U.S. patent application number 13/723541 was filed with the patent office on 2013-05-16 for percutaneously deliverable heart valve and methods associated therewith.
This patent application is currently assigned to COLIBRI HEART VALVE LLC. The applicant listed for this patent is COLIBRI HEART VALVE LLC. Invention is credited to R. David FISH, David PANIAGUA.
Application Number | 20130123914 13/723541 |
Document ID | / |
Family ID | 44542809 |
Filed Date | 2013-05-16 |
United States Patent
Application |
20130123914 |
Kind Code |
A1 |
FISH; R. David ; et
al. |
May 16, 2013 |
PERCUTANEOUSLY DELIVERABLE HEART VALVE AND METHODS ASSOCIATED
THEREWITH
Abstract
A prosthetic heart valve implantable by catheter without surgery
includes a substantially "dry" membrane or tissue material. In at
least one embodiment, the tissue is folded in a dry state to form a
tissue leaflet assembly that is then attached to a frame to form an
implantable prosthetic heart valve. Alternatively, one or more
tissue leaflets are operatively associated with a frame to form an
implantable prosthetic heart valve. The implantable prosthetic
heart valve is subsequently pre-mounted on an integrated catheter
delivery system. The catheter delivery system that includes the
implantable prosthetic heart valve is then packaged and transported
while the tissue remains dry. The implantable prosthetic heart
valve, while remaining substantially dry, can then be implanted
into the receiving patient.
Inventors: |
FISH; R. David; (Houston,
TX) ; PANIAGUA; David; (Houston, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COLIBRI HEART VALVE LLC; |
Broomfield |
CO |
US |
|
|
Assignee: |
COLIBRI HEART VALVE LLC
Broomfield
CO
|
Family ID: |
44542809 |
Appl. No.: |
13/723541 |
Filed: |
December 21, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13038361 |
Mar 1, 2011 |
8361144 |
|
|
13723541 |
|
|
|
|
61309109 |
Mar 1, 2010 |
|
|
|
Current U.S.
Class: |
623/2.11 |
Current CPC
Class: |
A61F 2/2415 20130101;
A61F 2/0095 20130101; A61F 2/2412 20130101; A61F 2/2418 20130101;
A61F 2/2427 20130101; A61F 2/2433 20130101; Y10T 156/10 20150115;
Y10T 29/49908 20150115; A61F 2220/0075 20130101 |
Class at
Publication: |
623/2.11 |
International
Class: |
A61F 2/24 20060101
A61F002/24 |
Claims
1.-38. (canceled)
39. An assembly, comprising: a prosthetic heart valve including: a
frame; and a tissue leaflet assembly attached to the frame; and a
package containing the prosthetic heart valve and a delivery
catheter, the prosthetic heart valve releasably secured to a
portion of the delivery catheter.
40. The assembly of claim 39, wherein the portion of the delivery
catheter to which the prosthetic heart valve is releasably secured
includes an expandable balloon.
41. The assembly of claim 39, wherein the portion of the delivery
catheter to which the prosthetic heart valve is releasably secured
includes a mandrel.
42. The assembly of claim 39, wherein the frame is self
expanding.
43. The assembly of claim 39, wherein tissue forming the tissue
leaflet assembly comprises treated pericardium tissue.
44. The assembly of claim 43, wherein the tissue leaflet assembly
attached to the frame is at least one of hydrated and not
substantially dry.
45. The assembly of claim 43, wherein the tissue leaflet assembly
attached to the frame is substantially dry.
46. The assembly of claim 45, wherein the treated pericardium
tissue has a moisture content of less than about 60% by weight of
the treated pericardium tissue.
47. The assembly of claim 39, wherein the frame comprises a
stent.
48. The assembly of claim 39, wherein the prosthetic heart valve
resides within a sheath.
49. An assembly, comprising: a prosthetic heart valve including: a
frame; and a tissue leaflet assembly attached to the frame, the
tissue leaflet assembly comprising a substantially dry treated
pericardium tissue; and a package containing the prosthetic heart
valve and a delivery catheter, the prosthetic heart valve
releasably secured in a collapsed configuration to a portion of the
delivery catheter, and wherein the prosthetic heart valve is
expandable to an expanded configuration.
50. The assembly of claim 49, wherein the portion of the delivery
catheter to which the prosthetic heart valve is releasably secured
includes an expandable balloon.
51. The assembly of claim 49, wherein the portion of the delivery
catheter to which the prosthetic heart valve is releasably secured
includes a mandrel.
52. The assembly of claim 49, wherein the frame is self
expanding.
53. The assembly of claim 49, wherein the substantially dry treated
pericardium tissue has a moisture content of less than about 60% by
weight of the substantially dry treated pericardium tissue.
54. The assembly of claim 49, wherein the frame comprises a
stent.
55. The assembly of claim 49, wherein the prosthetic heart valve
resides within a sheath.
56. An assembly, comprising: a prosthetic heart valve including: a
frame defining a lumen therein; and a tissue leaflet assembly
attached to the frame; and a package containing the prosthetic
heart valve and a delivery catheter, wherein a portion of the
delivery catheter resides within the lumen of the frame.
57. The assembly of claim 56, wherein the portion of the delivery
catheter that resides within the lumen of the frame includes an
expandable balloon.
58. The assembly of claim 56, wherein the portion of the delivery
catheter that resides within the lumen of the frame includes a
mandrel.
59. The assembly of claim 56, wherein the frame is self
expanding.
60. The assembly of claim 56, wherein tissue forming the tissue
leaflet assembly comprises treated pericardium tissue.
61. The assembly of claim 60, wherein the tissue leaflet assembly
attached to the frame is at least one of hydrated and not
substantially dry.
62. The assembly of claim 60, wherein the tissue leaflet assembly
attached to the frame is substantially dry.
63. The assembly of claim 62, wherein the treated pericardium
tissue has a moisture content of less than about 60% by weight of
the treated pericardium tissue.
64. The assembly of claim 56, wherein the frame comprises a
stent.
65. The assembly of claim 56, wherein the prosthetic heart valve
resides within a sheath.
66. The assembly of claim 56, wherein the portion of the delivery
catheter that resides within the lumen of the frame is coaxial with
the frame.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
U.S. patent application Ser. No. 13/038,361, filed on Mar. 1, 2011,
which claims the benefit of U.S. Provisional Patent Application No.
61/309,109 filed on Mar. 1, 2010, both applications of which are
incorporated herein by reference in their entireties.
Cross-reference is made to U.S. patent application Ser. No.
13/038,260 filed on Mar. 1, 2011, the content of which is
incorporated herein by reference.
FIELD
[0002] The present invention relates to the field of medical
devices, and more particularly, to a percutaneously deliverable
heart valve and a method of making a percutaneously deliverable
heart valve.
BACKGROUND
[0003] Heart valve disease is a common degenerative condition that
compromises physiologic function and causes limiting symptoms and
threat to life in millions of patients all over the world. There
are various underlying causes, but malfunction of heart valves is
ultimately expressed as insufficient conduction of blood through
the plane of the valve due to narrowing of the anatomic pathway
(stenosis), or as incompetent closure that allows blood to return
back through the valve again, thereby reducing the effective
forward conduction of blood through the valve (insufficiency or
regurgitation). These hemodynamic states lead to 1) deficiency of
cardiac output and 2) adverse loads on the pumping chambers of the
heart, both of which in turn lead to functional compromise of the
patient and often premature death unless effectively corrected.
[0004] Definitive corrective treatment of heart valve disease is
conventionally performed by open-chest surgical techniques, wherein
the valve is manipulated, repaired, or replaced with a prosthetic
valve under direct vision. Heart valve surgery is performed in
hundreds of thousands of cases yearly world-wide, but carries a
high burden of cost, morbidity, and mortality, especially in
susceptible patients who may be elderly or otherwise
physiologically compromised by collateral disease. Further, the
costs and resource requirements of the surgical enterprise restrict
the availability of heart valve replacement to many more patients
all over the world.
[0005] In pursuit of alternatives to heart valve surgery, over the
last ten years a number of development programs have brought
percutaneous, trans-catheter implantation of prosthetic heart
valves into commercial use in the European Union (EU) and into
pivotal clinical trials in the United States of America. Initial
clinical experience in the EU was directed toward patients who had
critical aortic valve stenosis, but were deemed to be at
unacceptably high risk for open-heart surgical valve replacement.
In several thousand such cases, utilizing both balloon-expandable
and self-expanding designs in two separate programs, percutaneous
heart valve replacement (PHVR) was shown to be feasible and
possibly competitive with surgery in selected patients with 12-18
month mortality rates of about 25%. Grube E., et al., Progress and
Current Status of Percutaneous Aortic Valve Replacement: Results of
Three Device Generations of the CoreValve Revalving System, Circ.
Cardiovasc Intervent. 2008; 1:167-175.
[0006] The application of PHVR thus far has been challenged by the
technical difficulties of the implantation sequence--especially in
the aortic valve position. The technique for available devices is
limited by the large caliber of the devices and their delivery
catheters; often, if it can be done at all in some smaller
arteries, open surgical exposure and management of the femoral
artery is required to insert the 18-24 French (6-8 mm diameter)
systems, and their bulkiness inside the central arteries can
threaten the safety of the delivery sequence. Further, access site
bleeding complications form a significant part of the adverse
events of the procedures.
[0007] Typically, the current PHV designs comprise a biological
membrane forming the operating leaflets of the valve, attached
within a metal frame, that is then collapsed onto a delivery
catheter or balloon, and then constrained within an outer sheath.
