U.S. patent application number 16/743092 was filed with the patent office on 2020-05-14 for guidewire.
This patent application is currently assigned to PneumRx, Inc.. The applicant listed for this patent is PneumRx, Inc.. Invention is credited to Scott Kaarto, Timothy Machold, Mark Mathis, Verna Rodriguez.
Application Number | 20200146688 16/743092 |
Document ID | / |
Family ID | 60182823 |
Filed Date | 2020-05-14 |
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United States Patent
Application |
20200146688 |
Kind Code |
A1 |
Machold; Timothy ; et
al. |
May 14, 2020 |
Guidewire
Abstract
Embodiments include a transition section for coupling a distal
section and a proximal section of the guidewire. The transition
section includes a main body having a first outer diameter;
proximal and distal pin extensions having second and third outer
diameters, wherein the proximal pin extension is configured to be
fixed to the proximal section of the guidewire, and the distal pin
extension is configured to be inserted into and fixed to the distal
section of the guidewire. The distal pin extension includes a bore
for receiving an inner core of the distal section of the guidewire.
The first outer diameter may be greater than the second and third
outer diameters. Also disclosed are methods of manufacturing a
guidewire with such a transition section.
Inventors: |
Machold; Timothy; (Moss
Beach, CA) ; Mathis; Mark; (Fremont, CA) ;
Rodriguez; Verna; (Santa Cruz, CA) ; Kaarto;
Scott; (Santa Clara, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PneumRx, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
PneumRx, Inc.
Santa Clara
CA
|
Family ID: |
60182823 |
Appl. No.: |
16/743092 |
Filed: |
January 15, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15719792 |
Sep 29, 2017 |
10555736 |
|
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16743092 |
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62402852 |
Sep 30, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 17/12104 20130101;
A61M 2025/09166 20130101; A61M 2210/1039 20130101; A61B 2017/1205
20130101; A61M 2025/09083 20130101; A61M 2025/09175 20130101; A61M
25/09 20130101; A61B 17/12031 20130101 |
International
Class: |
A61B 17/12 20060101
A61B017/12; A61M 25/09 20060101 A61M025/09 |
Claims
1. A transition section for coupling a distal section and a
proximal section of a guidewire, the transition section comprising:
a main body having a first outer diameter; a proximal pin extension
having a second outer diameter, wherein the proximal pin extension
extends proximally from the main body, and wherein the proximal pin
extension is configured to be fixed to the proximal section of the
guidewire; and a distal pin extension having a third outer
diameter, wherein the distal pin extension extends distally from
the main body, and wherein the distal pin extension is configured
to be inserted into and fixed to the distal section of the
guidewire, the distal pin extension comprising a bore for receiving
an inner core of the distal section of the guidewire; wherein the
first outer diameter is greater than the second and third outer
diameters.
2. The transition section of claim 1, wherein the proximal section
of the guidewire comprises a coil, and wherein the proximal pin
extension is configured to be fixed to an open end of the coil.
3. The transition section of claim 1, wherein the distal section of
the guidewire comprises a coil, and wherein the distal pin
extension is configured to be fixed to an open end of the coil.
4. The transition section of claim 1, wherein the proximal section
of the guidewire comprises a first coil and the distal section of
the guidewire comprises a second coil.
5. The transition section of claim 1, wherein the second outer
diameter and the third outer diameter are substantially same.
6. The transition section of claim 1, wherein the first outer
diameter is substantially same as an outer diameter of the distal
section of the guidewire and an outer diameter of the proximal
section of the guidewire.
7. The transition section of claim 1, wherein the proximal pin
extension and the distal pin extension extend coaxially from
opposite ends of the main body.
8. The transition section of claim 7, wherein the proximal pin
extension and the distal pin extension are cylindrical.
9. The transition section of claim 8, wherein the main body is
cylindrical.
10. The transition section of claim 1, wherein the transition
section is welded to the proximal section of the guidewire and the
distal section of the guidewire.
11. The transition section of claim 10, wherein the transition
section comprises a steel material.
