U.S. patent application number 13/200060 was filed with the patent office on 2012-04-05 for apparatus and method for delivery of biological sealant.
This patent application is currently assigned to Spinal Restorations, Inc.. Invention is credited to A. David Boccuti, Andrew Nicholas Gentile, J. Brent Ratz, John Spiridigliozzi, Thomas T. Washburn, John L. Wheeler, Gary Whipple.
Application Number | 20120083828 13/200060 |
Document ID | / |
Family ID | 46329543 |
Filed Date | 2012-04-05 |
United States Patent
Application |
20120083828 |
Kind Code |
A1 |
Wheeler; John L. ; et
al. |
April 5, 2012 |
Apparatus and method for delivery of biological sealant
Abstract
A device for delivery of biologic materials, comprising: a
cartridge having at least two cylinder bores for fluids to be
delivered, wherein each cylinder includes an exit port for a fluid,
a plunger within each cylinder for pushing the fluids out of the
cylinder, a housing adapted to receive the cartridge, wherein the
housing or cartridge includes an adaptor to receive and lock a
manifold that operably connects to the exit ports of the cartridge,
at least two toothed rams, wherein each toothed ram is at least
partially within a cylinder bore, a trigger connected to the
housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams, as well as methods of making the device,
methods of using the device to treat discs, kits including the
device.
Inventors: |
Wheeler; John L.; (Austin,
TX) ; Whipple; Gary; (Attleboro, MA) ;
Boccuti; A. David; (Arlington, MA) ; Washburn; Thomas
T.; (Concord, MA) ; Gentile; Andrew Nicholas;
(Waltham, MA) ; Ratz; J. Brent; (Winchester,
MA) ; Spiridigliozzi; John; (Sharon, MA) |
Assignee: |
Spinal Restorations, Inc.
|
Family ID: |
46329543 |
Appl. No.: |
13/200060 |
Filed: |
September 16, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11977441 |
Oct 24, 2007 |
8047407 |
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13200060 |
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11205760 |
Aug 17, 2005 |
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11977441 |
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11205784 |
Aug 17, 2005 |
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11205760 |
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11205775 |
Aug 17, 2005 |
7597687 |
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11205784 |
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Current U.S.
Class: |
606/213 ;
29/428 |
Current CPC
Class: |
A61L 2300/00 20130101;
A61B 17/0057 20130101; Y10T 29/49826 20150115; A61K 38/482
20130101; A61L 2400/06 20130101; A61L 27/225 20130101; A61L 27/50
20130101; B05C 17/00553 20130101; A61K 45/06 20130101; A61L 24/106
20130101; A61K 38/363 20130101; B05C 17/0116 20130101; A61B
2017/00495 20130101; A61L 27/54 20130101; A61B 17/00491 20130101;
A61L 2430/38 20130101; A61K 38/363 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 38/482 20130101 |
Class at
Publication: |
606/213 ;
29/428 |
International
Class: |
A61B 17/03 20060101
A61B017/03; B23P 17/04 20060101 B23P017/04 |
Claims
1. A device for delivery of biologic materials, comprising: a
cartridge having at least two cylinder bores for fluids to be
delivered, wherein each cylinder includes an exit port for a fluid,
a plunger within each cylinder for pushing the fluids out of the
cylinder, a housing adapted to receive the cartridge, wherein the
housing or cartridge includes an adaptor to receive and lock a
manifold that operably connects to the exit ports of the cartridge,
at least two toothed rams, wherein each toothed ram is at least
partially within a cylinder bore, a trigger connected to the
housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
2. The device of claim 1, wherein the cartridge is a separate
component from the housing that is inserted into the housing.
3. The device of claim 1, further comprising a pressure monometer
operably connected to measure the pressure in at least one
cylinder.
4. The device of claim 1, wherein the plungers are attached to the
rams.
5. The device of claim 1, wherein the wheel assembly includes an
inner toothed wheel sandwiched between two outer toothed wheels
each of smaller diameter than the inner wheel.
6. The device of claim 1, wherein the drive rack engages the wheel
assembly upon manual pressure to the trigger and wherein the drive
rack disengages the wheel assembly upon release of pressure on the
trigger, and falls away.
7. The device of claim 1, further comprising a fill manifold for
introducing fluids into the cylinder, wherein the fill manifold
comprises a fill manifold adaptor that couples to the adaptor of
the delivery device wherein the adaptor includes at least two exit
ports that each couple to the at least two exit ports of the
housing adaptor, at least two syringes, at least two conduits
wherein one end of the conduit connects to the syringe and a second
end of the conduit connects to an exit port of the fill manifold
adaptor.
8. The device of claim 1, further comprising a delivery manifold
for delivering the fluids, comprising a delivery adaptor that
includes at least two exit ports that each couple to the at least
two exit ports of the housing adaptor, at least two conduits having
two ends wherein a first end of each of the conduits connects to an
exit port of the delivery manifold, and wherein a second end of
each of the conduits connects to a duel port luer fittings, wherein
the luer fitting is configured to deliver fluid from one conduit to
an inner needle and wherein the luer fitting is configured to
deliver fluid from the second conduit to a space defined by the
exterior of the inner needle and by a second larger diameter needle
that connects to the luer fitting with the inner needle being
within the insider of the larger diameter needle.
9. The device of claim 8, wherein the inner needle does not extend
past a distal tip of the second needle.