After an initial dilation of the diseased valve with a large
balloon, this assembly is then advanced to the plane of the valve
and deployed by self-expansion or by balloon expansion.
[0008] The effective caliber of the valve delivery system is
determined by the total bulk of each coaxially mounted component.
The bulk of the PHV itself is determined by the diameter of the
frame and by the thickness, stiffness, and particular arrangement
of the inner membrane forming the operating leaflets of the valve.
The characteristic thickness of current PHV membranes is thus a
limiting factor in the ultimate delivery profile of the PHV. Such
characteristic membrane thickness is, in turn, a result of the
methods by which it is processed and ultimately delivered for use.
Typically, glutaraldehyde fixation (for protein cross-linking) of
animal tissue is employed to produce suitable biological membranes
for incorporation. Requirements for strength and durability have
determined the most useful ranges for tissue thickness and
cross-linking while typically imposing countervailing stiffness and
brittleness. Subsequent hydration in suitable solutions improves
these characteristics, but the hydrated membrane by this means also
gains thickness.
[0009] One of the evident requirements for a PHV design is that the
valve functions with a high degree of competence immediately on
deployment, since the patient's hemodynamic survival depends on it.
To this end, in part, like surgical valve prostheses, current PHV
designs are completed, transported, and delivered for use in a
hydrated state in a jar of solution. In use, commercially available
surgical and percutaneously implanted bioprosthetic heart valves
are rinsed and prepared before use in a "wet" state. More
particularly, commercially available prosthetic heart valves are
rinsed, crimped, and mounted in the catheterization lab.
Accordingly, problems with current commercially available
prosthetic heart valves include the time, cost and variability
associated with the necessity to rinse, crimp, and mount the valve
in the catheterization lab. That is, current mounting of prosthetic
heart valves in the catheterization lab imposes one or more of
delay, cost, technical burdens and possible errors. Avoiding one or
more of these problems would be advantageous. In addition, current
"wet" valve designs impose additional profile on the collapsed
valve. The hydrated membrane, while having desirable and necessary
flexibility for reliable operation immediately on deployment, also
imposes a large part of the thickness of the assembled and mounted
valve that compromises its deliverability.
[0010] Expanding on some of the problems described above, the use
of current PHVs in the catheter lab requires a number of
preparatory acts that are potentially troublesome and can prolong
the delivery sequence during a critical phase of the procedure.
Since PHVs are delivered for use "wet" in a preservative solution,
they have to be treated prior to insertion with a series of
cleansing and hydrating solutions. Once this is completed, the PHVs
have to be mounted on their delivery catheters. Special crimping
and mounting tools are needed in the case of the balloon-expandable
Edwards Sapien valve, for example. Accordingly, there is a need to
address the shortcomings discussed above.
SUMMARY
[0011] It is to be understood that the present invention includes a
variety of different versions or embodiments, and this Summary is
not meant to be limiting or all-inclusive. This Summary provides
some general descriptions of some of the embodiments, but may also
include some more specific descriptions of other embodiments.
[0012] In at least one embodiment, a substantially "dry" membrane
PHV system is provided wherein a tissue material is prepared and
folded in a dry state to form a tissue leaflet assembly.
Thereafter, the tissue leaflet assembly is attached to a frame to
form an implantable prosthetic heart valve that is subsequently
pre-mounted in an integrated catheter delivery system. The catheter
delivery system that includes the prosthetic heart valve is then
packaged and transported while the tissue leaflet assembly remains
substantially dry. The prosthetic heart valve is available for use
directly out of its package envelope. Accordingly, it can be
inserted into the body without need of hydration, crimping or
mounting tools, or other preparatory acts. That is, the tissue
forming the tissue leaflet assembly of the prosthetic heart valve
can be treated and dried, then while remaining dry, folded into a
tissue leaflet assembly. Thereafter, the tissue leaflet assembly is
at least partially rehydrated and then attached within a frame,
such as a stent, to form an implantable prosthetic heart valve. The
tissue leaflet assembly of the prosthetic heart valve is then
allowed to dry. The prosthetic heart valve can thereafter be
subsequently packaged, delivered, and shipped while the tissue
leaflet assembly of the prosthetic heart valve remains in a dry
condition. The prosthetic heart valve can then be implanted into
the receiving patient. Accordingly, the PHV system simplifies
arterial insertion, and, as the dry condition also confers lower
bulk and profile, procedural manipulation and associated
complications may be reduced if not eliminated. In addition, one or
more embodiments of the present invention widen the candidacy of
patients with smaller arteries for the PHV procedure. As an added
advantage, at least one embodiment of the present invention allows
the implantation to take place under shorten elapsed times at the
most critical phase of the procedure.
[0013] In at least one embodiment, a membrane PHV system is
provided wherein a tissue material is prepared and folded in a dry
state to form a tissue leaflet assembly, and further wherein the
tissue leaflet assembly is thereafter at least partially hydrated
and attached to a frame that is subsequently pre-mounted in an
integrated catheter delivery system.
[0014] In at least one embodiment, a membrane PHV system is
provided wherein a tissue material is prepared and folded in a dry
state to form a tissue leaflet assembly, and further wherein the
tissue leaflet assembly is at least partially hydrated and attached
to a frame to form the prosthetic heart valve. Thereafter, the
prosthetic heart valve is allowed to dry and subsequently
pre-mounted in an integrated catheter delivery system after which
the tissue leaflet assembly of the prosthetic heart valve remains
dry, and wherein the system is then associated with a package for
shipment while the tissue leaflet assembly remains dry.
[0015] In at least one embodiment, a membrane PHV system is
provided wherein a tissue material is prepared and then folded in a
dry state to form a tissue leaflet assembly, and further wherein
the tissue leaflet assembly is at least partially hydrated and
attached to a frame to form the prosthetic heart valve. Thereafter,
the prosthetic heart valve is allowed to dry and subsequently
pre-mounted in an integrated catheter delivery system after which
the tissue leaflet assembly of the prosthetic heart valve is then
at least partially hydrated and associated with a package for
shipment.
[0016] In at least one embodiment, an article adapted for
trans-catheter delivery into a patient is provided, comprising: a
prosthetic heart valve further comprising a treated tissue attached
to a frame, wherein the treated tissue comprises a thickness of
about 50 to 500 micrometers and an ultimate tensile strength of
greater than about 15 MegaPascals when at a water content of less
than about 50% by weight of the section of treated tissue. Here it
is noted that the tensile strength of the treated tissue described
herein is higher than the tensile strength of other known prepared
tissues, whether hydrated or dry. In at least one embodiment, the
water content of the treated tissue is less than about 40% by
weight of the treated tissue. In at least one embodiment, the
ultimate tensile strength is greater than about 20 MegaPascals. In
at least one embodiment, the treated tissue does not include a
matrix that has been exposed to a polymer infiltrate. In at least
one embodiment the treated tissue comprises a treated pericardium
tissue.
[0017] In at least one embodiment, the method further comprises
exposing the section of tissue to light energy for an exposure
duration, the exposure duration extending until there is no further
visible separation of lipid droplets from an exposed surface of the
section of tissue. In at least one embodiment, the light energy is
at least equivalent to exposing the section of tissue to a 25-100
watt light source, and more preferably, a 50 watt incandescent
light source with a flat radiant face situated at a distance of
about 10 centimeters from the exposed surface for about 15 minutes.
In at least one embodiment, the method further comprises: (d)
rinsing the section of tissue with distilled water and isopropyl
alcohol for a post-fixation period of time of not less than about 7
days; wherein step (d) occurs after step (c).
[0018] In at least one embodiment, an article adapted for
implantation in a patient is provided, comprising: a prosthetic
heart valve further comprising a treated tissue attached to a
frame, wherein the treated tissue comprises a water content of less
than about 60% by weight of the treated tissue. In at least one
embodiment, the treated tissue comprises a section of pericardium
tissue having an ultimate tensile strength of greater than about 12
MegaPascals. In at least one embodiment, the section of treated
tissue comprises a thickness of between about 50 to 300
micrometers. In at least one embodiment, the water content of the
treated tissue is less than about 40% by weight of the treated
tissue.
[0019] As used herein, the term "dry" (or "substantially dry") when
referring to the state of the tissue that forms the heart valve of
the percutaneous heart valve means a moisture content less than the
water moisture content of the tissue when the tissue is allowed to
fully rehydrate in the body of a patient. Typically, pericardium
tissue treated in accordance with one or more embodiments described
herein is about 70% by weight water when fully hydrated. Drying to
a constitution of less than 40% by weight of water usefully alters
the handling properties for purposes of folding and sewing the
tissue. As those skilled in the art will appreciate, the moisture
content of the tissue may vary when dry. For example, the moisture
content of the tissue when being folded and dry may be different
than the moisture content of the tissue when dry and being shipped
in a premounted state within a catheter delivery system.
[0020] Advantageously, at least one embodiment of the one or more
present inventions is directed to a prosthetic heart valve that is
mounted onto a valve delivery system and stored in a sterile
package. Accordingly, in at least one embodiment, an assembly is
provided, comprising:
a prosthetic heart valve including: a frame; and a tissue leaflet
assembly attached to the frame;
[0021] a percutaneously insertable valve delivery mechanism,
wherein the prosthetic heart valve is releasably mounted onto the
percutaneously insertable valve delivery mechanism; and
[0022] sterile packaging containing the prosthetic heart valve
releasably mounted onto the percutaneously insertable valve
delivery mechanism.