12. The transition section of claim 1, wherein the transition
section is dimensioned to pass through a catheter for introduction
into an airway of a lung of a patient.
13. The transition section of claim 1, wherein the main body is
cylindrical.
14. A method of manufacturing a guidewire with a distal section and
a proximal section coupled together, the method comprising:
disposing a proximal pin extension of a transition section
according to claim 1 within a bore of the proximal section of the
guidewire, wherein the proximal pin extension extends from a main
body of the transition section according to claim 1; disposing ng a
distal pin extension of the transition section according to claim 1
within a bore of the distal section of the guidewire, wherein the
distal pin extension extends from the main body of the transition
section according to claim 1; fixing the transition section
according to claim 1 to the proximal section of the guidewire and
the distal section of the guidewire; and fixing an inner core of
the distal section of the guidewire within a bore of the distal pin
extension, wherein the inner core comprises a wire that extends
through the distal section of the guidewire.
15. The method of claim 14, further comprising fixing a ball
structure at a distal end of the guidewire.
16. The method of claim 15, wherein fixing the ball structure at
the distal end of the guidewire comprises disposing the inner core
of the distal section of the guidewire within a bore of the ball
structure.
17. The method of claim 15, wherein fixing the ball structure at
the distal end of the guidewire comprises welding the ball
structure to the distal end of the distal section of the
guidewire.
18. The method of claim 14, further comprising flattening a segment
at a distal portion of the inner core, wherein the flattened
segment is configured to assist in steering a distal tip of the
guidewire.
19. The method of claim 18, further comprising disposing one or
more markers between the transition section according to claim 1
and the flattened segment of the inner core, wherein the markers
allow for remote monitoring by an imaging system.
20. The method of claim 14, further comprising welding the
transition section according to claim 1 to a portion of the
proximal section of the guidewire and a portion of the distal
section of the guidewire.
21. The method of claim 14, further comprising forming the distal
section of the guidewire from a wound coil, wherein a distal region
of the distal section is wound at a looser pitch than a proximal
region of the distal section, so as to provide flexibility at the
distal region.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Continuation of U.S. patent
application Ser. No. 15/719,792 filed Sep. 29, 2017 (Allowed);
which claims the benefit of U.S. Provisional Application No.
62/402,852 filed Sep. 30, 2016; the full disclosures which are
incorporated herein by reference in their entirety for all
purposes.
BACKGROUND OF THE INVENTION
[0002] The invention relates to guidewires suitable for use in the
deployment of implants for lung volume reduction.
[0003] In chronic obstructive pulmonary disease, damage to tissue
in certain parts of the lungs means that normal muscular inflation
and deflation of the lungs becomes less efficient. One method to
improve this situation is lung volume reduction, in which the
diseased tissue is compressed or collapsed so that the remaining
tissue can behave more normally. In one form of lung volume
reduction, one or more elongate spring implants are deployed into
the airways in the diseased lung tissue and are allowed to
contract, gathering up the diseased tissue as they do so. Implants
and systems for such treatments are disclosed in WO 2007/106495 and
WO 2010/030993. In both cases, implants are deployed into the
airways from catheter systems. The airways of the lungs are highly
branched and tortuous, and lung tissue can be easily damaged.
Therefore guidewires are used to determine the path to the airway
to be treated, the catheter for delivery of the implant being
advanced over the guidewire, which is then removed so that the
implant can be deployed through the properly positioned
catheter.
[0004] The guidewire must be capable of being pushed out of the
catheter and into airway, and rotated so that it advances in the
desired direction, while at the same time being small enough that
the delivery catheter can fit over it to be advanced into the lung
for proper delivery of the implant. In order to reduce the
likelihood of kinking due to the combination of compression and
torsion, a composite structure has been proposed for the guidewire,
comprising an inner core extending through an outer coil sheath. In
order to allow the guidewire to be advanced through the catheter,
the proximal part of the core is relatively thicker than the distal
part, which is thinner to provide the necessary flexibility to be
directed through the airways without damaging the lung tissue. One
result of this is that applying torque at the proximal end of the
guidewire to steer the distal end in the required direction can
result in significant wind-up between the core and coil, making
accurate control of the distal end difficult.
