U.S. patent application number 11/973526 was filed with the patent office on 2008-02-14 for systems, methods, and compositions for mixing and applying lyophilized biomaterials.
This patent application is currently assigned to NeoMend, Inc.. Invention is credited to Bruce Addis, Olexander Hnojewyj, Charles Milo.
Application Number | 20080038313 11/973526 |
Document ID | / |
Family ID | 29418407 |
Filed Date | 2008-02-14 |
United States Patent
Application |
20080038313 |
Kind Code |
A1 |
Addis; Bruce ; et
al. |
February 14, 2008 |
Systems, methods, and compositions for mixing and applying
lyophilized biomaterials
Abstract
A method of treating tissue lyophilizes a biocompatible polymer
having a functionality equal to or greater than three. The method
provides a protein solution. The method mixes the protein solution
with the lyophilized polymer to reconstitute the polymer and form a
mixture, wherein, upon mixing, the protein solution and the polymer
cross-link to form a material composition. The method applies the
material composition to a tissue region. The biocompatible polymer
can comprise, e.g., poly(ethylene glycol) PEG. The protein solution
can comprise, e.g., albumin.
Inventors: |
Addis; Bruce; (Redwood City,
CA) ; Milo; Charles; (Mountain View, CA) ;
Hnojewyj; Olexander; (Saratoga, CA) |
Correspondence
Address: |
Daniel D. Ryan;RYAN KROMHOLZ & MANION, S.C.
Post Office Box 26618
Milwaukee
WI
53226-0618
US
|
Assignee: |
NeoMend, Inc.
|
Family ID: |
29418407 |
Appl. No.: |
11/973526 |
Filed: |
October 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10141510 |
May 8, 2002 |
7279001 |
|
|
11973526 |
Oct 9, 2007 |
|
|
|
09780843 |
Feb 9, 2001 |
6949114 |
|
|
10141510 |
May 8, 2002 |
|
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|
09283535 |
Apr 1, 1999 |
6458147 |
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|
09780843 |
Feb 9, 2001 |
|
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09188083 |
Nov 6, 1998 |
6371975 |
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09283535 |
Apr 1, 1999 |
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Current U.S.
Class: |
424/423 ;
424/486; 424/78.06; 530/402; 604/506; 604/82; 606/214 |
Current CPC
Class: |
A61B 2017/00004
20130101; A61B 2017/0065 20130101; A61B 2017/00637 20130101; A61B
17/00491 20130101; A61B 2017/00495 20130101; A61P 17/02 20180101;
A61B 17/0057 20130101 |
Class at
Publication: |
424/423 ;
424/486; 424/078.06; 530/402; 604/506; 604/082; 606/214 |
International
Class: |
A61K 31/74 20060101
A61K031/74; A61F 2/06 20060101 A61F002/06; A61K 9/00 20060101
A61K009/00; A61M 31/00 20060101 A61M031/00; A61P 17/02 20060101
A61P017/02; C07K 1/107 20060101 C07K001/107 |
Claims
1. A method comprising providing a first container holding a
biocompatible polymer in lyophilized form, the biocompatible
polymer having a functionality equal to or greater than three,
providing a second container holding a protein solution introducing
the protein solution into the first container for mixing with the
polymer in lyophilized form to reconstitute the polymer and form a
mixture, wherein, upon mixing, the protein solution and the polymer
cross-link.
2. A method according to claim 1 wherein the biocompatible polymer
comprises poly(ethylene glycol) PEG.
3. A method according to claim 1 wherein the protein solution
comprises albumin.
4. A system comprising a first container holding a biocompatible
polymer in lyophilized form, the biocompatible polymer having a
functionality equal to or greater than three, a second container
holding a protein solution an applicator to introduce the protein
solution into the first container for mixing with the polymer in
lyophilized form to reconstitute the polymer and form a mixture,
wherein, upon mixing, the protein solution and the polymer
cross-link.
5. A system according to claim 4 wherein the biocompatible polymer
comprises poly(ethylene glycol) PEG.
6. A system according to claim 4 wherein the protein solution
comprises albumin.
7. A method of treating tissue comprising lyophilizing a
biocompatible polymer having a functionality equal to or greater
than three; providing a protein solution, mixing the protein
solution with the lyophilized polymer to reconstitute the polymer
and form a mixture, wherein, upon mixing, the protein solution and
the polymer cross-link to form a material composition, and applying
the material composition to a tissue region.
8. A method according to claim 7 wherein the biocompatible polymer
comprises poly(ethylene glycol) PEG.
9. A method according to claim 7 wherein the protein solution
comprises albumin.
10. A method comprising lyophilizing a biocompatible polymer having
a functionality equal to or greater than three, providing a protein
solution, and mixing the protein solution with the lyophilized
polymer to reconstitute the polymer and form a mixture, wherein,
upon mixing, the protein solution and the polymer cross-link to
form a material composition.
11. A method according to claim 10 wherein the biocompatible
polymer comprises poly(ethylene glycol) PEG.
12. A method according to claim 10 wherein the protein solution
comprises albumin.
13. A method of treating tissue comprising lyophilizing a
biocompatible polymer having a functionality equal to or greater
than three, providing a protein solution, providing a catheter,
mixing the protein solution with the lyophilized polymer to
reconstitute the polymer and form a mixture, wherein, upon mixing,
the protein solution and the polymer cross-link to form a material
composition, and applying the material composition through the
catheter to a tissue region.
14. A method according to claim 13 wherein the biocompatible
polymer comprises poly(ethylene glycol) PEG.
15. A method according to claim 13 wherein the protein solution
comprises albumin.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of co-pending U.S. patent
application Ser. No. 10/141,510, filed May 8, 2002 and entitled
"Systems, Methods, and Compositions for Achieving Closure of
Vascular Puncture Sites" (now U.S. Pat. No. 7,279,001), which is a
continuation-in-part of U.S. patent application Ser. No.
09/780,843, filed Feb. 9, 2001, and entitled "Systems, Methods, and
Compositions for Achieving Closure of Vascular Puncture Sites,"
which is a continuation-in-part of U.S. patent application Ser. No.
09/283,535, filed Apr. 1, 1999, and entitled "Compositions,
Systems, And Methods For Arresting or Controlling Bleeding or Fluid
Leakage in Body Tissue," which is itself a continuation-in-part of
U.S. patent application Ser. No. 09/188,083, filed Nov. 6, 1998 and
entitled "Compositions, Systems, and Methods for Creating in Situ,
Chemically Cross-linked, Mechanical Barriers."
FIELD OF THE INVENTION
[0002] The invention generally relates to the systems and methods
for delivering biocompatible materials to body tissue to affect
desired therapeutic results.
BACKGROUND OF THE INVENTION
[0003] There are many therapeutic indications today that pose
problems in terms of technique, cost efficiency, or efficacy, or
combinations thereof.
[0004] For example, following an interventional procedure, such as
angioplasty or stent placement, a 5 Fr to 9 Fr arteriotomy remains.
Typically; the bleeding from the arteriotomy is controlled through
pressure applied by hand, by sandbag, or by C-clamp for at least 30
minutes. While pressure will ultimately achieve hemostasis, the
excessive use and cost of health care personnel is incongruent with
managed care goals.
[0005] Various alternative methods for sealing a vascular puncture
site have been tried. For example, collagen plugs have been used to
occlude the puncture orifice. The collagen plugs are intended to
activate platelets and accelerate the natural healing process.
Holding the collagen seals in place using an anchor located inside
the artery has also been tried. Still, patient immobilization is
required until clot formation stabilizes the site. Other problems,
such as distal embolization of the collagen, rebleeding, and the
need for external pressure to achieve hemostasis, also persist.
[0006] As another example, devices that surgically suture the
puncture site percutaneously have also been used. The devices
require the practice of fine surgical skills to place needles at a
precise distance from the edges of the puncture orifice and to form
an array of suture knots, which are tightened and pushed from the
skin surface to the artery wall with a knot pusher, resulting in
puncture edge apposition.
[0007] There remains a need for fast and straightforward mechanical
and chemical systems and methods to close vascular puncture sites
and to accelerate the patient's return to ambulatory status without
pain and prolonged immobilization.
[0008] There also remains a demand for biomaterials that improve
the technique, cost efficiency, and efficacy of these and other
therapeutic indications.
SUMMARY OF THE INVENTION
[0009] One aspect of the invention provides a method comprising
providing a first container holding a biocompatible polymer in
lyophilized form, the biocompatible polymer having a functionality
equal to or greater than three. The method provides a second
container holding a protein solution. The method introduces the
protein solution into the first container for mixing with the
polymer in lyophilized form to reconstitute the polymer and form a
mixture, wherein, upon mixing, the protein solution and the polymer
cross-link. The biocompatible polymer can comprise, e.g.,
poly(ethylene glycol) PEG. The protein solution can comprise, e.g.,
albumin.
[0010] Another aspect of the invention provides a system comprising
a first container holding a biocompatible polymer in lyophilized
form, the biocompatible polymer having a functionality equal to or
greater than three. The system includes a second container holding
a protein solution. The systems includes an applicator to introduce
the protein solution into the first container for mixing with the
polymer in lyophilized form to reconstitute the polymer and form a
mixture, wherein, upon mixing, the protein solution and the polymer
cross-link. The biocompatible polymer can comprise, e.g.,
poly(ethylene glycol) PEG. The protein solution can comprise, e.g.,
albumin.