[0023] In at least one embodiment, the percutaneously insertable
valve delivery mechanism comprises a balloon catheter. In at least
one embodiment, the balloon catheter is a 12 to 14 French balloon
catheter. In at least one embodiment, the balloon catheter is less
than about 12 French. In at least one embodiment, the balloon
catheter is between about 5 to 12 French. In at least one
embodiment, the percutaneously insertable valve delivery mechanism
comprises a mandrel. In at least one embodiment, tissue forming the
tissue leaflet assembly within the sterile packaging is at least
one of hydrated and not substantially dry. In at least one
embodiment, tissue forming the tissue leaflet assembly within the
sterile packaging is substantially dry. In at least one embodiment,
the frame comprises a stent. In at least one embodiment, tissue
forming the tissue leaflet assembly comprises treated pericardium
tissue.
[0024] At least one embodiment of the one or more present
inventions includes a prosthetic heart valve for implantation in a
patient. Accordingly, a pre-packaged percutaneous, trans-catheter
deliverable prosthetic heart valve ready for implantation in a
patient is provided, comprising:
a frame; and,
[0025] a tissue leaflet assembly attached to the frame, the tissue
leaflet assembly comprising a substantially dry tissue.
[0026] In at least one embodiment, the substantially dry tissue
comprises treated pericardium tissue. In at least one embodiment,
the frame and tissue leaflet assembly attached thereto are operably
associated with a 12 to 14 French balloon catheter. In at least one
embodiment, the frame and tissue leaflet assembly attached thereto
are operably associated with a balloon catheter having a size of
less than about 12 French. In at least one embodiment, the frame
and tissue leaflet assembly attached thereto are operably
associated with a balloon catheter having a size of between about 5
to 12 French. In at least one embodiment, the substantially dry
tissue comprises a water moisture content of less than about 40% by
weight of the substantially dry tissue.
[0027] In at least another embodiment, an assembly for use with a
patient is provided, comprising:
[0028] a sealed sterile package containing a delivery system for
percutaneously deploying a heart valve in the patient, the heart
valve including:
[0029] a frame releasably mounted on the delivery system within the
sealed sterile package; and
a tissue leaflet assembly attached to the frame.
[0030] In at least one embodiment, the tissue leaflet assembly
comprises pericardium tissue.
[0031] In at least one embodiment, a method is provided,
comprising:
[0032] partially compressing and mounting a prosthetic heart valve
upon a delivery catheter, the prosthetic heart valve comprising a
tissue;
allowing the tissue to at least partially dry;
[0033] further compressing and mounting the prosthetic heart valve
upon the delivery catheter; and
[0034] sterilizing and packaging the prosthetic heart valve and
delivery catheter.
[0035] In at least one embodiment, the method further comprises
transporting the sterilized and packaged prosthetic heart valve and
delivery catheter. In at least one embodiment, the tissue comprises
treated pericardium tissue. In at least one embodiment, prior to
partially compressing and mounting the prosthetic heart valve upon
the delivery catheter, the tissue is at least one of (a) not
substantially dry, and (b) at least partially hydrated.
[0036] For the various embodiments described herein, the prosthetic
heart valve, including the tissue leaflet assembly, comprises
membrane tissue other than pericardium tissue.
[0037] In at least one embodiment, a method is provided,
comprising:
attaching pericardium tissue to a frame;
[0038] partially compressing and mounting the frame, with the
tissue attached thereto, upon a delivery catheter;
allowing the tissue to at least partially dry;
[0039] further compressing and mounting the frame, with the tissue
attached thereto, upon the delivery catheter; and
[0040] sterilizing and packaging the frame and delivery catheter,
with the tissue attached thereto.
[0041] In at least one embodiment, prior to partially compressing
and mounting the frame, the tissue is at least one of (a) not
substantially dry, and (b) at least partially hydrated. In at least
one embodiment, the method further comprises transporting the
sterilized and packaged frame, with the tissue attached thereto,
mounted upon the delivery catheter, to a surgical or medical
procedure facility. In at least one embodiment, prior to attaching
the tissue to the frame the tissue is folded to form a tissue
leaflet assembly. In at least one embodiment, the tissue leaflet
assembly comprises at least one cuff and at least one pleat.
[0042] In at least one embodiment, a method of preparing a
percutaneous, trans-catheter prosthetic heart valve is provided,
the method comprising:
providing a membrane tissue from an organism;
[0043] treating the membrane tissue with at least one chemical to
produce a treated membrane tissue;
drying the treated membrane tissue until it is a substantially dry
tissue; attaching the substantially dry tissue in a frame;
[0044] rehydrating the substantially dry tissue that is attached
within the frame to form a rehydrated tissue;
collapsing the frame with the rehydrated tissue attached thereto;
and
[0045] drying the rehydrated tissue within the collapsed frame
until it is a substantially dry tissue.
[0046] In at least one embodiment the method further comprises
compressing and mounting the frame, with the substantially dry
tissue attached thereto, upon a delivery catheter. In at least one
embodiment the method further comprises sterilizing and packaging
the frame, with the substantially dry tissue attached thereto,
mounted upon the delivery catheter. In at least one embodiment, the
treating comprises sterilizing the frame with the substantially dry
tissue attached thereto with exposure to at least one of ethylene
oxide, a proton beam, and gamma radiation. In at least one
embodiment, the method further comprises shipping the sterilized
and packaged frame with the substantially dry tissue attached
thereto, mounted upon the delivery catheter, to a surgery or
medical procedure facility. In at least one embodiment, prior to
the attaching step the dry tissue is not folded to provide a cuff
and/or a pleat. In at least one embodiment, prior to the attaching
step the dry tissue is folded to form a tissue leaflet assembly. In
at least one embodiment, the tissue leaflet assembly comprises at
least one cuff and at least one pleat.
[0047] In at least one embodiment, the method of preparing a
percutaneous, trans-catheter prosthetic heart valve further
comprises implanting the frame with the substantially dry tissue
attached thereto into a patient. In at least one embodiment, the
frame comprises a stent. In at least one embodiment, the method
further comprises mounting the frame and the tissue leaflet
assembly attached thereto upon a 12 to 14 French balloon catheter.
In at least one embodiment, the method further comprises mounting
the frame and the tissue leaflet assembly attached thereto upon a
balloon catheter having a size of less than about 12 French. In at
least one embodiment, the method further comprises mounting the
frame and the tissue leaflet assembly attached thereto upon a
balloon catheter having a size of between about 5 to 12 French. In
at least one embodiment, the method further comprises mounting the
frame and the tissue leaflet assembly attached thereto on a
mandrel. In at least one embodiment, the method of preparing a
percutaneous, trans-catheter prosthetic heart valve further
comprises immersion of the membrane tissue in buffered or
unbuffered 1-37.5% formalin for between about 3 days to 3 weeks. In
at least one embodiment, the method of preparing a percutaneous,
trans-catheter prosthetic heart valve further comprises immersion
of the membrane tissue in buffered or unbuffered 1-37.5% formalin
for between about 3 days to 5 weeks. In at least one embodiment the
treating comprises immersion of the membrane tissue in 100%
glycerol for greater than 3 weeks. In at least one embodiment the
treating comprises immersion of the membrane tissue in 0.1-25%
glutaraldehyde for between about 3 days to 3 weeks. In at least one
embodiment the treating comprises immersion of the membrane tissue
in 0.1-25% glutaraldehyde for between about 3 days to 5 weeks. In
at least one embodiment the treating comprises immersion of the
membrane tissue in oligomeric filtered 0.1-25% glutaraldehyde for
between about 3 days to 3 weeks. In at least one embodiment the
treating comprises immersion of the membrane tissue in oligomeric
filtered 0.1-25% glutaraldehyde for between about 3 days to 5
weeks. In at least one embodiment the treating comprises immersion
of the membrane tissue in the aforementioned formalin,
glutaraldehyde, or oligomeric filtered glutaraldehyde solutions
with the added free amino acids lysine and/or histidine. In at
least one embodiment the treating does not include contact and/or
exposure to a polymer to infiltrate and/or encapsulate tissue
fibers of the tissue.
[0048] In at least one embodiment, a method of preparing a
percutaneous, trans-catheter prosthetic heart valve is provided,
the method comprising:
[0049] providing a section of tissue harvested from a mammalian
organism; and
[0050] causing osmotic shocking of the section of tissue by
performing multiple rinses of the section of tissue with distilled
water. In at least one embodiment, the method further comprises
hydrating the section of tissue during a plurality of time
intervals using distilled water. In at least one embodiment the
section tissue comprises pericardium tissue. In at least one
embodiment, the method further comprises not using saline for
causing at least one of the osmotic shocking and the hydrating of
the tissue. In at least one embodiment, the method further
comprises pretreating the section of tissue with glycerol before
contacting the section of tissue with one or more of isopropyl
alcohol, glutaraldehyde and formalin. In at least one embodiment,
the method further comprises contacting the section of tissue with
a solution containing formalin after pretreating the section of
tissue with glycerol. In at least one embodiment, the method
further comprises contacting the section of tissue with a solution
containing glutaraldehyde after pretreating the section of tissue
with glycerol. In at least one embodiment, the method further
comprises pretreating the section of tissue with isopropyl alcohol
before contacting the section of tissue with either glutaraldehyde
and formalin. In at least one embodiment, the method further
comprises contacting the section of tissue with a solution
containing formalin after pretreating the section of tissue with
isopropyl alcohol. In at least one embodiment, the method further
comprises contacting the section of tissue with a solution
containing glutaraldehyde after pretreating the section of tissue
with isopropyl alcohol. In at least one embodiment, the method
further comprises exposing the section of tissue to light energy
for a period time, the period of time extending until there is no
further visible separation of lipid droplets from an exposed
surface of the section of tissue. In at least one embodiment, the
light energy is at least equivalent to exposing the section of
tissue to a 50 watt incandescent light source with a flat radiant
face situated at a distance of about 10 centimeters from the
exposed surface for about 15 minutes.
