U.S. patent application number 10/056895 was filed with the patent office on 2002-10-31 for compositions, systems, and methods for creating in situ, chemically cross-linked, mechanical barriers.
This patent application is currently assigned to NeoMend, Inc.. Invention is credited to Cruise, Gregory M., Hnojewyj, Olexander.
Application Number | 20020161399 10/056895 |
Document ID | / |
Family ID | 22691715 |
Filed Date | 2002-10-31 |
United States Patent
Application |
20020161399 |
Kind Code |
A1 |
Cruise, Gregory M. ; et
al. |
October 31, 2002 |
Compositions, systems, and methods for creating in situ, chemically
cross-linked, mechanical barriers
Abstract
A biocompatible and biodegradable barrier material is applied to
a tissue region, e.g., to seal a vascular puncture site. The
barrier material comprises a compound, which is chemically
cross-linked without use of an enzyme to form a non-liquid
mechanical matrix. The compound preferably includes a protein
comprising recombinant or natural serum albumin, which is mixed
with a polymer that comprises poly(ethylene) glycol (PEG), and,
most preferably, a multi-armed PEG polymer.
Inventors: |
Cruise, Gregory M.;
(Fremont, CA) ; Hnojewyj, Olexander; (Saratoga,
CA) |
Correspondence
Address: |
RYAN KROMHOLZ & MANION, S.C.
Post Office Box 26618
MILWAUKEE
WI
53226
US
|
Assignee: |
NeoMend, Inc.
|
Family ID: |
22691715 |
Appl. No.: |
10/056895 |
Filed: |
January 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10056895 |
Jan 25, 2002 |
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09188083 |
Nov 6, 1998 |
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6371975 |
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Current U.S.
Class: |
606/214 |
Current CPC
Class: |
B01F 25/4231 20220101;
B01F 33/50112 20220101; A61B 18/1487 20130101; A61B 2017/005
20130101; A61P 7/04 20180101; A61B 2017/00495 20130101; A61B
17/00491 20130101; A61B 18/1482 20130101; A61B 17/0057 20130101;
A61B 2090/064 20160201; A61B 2017/0065 20130101; A61B 2017/00084
20130101; A61M 25/0662 20130101; A61B 17/3415 20130101; A61B
2017/3492 20130101; B01F 25/4233 20220101; A61B 2017/00637
20130101 |
Class at
Publication: |
606/214 |
International
Class: |
A61D 001/00 |
Claims
We claim:
1. A method for creating a biocompatible and biodegradable barrier
to seal a vascular puncture site comprising the steps of providing
a first liquid component, providing a second liquid component, the
first and second liquid components being free of an enzyme, and
mixing the first and second liquid components by dispensing the
components into a catheter tube deployed at the vascular puncture
site, wherein, upon mixing, the first and second liquid components
chemically cross-link to form a mechanical non-liquid matrix
sealing the vascular puncture site.
2. A method for creating a biocompatible barrier comprising the
steps of mixing a protein solution and a polymer solution including
a derivative of a hydrophilic polymer with a functionality of at
least three, wherein, upon mixing, the protein solution and the
polymer solution cross-link to form a mechanical non-liquid
matrix.
3. A method for creating a biocompatible barrier comprising the
steps of providing a protein solution, providing a polymer solution
including a derivative of a hydrophilic polymer with a
functionality of at least three, and mixing the protein and polymer
solutions by dispensing the protein solution and the polymer
solution into a channel, wherein, upon mixing, the protein solution
and the polymer solution cross-link to form a mechanical non-liquid
matrix.
4. A method for creating a biocompatible barrier to seal a vascular
puncture site comprising the steps of providing a protein solution,
providing a polymer solution including a derivative of a
hydrophilic polymer with a functionality of at least three, and
mixing the protein and polymer solutions by dispensing the protein
solution and the polymer solution into a catheter tube deployed at
a vascular puncture site, wherein, upon mixing, the protein
solution and the polymer solution cross-link to form a mechanical
non-liquid matrix sealing the puncture site.
5. A method according to claim 2 or 3 or 4, wherein the protein
solution comprises recombinant or natural human serum albumin.
6. A method according to claim 5, wherein the human serum albumin
is at a concentration of about 25% or less.
7. A method according to claim 2 or 3 or 4, wherein the polymer is
comprised of poly(ethylene glycol)(PEG).
8. A method according to claim 7, wherein the PEG comprises a
multi-armed polymer structure.
9. A method according to claim 2 or 3 or 4, wherein the polymer
comprises a compound of the formula PEG-(DCR-CG)n, where PEG is
poly(ethylene glycol), DCR is a degradation control region, CG is a
cross-linking group, and n is equal to or greater than three.
10. A method according to claim 9, wherein the compound comprises a
multi-armed polymer structure.
11. A method according to claim 9, wherein the compound comprises
poly(ethylene glycol) tetra-succinimidyl glutarate.
12. A method according to claim 9, wherein the compound comprises
poly(ethylene glycol)tetra-succinimidyl succinate.
Description
RELATED APPLICATION
[0001] This application is a divisional of co-pending U.S. patent
application Ser. No. 09/188,083 filed Nov. 6, 1998.
FIELD OF THE INVENTION
[0002] The invention generally relates to the formation and
application of barrier materials in a tissue region, e.g., to close
vascular puncture sites in humans and other animals.
BACKGROUND OF THE INVENTION
[0003] There are over seven million diagnostic and therapeutic
coronary interventions performed each year. By far, the majority of
these interventions are performed using percutaneous puncture of
the femoral artery to gain access to the arterial system.
[0004] Once the intervention is concluded, the vascular puncture
site has to be sealed to prevent bleeding, while natural healing
processes close the puncture site. Conventional management of the
puncture site has typically involved external compression using,
e.g., digital pressure, C-clamps, or sandbags, followed by
immobilization and bedrest. Proper placement of compression devices
to stop bleeding calls for trained clinical skills. Likewise,
strong nursing skills are required to monitor for rebleeding. The
patient can suffer local discomfort, which may exceed the pain
associated with the diagnostic or therapeutic procedure requiring
vascular access in the first instance. Complications are not
uncommon, which can lead to prolonged hospitalization, transfusion,
and direct surgical repair of the puncture site.
[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 hemostatis, 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 four needles
at a precise distance from the edges of the puncture orifice and to
form an array of suture knots, which are tightened, 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.
SUMMARY OF THE INVENTION
[0008] The invention provides compositions, instruments, systems,
and methods, which, in use, produce fast and effective closure to
vascular puncture sites, and which allow a patient to return to
ambulatory status quickly following a vascular access
procedure.
[0009] One aspect of the invention a biocompatible and
biodegradable barrier material, which is applied to seal a vascular
puncture site. The barrier material comprises a compound, which is
chemically cross-linked without use of an enzyme to form a
non-liquid mechanical matrix.
[0010] In a preferred embodiment, the compound includes a protein
comprising recombinant or natural serum albumin. In this
embodiment, the compound also includes a polymer that comprises
poly(ethylene) glycol (PEG). Most preferably, the the PEG comprises
a multi-armed polymer.
[0011] In a preferred embodiment, the barrier material, applied to
seal a vascular puncture site, comprises a mixture of a first
liquid component and a second liquid component, which are
chemically cross-linked, without use of an enzyme, to form a
non-liquid mechanical matrix.
[0012] This aspect of the invention also provides a kit comprising
a first dispenser containing a first liquid component a second
dispenser containing a second liquid component. The kit includes
instructions for handling the first and second dispensers according
to a method comprising the steps of mixing the first and second
liquid components to chemically cross-link the first and second
components, without use of an enzyme, to form a non-liquid
mechanical matrix, and applying the mechanical matrix to seal a
vascular puncture site.
[0013] This aspect of the invention provides a chemically
cross-linked barrier material that is not formed through the use of
enzymes. Reliance upon enzymes as cross-linking agents can pose
problems with regard to availability, cost, and possible viral
transmission. The invention obviates these problems.
[0014] Another aspect of the invention provides a barrier material
comprising a protein portion and polymer portion forming a
cross-linked, hydrogel network. The barrier material is nontoxic,
biodegradable, and possesses the mechanical properties necessary to
seal arterial pressure.
[0015] In a preferred embodiment, the protein portion of the
barrier material is a biocompatible, readily available, water
soluble protein, such as a serum protein like albumin. The protein
solution is preferably buffered to a pH in the range of 7.0 to
10.0.
[0016] In a preferred embodiment, the polymer portion of the
barrier material is an electrophilic derivative of a hydrophilic
polymer with a functionality of at least three. The preferred
electrophilic group is an N-hydroxysuccinimide ester, due to its
speed of reaction and low toxicity.
[0017] In a preferred embodiment, the polymer includes a region
that controls degradation to impart biodegradation or
non-biodegradation to the barrier material. The most preferred
polymer for degradable barrier materials is poly(ethylene glycol)
tetra-succinimidyl glutarate, however a number different polymers,
electrophilic derivatives, and degradation control regions can be
utilized.