[0011] Another aspect of the invention provides a method of
treating tissue. The method lyophilizes a biocompatible polymer
having a functionality equal to or greater than three. The method
provides a protein solution. The method mixes the protein solution
with the lyophilized polymer to reconstitute the polymer and form a
mixture, wherein, upon mixing, the protein solution and the polymer
cross-link to form a material composition. The method applies the
material composition to a tissue region. The biocompatible polymer
can comprise, e.g., poly(ethylene glycol) PEG. The protein solution
can comprise, e.g., albumin.
[0012] Another aspect of the method provides a method. The method
lyophilizes a biocompatible polymer having a functionality equal to
or greater than three.
[0013] The method provides a protein solution. The method mixes the
protein solution with the lyophilized polymer to reconstitute the
polymer and form a mixture, wherein, upon mixing, the protein
solution and the polymer cross-link to form a material composition.
The biocompatible polymer can comprise, e.g., poly(ethylene glycol)
PEG. The protein solution can comprise, e.g., albumin.
[0014] Another aspect of the invention provides a method of
treating tissue. The method lyophilizes a biocompatible polymer
having a functionality equal to or greater than three. The method
provides a protein solution. The method provides a catheter. The
method mixes the protein solution with the lyophilized polymer to
reconstitute the polymer and form a mixture, wherein, upon mixing,
the protein solution and the polymer cross-link to form a material
composition. The method applies the material composition through
the catheter to a tissue region. The biocompatible polymer can
comprise, e.g., poly(ethylene glycol) PEG. The protein solution can
comprise, e.g., albumin.
DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a view of a system of functional instruments for
closure of a vascular puncture site e.g., following a vascular
access procedure, comprising a vascular puncture site access
assembly, to gain transcutaneous access to the vascular puncture
site for the purpose of delivering a biocompatible material closure
composition, and a formative component assembly, to house the
components of the biocompatible material closure composition prior
to use.
[0016] FIG. 2 is an enlarged section view of the proximal end of a
catheter assembly that forms a part of the vascular puncture site
access assembly shown in FIG. 1.
[0017] FIG. 3 is a cross section view of the inner and outer
catheter bodies that comprise the catheter assembly shown in FIG.
2, taken generally along section line 3-3 in FIG. 2.
[0018] FIG. 4A is an enlarged section view of the distal end of a
catheter assembly that forms a part of the vascular puncture site
access assembly shown in FIG. 1, showing the expandable structure
carried by the assembly in a collapsed condition.
[0019] FIG. 4B is an enlarged view of the wall of the expandable
structure shown in FIG. 4A, showing its open or woven configuration
that allows blood flow through the structure.
[0020] FIG. 5 is an enlarged section view of the distal end of a
catheter assembly that forms a part of the vascular puncture site
access assembly shown in FIG. 1, showing the expandable structure
carried by the assembly in an expanded condition.
[0021] FIG. 6 is an enlarged side section view of the junction
between the expandable structure and the outer catheter body of the
catheter assembly shown in FIGS. 4A and 5.
[0022] FIGS. 7A and 7B are perspective views of alternative arrays
of composition delivery nozzles located on the catheter assembly
that forms a part of the vascular puncture site access assembly
shown in FIG. 1.
[0023] FIG. 8 is an assembled section view of the components of
formative component assembly shown in FIG. 1.
[0024] FIG. 9 is an enlarged view illustrating the arrangement of
side holes in the first needle of the formative component assembly
shown in FIG. 1.
[0025] FIG. 10 is a perspective view of the individual components
of the formative component assembly shown in FIG. 1 and further
illustrating the catheter assembly shown in FIG. 2 and the
introducer/mixer assembly shown in FIG. 1 coupled together.
[0026] FIGS. 11-16 illustrate the use of the formative component
assembly to deliver a closure composition to a vascular puncture
site, wherein
[0027] FIGS. 11A and 11B are perspective views illustrating the
insertion of the vial component of the formative component assembly
shown in FIG. 1 into to the applicator component;
[0028] FIG. 12 is a perspective view illustrating the insertion of
the syringe component of the formative component assembly shown in
FIG. 1 into to the applicator component;
[0029] FIG. 13 is a perspective view illustrating the procedure of
coupling the assembled formative component assembly shown in FIG. 8
to the introducer/mixer assembly, which is coupled to the catheter
assembly as shown in FIG. 10;
[0030] FIG. 14 is a perspective view illustrating the advancement
of the syringe plunger component of the formative component
assembly and further illustrating the transfer of the liquid
component in the syringe into the vial containing the solid
component mixture of the liquid and the reconstituted solid
components in the vial;
[0031] FIG. 15 is a perspective view illustrating the urging of the
mixture from the vial through the second needle component of the
formative component assembly and into the introducer/mixer
assembly;
[0032] FIG. 16 is a perspective view illustrating the syringe and
vial after the mixture has been transferred from the vial to the
introducer/mixer assembly, and further illustrating residual
mixture in the vial;
[0033] FIG. 17 is a diagrammatic view of blood vessel puncture site
formed to enable the delivery of a diagnostic or therapeutic
instrument through a vascular sheath and over a guide wire;
[0034] FIG. 18 is a diagrammatic view of the blood vessel puncture
site shown in FIG. 17, after removal of the diagnostic or
therapeutic instrument and vascular sheath, keeping the guide wire
deployed;
[0035] FIG. 19 is a diagrammatic view of the blood vessel puncture
site shown in FIG. 18, during deployment of the vascular puncture
site access assembly shown in FIG. 1, the access assembly being
deployed over the guide wire with the expandable structure in a
collapsed condition;
[0036] FIG. 20 is a diagrammatic view of the blood vessel puncture
site shown in FIG. 19, with the vascular puncture site access
assembly deployed and the expandable structure in an expanded
condition serving as a positioner within the blood vessel for the
closure composition delivery nozzles outside the blood vessel;
[0037] FIG. 21 is a diagrammatic view of the blood vessel puncture
site shown in FIG. 20, as the closure composition is being
delivered through the closure composition delivery nozzles outside
the blood vessel; and
[0038] FIG. 22 is a diagrammatic view of the blood vessel puncture
site shown in FIG. 21, after removal of the vascular puncture site
access assembly and after the closure composition has formed a
barrier to seal the puncture site.
DETAILED DESCRIPTION
[0039] Although the disclosure hereof is detailed and exact to
enable those skilled in the art to practice the invention, the
physical embodiments herein disclosed merely exemplify the
invention that may be embodied in other specific structure. While
the preferred embodiment has been described, the details may be
changed without departing from the invention, which is defined by
the claims.
[0040] The systems and methods disclosed herein are shown in the
particular context of closing a vascular puncture site. That is
because the systems and methods are well suited for use in this
indication, and this indication thus provides a representative
embodiment for purposes of description. Still, it should be
appreciated that the systems and methods described can, with
appropriate modification (if necessary), be used for diverse other
indications as well, and in conjunction with delivery mechanisms
that are not necessarily catheter-based. For example, the systems
and methods can be used with delivery mechanisms which spray
materials, e.g., for the purpose of tissue sealing or adhesion
prevention. As another example, the systems and methods can be used
with delivery mechanisms which use cannulas, e.g., for the purpose
of filling tissue voids or aneurysms, or for tissue augmentation.
As yet another example, the systems and methods can be used to
deliver drug or cells to targeted locations.
System Overview
[0041] FIG. 1 shows a system 10 of functional instruments for
closure of a vascular puncture site e.g., following a vascular
access procedure.
[0042] As will be described in greater detail, the instruments of
the system 10 are, during use, deployed in a purposeful manner to
gain transcutaneous access to a vascular puncture site. The
instruments of the system 10 are manipulated to place a
biocompatible material composition outside the blood vessel at the
puncture site. The biocompatible material composition produces a
solid, three dimensional matrix that closes the puncture site.
[0043] In a preferred embodiment, the biocompatible material
composition is comprised of two or more formative components which
are mixed in a liquid state while being delivered by the system 10
transcutaneously to the puncture site. Upon mixing, the formative
components react, in a process called "gelation," to transform in
situ from the liquid state, to a semi-solid (gel) state, and then
to the biocompatible solid state.
[0044] In the solid state, the composition takes the form of a
non-liquid, three-dimensional network. Desirably, the solid
material composition exhibits adhesive strength (adhering it to
adjacent tissue), cohesive strength (forming a mechanical barrier
that is resistant to blood pressure and blood seepage), and
elasticity (accommodating the normal stresses and strains of
everyday activity). These properties provide an effective closure
to the vascular puncture site.
[0045] The solid material composition is also capable of
transforming over time by physiological mechanisms from the solid
state to a biocompatible liquid state, which can be cleared by the
body, in a process called "degradation."
[0046] As FIG. 1 shows, in one embodiment, the system 10 can be
contained, prior to use, in two functional kits 12 and 14.
[0047] The first kit 12 contains a vascular puncture site access
assembly 16. The purpose of the access assembly 16 is to gain
transcutaneous access to the vascular puncture site for the purpose
of delivering the biocompatible material composition.
[0048] The second kit 14 contains a formative component assembly 18
and directions for use 19. The purpose of the formative component
assembly 18 is to house the components of the biocompatible
material composition prior to use. As will be described in greater
detail later, these components are mixed and delivered by the
access assembly 16 to the puncture site. The directions for use 19
provide the user with a step-by-step procedure and information for
use of the assembly 18, as will be described in greater detail
later (see FIGS. 11-16).