[0051] With regard to delivery characteristics, another significant
advantage of an implantable prosthetic heart valve using a
relatively thin tissue component described herein is that the
implantable prosthetic heart valve offers a relatively low packing
volume as compared to commercially available prosthetic heart
valves. As a result, the implantable prosthetic heart valve
provides a relatively low catheter delivery profile, thereby
enabling implantation in patients possessing relatively small
diameter vascular systems.
[0052] In accordance with one or more embodiments, a dry tissue
membrane has substantially less mass than a wet membrane. By way of
example, a substantially dry pericardium tissue prepared by one or
more of the present embodiments has approximately 30% of the mass
of a wet pericardium tissue, and marked reduction in profile and
packing volume, thereby achieving a relatively low profile and
making it suitable for implantation in greater number of patients,
especially those having small diameter vascular systems. In
addition, a dry prosthetic heart valve does not require storage and
transport in preservative. A dry prosthetic heart valve can be
mounted on a delivery catheter at its location of manufacture,
which allows for pre-packaging of an integrated delivery system.
Together with a relatively low profile, embodiments of the
prosthetic heart valves thereby offer reliability and convenience
because the implantable prosthetic heart valve is pre-mounted upon
a delivery catheter and forms part of a pre-packaged delivery
system. In addition, a dry prosthetic heart valve does not require
rinsing, rehydration, or mounting upon a delivery catheter in a
catheterization lab. Therefore, a dry prosthetic heart valve can be
inserted directly from package into the body at a critical time
during the procedure. Advantageously, this avoids procedure time,
manipulation, and errors of mounting, crimping, and orienting
catheters and sheaths. Once at the surgical facility/location, the
dry prosthetic heart valve is inserted and delivered by balloon
catheter expansion in the plane of the diseased valve in the
standard way and the dry prosthetic heart valve begins to function
immediately, even in its dry state or not fully rehydrated state
(because some rehydration will occur upon flushing of the catheter
with the prosthetic heart valve residing therein), with rehydration
of the tissue membrane subsequently completing naturally in the
body.
[0053] Various components are referred to herein as "operably
associated." As used herein, "operably associated" refers to
components that are linked together in operable fashion, and
encompasses embodiments in which components are linked directly, as
well as embodiments in which additional components are placed
between the two linked components.
[0054] As used herein, "at least one," "one or more," and "and/or"
are open-ended expressions that are both conjunctive and
disjunctive in operation. For example, each of the expressions "at
least one of A, B and C," "at least one of A, B, or C," "one or
more of A, B, and C," "one or more of A, B, or C" and "A, B, and/or
C" means A alone, B alone, C alone, A and B together, A and C
together, B and C together, or A, B and C together.
[0055] As used herein, "sometime" means at some indefinite or
indeterminate point of time. So for example, as used herein,
"sometime after" means following, whether immediately following or
at some indefinite or indeterminate point of time following the
prior act.
[0056] Various embodiments of the present inventions are set forth
in the attached figures and in the Detailed Description as provided
herein and as embodied by the claims. It should be understood,
however, that this Summary does not contain all of the aspects and
embodiments of the one or more present inventions, is not meant to
be limiting or restrictive in any manner, and that the invention(s)
as disclosed herein is/are understood by those of ordinary skill in
the art to encompass obvious improvements and modifications
thereto.
[0057] Additional advantages of the present invention will become
readily apparent from the following discussion, particularly when
taken together with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] To further clarify the above and other advantages and
features of the one or more present inventions, a more particular
description of the one or more present inventions is rendered by
reference to specific embodiments thereof which are illustrated in
the appended drawings. It is appreciated that these drawings depict
only typical embodiments of the one or more present inventions and
are therefore not to be considered limiting of its scope. The one
or more present inventions is described and explained with
additional specificity and detail through the use of the
accompanying drawings in which:
[0059] FIG. 1 is a flow chart of a method associated with at least
of one embodiment of the present invention;
[0060] FIGS. 2A-2B are a flow chart illustrating elements of the
tissue preparation;
[0061] FIG. 3 is a flow chart illustrating elements of the drying
and sizing;
[0062] FIG. 4 is a flow chart illustrating elements of the valve
construction with attachment of tissue membrane leaflets to a
frame;
[0063] FIG. 5 is a flow chart illustrating elements of the mounting
of the valve into a delivery system;
[0064] FIG. 6 is a flow chart illustrating elements of the
ensheathing, sterilization, and packaging;
[0065] FIG. 7 is a flow chart illustrating elements of the delivery
of the valve into a patient;
[0066] FIG. 8A is a view of a one-piece section of tissue prior to
being folded;
[0067] FIG. 8B is a view of two (of three) separate pieces of
tissue after folding (detailed below);
[0068] FIG. 8C is a view of the two pieces of tissue shown in FIG.
8B after being sutured together at the pleat formed after folding
(detailed below);
[0069] FIG. 8D is a view of a tissue blank with the line of primary
fold shown using a dashed line;
[0070] FIG. 8E is a perspective view of the tissue blank being
folded along the primary fold line;
[0071] FIG. 8F is a 2-part figure showing the pleats fold lines and
pleats after folding;
[0072] FIG. 8G is a detail perspective view of a single pleat shown
in FIG. 8F;
[0073] FIG. 8H is a perspective schematic view of a folded and
seamed tissue leaflet assembly;
[0074] FIG. 8I is a perspective schematic view of a frame;
[0075] FIG. 8J is a perspective schematic view of the frame of FIG.
8I with the tissue leaflet assembly of FIG. 8H attached
thereto;
[0076] FIG. 8K is side elevation schematic view of the device shown
in FIG. 8J;
[0077] FIG. 8L is an end schematic view of the frame and tissue
leaflet assembly attached thereto;
[0078] FIG. 9 is a graph that shows actual stress-strain test
results for five tissue samples prepared in accordance with at
least one embodiment;
[0079] FIG. 10 is a schematic of a portion of a catheter with a
percutaneously deliverable heart valve mounted thereto;
[0080] FIG. 11A is a photo of an implantable prosthetic heart
valve, including a tissue leaflet assembly attached within a frame,
wherein the tissue is situated in a partially open orientation;
[0081] FIG. 11B is a drawing of an implantable prosthetic heart
valve, including a tissue leaflet assembly attached within a frame,
wherein the tissue is situated in a closed orientation;
[0082] FIG. 11C is a side cutaway view of an implantable prosthetic
heart valve, including a tissue leaflet assembly attached within a
frame, wherein the tissue is situated in a closed orientation;
[0083] FIG. 11D is another side cutaway view of an implantable
prosthetic heart valve, including a tissue leaflet assembly
attached within a frame, wherein the tissue is situated in a closed
orientation;
[0084] FIG. 12 is a photo of valve tissue after testing through
30,000,000 cycles of pumping used to model human heart conditions,
wherein the photo shows a smooth uniform surface;
[0085] FIG. 13 is a drawing of a surgeon holding a premounted
percutaneously deliverable heart valve associated with a catheter
and residing within sterile packaging;
[0086] FIG. 14 is a schematic of a simplified cutaway view of a
human heart, including heart valves that may be targeted for
receiving an embodiment of an implantable prosthetic heart
valve;
[0087] FIG. 15 is a schematic of a human aorta receiving a catheter
with an implantable prosthetic heart valve mounted thereto; and
[0088] FIG. 16 is a schematic of a human aorta with the implanted
prosthetic heart valve implanted at the site of the original
diseased aortic valve.
[0089] The drawings are not necessarily to scale.
DETAILED DESCRIPTION
[0090] Embodiments of the one or more inventions described herein
include one or more devices, assemblies and/or methods related to a
prosthetic heart valve. A prosthetic heart valve in accordance with
at least one embodiment described herein can be surgically
implanted, such as by percutaneous, trans-catheter delivery, to the
implantation site within the patient. One or more embodiments of
the prosthetic heart valves described herein have application for
at least aortic and pulmonary valve positions, including for
structural defects and diseased valves.
[0091] In at least one embodiment, biocompatible material is
attached within a frame to form an implantable prosthetic heart
valve, and then at a later time, the implantable prosthetic heart
valve is implanted within a patient, such as by way of a
percutaneous, trans-catheter delivery mechanism. Once implanted,
the prosthetic heart valve serves to regulate the flow of blood
associated with the patient's heart by allowing forward blood flow
and substantially preventing backflow or valvular
regurgitation.
[0092] Referring now to FIG. 1, a flow chart illustrates at least
one embodiment of a prosthetic heart valve preparation and delivery
method 100. The prosthetic heart valve preparation and delivery
method 100 generally includes a plurality of procedures to include
tissue preparation at 200, drying at 300, tissue leaflet assembly
construction and attachment to frame at 400 to form an implantable
prosthetic heart valve, mounting of the prosthetic heart valve
(that is, the frame with the tissue leaflet assembly) into a
delivery system at 500, ensheathing, sterilizing and packaging the
delivery system including the prosthetic heart valve at 600, and
finally, delivering the prosthetic heart valve into the patient at
700. Further detail of the prosthetic heart valve preparation and
delivery method 100 is provided below.