[0005] The invention attempt to address the problem of how to
provide more accurate control of the distal end while retaining the
necessary flexibility in the system.
SUMMARY
[0006] The various aspects of the present invention relate to
improved guidewires for use in deployment of lung volume reducing
implants, such as coils. One aspect provides a guidewire,
comprising: an outer sheath having a proximal end and a distal end,
and comprising a proximal section, a transition section, and a
distal section, wherein the proximal section extends from the
proximal end of the outer sheath to the transition section, and the
distal section extends from the transition section to the distal
end of the outer sheath, and wherein the distal section defines a
bore extending from the transition section to the distal end of the
outer sheath; and an inner core having a proximal end and a distal
end, wherein the inner core extends through the bore of the distal
section of the outer sheath, wherein the inner core is fixed to the
outer sheath at the transition section, and wherein the distal end
of the inner core is fixed to the distal end of the outer sheath at
the distal end of the sheath.
[0007] By fixing the inner core to the outer sheath at the
transition section, it is not necessary for the core to extend the
whole length of the sheath and so allows different physical
properties to be provided for the proximal and distal sections of
the sheath.
[0008] In one configuration, the proximal section of the outer
sheath defines a bore extending from the proximal end of the sheath
to the transition section. In this case, the bore of the proximal
section of the outer sheath can be substantially unobstructed
between the proximal end of the sheath and the transition
section.
[0009] The proximal section of the outer sheath and the distal
section of the outer sheath can comprise coils. In this case, the
coil comprising the proximal section of the outer sheath can have
different mechanical properties to the coil comprising the distal
section of the outer sheath. For example, the proximal section can
be configured to apply torque to the transition section and distal
section, and the distal section can be configured for
flexibility.
[0010] The transition section can comprise an adapter to which the
coils comprising the proximal and distal sections of the outer
sheath are fixed. In one example, the transition section comprises
a cylindrical body having a proximal pin extension for insertion
into and fixture to an open end of the coil comprising the proximal
section of the outer sheath, and a distal pin extension for
insertion into and fixture to an open end of the coil comprising
the distal section of the outer sheath, the distal pin extension
also comprising a bore for receiving and fixing the inner core.
This configuration allows a substantially constant outer diameter
across the transition section and so helps avoid snagging.
[0011] The proximal end of the inner core can be fixed to the outer
sheath at the transition section. The distal end of the outer
sheath and the distal end of the inner core can be fixed to a ball
structure. Thus the end of the structure can have a atraumatic
shape and so avoid damage to lung tissue as it is advanced.
[0012] The inner core can comprise a wire having a flattened
portion intermediate the proximal and distal ends. The proximal and
distal ends of the wire can have substantially the same diameter.
This allows modification from a simple wire structure to provide a
core that preferentially bends in one plane, assisting in directing
the guidewire though lung airways.
[0013] The outer sheath is dimensioned to pass through a catheter
for introduction into an airway of the lung of a patient.
[0014] The guidewire can further comprise an end fitting connected
to the proximal end of the proximal section and configured to allow
a user to apply torque to the proximal section. The end fitting can
comprise a hub that is permanently or removably connected to the
proximal end of the proximal section.
[0015] Another aspect provides a system comprising a first
catheter, a guidewire as defined above, and a second catheter,
wherein the first catheter is configured for introduction into the
major airways of the lung of a patient, the guidewire is configured
to be advanced from a lumen of the first catheter and further into
a predetermined airway in the lung of the patient, and the second
catheter is configured to be advanced through the lumen of the
first catheter and over the guidewire into the predetermined airway
of the lung of the patient. The system can further comprise an
implant configured for delivery through a lumen in the second
catheter and deployment into the predetermined airway of the lung
of the patient.