[0049] The kits 12 and 14 can take various forms. In the
illustrated embodiment, each kit 12 and 14 comprises a sterile
(e.g, sterilized by ethylene oxide gas), wrapped assembly.
The Access Assembly
[0050] As FIG. 1 shows, the access assembly 16 comprises a catheter
assembly 20 and a component introducer/mixer assembly 22.
The Catheter Assembly
[0051] The catheter assembly comprises a flexible inner catheter
body 24 that is slidably carried within a flexible outer catheter
body 24 (see FIGS. 2 to 5). The inner and outer catheter bodies 24
and 26 can be made from an extruded plastic material, e.g.,
PEBAX.TM. material. The outside diameter of the outer catheter body
26 can vary, e.g., from 6 Fr. to 10 Fr.
[0052] The outside diameter of the outer catheter body 26 is sized
to seal the tissue track 34 through which it is introduced, so that
its presence is hemostatic (see FIGS. 19-21). The tissue track 34
typically will have been previously formed by a vascular introducer
or cannula 28 (see FIG. 17), through which the desired therapeutic
or diagnostic instrument is first introduced (typically over a
guide wire 32) through a puncture site 36 into the vessel, e.g., to
perform coronary angioplasty. After performing the intended
procedure, the instrument 30 and introducer 28 are withdrawn (see
FIG. 18), leaving the puncture site 36 and the tissue track 34. The
outside diameter of the outer catheter body 26 is selected to match
the outside diameter of the vascular introducer 28, so that the
outer catheter body 26, when deployed, will block substantial flow
of blood from the puncture site 36 up the tissue track 34.
[0053] The proximal end of the outer catheter body 26 is secured,
e.g., by adhesive, to the distal end of a preformed y-shaped
adapter 38 (see FIG. 2). The adapter 38 serves as a handle for the
entire catheter assembly 20. A strain relief sheath 40 desirably
encompasses the outer catheter body 26 adjacent the handle 38.
[0054] The proximal end of the inner catheter body 24 extends
through and beyond the handle 38. The exposed end of the inner
catheter body 24 desirably carries a luer fitting 42, so that a
flushing fluid can be introduced through the inner catheter body
24. The inside diameter of the inner catheter body 24 defines an
interior lumen 44 (see FIG. 3) that is sized to accommodate passage
of the guide wire 32.
[0055] A carrier 46 is carried on a track 48 in the handle 38 for
fore and aft sliding movement. The inner catheter body 24 is
adhesively secured within the sliding carrier 46, so that fore and
aft movement of the carrier 46 in the track 48 affects sliding
movement of the inner catheter body 24 (as FIGS. 4A and 5 show). In
response to forward movement of the carrier 46 (as FIG. 4A shows),
the inner catheter body 24 slides in a distal direction within the
outer catheter body 26. In response to aft movement of the carrier
46 (as FIG. 5 shows), the inner catheter body 24 slides in a
proximal direction within the outer catheter body 26.
[0056] A spring biased latch mechanism 50 is desirably coupled to
the carrier 46. The latch mechanism 50 snap-fits into detents 52
(shown in FIG. 2) at the proximal and distal ends of the track 48,
to releasably lock the carrier 46 against movement. Finger pressure
releases the spring biased latch mechanism 50 from the detents 52,
to release the carrier 46 for movement between the proximal and
distal detents 52.
[0057] The interior diameter of the outer catheter body 26 (see
FIGS. 3 to 5) is larger than the exterior diameter of the inner
catheter body 24. In interior passage 54 is thereby defined between
them (see FIG. 3). A port 56 on the handle 38 communicates with the
passage 54 (see FIG. 2). The port 56 terminates with the component
introducer/mixer assembly 22 through intermediate tubing 58. Liquid
components introduced through the assembly 22 exit the passage 54
through one or more nozzles 60 formed near the distal end of the
outer catheter body 26 (see FIG. 6). As FIGS. 3 and 6 show, a thin
wall tube 62 (extruded, e.g., from a polyimide material) desirably
covers the inner catheter body 24, to prevent liquid components
within the passage 54 from adhesively bonding the inner catheter
body 24 to the outer catheter body 26. Free sliding motion of the
inner catheter body 24 within the tube 62 is thereby preserved.
[0058] The nozzles 60 can be arranged in different delivery
patterns. In one embodiment (as FIG. 7A shows), an array of nozzles
60, circumferentially spaced apart, is provided. In another
embodiment (as FIG. 7B shows), the nozzles 60A and 60B are spaced
apart along the axis of the outer catheter body 26, as well as
being staggered to face different directions about the axis.
[0059] The diameter of the nozzles 60 can also vary (e.g., from
0.02'' to 0.035''). The nozzles 60 can all share the same diameter.
Alternatively, the nozzles 60 can have different diameters, to
create preferential flow patterns (the liquid composition following
the path of less flow resistance in preference to a path of greater
flow resistance).
[0060] It is desired that the nozzles 60 reside outside the blood
vessel when the material composition is introduced. To help locate
the nozzles 60 outside the blood vessel, the catheter assembly 20
includes an expandable structure 64 located near to and distally of
the nozzles 60 (see FIGS. 4A and 5).
[0061] The wall 66 of the structure 64 desirably comprises an open
or woven or braided structure comprising interlaced or intersecting
strands or threads 68 (see FIG. 4B), e.g., made from an inert
biocompatable polymeric material, such as nylon. Alternatively, the
outer catheter body 26 can itself be slotted at circumferentially
spaced locations to form the structure 64. The proximal end of the
structure 64 is secured (see FIG. 6), e.g., by a fuse joint 70,
about a gland member 72 that encircles the thin wall tube 62. As
FIG. 6 also shows, the distal end of the outer catheter body 26 is
also secured, e.g., by adhesive, to the gland member 72. An o-ring
74 is also desired placed within the gland member 72 to prevent
leakage of liquid components from the passage 54 into the interior
of the structure 64.
[0062] The distal end of the structure 64 is secured, e.g., by
adhesive or a shrink-fit sleeve, to a region of the inner catheter
body 24 that extends beyond the outer catheter body 26. The inner
catheter body 24 also extends a distance distally beyond the
structure 64, forming a leader 76 (see FIGS. 4A and 5). In use, the
leader 76 is located inside the blood vessel immediately interior
to the puncture site 36 (like the leader 76 in FIGS. 19 and 20). In
use, the array of nozzles 60 is located outside the blood vessel
exterior to the puncture site 36 (like the nozzles 60 in FIG. 20).
Sliding movement of the inner catheter body 24 relative to the
outer catheter body 26 serves to mechanically expand (see FIG. 5)
and collapse (see FIG. 4A) the structure 64, so that this desired
positioning of the nozzles 60 and leader 76 can be achieved.
[0063] Since, in the illustrated embodiment, the structure 64
possesses a wall that is open or woven, the structure 64 permits
blood flow through it, thereby presenting a minimal disruption of
blood flow in the vessel during use. Due to the open or woven
configuration of the structure 64, the positioner can be deployed
in an expanded state within the artery prior to being seated
against the interior of the vessel wall, with minimal disruption of
blood flow. This allows the physician to proceed with the
deployment and positioning of the structure 64 within the vessel in
a deliberate fashion, without being rushed due to ancillary
considerations of attendant blood flow disruption. The open
structure 64 can be deployed while a patient is in an operating
room, and left deployed while the patient is wheeled from the
operating room to another suite, where the vessel closure procedure
is completed. In this way, the operating room, its staff, and its
equipment are made available for another procedure while the vessel
closure procedure is completed in another setting by a medically
trained person, who need not be a medical doctor.
[0064] Desirably, radiopaque marker bands 78 are secured to the
proximal and distal ends of the structure 64, as well as to the
distal-most end of the leader 76. Preferably, the three markers 78
appear at equidistant intervals when the structure 64 is in its
collapsed or stowed condition. Thus, when the structure 64 is in
its expanded condition, the markers 78 no longer appear
equidistant. In this way, the physician can readily gauge by
fluoroscopy the location of the distal-most end of the inner
catheter body 24, as well as the distance between the ends of the
structure 64 and, thereby, assess the position and configuration of
the inner catheter body 24 and the structure 64 near the puncture
site 36.
The Component Introducer/Mixer Assembly
[0065] Before mixing, the components for the material composition
are housed in the formative component assembly 18 contained in the
kit 14 (see FIG. 1), which will be described in greater detail
later.
[0066] As FIG. 10 shows, the proximal end of the introducer/mixer
assembly 22 includes a length of flexible intermediate tubing 58
that couples to the port 56 of the y-adapter/handle 38. The distal
end of the assembly 22 includes a luer fitting 84 that couples to
the formative component assembly 18 (see also FIG. 13).
[0067] Communicating with the tubing 58 in the direction of flow
into the passage 54, are an in-line syringe activated check valve
86, an in-line mixer 88, and an in-line air accumulator 90.
[0068] The in-line syringe activated check valve 86 can take
various forms. In the illustrated embodiment, the valve 84 takes
the form of a conventional, needleless slip luer lock valve made by
Qosina (Edgewood, N.Y.), Product Number 80360. The valve 84 is
normally closed to prevent back flow of blood or other liquid
material through the tubing 58. Back flow of blood, in particular,
from the passage is undesirable, as it creates the potential for
blood contact and deposits material in the introducer/mixer
assembly 22 that can interfere or compete with the desired reaction
between the liquid components that form the material composition.