[0093] At least one or more embodiments described herein include a
relatively thin tissue component. By way of example and not
limitation, in at least one embodiment the tissue has a thickness
of approximately 50-150 .mu.m, and further possesses
characteristics of pliability and resistance to calcification after
implantation. The relatively thin nature of the tissue used in the
implantable prosthetic heart valve assists with biocompatibility.
In addition, the relatively thin tissue component thereby provides
for a relatively low mass. As a result, an implantable prosthetic
heart valve using the tissue can accelerate to a relatively high
heart rate in beats per minute with competent function.
[0094] Tissue suitable for use in the one or more prosthetic heart
valves and/or one or more assemblies described herein is relatively
thin and can generally be considered to be a membrane. Those
skilled in the art will appreciate that both natural and synthetic
types of materials may be used to form a leaflet assembly of a
prosthetic heart valves. Accordingly, it is to be understood that
although treated pericardium tissue is described as a suitable
material for use in the leaflet assembly of a prosthetic heart
valve of one or more embodiments described herein, material other
than xenograft tissue membrane can be used, and indeed, xenograft
tissue membrane other than pericardium tissue can be used. More
specifically, synthetic materials may include, but are not limited
to, PTFE, PET, Dacron, and nylon. In addition, other than
pericardium tissue, xenograft tissue membrane may include, but is
not limited to, membrane material from the intestine, lung and
brain. Suitable material may also comprise allograft material, that
is, material from human sources. The listing of possible materials
is for exemplary purposes and shall not be considered limiting.
[0095] With reference now to FIG. 2A, the process associated with
preparation of a biocompatible tissue consistent with the
above-noted characteristics is described. In at least one
embodiment, pericardium tissue, such as porcine or bovine
pericardium tissue, is harvested at 204 and then processed to serve
as the biocompatible tissue for association with a frame, such as
by attaching within a frame. Accordingly, subsequent to the
harvesting at 204, the pericardium tissue is cleaned and
decellularized at 208. More particularly, in at least one
embodiment the tissue is initially cleaned with distilled water
using gentle rubbing and hydrodynamic pressure at 208 in order to
remove adherent non-pericardial and non-collagenous tissue. In at
least one embodiment, the hydrodynamic pressure at 208 is provided
by spraying the tissue with a relatively weak stream of liquid to
remove at least some of the non-collagenous material associated
with the tissue. The rinsing at 208 is to achieve effective
decellularization of the pericardium tissue through osmotic shock.
Typically, the thickness of the tissue in the cleaned condition
varies from about 50 to 500 micrometers, depending on the source of
raw tissue. Cleaning preferably continues until there is no visible
adherent non-pericardial or non-collagenous tissue.
[0096] With continued reference to FIG. 2A, after the tissue has
been cleaned and decellularized at 208, the tissue then undergoes
optional additional removal of lipids at 220 to further treat the
tissue for preventing immunologic response and calcification. More
particularly, the tissue first optionally undergoes a 100% glycerol
pretreatment at 224 while being positioned on a flat surface (e.g.,
an acrylic plate), after which the tissue becomes nearly
transparent.
[0097] At 228, the tissue optionally undergoes a "thermophotonic"
process. In at least one embodiment, the tissue is optionally
exposed to light energy for additional removal of lipids and for
initial cross-linking of the collagen. By way of example and not
limitation, in at least one embodiment a 25-100 watt incandescent
light source, and more preferably, a 50 watt incandescent light
source with a flat radiant face is employed at a distance of about
10 centimeters from the tissue surface, typically requiring 15
minutes of exposure before further visible separation of lipid
droplets from the tissue stops.
[0098] Still referring to FIG. 2A, the tissue is then cleaned again
in secondary cleaning at 232. More particularly, at 236 the tissue
is again rinsed with distilled water. Thereafter, at 240 the tissue
is rinsed with 25% isopropyl alcohol for periods of several hours
to several days and weeks, depending on the desired tissue
properties of pliability and tensile strength. By way of example
and not limitation, tissue has been successfully prepared by
rinsing with 25% isopropyl alcohol for a period of 7 days, and
after further treatment steps described herein, provided an
ultimate tensile strength of greater than 25 MegaPascals. Here, the
combination of tissue pliability and tensile strength is sought for
purposes of producing a material having property characteristics
suitable for being physically manipulated to form a tissue leaflet
assembly or other configuration appropriate for attaching with a
frame, while providing a tissue material that will operate properly
once implanted. These techniques are intended to conserve and
preserve collagen fibers, minimizing damage to the tissue and
improving tissue characteristics. The preparation and fixation
techniques produce tissue membrane material that may be rendered
and used at lesser thickness than typically rendered in the prior
art. Thinner membranes are more pliable, but with conventional
preparation techniques the tensile strength of the tissue is
sacrificed. Advantageously, the preparation techniques described
herein have produced membranes that have as much as three times the
tensile strength of a commercial product of the prior art. This
achieved strength is thus enabling for providing a tissue leaflet
assembly having a low profile with appropriate durability, even in
a substantially dry state. More particularly, the tissue possesses
a relatively high tensile strength. By way of example and not
limitation, testing has shown that embodiments of tissue prepared
as described herein provide a tissue with a tensile strength of
approximately three times the tensile strength of current
pericardial valve tissue, such as on the order of approximately 25
MegaPascals, thereby providing about 2000 times the physiologic
load strength for valve tissue. Moreover, testing of an embodiment
of an implantable prosthetic heart valve made with tissue prepared
as described herein and under a static load of greater than
approximately 250 mmHg showed less than approximately 14% leakage,
wherein such results are generally considered superior to surgical
tissue valve prostheses.
[0099] In at least one embodiment where isopropyl alcohol is
described as a rinsing agent, ethanol may be used in its place as
an alternative, although resulting tissue properties may vary.
[0100] With reference to FIG. 9, stress-strain curve results for
five different tissue samples prepared in accordance with an
embodiment are shown. For the testing results shown, the yield
stress or ultimate tensile strength was obtained by mounting strips
of tissue fixed at the ends in a linear force tester and increasing
the length by 0.3 mm/sec while recording resultant force (tension)
until the material ruptured or separated entirely; these
measurements were then used to calculate the stress-strain curves
depicted in FIG. 9. As illustrated in the graph, the yield stress
or ultimate tensile strength of the various tissue samples varied
from about 30 to about 50 MegaPascals. More particularly, for each
curve shown in FIG. 9, the testing procedures were the same. That
is, each of the curves shown pertain to separate pieces of tissue
that were subjected to the same test. The results show a minimum
ultimate tensile strength of 30 MegaPascals, with a range up to 50
MegaPascals. Accordingly, the illustrated test results demonstrate
consistency of the ultimate tensile strength results for the tissue
treatment process.
[0101] With reference back to FIG. 2A, the tissue is rinsed with
distilled water at 244 as a final cleaning step and for
rehydration.
[0102] Referring now to FIG. 2B, following the rinse with distilled
water at 244, treatment of the tissue continues. More particularly,
fixation for collagen cross-linking at 248 is achieved by
performing at least one of the following:
a. At 248a, immersion of the tissue in 1-37.5% formalin, ideally a
buffered solution, for between about 3 days to 5 weeks, and more
preferably, for between about 3 days to 4 weeks, and more
preferably yet, for between about 3 weeks to 4 weeks, at a
temperature of between about 4 to 37.degree. C., and more
preferably, 10% formalin for 6 days at 20.degree. C.; or b. At
248b, immersion of the tissue in 100% glycerol for up to 6 weeks at
between 4 to 37.degree. C., and more preferably, immersion of the
tissue in 100% glycerol for about 3 weeks at 20.degree. C.; or c.
At 248c, immersion of the tissue in 0.1-25% glutaraldehyde for
between about 3 days to 5 weeks, and more preferably, for between
about 3 days to 4 weeks, and more preferably yet, for between about
3 weeks to 4 weeks, at 0 to 37.degree. C., and more preferably,
immersion of the tissue in 0.25% glutaraldehyde for 7 days at
4.degree. C.; or d. At 248d, immersion of the tissue in 0.1-25%
glutaraldehyde (filtered to limit oligomeric content) for between
about 3 days to 5 weeks, and more preferably, for between about 3
days to 4 weeks, and more preferably yet, for between about 3 weeks
to 4 weeks, at 0 to 37.degree. C., and more preferably, 0.25%
glutaraldehyde for 7 days at 4.degree. C.; or e. At 248e, immersion
in the tissue in one of the above formalin, glutaraldehyde, or
oligomeric filtered glutaraldehyde solutions together with added
amino acids, lysine and/or histidine, wherein the concentration of
the amino acids, L-lysine or histidine, used as an additive to the
fixative is in the range of about 100-1000 milliMolar, with a
preferred value of about 684 mM.
[0103] In addition to the foregoing, combinations of the processes
listed above may be performed, including: step a followed by step
b; step a followed by step c; and step a followed by step d.
[0104] As those skilled in the art will appreciate, heat-shrink
testing may be conducted on tissue samples to correlate the
effectiveness of protein cross-linking. Here, results of
heat-shrink testing performed on one or more samples of tissue
prepared in accordance with at least one embodiment using formalin
showed that the tissue had a shrink temperature of 90.degree. C.