[0016] Another aspect provides method of deploying a lung volume
reduction implant into a predetermined airway of a lung of a
patient, comprising advancing the first catheter and the guidewire
into a major airway of the lung; advancing the second catheter and
guidewire through the lumen of the first catheter; advancing the
guidewire from the lumen of the second catheter and directing the
distal end of the guidewire further into the predetermined airway
by rotating the proximal end of the outer sheath so as to point the
distal end of the outer sheath in the direction of the
predetermined airway; withdrawing the guidewire from the second
catheter; and advancing a lung volume reduction implant through the
lumen of the second catheter and deploying the implant into the
predetermined airway.
[0017] Another aspect provides a system comprising: a first
catheter configured for introduction into the major airways of the
lung of a patient; a second catheter configured to be advanceable
through the lumen of the first catheter and further into a
predetermined airway in the lung of the patient; and a guidewire
according to any preceding aspects and configured to be advanced
through a lumen of the second catheter and further into the
predetermined airway, wherein the second catheter is configured to
be further advancable over the guidewire and further into the
predetermined airway of the lung of the patient. The system can
further comprise an implant configured for delivery through a lumen
in the second catheter and deployment into the predetermined airway
of the lung of the patient.
[0018] Another aspect provides a method of deploying a lung volume
reduction implant into a predetermined airway of a lung of a
patient, comprising: advancing the first catheter into a major
airway of the lung; advancing the second catheter and guidewire
through the lumen of the first catheter so as to extend into a
predetermined airway of the lung; further advancing the guidewire
from the lumen of the second catheter and directing the distal end
of the guidewire further into the predetermined airway by rotating
the proximal end of the outer sheath so as to point the distal end
of the outer sheath in the direction of the predetermined airway;
further advancing the second catheter over the guidewire further
into the predetermined airway; withdrawing the guidewire from the
second catheter; and advancing a lung volume reduction implant
through the lumen of the second catheter and deploying the implant
into the predetermined airway.
[0019] Other aspects of the invention will be apparent from the
following description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIGS. 1 and 2 illustrate the human respiratory system:
[0021] FIG. 3 shows an example of a guidewire;
[0022] FIG. 4 shows further detail of the distal end of the outer
sheath;
[0023] FIG. 5 shows further detail of the transition section;
[0024] FIG. 6 shows further detail of the distal end of the
core;
[0025] FIG. 7 shows the distal sheath section, the core, and the
transition section;
[0026] FIG. 8 shows further detail of the core;
[0027] FIG. 9 shows a system for placing a lung volume reduction
implant;
[0028] FIGS. 10 and 11 show details of an implant;
[0029] FIG. 12 illustrates delivery of the implant;
[0030] FIG. 13 shows a fluoroscopic image of an implant in the
position illustrated in FIG. 12;
[0031] FIG. 14 shows a fluoroscopic image of an implant in a lung
as the delivery catheter is removed;
[0032] FIG. 15 illustrates the system after delivery of the
implant.
DETAILED DESCRIPTION OF THE INVENTION
[0033] FIGS. 1 and 2 illustrate the human respiratory system,
including the trachea 12, which directs air from the nose 8 or
mouth 9 into the primary bronchus 16. Air enters the lung 20 from
the primary bronchus 16. As is shown in FIG. 2, the primary
bronchus 16 branches into the secondary bronchus 22, tertiary
bronchus 24, bronchioles 26, terminal bronchioles 28, and finally
into the alveoli 30.
[0034] FIGS. 3-8 illustrate various aspects of the guidewire. FIG.