[0018] Upon mixing, the polymer solution reacts with the protein
solution, forming a cross-linked network in a prescribed amount of
time. The rate of cross-linking can be controlled by the buffer in
the protein solution. The mechanical properties of the barrier
material can be controlled by the polymeric nature, structure, and
concentration in the reactive mixture. The electrophilic derivative
of the hydrophilic polymer not only reacts with the protein
solution, but also reacts with the surrounding tissue in the site
of application, creating an anchor for the material.
[0019] After the barrier material is formed, the degradation of the
barrier material is controlled by the selection of the degradation
control region. If degradation is desired, a degradation control
region is selected that is able to be hydrolytically or
enzymatically degraded in a physiological environment. The
degrading molecules of the hydrogel barrier matrix are cleared
through the kidneys and eliminated in the urine. If degradation is
not desired, a degradation control region is selected that is
stable in a physiological environment.
[0020] Another aspect of the invention provides systems and methods
for creating and applying a biocompatible barrier in a tissue
region. The systems and methods mix a protein solution and a
polymer solution including a derivative of a hydrophilic polymer
with a functionality of at least three. Upon mixing, the protein
solution and the polymer solution cross-link to form a mechanical
non-liquid matrix.
[0021] In a preferred embodiment, the systems and methods apply the
barrier material to seal a vascular puncture site.
[0022] Features and advantages of the inventions are set forth in
the following Description and Drawings, as well as in the appended
Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a plan view of a system for creating a mechanical
barrier to seal a vascular puncture site, showing the components of
the system prepackaged in a site access kit and a barrier component
kit;
[0024] FIG. 2 is an exploded plan view of the contents of the site
access kit and barrier component kit shown in FIG. 1, illustrating
their assembly for use;
[0025] FIG. 3 is an enlarged view of the distal end of the catheter
tube of a catheter device contained in the site access kit shown in
FIG. 1, showing two deformable regions in a relaxed condition for
deployment to a vascular puncture site;
[0026] FIG. 4 is an enlarged view of the distal end of the catheter
tube shown in FIG. 3, illustrating two deformable regions in an
enlarged condition, ready for use at the vascular puncture
site;
[0027] FIG. 5 is a schematic perspective view of the distal
catheter end in the relaxed condition shown in FIG. 3, when
deployed at a vascular puncture site;
[0028] FIG. 6 is a schematic perspective view of the distal
catheter end in the enlarged condition shown in FIG. 4, when
deployed at a vascular puncture site;
[0029] FIG. 7A is an exploded, perspective view of the site access
kit shown in FIG. 1;
[0030] FIG. 7B is an exploded, perspective view of the barrier
component kit shown in FIG. 1;
[0031] FIGS. 8A to 8D are perspective views showing the
manipulation of syringes contained in the barrier component kit
shown in FIG. 7B, to create a liquid PEG solution for use with the
system;
[0032] FIG. 9 is a perspective view of the barrier material
introducer/mixer contained in the site access kit shown in FIG. 1,
with the syringes containing the liquid albumin solution and the
liquid PEG solution (mixed as shown in FIGS. 8A to 8D) mounted and
ready for use;
[0033] FIG. 10 is a perspective view of the barrier material
introducer/mixer shown in FIG. 9 attached for operation with the
catheter device contained in the site access kit shown in FIG.
1;
[0034] FIG. 11 is a schematic, perspective view of the vascular
puncture site shown in FIG. 6, as the barrier material
introducer/mixer is being operated to convey a liquid mixture of
albumin and PEG solution into a tissue region outside the puncture
site;
[0035] FIG. 12 is a schematic, perspective view of the vascular
puncture site shown in FIG. 11, as the the liquid mixture of
albumin and PEG solution cross-links to form a non-liquid barrier
network in the tissue region outside the puncture site;
[0036] FIG. 13 is a schematic, perspective view of the vascular
puncture site shown in FIG. 12, with the non-liquid barrier network
remaining in the tissue region outside the puncture site, to seal
the puncture site, after withdrawal of the catheter device;
[0037] FIG. 14 is a plan view of an alternative embodiment of a
catheter device which can be used in association with the system
shown in FIG. 1, with the deformable region on the distal end shown
in a collapsed condition;
[0038] FIG. 15 is an enlarged view of the distal end of the
catheter device shown in FIG. 14, with the deformable region in an
expanded condition;
[0039] FIG. 16 is an enlarged sectional view of the distal end of
the catheter device shown in FIG. 15;
[0040] FIG. 17 is a schematic perspective view of the distal end of
the catheter device shown in FIG. 14, when deployed in the
collapsed condition at a vascular puncture site;
[0041] FIG. 18 is a schematic perspective view of the distal end of
the catheter device shown in FIG. 17, when expanded for use at the
vascular puncture site;
[0042] FIG. 19 is a schematic perspective view of the distal end of
the catheter device shown in FIG. 18, as barrier material is
dispensed in liquid form in tissue outside the vascular puncture
site;
[0043] FIG. 20 is the non-liquid barrier network formed after the
liquid barrier material cross-links in situ in tissue to seal the
vascular puncture site;
[0044] FIG. 21 is a perspective view of the barrier material
introducer/mixer shown in FIG. 9 when used in association with a
sprayer or a cannula, to dispense barrier material without use of a
catheter device;
[0045] FIG. 22 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior containing an array of
baffle funnels with staggered interruptions to establish a circular
flow path through the chamber for the purpose of accelerating
mixing of the liquid components of the barrier material;
[0046] FIG. 23 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior containing an array of
baffle walls with staggered interruptions to establish a
zig-zagging flow path through the chamber for the purpose of
accelerating mixing of the liquid components of the barrier
material;
[0047] FIG. 24 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior containing a spiral baffle
to establish a circular flow path through the chamber for the
purpose of accelerating mixing of the liquid components of the
barrier material;
[0048] FIG. 25 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior containing an array of
staggered baffle walls to establish a cascading flow path through
the chamber for the purpose of accelerating mixing of the liquid
components of the barrier material;
[0049] FIG. 26 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior establishing tangential
flow paths within through the chamber for the purpose of
accelerating mixing of the liquid components of the barrier
material;
[0050] FIG. 27 is an enlarged sectional view showing the interior
of a mixing chamber usable in association with the barrier material
introducer shown in FIG. 9, the interior containing multiple,
independent inlet ports to convey liquid components into the
chamber for the purpose of accelerating mixing of the liquid
components of the barrier material;
[0051] FIG. 28 is a side elevation view of an alternative
embodiment of an introducer/mixer, which can be used in association
with the system shown in FIG. 1;
[0052] FIG. 29 is a top view of an alternative embodiment of an
introducer/mixer of the type shown in FIG. 28, showing the presence
of skirts to resist side-to-side deflection of syringes supported
by the introducer/mixer; and
[0053] FIG. 30 is a side elevation view of an other alternative
embodiment of an introducer/mixer, which can be used in association
with the system shown in FIG. 1.
[0054] The invention may be embodied in several forms without
departing from its spirit or essential characteristics. The scope
of the invention is defined in the appended claims, rather than in
the specific description preceding them. All embodiments that fall
within the meaning and range of equivalency of the claims are
therefore intended to be embraced by the claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0055] FIG. 1 shows a system 10 of functional instruments for
sealing a vascular puncture site. As will be described in greater
detail, the instruments of the system 10 are, during use, deployed
in a purposeful manner to gain subcutaneous access to a vascular
puncture site. At the site, the instruments of the system 10 are
manipulated to introduce an inert barrier material in liquid form
outside the blood vessel at the puncture site. The material quickly
transforms into a non-liquid structure in situ, forming a barrier
outside the vessel, which mechanically seals the puncture. The
barrier exists long enough to prevent blood leakage while natural
healing processes close the puncture site. The barrier is, over
time, degraded by hydrolysis by in the host body and cleared by the
kidneys in the urine.
[0056] As FIG. 1 shows, in the illustrated embodiment, the system
10 is consolidated in two functional kits 12 and 14.
[0057] The first kit 14 contains a vascular puncture site access
assembly 16. The purpose of the access assembly 16 is to gain
subcutaneous access to the vascular puncture site for the purpose
of delivering the fluid barrier material.
[0058] The second kit 14 contains a barrier component assembly 18.
The purpose of the barrier component assembly 18 is to house the
components of the fluid barrier material 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, forming
the barrier.
[0059] The kits 12 and 14 can take various forms. In the
illustrated embodiment, each kit 12 and 14 comprises a sterile,
wrapped assembly, the details of which will be discussed in greater
detail later.
[0060] I. The Access Assembly
[0061] As FIG. 2 shows, the access assembly 16 comprises a catheter
device 20 and a barrier material introducer/mixer 22.
[0062] A. The Catheter Device
[0063] The catheter device 20 includes a flexible catheter tube 24
having a proximal end 26 and a distal end 28. The catheter tube 24
can be constructed, for example, using standard flexible, medical
grade plastic materials, like vinyl, nylon, poly(ethylene),
ionomer, poly(urethane), poly(amide), and poly(ethylene
terephthalate). The distal end 28 has an outside diameter of, e.g.,
4 Fr to 16 Fr. The proximal end 26 carries a handle 30 to
facilitate gripping and maneuvering the catheter tube 24 by a
physician.
[0064] As FIG. 3 shows, an interior lumen 32 extends through the
catheter tube 24. The lumen accommodates passage of a conventional
guide wire 40.