This compares favorably with samples prepared using glutaraldehyde,
wherein the shrink temperature was 80.degree. C. Accordingly,
formalin is a suitable variant of fixation. It is noted that
formalin was generally abandoned by the field, largely because of
material properties that were unfavorable and because of inadequate
or unstable protein cross-linking. Such problems have been overcome
through the pretreatments described herein, allowing production of
tissue with strength, pliability, and durability in a relatively
thin membrane. When used in a percutaneous deliverable heart valve
(also referred to herein as "prosthetic heart valve"), the tissue
characteristics imparted by the tissue preparation process
facilitate formation of a construct having a relatively
low-profile, which also thereby facilitates dry packaging of the
prosthetic heart valve. The same advantages are also achieved using
the pretreatments when using a glutaraldehyde process.
[0105] Referring still to FIG. 2B, after fixation for collagen
cross-linking at 248, an alcohol post-fixation treatment at 252 is
preferably performed by rinsing the tissue in distilled water at
256, and then at 260 rinsing the tissue in 25% isopropyl alcohol
for between about 30 minutes to 14 days or more at between about 0
to 37.degree. C., and more preferably, for at least about 7 days at
20.degree. C. At 264, the tissue undergoes a rinsing with distilled
water.
[0106] In accordance with at least one embodiment, treatment of the
tissue, including from the time of harvest to the time of
implantation or grafting, does not include contact and/or exposure
to a polymer to infiltrate and/or encapsulate tissue fibers of the
tissue.
[0107] Referring now to FIGS. 1 and 3, the drying process at 300 is
performed after the tissue preparation at 200. Thus, in accordance
with at least one embodiment, the tissue is dried under a load.
More particularly, for the tissue drying at 304, the tissue is
placed minimally stretched flat (that is, stretched just enough to
eliminate visible wrinkles and bubbles) on a flat surface (e.g., a
polymer or acrylic sheet) at 308, and held fixed at its edges at
312. Optionally, the joined tissue and underlying sheet are then
set in a slight curve. The tension maintains the substantially flat
structure of the tissue as it dries, thereby mitigating or
preventing excessive shrinkage, wrinkling, and/or curling at the
edges, and also making the rate of drying more uniform across the
surface of the tissue because of the surface tension between the
plate and the tissue. Alternatively, the tissue is dried while
compressed between acrylic plates. When drying the tissue, the
temperature is held at between about 4 to 37.degree. C., and more
preferably, between about 20 to 37.degree. C. (i.e., approximately
room temperature to normal human body temperature), and more
preferably, at about 20.degree. C. At 314, the drying process is
performed in substantially dark conditions (i.e., substantially no
visible light) for between about 6 hours to 5 days, and more
preferably, for about 72 hours. By way of example, the tissue is
dried in dark conditions at a temperature of about 20.degree. C.
for between about 6 hours to 5 days, and more preferably, for about
72 hours. As those skilled in the art will appreciate, drying the
tissue while the tissue is compressed between plates requires a
longer period of time.
[0108] In at least one embodiment, after drying, the tissue lots
are inspected at 316, such as by stereomicroscopy, to identify and
discard those with defects or discontinuities of the fiber matrix.
In addition, the preferential fiber direction for each piece is
identified to determine the necessary orientation of the free edge
of the pieces that will form the valve leaflets. Depending upon the
size (i.e., the area) of the tissue being prepared and the size of
tissue needed for a given valve, the tissue may be trimmed or
otherwise sized in optional sizing at 320, such as by cutting the
tissue into an appropriately sized and shaped sheet for valve
formation. Preferably, cutting of the tissue membrane is oriented
so that the resulting free edge of the leaflet is parallel to the
preferential fiber direction of the tissue membrane. Optionally,
the free edge of the leaflets may also be cut with a parabolic or
other curved profile to compensate for the downward angle from the
commissural leaflet attachment point to the central coaptation
point and to increase the total contact surface between the
coapting leaflets. This approach minimizes focal weaknesses in the
operating margins of the leaflet assembly and advantageously
distributes the principal loading forces of the operating valve
along the long axis of the collagen fibers. As a result, the tissue
is resistant to surface fracture and fraying. As shown in FIG. 3,
optional sizing at 320 is performed after the drying at 304 and
inspection at 316.
[0109] With reference now to FIG. 4, an embodiment associated with
forming a tissue leaflet assembly and attachment to a frame to form
a prosthetic heart valve at 400 is further described. It is to be
understood that the tissue generated from one or more of the tissue
preparation procedures described herein may be used for a variety
of devices or uses, and that use in a prosthetic heart valve is but
one possible application for utilizing the tissue. For example, the
tissue may be used in a shunt, or as graft material for repair or
modification of one or more human organs, including the heart and
its blood vessels. By way of further example, the tissue may be
used as a pericardial membrane patch for repair of congenital heart
defects. The tissue also has application as a prosthetic tissue in
tendon and ligament replacement, and as a tissue product for wound
management. Moreover, for use in a prosthetic heart valve, the
tissue may be configured in a variety of ways and attached to a
frame in a variety of ways. By way of example and not limitation,
in at least one embodiment, the prepared tissue is formed into a
tissue leaflet assembly at 404 by folding the tissue at 408,
preferably while the tissue is in a dry state, to form at least a
portion of the tissue leaflet assembly. Here, those skilled in the
art will appreciate that a completed tissue leaflet assembly may be
formed of a single monolithic piece of tissue 800, such as that
shown in FIG. 8A, or alternatively, as shown in FIGS. 8B and 8C, it
may be formed of a plurality of tissue pieces 802 that are
operatively connected, such as by gluing or sewing the tissue
pieces together along seams 804. As seen in FIG. 8C, the seams 804
are preferably situated at overlapping portions of pleats 832 of
the plurality of tissue pieces 802.
[0110] As those skilled in the art will further appreciate, a
single monolithic piece of tissue 800 or a plurality of tissue
pieces 802 may be used to form a prosthetic heart valve, wherein
the tissue leaflet assembly is not a folded construct. By way of
example and not limitation, a plurality of separate tissue pieces
may each be attached to a frame (such as by suturing) to form a
prosthetic heart valve. Thereafter, whether the prosthetic heart
valve is made of a folded tissue leaflet assembly or a plurality of
separate tissue pieces attached to a frame, the resulting
prosthetic heart valve may then be further manipulated for delivery
as a dry prosthetic heart valve.
[0111] In an alternative embodiment, tissue generated from one or
more of the tissue preparation procedures described herein may be
used to form a prosthetic heart valve that includes a frame, and
that may be implanted by a "trans-apical" approach in which the
prosthetic heart valve is surgically inserted through the chest
wall and the apex of the heart.
[0112] In yet another alternative embodiment, tissue generated from
one or more of the tissue preparation procedures described herein
may be used to form a prosthetic heart valve that does not include
a frame, and is not delivered via a catheter, but rather, is
implanted via a surgical opening through the patient's chest. In
such a case, the prosthetic heart valve may be packaged for
delivery as a dry prosthetic heart valve.
[0113] In still yet another alternative embodiment, tissue
generated from one or more of the tissue preparation procedures
described herein may be used to form a prosthetic heart valve that
includes a frame, but that is not delivered via a catheter, but
rather, is implanted via a surgical opening through the patient's
chest. In such a case, the prosthetic heart valve may be packaged
for delivery as a dry prosthetic heart valve.
[0114] As a further alternative to the embodiments described
herein, tissue may be implanted in a "wet" or hydrated state. For
example, a prosthetic heart valve utilizing a prepared tissue
described herein may be packaged for delivery as a hydrated
prosthetic heart valve. Accordingly, while a portion of the tissue
preparation process may include drying the tissue so that it may be
manipulated more easily, the tissue may then be hydrated at a later
point in time prior to implantation, and it may be maintained in a
hydrated condition up to and including packaging, delivery and
implantation into a patient. Advantages associated with using a
folded tissue leaflet assembly include that a folded structure
allows a relatively thin membrane to be used by avoiding suture
lines in loaded, dynamically active surfaces. Accordingly, a
sutureless leaflet assembly preserves long-term integrity. However,
it is to be understood that a prosthetic heart valve that does not
include a folded tissue leaflet assembly is encompassed by one or
more embodiments described herein.
[0115] With reference now to FIGS. 8D-8L, and in accordance with at
least one embodiment, for a prosthetic heart valve that includes a
tissue leaflet assembly formed of a folded tissue membrane, the
folding sequence for the tissue is shown for configuring the tissue
into a completed tissue leaflet assembly. More particularly, a
tissue blank 808 is shown in FIG. 8D, wherein the tissue blank 808
is a single monolithic piece of tissue 800. Depending upon the size
requirements for a given tissue leaflet assembly, a line of primary
fold or fold line 812 (shown as a dashed line) is visualized for
the tissue blank 808. As shown in FIG. 8D, the primary fold 814 is
achieved along the fold line 812 by folding the bottom edge 816 of
the tissue blank 808 toward the top edge 820, but leaving a cuff
portion 824 along the upper portion 828 of the tissue blank 808.
Here, it is noted that the direction of top and bottom are relative
to each other and are used as a convenience for describing the
folding sequence, wherein such directions correspond to the
orientation of the page illustrating the drawings. Advantageously,
the folding geometry of FIGS. 8D-8L forms cuffs 824 that are
continuous with the leaflets, thereby reducing the risk of aortic
insufficiency or leakage.
[0116] With reference now to FIG. 8F, after folding the tissue
blank 808 along fold line 812 to form primary fold 814, pleats are
formed by folding the tissue along its length. For the embodiment
shown in FIG. 8F, three pleats 832a, 832b, and 832c are shown. FIG.