3 shows a schematic view of an outer sheath of a guidewire,
comprising a proximal section 40, a transition section 42, and a
distal section 44. The proximal section 40 is formed of a spun coil
which has a tight pitch and is substantially gapless. An example of
such a coil is an HHS.RTM. (Helical Hollow Strand) Tube obtainable
from Fort Wayne Metals of Fort Wayne, Ind., USA. A suitable tube
can be formed from a single layer of 304V Spring Temper stainless
steel filament(s) of approximately 0.029 cm thickness to give a
coil tube of approximately 0.17 cm OD. The proximal section 40 can
have a bore that is substantially unobstructed so as to give
substantially consistent torque transmission and bending capability
along its length. The distal section 44 is formed from a wound
coil, such as 304V Spring Temper stainless steel wire of
approximately 0.025 cm thickness. A short section 46 near the
distal end of the distal section 44 is wound at a looser pitch so
as to provide a highly flexible region as is shown in FIG. 4. The
proximal and distal sections 40, 44 are connected to each other by
means of the transition section 42. FIG. 5 shows the transition
section 42 in more detail. The transition section 42 comprises a
substantially cylindrical main body 48 having proximal and distal
extensions 50, 52 extending coaxially from opposite ends. The
extensions 50, 52 are of reduced OD compared to the OD of the main
body 48 and are sized to fit inside the respective bores of the
proximal and distal sections 40, 44. The OD of the main body 48 is
substantially the same as that of the proximal and distal sections
40, 44. The transition section can also be made from stainless
steel and connected to the proximal and distal sections by welding.
A deviation can be provided in the transition section 42 so that
the outer coil tube is naturally in a slightly bent
configuration.
[0035] A hub 54 is affixed at the proximal end of the proximal
section 40 by which a user can apply torque to the guidewire. The
hub can be permanently affixed, such as by gluing, or can be
removable. A ball 56 can be welded to the distal end of the distal
section 44 to provide an atraumatic surface. The proximal section
40 can also include a marker section 58 to assist a user in
determining the extend of insertion of the guidewire into a
delivery system.
[0036] A core is provided inside the coil forming the distal
section 44, as shown in FIGS. 6 and 7. The core is formed of a wire
60 that is connected at one end in a bore 61 in the distal
extension 52 of the transition section 42, and at the other end is
a bore in the ball 56. The wire 60 is substantially cylindrical at
its ends, but has been flattened to a thickness of about half of
the original wire diameter at a position 62 close to the proximal
end so that it will preferably bend in a direction perpendicular to
the plane of the flattened section and assist in steering the end
in use. As is shown in FIG. 8, a series of markers 64 are
positioned along the core between the transition section 42 and the
flattened section 62. The markers can be made of a material visible
in a fluoroscopic imaging system, such as Pt/Ir.
[0037] In the configuration shown in these figures, distal section
44 is approximately half as long as the proximal section. The
overall length can be of the order of 120 cm, although other
lengths and ratios can be used according to requirements.
[0038] FIGS. 9-15 illustrate systems and methods using the
guidewire described above.
[0039] The system of FIG. 9 comprises a bronchoscope including a
bronchoscope catheter 100 having a camera 102 at its distal end
connected to a video processing system 104. A delivery catheter 106
extends through the lumen of the bronchoscope catheter 100. The
distal end 108 of the delivery catheter 106 is provided with
markers 110 visible to a fluoroscopic imaging system 112. A
guidewire 114 of the type described above extends through the lumen
of the delivery catheter 106 and can be advanced out of the distal
end 108. The end of the guidewire 114 also has markers 116
(corresponding to markers 64 described above). A dilator 118 can be
provided to endure a smooth transition between the outer surface of
the guidewire 114 and the outer surface of the delivery catheters
106.
[0040] The system of FIG. 9 is intended for use with an implant of
the type shown in FIGS. 10 and 11, although other shapes may also
be used. In its normal state, the implant comprises an elongate
member 120 that adopts a complex shape 122 comprising a series of
curved sections, each curve centered on a separate axis. The
implant 120 can be made from Nitinol wire and can have atraumatic
terminals at the ends and one or more length markers (not shown).
For delivery, the implant 120 is distorted into a relatively
straight configuration 124 and constrained in a delivery cartridge
126.