[0065] As will be described in greater detail later, the guide wire
40 typically will have been previously introduced subcutaneously,
through a wall of the vessel, to guide passage of a desired
therapeutic or diagnostic instrument into the vessel, e.g., to
perform coronary angioplasty. After performing the intended
procedure, the instrument is withdrawn, leaving the guide wire 40.
As FIG. 5 shows, the distal end 28 of the catheter tube 24 is
passed over the same guide wire 40 into the blood vessel.
Manipulation of the distal end 28 closes the vascular puncture site
and stops bleeding.
[0066] As FIGS. 3 and 4 show, the distal end 28 of the catheter
tube 24 includes a circumferentially spaced array of nozzles 34.
The barrier material is conveyed in liquid form and dispensed in a
circumferential manner through the nozzles 34 at the puncture
site.
[0067] As FIGS. 3 and 4 also show, the distal end 28 also includes
a flexible, elongated leader 36, which extends distally beyond the
nozzles 34. In use (see FIG. 5), the leader 36 is located inside
the blood vessel immediately interior to the puncture site. In use
(see FIG. 5), the array of nozzles 34 is located outside the blood
vessel immediately exterior to the puncture site.
[0068] Referring again to FIGS. 3 and 4, the distal end 28 also
includes a first deformable region 38, which is located between the
nozzles 34 and the leader 36. The region 38 normally presents a
generally cylindrical, low profile condition (shown in FIG. 3),
matching the leader 36. When in the low profile condition, the
region 38 follows the leader 36 over the guide wire into the vessel
(see FIG. 5).
[0069] The region 38 can be deformed into a radially enlarged
condition, which forms a positioner 42 (see FIG. 4). In use (see
FIG. 6), the positioner 42 resists passage of the leader 36 back
through the puncture site in response to rearward tension along the
catheter tube 24, as shown by arrow 132 in FIG. 6. Moreover, as
FIG. 6 shows, rearward tension along the catheter tube 24 seats the
positioner 42 against the interior of vessel wall at the puncture
site. The positioner 42 serves to position the nozzles 34 at a
proper distance outside the vessel. The positioner 42 also serves
to support the puncture site inside the vessel while the liquid
barrier material is introduced outside the vessel through the
nozzles 34.
[0070] Referring back to FIGS. 3 and 4, a second deformable region
44 is spaced a distance proximal to the nozzles 34. Like the
nozzles 34 (see FIG. 5), the deformable region 44 is intended,
during use, to lay outside the vessel.
[0071] The deformable region 44 presents a normally, generally
collapsed condition for deployment over the guide wire 40 (shown in
FIGS. 3 and 5). The deformable region 44 can be expanded into,
e.g., an elliptical dam 46 (see FIGS. 4 and 6). The dam 46 serves
block proximal egress of the liquid barrier material conveyed
through the nozzles 34.
[0072] The deformation of the regions 38 and 44 can be accomplished
in various ways. In the illustrated embodiment, the leader 36 moves
along a slide tube 48 (see FIGS. 3 and 4) toward and away from the
nozzles 34. A push-pull lever 50 on the handle 30 (shown in FIG. 2)
is coupled by a stylet 52 to the leader 36 to affect axial movement
of the leader 36 along the slide tube 48.
[0073] In this arrangement, the region 38 comprises a generally
elastic material surrounding the slide tube 48. The material is
attached at one end to the leader 36 and at the other end to the
catheter tube 24 near the nozzles 34. Drawing the leader 36 toward
the nozzles 34 pushes against and radially deforms the material
into the positioner 42. Advancement of the leader 36 away from the
nozzles 34 relaxes the material.
[0074] In the illustrated embodiment, the second region 44
comprises an expandable balloon material attached about the
catheter tube 24. The catheter tube 24 includes an interior lumen
56 (shown in FIGS. 3 and 4), which communicates with the interior
of the balloon material. A fitting 54 carried by the handle 30 (see
FIG. 2) communicates with the lumen 56. The fitting 54 couples the
lumen to an auxiliary syringe 126, which injects air under pressure
through the lumen 56 into the space surrounded by the balloon
material, causing the material to expand and form the dam 46.
[0075] B. Barrier Material Introducer/Mixer
[0076] As will be described in greater detail later, the barrier
material is formed from two liquid components, which are mixed at
the instant of use. The two components cross-link to form the
non-liquid barrier.
[0077] Before mixing, the components are housed in sterile
dispensing syringes 60 and 62 contained in the kit 14 (see FIG. 1).
As FIG. 2 shows, the barrier material introducer/mixer 22 receives
the two dispensing syringes 60 and 62 for use in association with
the catheter device 20. The barrier material introducer/mixer 22
allows the physician to uniformly express the two components in a
liquid state from the dispensing syringes 60 and 62.
[0078] The barrier material introducer/mixer 22 also mixes the
components while flowing in the liquid state from the dispensing
syringes 60 and 62. This obviates the need for static mixing prior
to dispensing. This mixing of liquid components within a flow
channel will, in shorthand, be called "channel-mixing."
[0079] To accomplish these functions (see FIG. 2), the barrier
material introducer/mixer 22 includes syringe support 64. The
support 64 includes side-by-side channels 66. Each channel 66
accommodates in a snap-friction-fit the barrel 78 of a conventional
syringe of desired size, e.g., 3 cc (as FIGS. 9 and 10 also
show).
[0080] The barrier material introducer/mixer 22 also includes a
syringe clip 68. The syringe clip 68 includes spaced apart walls 70
forming an interior race 72. As FIGS. 9 and 10 show, the race 72
receives in a sliding friction fit the thumb rests 74 of the
dispensing syringe pistons 76, in axial alignment with the syringe
barrels 78 carried by the syringe support 64. The syringe clip 68
mechanically links the syringe pistons 76 together for common
advancement inside their respective syringe barrels 78.
[0081] To facilitate handling (see FIGS. 2, 9 and 10 ), the syringe
support 64 includes opposed finger rests 80, and the syringe clip
68 includes a thumb rest 82. The orientation of these rests 80 and
82 parallel the orientation of the finger rests and thumb rests of
a single syringe. The physician is thereby able to hold and operate
multiple syringes 60 and 62 in the same way as a single
syringe.
[0082] The barrier material introducer/mixer 22 also includes a
joiner 84. The joiner 84 includes side by side female luer fittings
86. The female luer fittings 86 each receives the threaded male
luer fitting 88 at the dispensing end of the dispensing syringes 60
and 62. The female luer fittings 86 are axially aligned with the
barrels 78 of the dispensing syringes 60 and 62 carried in the
syringe support 64.
[0083] The physician is thereby able to quickly and conveniently
ready the dispensing syringes 60 and 62 for use by securing the
dispensing syringes to the joiner 84, snap fitting the syringe
barrels 78 into the syringe support 64, and slide fitting the
syringe thumb rests 74 into the clip 68.
[0084] The joiner 84 includes interior channels 90 coupled to the
female luer fittings 86. The channels 90 merge at a Y-junction into
a single outlet port 92. The joiner 84 maintains two fluids
dispensed by the syringes 60 and 62 separately until they leave the
joiner 84. This design minimizes plugging of the joiner 84 due to a
mixing reaction between the two fluids. The syringe clip 68 ensures
even application of individual solutions through the joiner 84.
[0085] The barrier material introducer/mixer 22 further includes a
mixing chamber 94, which, in use, is coupled to the single outlet
port 92 (as FIG. 10 shows). Expressed in tandem from the dispensing
syringes 60 and 62, which are mechanically linked together by the
joiner 84, support 64, and clip 68, the two components of the
barrier material come into contact in the liquid state in the
mixing chamber 94. Channel-mixing of the two components occurs as
they flow through the mixing chamber 94 under pressure from
operation of the mechanically linked dispensing syringes 60 and
62.
[0086] In the illustrated embodiment (see FIGS. 2 and 10), the
mixing chamber 94 is carried at the end of a tube 96 attached to
the handle 30 of the catheter device 20. The tube 96 communicates
with interior lumens 134 in the catheter tube 24 (shown in FIG. 3),
which, in turn, are coupled to the dispensing nozzles 34. The
mixing chamber 94 includes a luer fitting 98, which threadably
connects with the single outlet port 92 of the joiner 84.
[0087] The parts of the barrier material introducer/mixer 94 are
made, e.g., by molding medical grade plastic materials, such as
polycarbonate and acrylic.
[0088] II. Barrier Component Assembly
[0089] The barrier component assembly 18 includes the already
described dispensing syringes 60 and 62 for the two components of
the barrier material.
[0090] According to the invention, the barrier material comprises a
compound that is chemically cross-linked without the use of an
enzyme, to form a non-liquid mechanical matrix.
[0091] As defined in this Specification, an "enzymatically
cross-linked" barrier material is formed by the mixture of an
enzyme and a substrate. Solutions of the substrate and enzyme can
be delivered to the application site simultaneously, or separate
solutions of the enzyme and substrate can be mixed at the
application site. The enzyme cross-links to the substrate,
transforming the solution to a solid. Examples of these materials
include fibrin glue (in which the enzyme is thrombin and the
substrate is fibrinogen), and transglutaminase cross-linked
materials (in which the enzyme is transglutaminase and the
substrate is selected from materials containing amino groups.