Connection of a conventional luer fitting carried by the formative
component assembly 18 (for example, fitting 132 shown in FIGS. 10
and 13) opens the valve 86 to allow the introduction of the liquid
components that form the material composition.
[0069] The components of the material composition come into contact
in the liquid state in the in-line mixer 88. In this way, effective
mixing can be achieved outside the catheter assembly 20 that is not
dependent solely upon the dimensions or lengths of the flow paths
within the catheter assembly 20. The mixer 88 comprises a mixing
structure, which can vary. For example, the mixer 88 can comprise a
spiral mixer manufactured by TAH Industries, Inc. (Robbinsville,
N.J.), Part Number 121-090-08.
[0070] The in-line air accumulator 90 comprises a chamber that has
an interior volume sized to trap air that can reside in the
material composition applicator at time of use.
The Formative Component Assembly
[0071] The components forming the material composition can vary.
Generally speaking, however, the components will include a solid
component and a liquid component, which serves as a diluent for the
solid component. Mixing of these two components initiates a
chemical reaction, by which the liquid mixture transforms into a
solid composition. It is the purpose of the formative component
assembly 18 to facilitate the mixing of these two components and
introduction of the mixture into the introducer/mixer assembly 22
and delivery to the catheter assembly 20.
[0072] The formative component assembly 18 can comprise individual
syringes in which the components are separately contained. Further
details of this arrangement are disclosed in copending U.S. patent
application Ser. No. 09/187,384, filed Nov. 6, 1998 and entitled
"Systems and Methods for Applying Cross-Linked Mechanical
Barriers," which is incorporated herein by reference.
[0073] With reference to FIG. 8, an alternative arrangement
provides a unitary applicator 92 in which a vial 94 holding a solid
component 96 and a syringe 98 holding a liquid component 100 can be
placed and kept separate in interior compartments.
[0074] Axial advancement of the syringe plunger 102 propels the
liquid 100 into the vial 94 and brings the two components 96 and
100 together within the vial 94 by placing the solid component 96
into suspension within the liquid component 100. The force created
by this process also urges the liquid suspension into the
introducer/mixer assembly 22 for further mixing and delivery to the
catheter assembly 20.
[0075] The applicator 92 includes a partition 104 that divides the
applicator 92 into a first compartment 106 and a second compartment
108, each having an open end 110. The first compartment 106 is
sized and configured to receive and hold the vial 94. The first
compartment 106 includes a flanged end region 112 that serves to
support the applicator 92 in an upright position (e.g., standing on
a table). The flanged region 112 further serves to receive a cap
114, as will be described in greater detail later. The second
compartment 108 is sized and configured to receive and hold the
syringe 98. While the illustrated embodiment shows the applicator
92 and compartments 106 and 108 having a generally cylindrical
shape, the invention contemplates other configurations not
necessarily accommodating a vial 94 and/or syringe 98.
[0076] The applicator 92 can be made of any suitable inert, rigid
plastic or metal material. In a representative embodiment, the
first compartment 106 is 21/2% inches long, the second compartment
108 is 2 inches long, and the applicator 92 is 1 inch high. This
arrangement readily accommodates a conventional vial 94 and a
conventional syringe 98.
[0077] The syringe 98 can be a conventional syringe 98 having a
plunger 102. The dispensing end 116 includes a luer fitting 118.
The syringe 98 is aseptically pre-filled with the liquid component
100 and a cap 119 is placed over the dispensing end 116 to prevent
leakage and evaporation of the contents.
[0078] A first needle 120 extends along the central line axis of
the applicator 92 and couples the syringe 98 to the vial 94 via a
luer fitting 122 that mates with the luer fitting 118 on the
syringe 98. The needle 120 thereby provides communication between
the first and second compartments 106 and 108. Desirably, the
needle 120 includes a plurality of side holes 124 that serve to
uniformly introduce the contents of the syringe 98 into the vial 94
(see FIG. 9).
[0079] A second needle 126 is offset from the central line axis of
the applicator 92 and serves to couple the vial 94 to a molded
passage 128 that traverses the wall of the second compartment 108.
The molded passage 128 is coupled to the proximal end of a length
of flexible tubing 130. The distal end of the tubing 130 includes a
luer fitting 132 adapted to couple to the leur fitting 84 on the
introducer/mixer assembly 22. This arrangement provides fluid
communication between the vial 94 and the introducer/mixer assembly
22. Optionally, an in-line air vent 131 (shown in phantom lines in
FIG. 10), made, e.g., from a sintered plastic material, can be
located in the tubing 130, or otherwise placed in communication
with the tubing 130, to allow residual air to vent from fluid prior
to entering the introducer/mixer assembly 22.
[0080] The vial 94 is a conventional pharmaceutical vial 94 sized
to hold the solid component 96 and a pre-defined volume of the
liquid component 100, i.e., the volume of liquid component 100
pre-filled in the syringe 98. The vial 94 includes a septum 134
configured to be pierced and penetrated by the needles 120 and 126
when the vial 94 is properly positioned within the first
compartment 106.
[0081] To aid in positioning and securing of the vial 94 within the
compartment 106, the applicator 92 includes a selectively removable
cap 114, as previously noted. The cap 114 mates with the applicator
92, e.g., by snap-fit engagement with the flanged region 112 on the
applicator 92. Desirably, the cap 114 extends into the first
compartment 106 to position and hold the vial 94 in a desired
position after the septum 134 has been pierced by the needles 120
and 126.
[0082] FIG. 10 shows the individual components of the formative
component assembly 18. In use, the physician (or assistant) removes
the cap 114 from the applicator 92. As seen in FIG. 11A, with the
cap 114 removed, the physician slides the first compartment 106
over the vial 94. During this step, the vial 94 can be placed on a
counter, table, or other flat support surface. As seen in FIG. 11B,
the cap 114 is then placed beneath the vial 94 (e.g., on the
counter or table), and the physician continues to slide the first
compartment 106 over the vial 94, to finish piercing the vial
septum 134 with the needles 120 and 126 and locating the vial 94
fully into the first compartment 106. The cap 114 thereafter holds
the vial 94 in this position.
[0083] The cap 119 is then removed from the syringe 98 and residual
air is expressed from the syringe 98, e.g., by holding the syringe
98 with the dispensing end 116 upright and gently tapping the
syringe 98 until essentially all of the residual air rises to the
dispensing end 116 and then advancing the plunger 102 until the air
is expelled (not shown).
[0084] As FIG. 12 shows, the syringe 98 is then placed within the
second compartment 108 and rotated (represented by arrow) to couple
the syringe 98 to the first needle 120 through leur fittings 118
and 122. With the syringe 98 and vial 94 in place within the
applicator 92 and the formative assembly 18 ready for use, as seen
in FIG. 13, the assembly 18 can then be coupled to the
introducer/mixer assembly 22 (shown in phantom lines) by coupling
(represented by arrows) leur fittings 84 and 132.
[0085] As will be apparent, alternatively, the syringe 98 can be
coupled to the first needle 120 prior to the vial 94 being placed
in the first compartment 106.
[0086] With reference now to FIG. 14, the formative component
assembly 18 is then placed in an upright position (i.e., vial
septum 134 pointing upward and dispensing end 116 of the syringe 98
pointing downward). The plunger 102 is then advanced (represented
by arrow) to transfer the contents of the syringe 98 through the
first needle 120 into the vial 94. If desired, the assembly 18 can
be stood on a counter, table, or other flat surface as the plunger
102 is advanced. Alternatively, the plunger 102 can be advanced in
conventional fashion by the thumb of the physician while the
syringe 98, with attached applicator 92, are held between the
forefinger and middle finger, as FIG. 14 shows.
[0087] The propulsion of the liquid component 100 into the vial 94
reconstitutes the solid component 96, mixes the components 96 and
100 (represented by arrows in FIG. 14), and begins the reaction
process. As previously noted, side holes 124 in the first needle
120 assure components 96 and 100 mix quickly and uniformly (see
FIG. 9).
[0088] Fluid pressure created by operation of the syringe 98 urges
the mixture into and through the second needle 126, into the
introducer/mixer assembly 22, as indicated by arrows in FIG. 15.
The introducer/mixer assembly 22 further mixes the mixture and rids
the fluid path of residual air, as previously described. The
mixture flows through the introducer/mixer assembly 22 and through
the catheter assembly 20 and exits the assembly 22 through the
nozzles 60, as also previously described.
[0089] With reference now to FIG. 16, the plunger 102 is advanced
until essentially all of the liquid component 100 is transferred
from the syringe 98 to the vial 94. Generally concurrently, the
mixture is transferred from the vial 94 into the introducer/mixer
22, with only minimal residual mixture remaining in the vial 94. As
will apparent to one skilled in the art, the volume of components
96 and 100 are calculated to account for this residual volume.
[0090] It should be appreciated that the applicator 92 can be
coupled to diverse forms of fluid delivery systems. It can, as
shown, be coupled to a catheter-based system. It can alternatively,
depending upon the indicated use, be coupled to a spray applicator
or to a cannula.