[0041] In use, the bronchoscope catheter 100 of FIG. 9 is advanced
into the upper airways of a patient either to the extent of its
available length, or until its physical size prevents further
insertion without damage to the lung tissue. The delivery catheter
106, together with the guidewire 114, is advanced through the lumen
of the bronchoscope catheter and into the airway. The guidewire 114
is then further advanced along the delivery catheter 106 from the
proximal end so as to extend from the distal end 108 and project
further into the airway. The mark 58 can be positioned so as to
indicate when the distal end of the guidewire 114 is at the distal
end of the catheter 108. As the guidewire 114 is advanced further,
it can be steered by applying a torque to the hub 54, the deviation
allowing the distal end to be pointed in a required direction and
the flexible section 46 and flattened core section 62 allowing the
end to be eased into the required airway on contact with the wall
of the airway. Progress can be monitored either via the viewing
field of the bronchoscope, or by use of the remote fluoroscopic
imaging system 112 once the end has passed out of this field of
view. The deployment catheter 106 can be advanced with the
guidewire 114 until its distal end 118 is at or near the distal end
of the guidewire 114 in the airway of interest.
[0042] The proximal section 40 is not configured to extend beyond
the distal end 118 of the delivery catheter 106. Consequently, the
proximal section 40 can be configured for axial compression and
torque transmission, together with the necessary degree of
flexibility to be fed into the bronchoscope catheter 100. In the
example described above, this is achieved using the tight pitch
spun coil structure for the proximal section 40. By avoiding the
need for the core 60 to extend to the hub 54, the proximal section
40 can be more flexible than the previously proposed structure and
so provides for easier insertion into the catheter 106. The marker
58 can be positioned so as to indicate that the distal end of the
guidewire 114 is at or near the distal end 118 of the delivery
catheter 106, indicating to the user that further progress must be
monitored using one or other of the imaging systems 104, 112.
[0043] By providing an asymmetry in the guidewire construction,
such as a deviation at the transition section 42, the distal end
can be directed off axis. This, together with the flexible region
46 and the flattened portion 62 of the core 60 means that when the
distal end reaches an airway junction 128, torque can be applied at
the hub 54 to cause the distal end to move radially in the airway,
the flattened section 62 providing for preferential bending in the
plane perpendicular to the plane of the flattened section 62. The
provision of the atraumatic ball 58 and flexible end 46 mean that
the airway tissue can provide a reaction surface to allow control
of the position without damage to the tissue.
[0044] Once the delivery catheter 106 is in position, it can be
secured and the guidewire 114 withdrawn from the delivery catheter
106. The cartridge 126 carrying the implant 120 can then be
connected in its place, and the implant 120 advanced along the
delivery catheter 106 by a pusher device having a detachable
connector 130 as shown in FIG. 12. FIG. 13 shows remote imaging
system view of the implant 120 at the end of the delivery catheter
106. The implant 120 is held in place by the pusher device 130 and
the delivery catheter 106 is withdrawn, allowing the implant 120 to
return to its as-manufactured shape (FIG. 14), reducing the volume
of lung tissue in that region as it does so. Once the implant 120
is completely outside the delivery catheter 106, the connector 130
is detached (FIG. 15) and the bronchoscope and delivery catheters
100, 106 can be withdrawn from the lung.
[0045] Other variations are within the spirit of the present
invention. Thus, while the invention is susceptible to various
modifications and alternative constructions, certain illustrated
embodiments thereof are shown in the drawings and have been
described above in detail. It should be understood, however, that
there is no intention to limit the invention to the specific form
or forms disclosed, but on the contrary, the intention is to cover
all modifications, alternative constructions, and equivalents
falling within the spirit and scope of the invention, as defined in
the appended claims.
[0046] In the previous description, various embodiments of the
present invention are described. For purposes of explanation,
specific configurations and details are set forth in order to
provide a thorough understanding of the embodiments. However, it
will also be apparent to one skilled in the art that the present
invention may be practiced without the specific details.
Furthermore, well-known features may be omitted or simplified in
order not to obscure the embodiment being described.
[0047] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context. The terms "comprising,"
"having," "including," and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to,")
unless otherwise noted. The term "connected" is to be construed as
partly or wholly contained within, attached to, or joined together,
even if there is something intervening. Recitation of ranges of
values herein are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range, unless otherwise indicated herein, and each separate value
is incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate embodiments of the invention
and does not pose a limitation on the scope of the invention unless
otherwise claimed. No language in the specification should be
construed as indicating any non-claimed element as essential to the
practice of the invention.
[0048] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
[0049] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
* * * * *