[0092] As further defined in this Specification, a "chemically
cross-linked" barrier material refers to all barrier materials not
formed through the use of enzymes. Cross-linking can occur, e.g.,
as a result of energy (heat or light), or cross-linking chemical
reactions (active esters, isocyanates, epoxides). Examples of these
materials includes photo-cross-linked acrylates and nucleophilic
attack of electrophiles.
[0093] In a preferred embodiment, the barrier material is a
protein/polymer composite hydrogel. The material is nontoxic,
biodegradable, and possesses suitable mechanical properties to seal
arterial pressure.
[0094] The barrier material is most preferably formed from the
mixture of a protein solution and a solution of an electrophilic
derivative of a hydrophilic polymer with a functionality of at
least three. The barrier material of this composition has
sufficient cohesive strength, adhesive strength, and elasticity to
seal arterial pressure. The rate of cross-linking and gelation can
be controlled through buffer selection and concentration. The rate
of degradation after cross-linking can be controlled through the
selection of a degradation control region.
[0095] A. Barrier Material Components
[0096] 1. Natural Plasma-Based Protein
[0097] In the illustrated embodiment (see FIG. 1), the first
dispensing syringe 60 contains a concentration of buffered protein
solution 100. The protein solution is supplemented with the
appropriate buffers, sterile filtered, aseptically filled into the
syringe 60, and the syringe 60 is capped for storage prior to
use.
[0098] Suitable proteins for incorporation into barrier material
include non-immunogenic, hydrophilic proteins. Examples include
solutions of albumin, gelatin, antibodies, serum proteins, serum
fractions, and serum. Also, water soluble derivatives of
hydrophobic proteins can also be used. Examples include collagen,
fibrinogen, elastin, chitosan, and hyaluronic acid. The protein can
be produced from naturally occurring source or it may be
recombinantly produced.
[0099] The preferred protein solution is 25% human serum albumin,
USP. Human serum albumin is preferred due to its biocompatibility
and its ready availability.
[0100] Buffer selection and concentration maintains the pH of the
reactive mixture. Buffers that are well tolerated physiologically
can be used. Examples include carbonate and phosphate buffer
systems. Care should be taken to select buffers that do not
participate in or interfere with the cross-linking reaction. The
preferred range of buffer concentration is from about 0.01 M to
about 0.3 M, and the preferred range of pH is from about 7.0 to
about 10.0. A preferred buffer system for vascular puncture sealing
is phosphate buffer at a concentration of 0.05 M at a pH value of
about 8 to about 9. As will be described later, there is a
relationship between pH and the time for cross-linking (also called
"gelation").
[0101] As will be described in greater detail later, the syringe 60
is kept before use within inner and outer wraps, which are
peripherally sealed by heat or the like. The wraps are made, at
least in part, from a material that is permeable to ethylene oxide
sterilization gas, e.g., TYVEK.TM. plastic material available from
Du Pont. The outer surfaces of syringe 60 can thereby be sterilized
using ethylene oxide gas.
[0102] 2. Electrophilic Water Soluble Polymer
[0103] In the illustrated embodiment (still referring principally
to FIG. 1), the second dispensing syringe 62 contains an inert,
electrophilic, water soluble polymer 102. The polymer cross-links
the protein to form an inert, three dimensional mechanical network
or matrix. The matrix forms a mechanical barrier, which, when
appropriately positioned in tissue at a vascular puncture site
outside the vessel, serves to seal the puncture site. The barrier
is, over time, resorbed.
[0104] The polymer 102 comprises a hydrophilic, biocompatible
polymer, which is electrophilically derivatized with a
functionality of at least three. A number of polymers could be
utilized, including poly(ethylene glycol), poly(ethylene oxide),
poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline),
and poly (ethylene glycol)-co-poly (propylene glycol) block
copolymers. The polymer portion is not restricted to synthetic
polymers as polysaccharides, carbohydrates, and proteins could also
be electrophilically derivatized.
[0105] Preferably, the polymer 102 is comprised of poly(ethylene
glycol) (PEG) with a molecular weight between 1,000 and 30,000
g/mole, more preferably between 2,000 and 15,000 g/mole, and most
preferably between 10,000 and 15,000 g/mole. PEG has been
demonstrated to be biocompatible and non-toxic in a variety of
physiological applications.
[0106] The preferred polymer can be generally expressed as
compounds of the formula:
PEG-(DCR-CG).sub.n
[0107] where:
[0108] DCR is a degradation control region.
[0109] CG in a cross-linking group.
[0110] n.gtoreq.3
[0111] While the preferred polymer is a multi-armed structure, a
linear polymer with a functionality of at least three can also be
used. The desired functionality of the PEG polymer for forming the
barrier can be expressed in terms of (i) how quickly the polymer
cross-links the protein and transforms to a nonfluent gel state
(i.e., the mechanical barrier material) (a preferred gelation time
is under three minutes), and (ii) the mechanical properties of the
barrier after gelation in terms of its liquid sealing
characteristics, physical strength, resistance to fragmentation
(i.e., brittleness), and bioresorption. The optimization of both
attributes (i) and (ii) is desirable.
[0112] The inventors have discovered that 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.
[0113] The use of PEG polymers with functionality of greater than
three provides a surprising advantage. 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 results in superior sealing
properties with reduced brittleness, facilitating reentry through
the nonfluid barrier material, without fragmentation. Additionally,
25% human serum albumin, USP is commercially available from several
sources, however higher concentrations of USP albumin 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.
[0114] In the illustrated embodiment, the polymer 102 is initially
packaged prior to use in the second dispensing syringe 92 in an
inert atmosphere (e.g., argon) in a stable, powder form. In this
arrangement, the barrier component assembly 18 includes a third
syringe 104, which contains sterile water 106 for dissolution of
the powder polymer 102 just before mixing with the albumin
component 100.
[0115] In facilitating mixing, a stopcock valve 108 is secured to
the luer fitting 88 at the dispensing end of the second dispensing
syringe 62. The dispensing end 110 of the water syringe 104 couples
to the stopcock valve 108, so that the water 106 can be mixed with
the polymer 102 in the dispensing syringe 72 prior to use. Further
details of the preparation of the polymer prior to use will be
described later.
[0116] In the illustrated embodiment, the second and third
dispensing syringes 62 and 104 are placed in inner and outer wraps
peripherally sealed by heat. The wraps are made, at least in part,
from a material that is transparent to electron beam irradiation.
The contents of the second and third dispensing syringes 62 and 104
can thereby be sterilized, e.g., by exposure to electron beam
irradiation.
[0117] a. Selection of the Degradation Control Region DCR
[0118] The rate of degradation is controlled by the selection of
chemical moiety in the degradation control region DCG. If
degradation is desired, a hydrolytically or enzymatically
degradable moiety can be selected,
[0119] 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.-valerolactone), poly(.gamma.-butyrolactone),
poly(amino acids), poly(anhydrides), poly(orthoesters),
poly(orthocarbonates), and poly(phosphoesters).
[0120] Examples of enzymatically degradable regions include
Leu-Glyc-Pro-Ala (collagenase sensitive linkage) and Gly-Pro-Lys
(plasmin sensitive linkage).
[0121] The preferred degradable control regions for degradable
barrier materials are ester containing linkages, as are present
when succinic acid or glutaric acid are coupled to a PEG molecule.
The preferred degradable control regions for nondegradable barrier
materials are ether containing linkages. The barrier material can
also be created without the introduction of a degradation control
region.
[0122] b. Selection of the Cross-Linking Group CG
[0123] The cross-linking group is responsible for the cross-linking
of the albumin, as well as the binding to the tissue substrate. The
cross-linking group can be selected to selectively react with
sulfhydryl groups, selectively react with amines, or can be
selected to react with sulfhydryl, primary amino, and secondary
amino groups. Cross-linking groups that react selectively with
sulfhydryl groups include vinyl sulfone, N-ethyl maleimide,
iodoacetamide, and orthopyridyl disulfide. Cross-linking groups
specific to amines include aldehydes. Non-selective electrophilic
cross-linking groups include active esters, epoxides,
carbonylimidazole, nitrophenyl carbonates, tresylate, mesylate,
tosylate, and isocyanate. The preferred cross-linking group is an
active ester, specifically an ester of N-hydroxysuccinimide.
[0124] To minimize the liberation of heat during the cross-linking
reaction, the concentration of the cross-linking groups 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 preferred
embodiment, the cross-linking group portion comprising a
N-hydroxysuccinimide ester has demonstrated ability to participate
in the cross-linking reaction with albumin without presenting the
risk of local or systemic immune responses in humans.
[0125] c. Preferred Multiple Arm PEG Polymer
[0126] In a preferred embodiment, the polymer is comprised of a
4-arm PEG with a molecular weight of about 10,000 g/mole, the
degradation control region is comprised of glutaric acid, and the
cross-linking group is comprised of a N-hydroxysuccinimide ester.
Thus, a preferred polymer is poly(ethylene glycol)
tetra-succinimidyl glutarate, which is available from Shearwater
Polymers, Huntsville, Ala. The preferred polymer will, in
shorthand, be called 4-PEG-SG. The polymer is dissolved in water
prior to use. Preferred concentrations of the polymer are from 5%
to 35% w/w in water.