The Material Composition
[0091] The components 96 and 100 of the material composition can
vary. In a preferred embodiment, the solid component 96 comprises
an electrophilic (electrode withdrawing) material having a
functionality of at least three. The liquid component 100 comprises
a solution containing a nucleophilic (electron donator) material
and a buffer. When mixed under proper reaction conditions, the
electrophilic material and buffered nucleophilic material react, by
cross-linking with each other. The cross-linking of the components
form the composition. The composition physically forms a mechanical
barrier 136 (see FIG. 22), which can also be characterized as a
hydrogel.
[0092] The type and concentration of the buffer material controls
the pH of the liquid and solid components 100 and 96, when brought
into contact for mixing. The buffer material desirably establishes
an initial pH in numeric terms, as well regulates change of the pH
over time (a characteristic that will be called the "buffering
capacity").
[0093] The barrier composition 136 exhibits desired mechanical
properties. These properties include adhesive strength (adhering it
to adjacent tissue), cohesive strength (forming a mechanical
barrier that is resistant to blood pressure and blood seepage), and
elasticity (accommodating the normal stresses and strains of
everyday activity). These properties, as well as the relative rapid
rate of gelation that can be achieved, serve to provide a fast and
effective closure to the vascular puncture site.
[0094] The barrier composition 136 is also capable of transforming
over time by physiological mechanisms from the solid state to a
biocompatible liquid state, which can be cleared by the body, in a
process called "degradation."
[0095] The time period that begins when the electrophilic,
nucleophilic, and buffer components have been mixed and ends when
the composition has reached the semi-solid (gel) state will be
called the "gelation time." When in this state, the barrier
composition 136 possesses sufficient cohesive and adhesive strength
to impede blood flow, but still retains a self-sealing property,
possessing the capacity to close in upon and seal the tract left by
the catheter in the composition when the physician removes the
catheter. For sealing a vascular puncture site, the barrier
composition 136 preferably possesses a gelation time that is in the
range of fifteen to sixty seconds. A gelation time in the range of
fifteen to thirty seconds is most preferred. This period allows the
components forming the barrier composition 136 to flow first in a
liquid state, and then in the semi-solid (gel) state, outward along
the axis of the blood vessel. The flow of components during
gelation fills surface irregularities in the tissue region of the
vascular puncture site, before solidification occurs. A gelation
time period of between 10 and 40 seconds also falls well within the
time period a physician typically needs to manipulate and remove
the catheter assembly 20 after delivery of the components to the
puncture site 36. With an experienced physician, the catheter
manipulation and removal time period can be as quick as 10 to 40
seconds, but it can extend, due to circumstances, upwards to 2
minutes. With a gelation time falling within the preferred range,
the formation of the barrier composition does not require a
physician to "watch the clock," but rather attend only to the
normal tasks of injecting the material and then manipulating and
removing the catheter assembly. With a gelation time falling within
the preferred range, it has been discovered that, if the catheter
assembly 20 is removed in 15 seconds to 2 minutes following initial
mixing, the barrier composition 136 has reached a physical state
capable of performing its intended function, while still
accommodating a sealed withdrawal of the catheter assembly 20.
Desirably, after removal of the catheter assembly 20, the physician
applies localized and temporary finger pressure to the skin surface
above the barrier composition 136 for a period of about 5 minutes,
to aid in the closure of the catheter tract in the composition, as
the composition 136 reaches its solid state.
[0096] The barrier composition 136 preferably possesses sufficient
adhesive strength to prevent dislodging from the arteriotomy, once
formed. The composition 136 also has sufficient cohesive strength
to prevent rupture under arterial pressure, i.e., up to about 200
mm Hg. The barrier composition 136 seals the arteriotomy for up to
15 days post-application before loss of mechanical properties
through degradation, and degrades by 30 to 90 days
post-application.
[0097] The gelation time (which indicates the rate at which the
cross-linking reaction occurs) is controlled, inter alia, by the
reaction pH, which the buffer component establishes. The reaction
pH controls the reactivity of nucleophilic groups in the second
component 100, which react with the electrophilic groups in the
first component 96. Generally speaking, the higher the reaction pH
is, the larger is the fraction of nucleophilic groups available for
reaction with the electrophilic groups, and vice versa.
[0098] To achieve a relatively rapid gelation time, a relatively
high initial reaction pH (which, for the illustrated components, is
above 8) is desirable at the time initial mixing of the components
occurs. On the other hand, by the time the mixture is brought into
contact with body tissue at the vascular puncture site, it is
desirable that the mixture possess a more physiologically tolerated
pH level (approximately 7.4).
[0099] However, it has been discovered that, if the initial
reaction pH is too high (which, for the illustrated components, is
believed to be a pH approaching about 9), the gelation time may be
too rapid to consistently accommodate the time period a physician
typically requires to remove the catheter, particularly if the time
period approaches the two minute mark. In this instance, by the two
minute mark, substantial solidification of the composition 136 can
occur, and the composition 136 can lack the cross-linking capacity
to close in about the catheter tract left in the composition upon
removal of the catheter. Under these circumstances, blood leakage
and hematoma formation can result after removal of the catheter
assembly 20.
[0100] Achieving and sustaining a reaction pH to meet a targeted
gelation time is therefore a critical criteria. It has been
discovered that, by purposeful selection of the electrophilic,
nucleophilic, and buffer components, (i) an initially high reaction
pH can be established that is conducive to rapid gelation, before
contact with body tissue occurs, and (ii) the reaction pH can be
lowered as gelation progresses, as the mixture is delivered through
the catheter into contact with body tissue at the vascular puncture
site 36. At the same time, by purposeful selection of the
components, the rate at which the pH is lowered during delivery can
be mediated, so that gelation is sustained at a rate that meets the
gelation time requirements to achieve the desired in situ formation
of the composition 136, one that also possesses sufficient
cross-linking capacity to close about the catheter tract following
removal of the catheter assembly 20 after a time period a physician
typically needs to perform this task.
The Electrophilic Component
[0101] In its most preferred form, the electrophilic (electrode
withdrawing) material 96 comprises a hydrophilic, biocompatible
polymer that is electrophilically derivatized with a functionality
of at least three. Examples include poly(ethylene glycol),
poly(ethylene oxide), poly(vinyl alcohol),
poly(vinylpyrrolidinone), poly(ethyloxazoline), and poly(ethylene
glycol)-co-poly(propylene glycol) block copolymers.
[0102] As used herein, a polymer meeting the above criteria is one
that begins with a multiple arm core (e.g., pentaerythritol) and
not a bifunctional starting material, and which is synthesized to a
desired molecular weight (by derivatizing the end groups), such
that polymers with functional groups greater than or equal to three
constitute (according to gel permeation chromotography--GPC) at
least 50% or more of the polymer blend.
[0103] The material 96 is not restricted to synthetic polymers, as
polysaccharides, carbohydrates, and proteins could be
electrophilically derivatized with a functionality of at least
three. In addition, hybrid proteins with one or more substitutions,
deletions, or additions in the primary structure may be used as the
material 96. In this arrangement, the protein's primary structure
is not restricted to those found in nature, as an amino acid
sequence can be synthetically designed to achieve a particular
structure and/or function and then incorporated into the material.
The protein of the polymer material 96 can be recombinantly
produced or collected from naturally occurring sources.
[0104] Preferably, the polymer material 96 is comprised of
poly(ethylene glycol) (PEG) with a molecular weight preferably
between 9,000 and 12,000, and most preferably 10,500.+-.1500. PEG
has been demonstrated to be biocompatible and non-toxic in a
variety of physiological applications. The preferred concentrations
of the polymer are 5% to 35% w/w, more preferably 5% to 20% w/w.
The polymer can be dissolved in a variety of solutions, but sterile
water is preferred.
[0105] The most preferred polymer material 96 can be generally
expressed as compounds of the formula: PEG-(DCR-CG).sub.n
[0106] Where: [0107] DCR is a degradation control region. [0108] CG
is a cross-linking group. [0109] n.gtoreq.3
[0110] The electrophilic CG is responsible for the cross-linking of
the preferred nucleophilic material 96, as well as binding the
composition 136 to the like material in the surrounding tissue, as
will be described later. The CG can be selected to selectively
react with thiols, selectively react with amines, or react with
thiols and amines. CG's that are selective to thiols include vinyl
sulfone, N-ethyl maleimide, iodoacetamide, and orthopyridyl
disulfide. CG's that are selective to amines include aldehydes.
Non-selective electrophilic groups include active esters, epoxides,
oxycarbonylimidazole, nitrophenyl carbonates, tresylate, mesylate,
tosylate, and isocyanate. The preferred CG's are active esters,
more preferred, an ester of N-hydroxysuccinimide. The active esters
are preferred since they react rapidly with nucleophilic groups and
have a non-toxic leaving group, e.g., hydroxysuccinimide.
[0111] The concentration of the CG in the polymer material 96 can
be used to control the rate of gelation. However, changes in this
concentration typically also result in changes in the desired
mechanical properties of the hydrogel.
[0112] The rate of degradation is controlled by the degradation
control region (DCR), the concentration of the CG's in the polymer
solution, and the concentration of the nucleophilic groups in the
protein solution. Changes in these concentrations also typically
result in changes in the mechanical properties of the hydrogel, as
well as the rate of degradation.
[0113] The rate of degradation (which desirably occurs in about 30
days) is best controlled by the selection of the chemical moiety in
the degradation control region, DCR. If degradation is not desired,
a DCR can be selected to prevent biodegradation or the material can
be created without a DCR. However, if degradation is desired, a
hydrolytically or enzymatically degradable DCR can be selected.