8G illustrates a detail drawing of a single pleat 832
representative of one of pleats 832a-c. In FIG. 8G, the inner
leaflet layer free edge 836 is shown, as is the valve sinus 840 and
the commissure folds 844.
[0117] Referring again to FIG. 4 as well as FIG. 8H, at 412 the
folded tissue is seamed to form a folded tissue leaflet assembly.
More particularly, FIG. 8H shows a schematic perspective drawing of
tissue leaflet assembly 848, wherein the pleated tissue construct
shown in the bottom half of FIG. 8F is seamed, such as along seam
850, to form a substantially tubular construct. At 416, the folded
tissue leaflet assembly 848 is maintained dry or is partially
hydrated prior to mounting the tissue leaflet assembly in a frame.
At 420, the tissue leaflet assembly 848 is then attached within a
frame, such as frame 852 shown in FIG. 8I. The tissue leaflet
assembly 848 attached within a frame 852 forms an implantable
prosthetic heart valve 860, such as that shown in the schematic
perspective drawing of FIG. 8J, side elevation view FIG. 8K, as
well as that shown in the photo of FIG. 11A, and drawing of FIG.
11B. FIG. 8K illustrates possible suture points 864 where the
tissue leaflet assembly 848 can be sutured to the frame 852. That
is, the tissue leaflet assembly 848 may be attached within the
frame 852, such as by suturing the outer layer of the tissue
leaflet assembly 848 to the frame. In the foregoing sentence, and
as used herein, it is noted that the term "attached" means that the
tissue leaflet assembly 848 is secured to the frame 852, although
the inner leaflet layer free edges 836 are able to readily move
during operation of the prosthetic heart valve 860.
[0118] Referring now to FIG. 11C, a cutaway side elevation view of
a prosthetic heart valve 860 that includes a frame 852 with a
tissue leaflet assembly 848 attached therein is shown. The tissue
membrane leaflet assembly 848 is disposed coaxially within the
frame 852. As shown in FIG. 11C, the valve 860 is illustrated in
the closed position with the leaflet free edges 836 in at least
partial contact with each other. An arc 1112 of the leaflet free
edges 836 (out of plane of the cutaway view) is continuous with
pleats 832 at the radial edge of the tissue leaflet assembly 848,
and may be seen in the alternate view shown in FIG. 8L. The tissue
membrane leaflet assembly 848 is attached to the frame 852 along
the axially oriented membrane pleats 832, as illustrated again in
FIG. 8L. The extended cuff layer is attached circumferentially at
the distal edge 1104 of the frame 852. By way of example and not
limitation, continuous suture attachment 1108 may be used to attach
the extended cuff layer to the distal edge 1104.
[0119] Referring now to FIG. 11D, an embodiment is shown wherein
the cuff layer is not extended distally to the distal edge 1104 of
the frame 852. As shown in FIG. 11D, the distal edge of the cuff
layer is attached circumferentially to an inner aspect of the frame
852, such as along those possible suture points 864 illustrated in
FIG. 8K. As a result, a distal portion 1116 of the frame 852 does
not include any portion of the tissue leaflet assembly 848, such as
the cuff layer. However, with the valve 860 in the closed position
the leaflet free edges 836 still at least partially contact each
other.
[0120] With reference now to FIG. 8L, an end view of the prosthetic
heart valve is shown. As depicted in FIG. 8L, the pleats 832 are
used as the portion of the tissue leaflet assembly 848 to attach to
the frame 852. As can be seen in FIG. 8L, the outer cuff layer is
attached to the frame members of frame 852. When the prosthetic
heart valve 860 is closed, the cusps 868 formed by the inner
leaflet layer are generally situated as depicted in FIG. 8L. FIG.
12 is a photo of the tissue leaflets of a prosthetic heart valve
after 30,000,000 cycles of testing to model performance if
associated with a human heart. In testing, the prosthetic heart
valve 860 has demonstrated a natural opening gradient of
approximately 5 mmHg.
[0121] It will be appreciated by one of ordinary skill in the art
that the tissue leaflet assembly 848 described and shown herein is
but one possible construct for forming a flow control mechanism
that can be attached to a frame to regulate the flow of blood in a
patient's vascular system upon deployment. That is, the illustrated
tissue leaflet assembly 848 is provided by way of example and not
limitation, and in no way should be interpreted to limit the
geometries of membrane leaflet assemblies that can be used to
regulate fluid flow. Accordingly, other leaflet configurations and
constructs are considered encompassed by claims directed to or
otherwise including premounted percutaneously deliverable
valves.
[0122] As those skilled in the art will appreciate, the frame 852
may be a stent or a structure having similarities to a stent. The
frame 852 essentially serves as a holding mechanism for the tissue
leaflet assembly 848 that can then be inserted percutaneously into
a patient, wherein the frame 852 serves as a way to anchor the
folded tissue leaflet assembly 848 to a vascular portion (e.g., in
situ arterial tissue) of the patient. Thus, at 424 the tissue
leaflet assembly 848 is inserted into a frame 852. More
particularly, at 424a the frame 852 may comprise a
balloon-expandable frame, or alternatively, at 424b a
self-expanding frame may be used. After the tissue leaflet assembly
is inserted into the frame, at 428 the folded tissue leaflet
assembly 848 is attached to the frame 852, such as by suturing the
tissue leaflet assembly 848 to the frame 852 to form an implantable
prosthetic heart valve 860, such as that shown in FIG. 8L. In at
least one embodiment, after attaching the tissue leaflet assembly
848 within the frame 852 and connecting the tissue leaflet assembly
848 to the frame 852 to form an implantable prosthetic heart valve
860, at 432 the prosthetic heart valve 860 is fully hydrated for
inspection and testing. Thereafter, the fully constructed
implantable prosthetic heart valve 860 may be dried and maintained
in a substantially dry condition. Accordingly, as those skilled in
the art will appreciate, one or more embodiments described herein
provide a tissue 800 suitable for implanting in a human, wherein
the implantable tissue may be allowed to dry prior to implanting,
or it may be hydrated prior to implanting. In addition, the tissue
800 is suitable for use in forming a tissue leaflet assembly 848
for use in a prosthetic heart valve, including an implantable
prosthetic heart valve 860 that can be implanted with its tissue
leaflet assembly in a dry state, or with its tissue leaflet
assembly in a partially or fully hydrated state.
[0123] One or more of the embodiments of the tissue leaflet
assemblies described herein may be implanted into the patient using
a balloon-expandable frame or a self-expanding frame. Expandable
frames are generally conveyed to the site of the target valve on
balloon catheters. For insertion, the expandable frame is
positioned in a compressed configuration along the delivery device,
for example crimped onto the balloon of a balloon catheter that is
part of the delivery device intended for coaxial mounting on a
guidewire. After the expandable frame is positioned across the
plane of the valve, the expandable frame is expanded by the
delivery device. For a self-expanding frame, commonly a sheath is
retracted, allowing expansion of the self-expanding frame.
[0124] In at least one embodiment, the frame comprises a metal
alloy frame possessing a high strain design tolerance that is
compressible to a relatively small diameter. By providing a device
with a low profile, the implantable prosthetic heart valve 860
allows standard retrograde arterial aortic delivery via femoral
artery insertion, without surgical cutdown or general anesthesia.
This is achieved by providing the prosthetic heart valve on a
premounted delivery system with the tissue leaflet assembly or
tissue membrane construct in a substantially dry condition.
[0125] In accordance with one or more embodiments, a dry tissue
membrane has substantially less mass than a wet membrane. By way of
example, a substantially dry pericardium tissue prepared by one or
more of the present embodiments has approximately 30% of the mass
of a wet pericardium tissue, and marked reduction in profile and
packing volume, thereby achieving a relatively low profile and
making it suitable for implantation in greater number of patients,
especially those having small diameter vascular systems. In
addition, a dry prosthetic heart valve does not require storage and
transport in preservative. A dry prosthetic heart valve can be
mounted on a delivery catheter at its location of manufacture,
which allows for pre-packaging of an integrated delivery system. In
the foregoing sentence, it is noted that the term "mounted" means
that the prosthetic heart valve 860 is temporarily associated with
the delivery catheter. Together with a relatively low profile,
embodiments of the prosthetic heart valve thereby offer reliability
and convenience because the implantable prosthetic heart valve 860
is pre-mounted upon its delivery catheter and forms part of a
pre-packaged delivery system. In addition, a dry prosthetic heart
valve does not require rinsing, rehydration, or mounting in a
catheterization lab. Therefore, a dry prosthetic heart valve can be
inserted directly from package into the patient's body at a
critical time during the procedure. Advantageously, this avoids
procedure time, manipulation, and errors of mounting, crimping, and
orienting catheters and sheaths. Once at the surgical
facility/location, the dry prosthetic heart valve is inserted and
delivered by balloon catheter expansion in the plane of the target
valve in the standard way and the dry prosthetic heart valve begins
to function immediately, even without specific steps to rehydrate
the tissue membrane portion of the heart valve from its dry state,
with hydration of the tissue membrane subsequently occurring
rapidly and naturally in the body. More particularly, hydration of
the tissue membrane portion occurs rapidly and begins with simple
preparatory flushing of catheter lumens with saline. Thereafter,
hydration continues with device insertion and dwelling into the
central blood vessels, and completes naturally after deployment in
the patient's body.
[0126] The low profile of the implantable prosthetic valve is
particularly advantageous for patient's having relatively small
diameter vascular systems. Table 1 provides aortic and pulmonary
valve prosthesis sizing.