[0127] The solution of 4-PEG-SG mixes with 25% serum albumin to
form a liquid solution that quickly cross-links to form a
non-liquid, three dimensional network for the barrier. With these
barrier material formulations, it is possible to intimately mix the
water soluble polymer with the albumin protein without static
mixing. Effective mixing occurs as the multiple arm PEG polymer and
albumin are jointly passed through a confined flow path. This
beneficial phenomenon has been earlier referred to in this
specification as "channel-mixing."
[0128] As will be demonstrated later, the rate of reaction can be
controlled by the pH of the reactive solution. An increase in
temperature is not observed during formation of the barrier
network, due to the low concentration of reactive groups, which
account for only about 1% of the total mass. In a typical clinical
application, about 50 mg of a non-toxic leaving group is produced
during the cross-linking reaction, which is a further desired
result.
[0129] The resulting nonfluent barrier material created by mixing
25% albumin and 4-PEG-SG is approximately 80% water, 13% albumin,
and 7% PEG. The barrier material is well tolerated by the body,
without invoking a severe foreign body response. Over a controlled
period of time, the barrier material is degraded via hydrolysis.
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 barrier material are cleared from the
bloodstream by the kidneys and eliminated from the body in the
urine. In a preferred embodiment of the invention, the barrier
material loses its physical strength during the first twenty days,
and total resorption occurs in about 4 weeks.
[0130] The following Examples demonstrate the superior features of
the barrier material of the invention.
EXAMPLE 1
[0131] Preparation of Cross-Linked Barrier Networks
[0132] Cross-linked barrier networks were formed by the mixture of
an 4-PEG-SG and albumin. A solution of 4-PEG-SG was prepared by
dissolving 0.40 g in 2.0 mL of water. The albumin solution
consisted 25% human serum alburmin, USP (Plasbumin-25, Bayer
Corporation), as received.
[0133] Dispensing syringes containing 2.0 mL of the polymer
solution and 2.0 mL of albumin solution were connected to the
joiner 84, to which a spray head was coupled. The solutions were
sprayed into a polystyrene weigh boat. A cross-linked barrier
network formed at room temperature in about 90 seconds.
EXAMPLE 2
[0134] Control of the Rate of Gelation
[0135] The rate of formation of the cross-linked barrier network of
4-PEG-SG and albumin (i.e., gelation) can be controlled by the pH
of the reactive solution. To increase the rate of cross-linking,
the pH of the solution is increased, and conversely, to decrease
the rate of cross-linking, the pH of the solution is decreased. The
pH of the solution is controlled by both the buffer strength and
buffer pH.
[0136] Table 1 shows the effect of buffer strength on the rate of
gelation of 17% w/w 4-PEG-SG in water for injection and 25% human
serum albumin, USP at room temperature. The rate of gelation can
also be controlled by adjusting the pH of the buffer at a constant
buffer concentration. The buffer was placed in the solution of
albumin. The gelation time is the amount of time required for the
formulation to transform from the liquid state to the cross-linked
solid state.
1TABLE 1 Effect of Buffer Strength and Buffer pH on Gel Formation
Buffer Concentration Buffer pH Gelation Time 300 mM 9 <1 sec 200
mM 9 5 sec 100 mM 9 10 sec 50 mM 9 20 sec 0 mM 7 90 sec
EXAMPLE 3
[0137] Channel-Mixing
[0138] A solution of 4-PEG-SG was prepared by dissolving 0.40 g in
2.0 mL of water. The albumin solution consists 25% human serum
albumin, USP (Plasbumin-25, Bayer Corporation), buffered to pH
9.0.
[0139] Syringes containing 2.0 mL of the polymer solution and
albumin solution were connected to the joiner 84. A cannula channel
having an inside diameter of 1 mm and a length of 20 cm was
attached to the outlet port 92 of the joiner 84. The solutions were
expressed through the cannula channel into a polystyrene weigh
boat.
[0140] The barrier network formed at room temperature in about 20
seconds. Qualitatively, the mechanical properties of the barrier
network when sprayed (as in Example 1) and the barrier network when
expressed through the cannula channel were equivalent.
[0141] This demonstrates that the barrier network can be formed by
channel-mixing the liquid components, without static mixing, by
delivery through a small diameter channel.
[0142] III. Puncture Site Closure Using the System
[0143] A. The Kits
[0144] As FIGS. 7A and 7B show, in the illustrated embodiment, each
kit 12 and 14 includes an interior tray 112 made, e.g., from die
cut cardboard, plastic sheet, or thermo-formed plastic
material.
[0145] The catheter device 20 and barrier material introducer/mixer
22 are carried by the tray 112 in the first kit 12. The first,
second, and third syringes 60, 62, and 114 and stopcock valve 108
are carried by the tray 112 in the second kit 14.
[0146] Each kit 12 and 14 presents its contents in a user-friendly
orientation on the tray 112, to facilitate quick preparation of the
barrier material using straightforward, intuitive steps, and the
subsequent attachment of the dispensing syringes 60 and 62 to the
catheter device 20.
[0147] As shown in FIG. 7A, the kit 12 includes an inner wrap 114,
which is peripherally sealed by heat or the like, to enclose the
tray 112 from contact with the outside environment. One end of the
inner wrap 114 includes a conventional peel away seal 116. The seal
116 provides quick access to the tray 112 at the instant of use,
which preferably occurs in a suitable environment, such as within a
catheterization lab.
[0148] The kit 12 is further wrapped in an outer wrap 118, which is
also peripherally sealed by heat or the like, to enclose the
interior tray 112. One end of the inner wrap 118 includes a
conventional peel away seal 120, to provide quick access to the
interior tray 112 and its contents.
[0149] The outer wrap 118 and the inner wrap 114 are made, at least
in part, from a material that is permeable to ethylene oxide
sterilization gas, e.g., TYVEK.TM. plastic material (available from
DuPont). Kit 12 is sterilized utilizing ethylene oxide gas or
electron beam irradiation.
[0150] As shown in FIG. 7B, kit 14 includes a polymer package 138
(which contains the prefilled powder polymer syringe 62 and water
syringe 104) and an albumin package 140 (which contains the
prefilled albumin syringe 64). Each polymer package 138 and albumin
package 140 includes an individual wrap 142, which is peripherally
sealed by heat or the like, to enclose package 138 and 140 from
contact with the outside environment. One end of the individual
wrap 142 includes a conventional peel away seal 144, to provide
quick access to the contents of the packages 138 and 140 at the
instant of use, such as within a catheterization lab.
[0151] Polymer package 138 and albumin package 140 are further
wrapped in an outer wrap 118, which is also peripherally sealed by
heat or the like. One end of the outer wrap 118 includes a
conventional peel away seal 148, to provide quick access to the
packages 138 and 140. After sterilization treatment, the packages
138 and 140 and the tray 112 are further wrapped in container 146
for the user's convenience.
[0152] The wraps 142 and 118 are made, at least in part, from a
material that is permeable to ethylene oxide sterilization gas,
e.g., TYVEK.TM. plastic material (available from DuPont). The
albumin package 140 is prepared, sterilized utilizing ethylene
oxide gas, and placed into kit 14. The polymer package 138 is
prepared, sterilized utilizing electron beam irradiation, and place
into kit 14.
[0153] In the illustrated embodiment, each kit 12 and 14 also
preferably includes directions 122 for using the contents of the
kit to carry out a desired procedure. Exemplary directions 122 will
be described later.
[0154] B. Use of the Kits to Access and Seal a Vascular Puncture
Site
[0155] The directions 122 can, of course vary, according to the
particularities of the desired procedure. Furthermore, the
directions 122 need not be physically present in the kits 12 and
14. The directions 122 can be embodied in separate instruction
manuals, or in video or audio tapes.
[0156] In the illustrated embodiment, exemplary directions 122 are
described, which instruct the physician how to use of the system 10
to close a vascular puncture site following percutaneous
transliminal coronary angioplasty.
[0157] It should be appreciated that the specific contents of the
directions 122 are merely exemplary. The objectives set forth in
the exemplary directions 122 can be accomplished in different ways,
using different devices, and different sequences of steps.
[0158] It should also be appreciated that the use of the system 10
is not limited to angioplasty procedures. The system 10 can be used
with other diverse procedures, which provide vascular access
through a puncture site.
[0159] In the illustrated embodiment, at the time the system 10 is
readied for use, the guide wire 40 has already been deployed
through a conventional introducer through a vascular puncture site
into, e.g., the femoral artery. An angioplasty balloon has been
deployed over the guide wire 40 through the puncture site and into
the artery. The angioplasty balloon has been advanced over the
guide wire 40 to the occluded treatment site. The balloon has been
expanded and manipulated to open the occluded site. The balloon has
been withdrawn over the guide wire 40.
[0160] When use of the system 10 is desired, the outer wrap 118 of
the kits 12 and 14 are removed. The trays 112, still contained in
the inner wraps 118, are placed in the sterile operating field.
[0161] The physician opens the inner wrap 118 of the second kit 14
to gain access the first, second, and third syringes 60, 62, and
104.