Examples of hydrolytically degradable moieties include saturated
di-acids, unsaturated di-acids, poly(glycolic acid), poly(DL-lactic
acid), poly(L-lactic acid), poly(.xi.-caprolactone),
poly(.delta.-valero-lactone), poly(.gamma.-butyrolactone),
poly(amino acids), poly(anhydrides), poly(orthoesters),
poly(ortho-carbonates), and poly(phosphoesters), and derivatives
thereof. A preferred hydrolytically degradable DCR is gluturate.
Examples of enzymatically degradable DCR's include Leu-Gly-Pro-Ala
(collagenase sensitive linkage) and Gly-Pro-Lys (plasmin sensitive
linkage). It should also be appreciated that the DCR could contain
combinations of degradable groups, e.g. poly(glycolic acid) and
di-acid.
[0114] While the preferred polymer is a multi-armed structure, a
linear polymer with a functionality, or reactive groups per
molecule, of at least three can also be used. The utility of a
given PEG polymer significantly increases when the functionality is
increased to be greater than or equal to three. The observed
incremental increase in functionality occurs when the functionality
is increased from two to three, and again when the functionality is
increased from three to four. Further incremental increases are
minimal when the functionality exceeds about four.
[0115] A preferred polymer may be purchased from SunBio Company
((PEG-SG).sub.4, having a molecular weight of 10,500.+-.1500)(which
will sometimes be called the "SunBio PEG").
The Nucleophilic Component
[0116] In a most preferred embodiment, the nucleophilic material
100 includes non-immunogenic, hydrophilic proteins. Examples
include serum, serum fractions, and solutions of albumin, gelatin,
antibodies, fibrinogen, and serum proteins. In addition, water
soluble derivatives of hydrophobic proteins can be used. Examples
include solutions of collagen, elastin, chitosan, and hyaluronic
acid. In addition, hybrid proteins with one or more substitutions,
deletions, or additions in the primary structure may be used.
[0117] Furthermore, the primary protein structure need not be
restricted to those found in nature. An amino acid sequence can be
synthetically designed to achieve a particular structure and/or
function and then incorporated into the nucleophilic material 100.
The protein can be recombinantly produced or collected from
naturally occurring sources.
[0118] The preferred protein solution is 25% human serum albumin,
USP. Human serum albumin is preferred due to its biocompatibility
and its ready availability.
[0119] The uses of PEG polymers with functionality of greater than
three provides a surprising advantage when albumin is used as the
nucleophilic material 100. When cross-linked with higher
functionality PEG polymers, the concentration of albumin can be
reduced to 25% and below. Past uses of difunctional PEG polymers
require concentrations of albumin well above 25%, e.g. 35% to 45%.
Use of lower concentrations of albumin result in superior tissue
sealing properties with increased elasticity, a further desired
result. Additionally, 25% human serum albumin, USP is commercially
available from several sources, however higher concentrations of
human serum albumin, USP are not commercially available. By using
commercially available materials, the dialysis and ultrafiltration
of the albumin solution, as disclosed in the prior art, is
eliminated, significantly reducing the cost and complexity of the
preparation of the albumin solution.
[0120] To minimize the liberation of heat during the cross-linking
reaction, the concentration of the cross-linking groups of the
fundamental polymer component is preferably kept less than 5% of
the total mass of the reactive solution, and more preferably about
1% or less. The low concentration of the cross-linking group is
also beneficial so that the amount of the leaving group is also
minimized. In a typical clinical application, about 50 mg of a
non-toxic leaving group is produced during the cross-linking
reaction, a further desired result. In a preferred embodiment, the
CG comprising an N-hydroxysuccinimide ester has demonstrated
ability to participate in the cross-linking reaction with albumin
without eliciting adverse immune responses in humans.
The Buffer Component
[0121] In the most preferred embodiment, a PEG reactive ester
reacts with the amino groups of the albumin and other tissue
proteins, with the release of N-hydroxysuccinimide and the
formation of a link between the PEG and the protein. When there are
multiple reactive ester groups per PEG molecule, and each protein
has many reactive groups, a network of links form, binding all the
albumin molecules to each other and to adjacent tissue
proteins.
[0122] This reaction with protein amino groups is not the only
reaction that the PEG reactive ester can undergo. It can also react
with water (i.e., hydrolyze), thereby losing its ability to react
with protein. For this reason, the PEG reactive ester must be
stored dry before use and dissolved under conditions where it does
not hydrolyze rapidly. The storage container for the PEG material
desirably is evacuated by use of a vacuum, and the PEG material is
stored therein under an inert gas, such as Argon or Nitrogen.
Another method of packaging the PEG material is to lyophilize the
PEG material and store it under vacuum, or under an inert gas, such
as Argon or Nitrogen, as will be described in greater detail later.
Lyophilization provides the benefits of long term storage and
product stability, as well as allows rapid dissolution of the PEG
material in water.
[0123] The conditions that speed up hydrolysis tend to parallel
those that speed up the reaction with protein; namely, increased
temperature; increased concentration; and increased pH (i.e.,
increased alkali). In the illustrated embodiment, temperature
cannot be easily varied, so varying the concentrations and the pH
are the primary methods of control.
[0124] It is the purpose of the buffer material (which is added to
the nucleophilic albumin material 100 prior to mixing with the
electrophilic PEG material 96) to establish an initial pH to
achieve a desired gelation time, and to sustain the pH as added
acid is produced by the release of N-hydroxysuccinimide during
cross linking and hydrolysis.
[0125] pH is the special scale of measurement established to define
the concentration in water of acid (H+) or alkali (OH--) (which,
strictly speaking, indicates hydrogen ion activity). In the pH
scale, solutions of acid (H+) in water have a low pH, neutrality is
around pH 7, and solutions of base (OH--) in water have a high pH.
The pH scale is logarithmic. A change of one pH unit (e.g., from pH
9 to pH 10) corresponds to a ten-fold change in concentration
(i.e., hydrogen ion activity). Thus, reactions which are increased
by alkali, such as hydrolysis of PEG reactive ester, are expected
to increase in rate by a factor of ten for each unit increase in
pH.
[0126] The buffer material is a mixture of molecules, added to the
albumin, that can moderate pH changes by reacting reversibly with
added acid (H+) or base (OH--). The pH moderating effect can be
measured by titration, i.e., by adding increasing amounts of H+ or
OH-- to the buffer material, measuring the pH at each step, and
comparing the pH changes to that of a similar solution without the
buffer.
[0127] Different buffers exert a maximum pH moderating effect
(i.e., the least change in pH with added H+ or OH--) at different
pH's. The pH at which a given buffer exerts its maximum pH
moderating effect is called its pK.
[0128] Even when the pH matches the pK for a given buffer, added
acid or base will produce some change in pH. As the pH changes from
the pK value, the moderating effect of the buffer decreases
progressively (e.g., 67% less at +/-1 pH unit from pK, and 90% less
at +/-1.6 pH unit from pK). The moderating effect is also
proportional to the buffer concentration. Thus, increasing the
buffer concentration increases the ability to moderate pH
changes.
[0129] The overall buffering effect at any pH is the sum of all
buffering species present, and has also been earlier called the
buffering capacity. The higher the buffering capacity, the more
acid or base must be added to produce a given pH change. Stated
differently, the higher the buffering capacity, the longer a given
buffer is able to sustain a targeted pH range as acid or base is
being added to change the pH.
[0130] Albumin itself contains amino, carboxyl, and other groups,
which can reversible react with acid and base. That is, albumin
itself is a buffer. Also, due to the many different buffering
groups that albumin possesses, albumin (e.g., Plasbumin) can buffer
over a relatively broad pH range, from below pH 6 to over pH 10.
However, it has been discovered that albumin lacks the buffering
capacity to, by itself, counterbalance the additional acid (H+)
that is produced as a result of hydrolysis and the PEG-albumin
cross-linking, given the PEG concentrations required to meet the
therapeutic objectives for the composition. Thus, in the preferred
embodiment, a buffer material must be added to the albumin to
provide the required buffering capacity.
[0131] The buffer material must meet several criteria. The buffer
material must be (1) non-toxic, (2) biocompatible, (3) possess a pK
capable of buffering in the pH range where the desirable gelation
time exists, and (4) must not interfere with the reaction of
protein with the selected PEG reactive ester. Amine-containing
buffers do not meet criteria (4).
[0132] To meet criteria (3), the buffer material should have a
buffering capacity at the desired cross-linking pH (i.e., according
todicated by its pK) that is high enough to counterbalance the
additional acid (H+) produced as a result of the cross-linking
reaction and hydrolysis, i.e., to keep the pH high enough to
achieve the desired gelation time.
[0133] It has been discovered, through bench testing, that when
cross-linking the SunBio PEG with albumin (Plasbumin), a range of
gelation times between an acceptable moderate time (about 30
seconds) to a rapid time (about 2 seconds) can be achieved by
establishing a pH range from about 8 (the moderate times) to about
10 (the rapid times). Ascertaining the cross-linking pH range aids
in the selection of buffer materials having pK's that can provide
the requisite buffering capacity within the pH range.
[0134] Phosphate, tris-hydroxymethylaminomethane (Tris), and
carbonate are all non-toxic, biocompatible buffers, thereby meeting
criteria (1) and (2). Phosphate has a pK of about 7, which provides
increased buffering capacity to albumin at pH's up to about 8.5.
