatic feature may have a fixed shape
while the other feature may have a deformable shape (see FIG. 52).
In still other alternatives, both the proximal feature and the
distal feature may include deformable shapes (See FIG. 53). The
various atraumatic features described herein may be used in any
combination. Moreover, the general construction, size, shape and
dimension of the proximal and the distal atraumatic features may be
converted to structures that may be inflated with gas, liquid or
gel.
[0255] In one aspect of the present invention, the proximal and
distal ends of the device are in close proximity once the device is
implanted into a residence site. In one aspect, the proximal end is
within 1 cm to 7 cm the distal end. In another aspect, the proximal
end is within 1 cm to 3 cm of the distal end. In still another
aspect, the proximal end is within 1 cm to 5 cm of the distal end.
In still another aspect, the proximal and distal ends be separated
by 1 cm or less or may even urge the adjacent tissue into contact.
However, in these embodiments, the contact will urge tissue
movement and may produce contact between the stomach and the
duodenum but without providing sufficient pressure against the
involved tissue to form a pressure necrosis or cause erosion or
damage to the involved tissue.
Terms and Conventions
[0256] Unless defined otherwise, all technical terms used herein
have the same meanings as commonly understood by one of ordinary
skill in the art of gastrointestinal interventional technologies.
Specific methods, devices, and materials are described in this
application, but any methods and materials similar or equivalent to
those described herein can be used in the practice of the present
invention. While embodiments of the invention have been described
in some detail and by way of exemplary illustrations, such
illustration is for purposes of clarity of understanding only, and
is not intended to be limiting. Still further, it should be
understood that the invention is not limited to the embodiments
that have been set forth for purposes of exemplification, but is to
be defined only by a fair reading of claims that are appended to
the patent application, including the full range of equivalency to
which each element thereof is entitled.
* * * * *