[0162] In the illustrated embodiment, the directions 122 for use
instruct the physician to remove from the second kit tray 112 the
second dispensing syringe 62, which contains, in sterile powder
form, a predetermined amount of the polymer 102 (e.g., about 0.3 to
0.5 g). The directions 122 also instruct the physician to remove
from the second kit 14 the third syringe 104, which contains
sterile water 106 (e.g., about 2 cc). Both are contained in the
polymer package 138.
[0163] As FIG. 8A shows, the directions 122 instruct the physician
to couple the dispensing end of the water syringe 104 to the
stopcock valve 108 on the second dispensing syringe 62. The
stopcock valve 108 is closed at this point. As instructed by the
directions 122, the physician opens the stopcock valve 108 (see
FIG. 8B) and transfers water from the water syringe 104 into the
powder 100 in the second dispensing syringe 62 (see FIG. 8C). The
physician is instructed to repeatedly transfer the water and powder
mixture between the two syringes 62 and 104, to syringe-mix the
powder and water until all solids are dissolved. The syringe-mixing
places the water soluble, polymer material into solution. The
syringe-mixing process generally takes about two minutes.
[0164] After syringe mixing, the physician, following the
directions 122, transfers the PEG solution 136 (about 2 cc) into
one of the syringes (which, in the illustrated embodiment, is the
second syringe 62). The physician waits for bubbles to dissipate,
which generally takes about an additional two minutes.
[0165] According to the directions 122, the physician now closes
the stopcock valve 108 (as FIG. 8D shows). The physician removes
the stopcock valve 108 by unscrewing it from the luer fitting on
the dispensing end of the second syringe 62. The PEG solution 136
is ready for use. Mixing of the PEG solution 136 should take place
generally within one hour of use. If the PEG solution 136 remains
unused over one hour after mixing, it should be discarded.
[0166] The directions 122 instruct the physician to remove from the
second kit tray 112 the dispensing syringe 60 containing the
albumin 100. As before described, the albumin 100 has been premixed
in a buffered form to the desired concentration (e.g., 25%), then
sterile filtered, and aseptically filled into the syringe 60. A
closure cap normally closes the dispensing end inside the tray
112.
[0167] The physician now, or at a previous time, opens the outer
wrap 118 of the first kit 12 to gain access to the catheter device
20 and barrier material introducer/mixer 22. Using an auxiliary
syringe (not shown), the physician is instructed to instructed to
flush the interior lumen leading to the nozzles 34 with sterile
saline. The physician is also directed to flush the interior
guidewire lumen 32 with sterile saline. The physician attaches
another auxiliary syringe 126 filled with about 1 cc of air to the
fitting 54 for inflating the deformable region 44 to confirm its
functionality, and then returns the deformable region 44 to the
collapsed state.
[0168] As illustrated in FIG. 9, the directions 122 instruct the
physician to remove the closure cap and screw the dispensing end of
the first syringe 60 to the luer fitting 86 on the joiner 84. The
physician is also instructed to screw the dispensing end of the
second syringe 62 (now containing the mixed PEG solution 136) to
the other luer fitting 86 on the joiner 84.
[0169] Following the directions 122 (as FIG. 9 also shows), the
physician snaps the barrels 78 of the syringes 60 and 62 to the
holder channels 66. The physician captures the thumb rests 74 of
the two syringes 60 and 62 inside the race 72 of the syringe clip
68. The directions 122 instruct the physician to attach the joiner
84 to the mixing channel 94 (as FIG. 10 shows).
[0170] The physician is now ready to deploy the catheter tube 24.
As FIG. 5 shows, the physician is instructed to pass the distal end
28 of the catheter tube 24 over the guide wire 40 through the
puncture site. The physician advances the distal end 28 to situate
the first deformable region 38 inside the vessel, while the nozzles
34 are deployed outside the vessel. The physician can monitor the
advancement tactilely, without using fluoroscopy. However, the
physician can use fluoroscopy or an other form of visualization, if
desired.
[0171] According to the directions 122 (as FIG. 6 shows), the
physician pulls the lever 50 rearward, causing the first deformable
region 38 to expand radially into the positioner 42. The physician
is instructed to place slight rearward tension on the catheter tube
24 (shown by arrow 132 in FIG. 6), to bring the positioner 42 into
contact with the interior of the vessel. The physician will, by
tactile feedback, know that the positioner 42 has contacted the
vessel interior. Due to the slight rearward tension, the positioner
42 seats against and supports the puncture site. The guide wire
lumen 32 of the catheter tube 24 can be used to inject suitable
contrast media to aid in the visualization of the puncture site
region.
[0172] While maintaining slight rearward tension on the catheter
tube 24, the physician is instructed to manipulate the syringe 126
to inject air (e.g. about 0.7 cc to 0.8 cc) into the second
deformable region 44. The second deformable region 44 expands (as
FIG. 6 shows), forming the dam 46 outside the vessel.
[0173] The physician is instructed to continue to apply a slight
rearward tension on the catheter tube 24, sufficient to keep the
positioner 42 against the interior of the vessel, without pulling
it through the vessel wall.
[0174] The physician is instructed to grasp the finger rests 80 and
thumb rest 82 of the barrier material introducer/mixer 22, as if
grasping an ordinary syringe. The physician expresses the albumin
100 from the first dispensing syringe 60 while simultaneously also
expressing the PEG solution 136 from the second dispensing syringe
62.
[0175] The albumin and PEG solutions come into contact in the
mixing chamber 94 and, from there, proceed through the catheter
tube 24 to the nozzles 34. The albumin 100 and PEG solution 136
intimately channel-mix in transit.
[0176] As FIG. 11 shows, the mixture of albumin 100 and PEG
solution 136 flows in liquid form through the nozzles 34. Conveyed
circumferentially about the catheter tube 24 by the nozzles 34, the
liquid mixture 130 of albumin 100 and PEG solution 136 enters and
fills the tissue region surrounding the puncture site.
[0177] As FIG. 12 shows, according to the directions 122, the
physician waits the requisite gelation period, during which the
liquid mixture 130 of albumin 100 and PEG material 136 transform
into a non-fluid barrier network 128 outside the puncture site.
Using 4-PEG-SG and albumin, the gelation period is about 15 to 60
seconds.
[0178] During the gelation period, the physician is instructed to
continue to apply a slight rearward tension on the catheter tube 24
to seat the positioner 42 against the interior vessel wall. This,
in effect, suspends the vessel on the distal end of the catheter
tube 24, while the solid barrier network 128 forms outside the
vessel to seal the puncture site. The positioner 42 and the
catheter tube 24 resist seepage of the liquid mixture 130 into the
vessel during the gelation period.
[0179] After the requisite gelation period, the physician is
instructed to push the lever 50 forward to relax the positioner 42.
The physician also relieves air pressure from the dam 46. The
physician withdraws the guide wire 40 and the distal end 28 of the
catheter tube 24 from the vessel. As shown by FIG. 13, during
withdrawal, the distal end 28 and the guide wire 40 pass through
the barrier network 128 that has, by now, formed over the puncture
site. If desired, the guidewire 40 may be left in place for removal
at a future time.
[0180] After withdrawing the catheter tube 24, the physician is
instructed to apply manual pressure to the skin over the blood
vessel, e.g., for about three minutes, to aid in the sealing
process. This time allows the barrier material to fully cross-link.
The physician then confirms that the puncture site has been sealed
by observing the lack of blood seepage about the guide wire 40
access.
[0181] The puncture site of the vessel naturally closes and heals.
As FIG. 13 shows, the presence of the barrier network 128 outside
the puncture site prevents blood leakage while natural healing
takes place. The barrier network 128 obviates the need for the
patient to forgo ambulation and normal activities while this
natural healing process takes place. The body resorbs the barrier
network 128 over time, e.g., within 30 days.
EXAMPLE 4
[0182] Femoral Puncture Site Closure
[0183] A solution of 4-arm PEG succinimidyl glutarate, MW 10,000
(Shearwater Polymers, Huntsville, Ala.) was prepared by dissolving
0.40 g in 2.0 mL of water for injection. The albumin solution
consists 25% human serum albumin, USP (Plasbumin-25, Bayer
Corporation), buffered to pH 9.0.
[0184] Syringes containing 2.0 mL of the polymer solution and 2.0
mL of albumin solution were connected to the joiner coupled to the
catheter device having an 8 French catheter tube 24.
[0185] Aseptically, the distal end of the catheter tube 24 was
inserted into the femoral artery of a sedated sheep. The first and
second deformable regions were enlarged inside and outside the
artery. The material in the dispensing syringes were simultaneously
injected through the mixing chamber into the catheter tube 24, and
dispensed through the nozzles 34 at the tissue site.
[0186] Twenty seconds was allowed for gelation. The deformable
regions were relaxed, and the catheter tube 24 was withdrawn from
the artery.
[0187] Direct pressure was applied to the artery for an additional
3 minutes to allow the barrier material to fully harden. When the
pressure was relieved, blood loss through the tissue track or
hematoma formation was not observed. Doppler analysis confirmed
blood flow distally from the arteriotomy. The time between
application of liquid barrier material to the formation of a
non-liquid barrier to affect complete sealing was 3.5 minutes.