Tris has a pK of about 8, which provides increased buffering
capacity to albumin at pH's up to about 9.5. Addition of Tris to
albumin (Plasbumin) at a concentration of 60 mM approximately
doubles the buffering capacity of the albumin at a pH near 9.
Carbonate has a pK of about 10, and provides increased buffering
capacity to albumin in the higher pH ranges. Depending upon the
gellation time that is targeted, formulations of Tris, carbonate,
and albumin can be used for the buffer material.
EXAMPLE
Carbonate Buffer/Tris Buffer Formulations
[0135] Albumin (Human 25%, Plasbumin.RTM.-25 manufactured by Bayer
Corporation) was buffered using Sodium Carbonate Anhydrous
(Na.sub.2CO.sub.3) (FW 106.0) ("Carbonate Buffer") mixed with
Tris-hydroxymethylaminomethane (C.sub.4H.sub.11NO.sub.3) (FW 121.1)
("Tris Buffer"). The buffered albumin formulations (2 cc) were
mixed with 2 cc of the SunBio PEG (0.45 g of PEG suspended in 2.2
cc of water), to provide 17% w/w PEG solids. The components were
mixed in the manner described in Example 1. The pH of the buffered
albumin formulation (albumin plus buffer material) and the gelation
time (as described above) and were recorded.
[0136] Table 1 summarizes the results: TABLE-US-00001 TABLE 1
Albumin Carbonate Tris Device Gelling (Human Buffer Buffer (Outside
Time 25%) (ml) (grams) (grams) pH Diameter) (Seconds) 20 0 0.217
8.3 7 Fr 11 20 0 0.290 8.5 7 Fr 7-8 20 0.075 0.145 8.7 7 Fr 5-6 20
0.138 0.145 9.0 7 Fr 2-3
[0137] Table 1 shows rapid gelation times. This is believed due to
the larger concentration of multiple functionality PEG in the
SunBio PEG, as well as the enhanced buffering capacity that the
Tris Buffer (pK 8) provides in the lower pH range (7 to 9). It is
also believed that the gelation time will also vary, given the same
composition, according to the size and configuration of the
delivery device. The addition of Carbonate Buffer (in the pH 8.7
and pH 9 compositions) leads to a further decrease in gelation
time, at an increased pH.
[0138] Tests of pH 8.3 and pH 8.5 compositions in Table 1 have
demonstrated that both composition are successful in sealing
femoral puncture sites in sheep in 25 to 40 seconds. The tests also
show that either composition possesses sufficient cross-linking
capacity to close about the catheter tract following removal of the
catheter upwards to two minutes after delivery of the material.
Both compositions thereby readily accommodate variations in
procedure time.
[0139] Tests of pH 8.7 composition in Table 1 have also
demonstrated that the composition is successful in sealing femoral
puncture sites in sheep in 25 to 40 seconds. The tests also show
that, due to the more rapid gelation time, the composition does not
possesses sufficient cross-linking capacity to consistently close
about the catheter tract following removal of the catheter two
minutes after delivery of the material. In this respect, the pH 8.7
composition, despite its faster gelation time, is not as
accommodating to changes in procedure time as the pH 8.3 and pH 8.5
compositions, described above. For these reasons, the most
preferred range for vessel puncture sealing is between pH 8.3 and
pH 8.5.
[0140] Further details of the material composition are found in
copending U.S. patent application Ser. No. 09/780,014, filed Feb.
9, 2001, and entitled "Systems, Methods, and Compositions for
Achieving Closure of Vascular Puncture Sites.
REPRESENTATIVE EMBODIMENT
[0141] In a representative embodiment employed with a 7 FR device,
the vial 94 contains 600 mg.+-.10% of lyophilized SunBio PEG-SG
(4-arm polyethylene glycol tetrasuccinimidyl glutarate--MW
10,500.+-.1500). The lyophilization process will be described in
detail later. The syringe 98 contains 6 ml of water and 2 ml of
buffered 25% w/w human serum albumin, USP. The buffered 25% albumin
is made by adding 0.217 g. of Tris-hydroxymethlaminomethane
(C.sub.4H.sub.11NO.sub.3) (FW 121.1) (TRIS Buffer) to 20 cc of
Bayer Plasbumin.RTM.-25 to obtain a pH between 8.0 and 8.7, most
preferably between 8.3 and 8.5. This composition is described in
Table 1.
The Lyophilization Process
[0142] The PEG material is moisture sensitive, i.e., it can be
subject to rapid degradation upon exposure to moisture. This
moisture sensitivity can limit the stability of the PEG material
and thus its long-term storage or "shelf life." Therefore, as
previously noted, it may be desirable that the PEG material be
lyophilized and stored under vacuum or inert gas. During
lyophilization, a solid substance is isolated from solution by
freezing the solution and evaporating the ice under vacuum. The
process removes essentially all moisture from the solid substance.
By removing essentially all moisture from the PEG, the shelf life
can be significantly extended.
[0143] A representative lyophilization procedure employing a Stokes
Lyophilizer follows:
Sterilize Lyophilizer
[0144] In preparing lyophilizer, clean the chamber before use. The
sterilization cycle can be run, if needed, to clean the chamber.
Before sterilizing chamber, inspect for broken glass, stoppers,
residual spilled product, and tape. Clean chamber shelves with
alcohol. Check and replace vacuum pump oil as required.
[0145] 2. Pre-freeze lyophilizer at least 120 minutes before
loading the vials into the lyophilizer.
[0146] 3. Fill vials with 4 ml polymer solution (10% to 20% w/w
solution, most desirably 15% w/w solution, PEG-SG in aqueous
solution (sterile water)).
[0147] 4. Place vials in trays into the lyophilizer.
[0148] 5. Complete lyophilization according to the following table,
to yield, in each vial 600 mg.+-.10% of lyophilized PEG-SG
material. TABLE-US-00002 Pre-Freeze Segment Segment Vacuum Ramp/
Number Description Temperature Time (mTorr) Soak 1 Loading
-50.degree. C. 1 minute Off Ramp 2 Pre-freeze -50.degree. C. Max.
time Off Soak 3 Pre-freeze -50.degree. C. 60 minutes Off Ramp 4
Pre-freeze -40.degree. C. 10 minutes 50 Ramp
[0149] TABLE-US-00003 Primary Dry Segment Segment Temper- Vacuum
Ramp/ Number Description ature Time (mTorr) Soak 1 Primary
+10.degree. C. 1200 minutes 50 Ramp Drying 2 Primary +20.degree. C.
1200 minutes 50 Ramp Drying 3 Primary +20.degree. C. 1920 minutes
50 Soak Drying
[0150] TABLE-US-00004 Cycle End Segment Description Temperature
Time Ramp/Soak N.sub.2 Backfill +20.degree. C. 30 min. to Soak 14.7
PSIA Stoppering +20.degree. C. N/A N/A
[0151] In use, the 600 mg.+-.10% lyophilized PEG-SG material in
each vial is reconstituted with 2 ml buffered human serum albumin
(25%) and 6 ml water.
Representative Use of the System to Deliver Material Compositions
to Close Vascular Puncture Sites
The Introduction Stage
(The Composition Liquid Phase)
[0152] In the first stage (see FIG. 19), the physician primes the
selected catheter assembly 20 and selected introducer/mixing
assembly 22 with sterile water or saline. The physician then
introduces the selected catheter assembly 20 through the tissue
track 34 partially into the blood vessel through the vascular
puncture 36. As FIG. 19 shows, the structure 64 is in a collapsed
condition at this stage.
[0153] Typically, the catheter assembly 20 is introduced along a
guide wire 32. As earlier explained and as shown in preceding FIGS.
17 and 18, the guide wire 32 will have been previously introduced
percutaneously, through a wall of the blood vessel, to guide
passage of a desired therapeutic or diagnostic instrument 30 into
the blood vessel. As also previously explained, the diameter of the
outer catheter body 26 of the catheter assembly 20 is preferably
sized to seal, but not enlarge, the tissue track 34. In other
words, the outside diameter of the outer catheter body 26
substantially matches the outside diameter of the vascular
introducer 28 (by now retracted).
[0154] As FIG. 20 shows, the structure 64 is expanded within the
blood vessel (as previously described). The physician applies back
pressure on the catheter assembly 20, bringing the expanded
structure 64 into contact with the interior of the vessel wall. By
gauging the back pressure, the physician locates the nozzles 60
outside the puncture site 36, as FIG. 20 shows. The physician links
the formative component assembly 18 through the introducer/mixer
assembly 22 to the catheter assembly 20 (as shown in FIG. 13).
[0155] Operation of the formative component assembly 18, as
previously described, expresses the components 96 and 100, while in
liquid form, through the mixer 88 and down the catheter assembly 20
toward the nozzles 60. The gelating components 138 flow out the
nozzles 60 and into the subcutaneous tissue surrounding the vessel,
as FIG. 21 shows. The catheter assembly 20, which is sized to seal
the tissue track 34, blocks substantial flow in a path up the
tissue track 34. Thus, the gelating components 138 are directed in
a flow radially away from the axis of the catheter assembly 20 and
along the axis of the vessel, as FIG. 21 shows.