TABLE-US-00001 TABLE 1 Aortic and Pulmonary Valve Prosthesis Sizing
Collapsed Implantable Collapsed Implantable Aorta/Pulmonary
Prosthetic Heart Valve Prosthetic Heart Valve Valve Diameter Size
(French) Diameter 19-21 mm 12 French 4.0 mm 22-26 mm 14 French 4.7
mm 27-30 mm 16 French 5.3 mm
[0127] For most human patients, the femoral artery has a diameter
of between about 5-8 mm. Accordingly, it is apparent that
embodiments of the collapsed implantable prosthetic heart valves
860 described herein offer a low profile that enables a larger
group of patients to qualify for receiving an implantable
prosthetic heart valve 860. As a result of the sizing advantages
offered by one or more embodiments of implantable prosthetic heart
valves 860 described herein, virtually no candidate patients would
be excluded from treatment with an implantable prosthetic heart
valve 860 without open heart surgery and without general anesthesia
on the basis of inadequate femoral blood vessel access caliber. In
addition, one or more embodiments of the implantable prosthetic
heart valve 860 described herein feature a scalable construct,
wherein the implantable prosthetic heart valves 860 can be produced
to accommodate target valve diameters ranging between 6-35 mm, and
wherein the implantable prosthetic heart valves 860 offer
consistent function using fundamentally a single design.
[0128] Referring now to FIG. 5, the mounting of the implantable
prosthetic heart valve 860 into a delivery system at 500 is further
described. More particularly, at 504 an implantable prosthetic
heart valve 860 (also referred to herein as a percutaneously
deliverable heart valve) is collapsed. The initial phase of
collapsing the percutaneously deliverable heart valve is executed
with the tissue membrane in a hydrated condition. That is, since
the percutaneously deliverable heart valve 860 includes the frame
852 with the tissue leaflet assembly 848 attached within the frame
852, the percutaneously deliverable heart valve 860 is collapsed
down as an integral unit. If a balloon-expandable frame is used,
then an axial puller may be utilized to collapse down the frame 852
of the percutaneously deliverable heart valve 860 without the
application of force directly to the sides of the frame 852. This
procedure offers the advantage of preserving the cell structure of
the frame 852 while also maintaining the orientation of the
leaflets of the tissue leaflet assembly 848 as the percutaneously
deliverable heart valve 860 is compressed. The proper orientation
and disposition of the leaflets is facilitated by the hydrated
state of the leaflets. This assists in preventing tissue prolapse
or bulging of the tissue 800 or 802 through the frame 852. In
addition, this technique reduces recompression strain on the metal
frame 852 (e.g., a stent) that can tend to compromise fatigue life
of the frame 852. This technique also tends to promote the
circumferentially uniform collapsing of cells in the frame 852,
thereby mitigating bunching of the tissue that forms the tissue
leaflet assembly 848 of the percutaneously deliverable heart valve
860. For a self-expanding frame, the sides are forced to collapse
by providing a radial compression force to the frame and may be
assisted by axial traction force.
[0129] With further reference to FIG. 5, the percutaneously
deliverable heart valve 860 (i.e., the frame 852 with the tissue
leaflet assembly 848 attached thereto) is collapsed in an initially
hydrated state. At 508 the delivery mandrel or balloon is inserted
into a delivery sheath, and the mounting segment is then extended
out the end of the sheath. Thereafter, at 512 the sheath and frame
are coaxially mounted and then compressed with initial crimping
onto the mounting segment with the tissue leaflet assembly 848
still in a hydrated state. At 516, the tissue leaflet assembly 848
of the percutaneously deliverable heart valve 860 is then allowed
to dry, which further reduces the volume and profile of the tissue
membrane leaflets, permitting further compression by radial force.
Accordingly, in the final compression step, the percutaneously
deliverable heart valve 860 is then further crimped with a
circumferential crimping tool at 520 to finally mount the
compressed valve/frame onto the delivery mandrel or balloon
catheter.
[0130] Referring now to FIG. 6, the ensheathing, sterilization and
packaging at 600 is described. More particularly, once the
percutaneously deliverable heart valve 860 is coaxially mounted and
crimped on a delivery mandrel or balloon catheter as described
above and shown in FIG. 5, the assembly is then inserted at 604
into a distal end of a delivery sheath, such as by "backloading"
the assembly into position with a distal end of the percutaneously
deliverable heart valve 860 contained within the delivery sheath
proximate the end of the sheath. Reference here is made to FIG. 10
that schematically illustrates catheter 1000 with an implantable
prosthetic heart valve 860 mounted thereto.
[0131] With further reference to FIG. 6, at 608 the percutaneously
deliverable heart valve 860 and delivery catheters are sterilized,
such as by using by one or more of ethylene oxide, proton beam, or
gamma radiation. At 612, the assembly is then optionally packaged
in a sterile package. Additional elements are optionally shipped
with the assembly, wherein, by way of example, such elements may
include any necessary delivery tools and documentation. In at least
one embodiment, the package may optionally contain a device to
control the water vapor content within the sealed volume of the
package. FIG. 13 depicts a surgeon holding a sterile package 1300
containing a premounted percutaneously implantable prosthetic heart
valve.
[0132] Referring now to FIG. 7, a flow chart illustrating the
general procedure associated with implantation of the
percutaneously deliverable heart valve 860 is provided. More
particularly, at 704, catheter access is gained to the patient's
femoral artery and a guidewire is placed through the plane of the
diseased valve that is targeted to receive the implant. FIG. 14 is
a schematic of a simplified cutaway view of a human heart,
including heart valves that may be targeted for receiving an
embodiment of an implantable prosthetic heart valve. FIG. 15
illustrates the aorta with the guidewire placed through the
diseased aortic valve. At 708, the percutaneously deliverable heart
valve 860 in the form of a prepackaged assembled dry prosthetic
heart valve is removed from the sterile packaging. The dry
prosthetic heart valve assembly, including its lumens, are
preferably flushed and prepared in the usual fashion for standard
balloons and catheters that do not contain a biocompatible tissue.
Advantageously, implantation of the dry prosthetic heart valve
assembly can be conducted without specific maneuvers for
rehydration of the tissue leaflet assembly 848 of the
percutaneously deliverable heart valve 860. Some rehydration of the
tissue leaflets may occur as a consequence of the routine flushing
of the catheter lumens in preparation for use as with any other
catheters. Additionally, implantation of the dry prosthetic heart
valve assembly can proceed without additional cleaning steps, such
as by having to use alcohol or water rinsing solutions. In
addition, further mounting of the dry tissue leaflet assembly 848
that resides in the frame 852 of the percutaneously deliverable
heart valve 860 is not needed, thereby obviating the need for
another mounting step. Accordingly, the percutaneously deliverable
heart valve 860 can essentially be implanted percutaneously in its
dry state. At 712, the carrier catheter or balloon catheter is then
coaxially mounted and advanced over the guidewire, such as under
fluoroscopic vision initially to the level of the great vessel
where it can be inspected under fluoroscopy. At 716, and after the
nominal position and configuration is confirmed, the delivery
system is advanced through the plane of the diseased valve under
fluoroscopy, and the covering sheath is withdrawn, either at this
point or during the advance prior to it, thus exposing the mounted
implantable prosthetic heart valve 860 in place. At 720, in the
case of a balloon expandable frame, and assuming the delivery
approach involving the pre-mounting of the percutaneously
deliverable heart valve 860 on the expansion balloon, the balloon
is then inflated, deploying the percutaneously deliverable heart
valve 860 in the plane of the valve. At 724, the leaflets of the
percutaneously deliverable heart valve 860 operate immediately. The
deployed prosthetic heart valve 860 is shown in FIG. 16, wherein
the tissue leaflet assembly 848 serves to properly control the flow
blood.
[0133] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. All changes which come
within the meaning and range of equivalency of the claims are to be
embraced within their scope.
[0134] The one or more present inventions, in various embodiments,
include components, methods, processes, systems and/or apparatus
substantially as depicted and described herein, including various
embodiments, subcombinations, and subsets thereof. Those of skill
in the art will understand how to make and use the present
invention after understanding the present disclosure.
[0135] The present invention, in various embodiments, includes
providing devices and processes in the absence of items not
depicted and/or described herein or in various embodiments hereof,
including in the absence of such items as may have been used in
previous devices or processes (e.g., for improving performance,
achieving ease and/or reducing cost of implementation).
[0136] The foregoing discussion of the invention has been presented
for purposes of illustration and description. The foregoing is not
intended to limit the invention to the form or forms disclosed
herein. In the foregoing Detailed Description for example, various
features of the invention are grouped together in one or more
embodiments for the purpose of streamlining the disclosure. This
method of disclosure is not to be interpreted as reflecting an
intention that the claimed invention requires more features than
are expressly recited in each claim. Rather, as the following
claims reflect, inventive aspects lie in less than all features of
a single foregoing disclosed embodiment. Thus, the following claims
are hereby incorporated into this Detailed Description, with each
claim standing on its own as a separate preferred embodiment of the
invention.
[0137] Moreover, though the description of the invention has
included description of one or more embodiments and certain
variations and modifications, other variations and modifications
are within the scope of the invention (e.g., as may be within the
skill and knowledge of those in the art, after understanding the
present disclosure). It is intended to obtain rights which include
alternative embodiments to the extent permitted, including
alternate, interchangeable and/or equivalent structures, functions,
ranges or acts to those claimed, whether or not such alternate,
interchangeable and/or equivalent structures, functions, ranges or
acts are disclosed herein, and without intending to publicly
dedicate any patentable subject matter.
* * * * *