[0188] The treated sheep was upright and bearing weight evenly on
its legs within 45 minutes after deployment of the barrier
material. After about one hour from the completion of the
procedure, hay was placed in the pen. The sheep immediately began
eating. Approximately 2 hours after the procedure, the animal was
bright, alert, and responsive without a hematoma. The animal did
not exhibit any adverse effects from the treatment and was
indistinguishable from non-treated sheep.
[0189] Thirty days post-operative, the animal was sacrificed and
the femoral artery was removed en bloc, placed in formalin, and
evaluated using standard histological techniques. Approximately 10%
of the implanted material was still remaining at thirty days. The
evaluating pathologist noted a foreign body response to the
material that was consistent with a biodegrading material.
Additional studies have shown that, after the material has entirely
degraded, the tissue returns to a quiescent state.
EXAMPLE 5
[0190] Additional Femoral Puncture Site Closure Procedures in
Sheep
[0191] A number of additional procedures have been performed using
the barrier material in various sizes of puncture sizes using
heparinized sheep. The following Table summarizes the results:
2TABLE 2 Femoral Sealing Results (Heparinized Sheep) Total
Procedure Time Less Bleeding than 10 Stopped in Minutes less than 3
(Measured minutes Between (Measured Insertion of Between Catheter
Tube Material and Stoppage Application of Bleeding Catheter and
When After Removal Barrier tube 24 Number of Bleeding of Catheter
Material Diameter Procedures Stopped) Tube) 4-arm PEG/ 6 Fr 1 1 of
1 Not Applicable Albumin 4-arm PEG/ 8 Fr 3 2 of 3 3 of 3 Albumin
4-arm PEG/ 8 Fr 3 2 of 3 3 of 3 Albumin + Heparin
EXAMPLE 6
[0192] Additional Femoral Puncture Site Closure Procedures in
Pigs
[0193] A number of additional procedures have been performed using
the barrier material in various sizes of puncture sizes in pigs.
The procedure used in the porcine experiments is identical to that
used in the ovine experiments.
[0194] The following Table summarizes the results.
3TABLE 3 Femoral Sealing Results (Pigs) Total Procedure Time Less
Bleeding than 10 Stopped in Minutes less than 3.5 (Measured minutes
Between (Measured Insertion of Between Catheter Tube Material and
Stoppage Application of Bleeding Catheter and When After Removal
Barrier tube 24 Number of Bleeding of Catheter Material Diameter
Procedures Stopped) Tube) 4-arm PEG/ 8 Fr 4 3 of 4 4 of 4 Albumin
4-arm PEG/ 7 Fr 1 1 of 1 Not Applicable Albumin
[0195] IV. Alternative Embodiments
[0196] A. Catheter Device
[0197] FIG. 14 shows an alternative embodiment of a catheter device
220 that the system 10 can incorporate instead of the catheter
device 20.
[0198] Like the catheter device 20, the catheter device 220
includes a flexible catheter tube 224 having a proximal end 226 and
a distal end 228. The catheter tube 224 can be constructed from the
same medical grade plastic materials as the catheter tube 24,
already described. As with the catheter tube 24, the distal end 228
has an outside diameter of, e.g., 4 Fr to 16 Fr. Unlike the distal
end 28, the distal end 228 has a uniform diameter along its entire
length, which also matches the outside diameter of the entire
catheter tube 24.
[0199] The proximal end 226 carries a handle 230 to facilitate
gripping and maneuvering the catheter tube 224 by a physician. As
shown in FIG. 14, the handle 230 is of reduced size, compared to
the handle 30. The reduced size of the handle 230 facilitates
holding the handle 330 between the forefinger and thumb, for better
fine control and tactile feedback.
[0200] As FIG. 16 shows, an interior lumen 232 extends through the
catheter tube 224. The lumen accommodates passage of a conventional
guide wire 40, as already described.
[0201] Like the catheter device 20, the catheter device 220
includes, at its distal end 228, a circumferentially spaced array
of nozzles 234 (see FIG. 15). The barrier material is conveyed in
liquid form and dispensed in a circumferential manner through the
nozzles 234 at the puncture site.
[0202] As FIG. 15 shows, the distal end 228 includes a single
deformable region 238, which is located a short distance from the
nozzles 234. Unlike the catheter device 20, the distal end 228 of
the catheter device 220 does not includes a leader, extending
distally from the deformable region 238. The distal end 228
terminates a short distance from the deformable region 238.
[0203] The deformable region 238 normally presents a generally
cylindrical, low profile condition (shown in FIG. 14), presenting
an outside diameter that is generally the same as the distal end
238 itself. When the low profile condition, the region 238 passes
over the guide wire into the vessel (as FIG. 17 shows).
[0204] The region 238 can be deformed into a radially enlarged
condition, which forms a positioner 242 (see FIG. 15). In use (see
FIG. 18), the positioner 242 resists passage through the puncture
site in response to rearward tension along the catheter tube 224,
as shown by arrow 132 in FIG. 18. The positioner 242 serves to
position the nozzles 234 at a proper distance outside the vessel,
while the liquid barrier material is introduced outside the vessel
through the nozzles 34.
[0205] Unlike the catheter device 20, the catheter device 220 does
not include a second deformable region spaced proximal to the
nozzles 34. It has been found that the gelation of the liquid
barrier material, as described above, occurs quickly enough to
obviate the need for a proximal dam.
[0206] The deformation of the region 238 can be accomplished in
various ways. In the illustrated embodiment, the region 238
comprises an expandable balloon material attached about the
catheter tube 224. The catheter tube 224 includes an interior lumen
256 (shown in FIG. 16), which communicates through an aperture 258
with the interior of the balloon material. A fitting 254 carried by
the handle 230 (see FIG. 14) communicates with the lumen 256. The
fitting 254 couples the lumen to an auxiliary syringe 126, which
injects air under pressure through the lumen 256 into the space
surrounded by the balloon material, causing the material to expand
and form the positioner 242.
[0207] As FIG. 14 shows, a mixing chamber 294 is carried at the end
of a tube 296 attached to the handle 230 of the catheter device
220. The tube 296 communicates with interior lumens 334 in the
catheter tube 224 (shown in FIG. 16), which, in turn, are coupled
to the dispensing nozzles 234. The mixing chamber 294 includes a
luer fitting 298, which threadably connects with the single outlet
port 92 of the joiner 84 (see FIG. 17).
[0208] In use, the barrier material introducer/mixer 22 expresses
the albumin 100 and polymer solution 136 in tandem from the
dispensing syringes 60 and 62, which are mechanically linked
together by the joiner 84, support 64, and clip 68, in the manner
already described. The two components of the barrier material come
into contact in the liquid state in the mixing chamber 294.
Channel-mixing of the two components occurs as they flow through
the mixing chamber 294 to the nozzles 234.
[0209] Prior to deploying the catheter device 220 for use, the
physician prepares the PEG solution 136, and couples the syringes
60 and 62 to the barrier introducer/mixer 22, in the manners
previously described.
[0210] As FIG. 17 shows, according to appropriate instructions 122,
the physician is instructed to pass the distal end 228 of the
catheter tube 224 over the guide wire 40 through the puncture site.
The physician advances the distal end 228 to situate the deformable
region 238 inside the vessel, while the nozzles 234 are deployed
outside the vessel. The physician can monitor the advancement
tactilely. The presence of the uniform diameter distal end 228
seals the puncture site.
[0211] According to the directions 122 (as FIG. 18 shows) the
physician is instructed to attach an auxiliary syringe 126 filled
with about 1 cc of air to the fitting 254. The phsyician injects
the air to inflate the region 238, which expands radially into the
positioner 242. The physician is then instructed to place slight
rearward tension on the catheter tube 224 (shown by arrow 132 in
FIG. 18), to bring the positioner 242 into contact with the
interior of the vessel. Due to the slight rearward tension, the
positioner 242 seats against and supports the puncture site. The
physician will, by tactile feedback, know that the positioner 42
has contacted the vessel interior. The guidewire lumen 32 of the
catheter tube 24 can be used to inject suitable contrast media to
aid in the visualization of the puncture site region.
[0212] The physician is instructed to continue to apply a slight
rearward tension on the catheter tube 224, sufficient to keep the
positioner 242 against the interior of the vessel, without pulling
it through the vessel wall.
[0213] The physician is instructed to grasp the finger rests 80 and
thumb rest 82 of the barrier material introducer/mixer 22, as if
grasping an ordinary syringe. The physician expresses the albumin
100 from the first dispensing syringe 60 while simultaneously also
expressing the PEG solution 136 from the second dispensing syringe
62.
[0214] The albumin and PEG solutions come into contact in the
mixing chamber 294 and, from there, proceed through the catheter
tube 224 to the nozzles 234. The albumin 100 and PEG solution 136
intimately channel-mix in transit.
[0215] As FIG. 19 shows, the mixture of albumin 100 and PEG
solution 136 flows in liquid form through the nozzles 234. The
liquid mixture 130 of albumin 100 and PEG solution 136 enters and
fills the tissue region surrounding the puncture site.
[0216] As FIG. 19 shows, according to the directions 122, the
physician waits the requisite gelation period, during which the
liquid mixture 130 of albumin 100 and PEG material 136 transform
into a non-fluid barrier network 128 outside the puncture site.