[0156] In FIG. 21, the nozzles 60 are arranged in a
circumferentially spaced array, as shown in FIG. 7A. The array is
desirably close to the puncture site 36. If the blood vessel has be
accessed before in the same region, scar tissue may be present
adjacent to the puncture site 36, and the nozzles 60, arranged as
shown in FIG. 7A, may reside in the scar tissue region. The scar
tissue could interfere with the passage of the gelating components
138. In this circumstance, it may be desirable to arrange the
nozzles 60 in the superior-inferior pattern shown in FIG. 7B, in
which another array of superior nozzles 60B (located free of the
scar tissue region) are axially spaced away from the array of
inferior nozzles 60A (located within the scar tissue region). In
this arrangement, it is desirable to size the superior nozzles 60B
smaller than the inferior nozzles 60A. For example, the superior
nozzles 60B can have an outside diameter of about 0.020 inches,
whereas the inferior nozzles 60A can have an outside diameter of
about 0.035 inches. The differential sizing of the nozzles 60A and
60B creates differential flow, creating a preferred normal flow
path (of least flow resistance) through the inferior nozzles 60A,
but allowing alternative flow through the superior nozzles 60B
should increased flow resistance be encountered through the
inferior nozzles 60A due to surrounding tissue morphology.
[0157] The spacing between the nozzles 60A and 60B can also vary.
For example, the inferior nozzles 60A can be spaced from the
structure 64 by 3 to 10 mm, whereas the superior nozzles 60B can be
further spaced 5 to 15 mm from the structure 64.
[0158] The size of the catheter assembly 20 is selected according
to the outside diameter of the introducer sheath 28 used during the
preceding therapeutic or diagnostic procedure, during which the
arteriotomy was made. For example, a 6 Fr introducer sheath 28
typically has an outside diameter of 7 Fr, so a 7 Fr diameter
catheter assembly 20 is selected to seal the arteriotomy after
removal of the introducer sheath 28. The gelating composition 138
is delivered in a liquid state adjacent to the arteriotomy, while
the catheter assembly 20 prevents the liquid from filling the
tissue track 34. This feature ensures that the material composition
remains at the arteriotomy for maximum efficacy.
[0159] The incoming flow, directed in this manner, creates a tissue
space about the puncture site 36 along the axis of the vessel. The
gelating components 138 fill this space.
[0160] In the gelation process, the electrophilic component and the
nucleophilic component cross-link, and the developing composition
138 gains cohesive strength to close the puncture site 36. The
electrophilic component also begins to cross-link with nucleophilic
groups on the surrounding tissue mass. Adhesive strength forms,
which begins to adhere the developing composition to the
surrounding tissue mass.
[0161] During the introduction stage, before internal cohesive and
tissue adhesive strengths fully develop, a portion of the gelating
components 138 can enter the blood vessel through the puncture site
36. Upon entering the blood stream, the gelating components 138
will immediately experience physical dilution. The dilution expands
the distance between the electrophilic component and the
nucleophilic component, making cross-linking difficult. In
addition, the diluted components now experience an environment
having a pH (7.3 to 7.4) lower than the an effective reactive pH
for cross-linking (which is above 8) (as an example, a typical
gelation time at pH 8.3 is about 15 to 20 seconds, whereas a
typical gelation time at pH 7.4 is over 10 minutes). As a result,
incidence of cross-linking within the blood vessel, to form the
hydrogel composition, is only a fraction of what it is outside the
vessel, where gelation continues.
[0162] Furthermore, the diluted electrophilic component will absorb
nucleophilic proteins present in the blood. This reaction further
reduces the reactivity of the electrophilic component. In blood,
the diluted electrophilic component is transformed into a
biocompatible, non-reactive entity, which can be readily cleared by
the kidneys and excreted. The diluted nucleophilic component 100 is
a naturally occurring protein that is handled in normal ways by the
body.
[0163] The Introduction Stage (The Composition Liquid Phase)
preferably last about 5 to 30 seconds from the time the physician
begins to mix the components 96 and 100.
The Localized Compression Stage (The Semi-Solid Composition
Phase)
[0164] The second stage begins after the physician has delivered
the entire prescribed volume of components 96 and 100 to the tissue
mass of the vessel puncture site 36 and allowed the cross-linking
of the components 96 and 100 to progress to the point where a
semi-solid gel occupies the formed tissue space.
[0165] At this point (as FIG. 22 shows), the physician collapses
the structure 64 and withdraws the catheter assembly 20 and guide
wire 32 from the tissue track 34. The physician now simultaneously
applies localized and temporary compression to the exterior skin
surface surrounding the tissue track 34.
[0166] The application of localized pressure serves two purposes.
It is not to prevent blood flow through the tissue track 34, as
cross-linking of the components 96 and 100 has already proceeded to
create a semi-solid gel having sufficient cohesive and adhesive
strength to impede blood flow from the puncture site. Rather, the
localized pressure serves to compress the tissue mass about the
semi-solid gel mass. This compression brings the semi-solid gel
mass into intimate contact with surrounding tissue mass, while the
final stages of cross-linking and gelation take place.
[0167] Under localized compression pressure, any remnant catheter
track existing through the gel mass will also be closed.
[0168] Under localized compression pressure, surface contact
between the adhesive gel mass and tissue is also increased, to
promote the cross-linking reaction with nucleophilic groups in the
surrounding tissue mass. Adhesive strength between the gel mass and
tissue is thereby allowed to fully develop, to firmly adhere the
gel mass to the surrounding tissue as the solid composition 136
forms in situ.
[0169] During this stage, blood will also contact the vessel-side,
exposed portion of the gel mass, which now covers the tissue
puncture site. The electrophilic component will absorb nucleophilic
proteins present in the blood, forming a biocompatible surface on
the inside of the vessel.
[0170] The Localized Compression Stage (The Composition Semi-Solid
(Gel) Phase) preferably last about 3 to 10 minutes from the time
the physician withdraws the catheter assembly 20.
The Hemostasis Stage
The Composition Solid Stage
[0171] At the end of the Localized Compression Stage, the solid
composition 136 has formed (as FIG. 22 shows). Hemostasis has been
achieved. The individual is free to ambulate and quickly return to
normal day-to-day functions.
[0172] The mechanical properties of the solid composition 136 are
such to form a mechanical barrier. The composition 136 is well
tolerated by the body, without invoking a severe foreign body
response.
[0173] The mechanical properties of the hydrogel are controlled, in
part, by the number of crosslinks in the hydrogel network as well
as the distance between crosslinks. Both the number of crosslinks
and the distance between crosslinks are dependent on the
functionality, concentration, and molecular weight of the polymer
and the protein.
[0174] Functionality, or the number of reactive groups per
molecule, affects the mechanical properties of the resulting
hydrogel by influencing both the number of and distance between
crosslinks. As discussed previously, the utility of a given polymer
significantly increases when the functionality is increased to be
greater than or equal to three. The observed incremental increase
in functionality occurs when the functionality is increased from
two to three, and again when the functionality is increased from
three to four. By increasing the functionality of the polymer or
protein at a constant concentration, the concentration of
crosslinking groups available for reaction are increased and more
crosslinks are formed. However, increased mechanical properties
cannot be controlled with functionality alone. Ultimately, the
steric hindrances of the protein or polymer to which the reactive
groups are attached predominate and further changes in the
mechanical properties of the hydrogel are not observed. The effect
of functionality is saturated when the functionality reaches about
four.
[0175] The concentration of the protein and polymer also affect the
mechanical properties of the resulting hydrogel by influencing both
the number of and distance between crosslinks. Increasing the
protein and polymer concentration increases the number of available
crosslinking groups, thereby increasing the strength of the
hydrogel. However, decreases in the elasticity of the hydrogel are
observed as the concentration of the protein and polymer is
increased. The effects on the mechanical properties by
concentration are limited by the solubility of the protein and
polymer.
[0176] The polymer and protein molecular weight affects the
mechanical properties of the resulting hydrogel by influencing both
the number of and distance between crosslinks. Increasing the
molecular weight of the protein and polymer decreases the number of
available crosslinking groups, thereby decreasing the strength of
the hydrogel. However, increases in the elasticity of the hydrogel
are observed with increasing molecular weight of the protein and
polymer. Low molecular weight proteins and polymers result in
hydrogels that are strong, but brittle. Higher molecular weight
proteins and polymers result in weaker, but more elastic gels. The
effects on the mechanical properties by molecular weight are
limited by the solubility of the protein and polymer. However,
consideration to the ability of the body to eliminate the polymer
should be made, as large molecular weight polymers are difficult to
clear.
The Degradation Stage (The Composition Re-Absorption Phase)
[0177] Over a controlled period, the material composition is
degraded by physiological mechanisms. Histological studies have
shown a foreign body response consistent with a biodegradable
material, such as VICRYL.TM. sutures. As the material is degraded,
the tissue returns to a quiescent state. The molecules of the
degraded genus hydrogel composition are cleared from the
bloodstream by the kidneys and eliminated from the body in the
urine. In a preferred embodiment of the invention, the material
loses its physical strength during the first fifteen days, and
totally resorbs in about four to eight weeks, depending upon the
person's body mass.
[0178] The foregoing is considered as illustrative only of the
principles of the invention. Furthermore, since numerous
modifications and changes will readily occur to those skilled in
the art, it is not desired to limit the invention to the exact
construction and operation shown and described. While the preferred
embodiment has been described, the details may be changed without
departing from the invention, which is defined by the claims.
* * * * *