During the gelation period, the physician is instructed to continue
to apply a slight rearward tension on the catheter tube 224 to seat
the positioner 242 against the interior vessel wall, as the solid
barrier network 128 forms outside the vessel to seal the puncture
site. The catheter tube 224 resists seepage of the liquid mixture
130 into the vessel during the gelation period.
[0217] After the requisite gelation period, the physician is
instructed to operate the syringe 126 to remove air pressure and
collapse the positioner 242. The physician withdraws the guide wire
40 and the distal end 228 of the catheter tube 24 from the vessel.
As shown by FIG. 20, during withdrawal, the distal end 28 and the
guide wire 40 pass through the barrier network 128 that has, by
now, formed over the puncture site.
[0218] After withdrawing the catheter tube 24, the physician is
instructed to apply manual pressure to the skin over the blood
vessel, e.g., for about three minutes, to aid in the sealing
process. This time allows the barrier material to fully cross-link.
The physician then confirms that the puncture site has been sealed
by observing the lack of blood seepage about the guide wire
access.
[0219] The puncture site of the vessel naturally closes and heals.
As FIG. 20 shows, the presence of the barrier network 128 outside
the puncture site prevents blood leakage while natural healing
takes place. The body resorbs the barrier network 128 over time,
e.g., within 30 days.
[0220] C. Mixing Chambers
[0221] There are various alternative constructions for a mixing
chamber 94 usable in association with the barrier material
introducer/mixer 22. The construction selected depends upon the
particular geometry and size of a given mixing chamber, as well as
how readily the components of the barrier material intimately mix
to initiate the cross-linking reaction.
[0222] In the illustrated embodiment, the enhanced functionality of
the preferred 4-PEG-SG material allows channel mixing to take
place, as the components of the barrier are conveyed in tandem to
the targeted puncture site. In this arrangement, the mixing chamber
94 serves the function of rapidly guiding the polymer solution 136
and the protein solution 100 into intimate flow contact as they
leave the port 92.
[0223] The mixing chamber 94 can, if desired, include other
structure to mechanically enhance and accelerate the mixing
effect.
[0224] For example, as shown in FIG. 22, a mixing chamber 94 can
include an array of interior funnel walls 156. The funnel walls 156
include interruptions 158, which are arranged in a alternative
pattern along the flow center and along the flow perimeter of the
chamber 154. Polymer solution 136 and protein solution 100 are
directed through the interruptions 158 in a circumferential and
circular flow path through the chamber 154. The circumferential and
circular flow of the polymer solution 136 and protein solution 100
accelerates the channel-mixing process.
[0225] Alternatively (as FIG. 23 shows), baffle walls 166 can be
arranged perpendicular to the flow path through the mixing chamber
94. The baffle walls 166 include staggered interruptions 168. The
interruptions 168 cause the polymer solution 136 and protein
solution 100 to advance through the chamber 94 in a zig-zagging
path, from one side of the chamber 94 to the other. The zig-zagging
path is particularly advantageous if the polymer solution 136 and
protein solution 100 are introduced into the chamber 94 through
separate inlet ports 170 and 172).
[0226] Alternatively, baffles 160 can be arranged about a hub 162
in a spiral pattern (as FIG. 24 shows) or in a non-spiral pattern
(as FIG. 25 shows). The baffles 160 establish a cascading flow
within the chamber 94 to accelerate mixing of the polymer solution
136 and protein solution 100. The hub 162 can include an interior
lumen 164 to accommodate passage of, e.g., the guide wire 40 or the
air conveyed to expand a deformable region on the distal end of the
catheter tube 24 or 224.
[0227] As FIG. 26 shows, the polymer solution 136 and the protein
solution 100 can be introduced into the chamber 94 through separate
tangential ports 174 and 176, which are diagonally spaced apart.
The chamber 94 includes a center outlet port 178. Solutions 100 and
136 entering the ports 174 and 176 flow in a swirling pattern about
the periphery of the chamber 94, before exiting the center outlet
port 178. The swirling flow pattern accelerates intimate
mixing.
[0228] As shown in FIG. 27, the chamber 94 can include multiple
spaced apart inlet ports 180, 182, 184, 186 arranged about a common
center outlet port 188. The ports 180, 182, 184, 186, and 188 are
arranged parallel to the intended flow path through the chamber 94.
Polymer solution 136 is introduced through opposed ports 180 and
184, while protein solution is introduced through the opposed ports
182 and 186. The multiple spaced-apart inlet paths feeding a common
center outlet port 188 enhance the desired mixing effect of the
chamber 94.
[0229] C. Other Uses for the Barrier Material Introducer/Mixer
[0230] The barrier material introducer/mixer 22 can be used to
dispense barrier material without association with the catheter
device 20 or 220. As FIG. 21, the outlet port 92 can be coupled to
various dispensing devices, such as a sprayer 150 or a cannula or
needle 152.
[0231] The physician can select the sprayer 150 and operate the
material introducer/mixer 22 in the manner previously described, to
locally dispense the barrier material (or an other tissue adhesive
or sealing material) at an exposed puncture or suture site, e.g.,
during an open surgical procedure or on the skin. Atomization
through the sprayer 150 will mix the liquid components of the
barrier or adhesive material sufficiently to initiate the
cross-linking reaction.
[0232] Alternatively, the physician can select the cannula 152 and
operate the material introducer/mixer 22 to inject the barrier
material (or other selected material) at a targeted subcutaneous
puncture site. Passage of the liquid components of the barrier or
other material through the cannula 152 will channel-mix the
materials sufficiently to initiate the cross-linking reaction.
[0233] It should thus be appreciated that the barrier material
introducer/mixer 22 can be used in diverse ways throughout the body
for dispensing any material formed by intimate mixing of two liquid
components conveyed in tandem to a targeted treatment site. The
barrier material introducer/mixer 22 can be used for exterior or
interior introduction and application of any such material, with or
without catheter access.
[0234] D. Introducer/Mixer
[0235] FIG. 28 shows an alternative embodiment of an
introducer/mixer 300. In this embodiment, a molded joiner 320
includes side-by-side female luer fittings 304. Each fitting 304
receives the threaded male luer fittings 306 of the dispensing
syringes 60 and 62. A syringe clip 308 also preferably links the
syringe pistons 76 for simultaneous advancement when dispensing
materials from the syringes 60 and 62.
[0236] In this alternative embodiment, the introducer/mixer 300
does not include a separate channeled syringe support member (as
shown by reference numeral 34 in FIG. 2). The molded strength of
the female luer fittings 304 on the joiner 302, can, when threaded
to the male fittings 306, itself be sufficient to hold the syringes
60 and 62 during dispensement of their liquid contents, as already
described. This reduces the number of parts required for the
introducer/mixer 300.
[0237] As FIG. 29 shows, the joiner 302 can include opposing skirts
310 molded to peripherally surround the fittings 304. The skirts
310 resist side-to-side deflection of the syringes 60 and 62, when
held by the joiner 302.
[0238] As FIG. 28 shows, the joiner 302 includes interior channels
312 and 314, which are coupled to the luer fittings 304. The
interior channels 312 and 314 criss-cross within the joiner 302,
without fluid communication. The criss-crossing channels 312 and
314 keep the liquid contents of the syringes 60 and 62 free of
mixing. The channels 312 terminate with separate outlet ports 316
and 318.
[0239] As FIG. 28 also shows, in use, the joiner 302 is coupled to
a mixing chamber 320, which is of the type shown in FIG. 27. The
liquid contents of the syringes 60 and 62 are transported through
the outlet ports 316 and 318 from the joiner 302 into separate,
spaced-apart ports 322 in the mixing chamber 320. The ports 322
lead to a common center outlet port 324. As before explained, the
flow of the liquid contents through separate spaced-apart inlet
ports 322 into a common outlet port 324 enhances the mixing effects
of the chamber 320.
[0240] FIG. 30 shows yet another alternative embodiment of an
introducer/mixer 326. In this embodiment, a molded joiner 328
includes female luer fittings 330, to receive the threaded male
luer fittings 306 of the dispensing syringes 60 and 62. In this
embodiment, the fittings 330 extend in a generally v-shape, at an
angle and not parallel with respect to each. This allows the main
body of the joiner 328 to be reduced in size. A syringe clip (not
shown) can be used to link the syringe pistons coupled to the
joiner 328 for simultaneous advancement.
[0241] In this alternative embodiment, the introducer/mixer 326
also does not include a separate channeled syringe support member
(as shown by reference numeral 34 in FIG. 2). The molded strength
of the female luer fittings 330 itself can be sufficient to support
the syringes 60 and 62 during use. As FIG. 30 shows, an
intermediate wall 332 can be provided between the fittings 330 to
resist inward deflection of the syringes 60 and 62 during use.
[0242] As FIG. 30 shows, the joiner 328 includes criss-crossing
interior channels 334 and 336, like those shown in FIG. 28. The
channels 334 and 336 terminate with separate outlet ports 338 and
340, which, in use, are coupled to a mixing chamber 342 of the type
shown in FIG. 28 and previously described.
[0243] Of course, the joiners 302 and 328 can be coupled to other
types of mixing chambers.
[0244] The features of the invention are set forth in the following
claims.
* * * * *