10. A method of making a device for delivery of biologic materials,
comprising: providing a cartridge having at least two cylinder
bores for fluids to be delivered, wherein each cylinder includes an
exit port for a fluid, providing a plunger within each cylinder for
pushing the fluids out of the cylinder, providing a housing adapted
to receive the cartridge, wherein the housing or cartridge includes
an adaptor to receive and lock a manifold that operably connects to
the exit ports of the cartridge, providing at least two toothed
rams, wherein each toothed ram is at least partially within a
cylinder bore, providing a trigger connected to the housing,
wherein the trigger includes a toothed drive rack, providing a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
11. The method of claim 10, wherein the housing and the cartridge
are together monolithic.
12. The method of claim 10, wherein the cartridge is a separate
component from the housing that is inserted into the housing.
13. The method of claim 10, further comprising providing a pressure
monometer operably connected to measure the pressure in at least
one cylinder.
14. The method of claim 10, wherein the plungers are attached to
the rams.
15. The method of claim 10, wherein the wheel assembly includes an
inner toothed wheel sandwiched between two outer toothed wheels
each of smaller diameter than the inner wheel.
16. The method of claim 10, wherein the drive rack engages the
wheel assembly upon manual pressure to the trigger and wherein the
drive rack disengages the wheel assembly upon release of pressure
on the trigger, and falls away.
17. The method of claim 10, further comprising providing a fill
manifold for introducing fluids into the cylinder, wherein the fill
manifold comprises a fill manifold adaptor that couples to the
adaptor of the delivery device wherein the adaptor includes at
least two exit ports that each couple to the at least two exit
ports of the housing adaptor, at least two syringes, at least two
conduits wherein one end of the conduit connects to the syringe and
a second end of the conduit connects to an exit port of the fill
manifold adaptor.
18. The method of claim 10, further comprising providing a delivery
manifold for delivering the fluids, comprising a delivery adaptor
that includes at least two exit ports that each couple to the at
least two exit ports of the housing adaptor, at least two conduits
having two ends wherein a first end of each of the conduits
connects to an exit port of the delivery manifold, and wherein a
second end of each of the conduits connects to a duel port luer
fittings, wherein the luer fitting is configured to deliver fluid
from one conduit to an inner needle and wherein the luer fitting is
configured to deliver fluid from the second conduit to a space
defined by the exterior of the inner needle and by a second larger
diameter needle that connects to the luer fitting with the inner
needle being within the insider of the larger diameter needle.
19. The method of claim 10, wherein the inner needle does not
extend past a distal tip of the second needle.
20. A kit for treating a disc, comprising: fibrinogen, thrombin,
and a device for delivery of biologic materials, wherein the device
comprises: a cartridge having at least two cylinder bores for
fluids to be delivered, wherein each cylinder includes an exit port
for a fluid, a plunger within each cylinder for pushing the fluids
out of the cylinder, a housing adapted to receive the cartridge,
wherein the housing or cartridge includes an adaptor to receive and
lock a manifold that operably connects to the exit ports of the
cartridge, at least two toothed rams, wherein each toothed ram is
at least partially within a cylinder bore, a trigger connected to
the housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
21. The kit of claim 20, the cartridge is a separate component from
the housing that is inserted into the housing, wherein the kit
further comprises a pressure monometer operably connected to
measure the pressure in at least one cylinder; wherein the plungers
are attached to the rams; wherein the wheel assembly includes an
inner toothed wheel sandwiched between two outer toothed wheels
each of smaller diameter than the inner wheel; wherein the drive
rack engages the wheel assembly upon manual pressure to the trigger
and wherein the drive rack disengages the wheel assembly upon
release of pressure on the trigger, and falls away; wherein the kit
further comprises a fill manifold for introducing fluids into the
cylinder, wherein the fill manifold comprises a fill manifold
adaptor that couples to the adaptor of the delivery device wherein
the adaptor includes at least two exit ports that each couple to
the at least two exit ports of the housing adaptor, at least two
syringes, at least two conduits wherein one end of the conduit
connects to the syringe and a second end of the conduit connects to
an exit port of the fill manifold adaptor; wherein the kit further
comprises a delivery manifold for delivering the fluids, comprising
a delivery adaptor that includes at least two exit ports that each
couple to the at least two exit ports of the housing adaptor, at
least two conduits having two ends wherein a first end of each of
the conduits connects to an exit port of the delivery manifold, and
wherein a second end of each of the conduits connects to a duel
port luer fittings, wherein the luer fitting is configured to
deliver fluid from one conduit to an inner needle and wherein the
luer fitting is configured to deliver fluid from the second conduit
to a space defined by the exterior of the inner needle and by a
second larger diameter needle that connects to the luer fitting
with the inner needle being within the insider of the larger
diameter needle; and wherein the inner needle does not extend past
a distal tip of the second needle.
22. A method of making a kit, comprising providing fibrinogen,
providing thrombin, and providing a device for delivery of biologic
materials, wherein the device comprises: a cartridge having at
least two cylinder bores for fluids to be delivered, wherein each
cylinder includes an exit port for a fluid, a plunger within each
cylinder for pushing the fluids out of the cylinder, a housing
adapted to receive the cartridge, wherein the housing or cartridge
includes an adaptor to receive and lock a manifold that operably
connects to the exit ports of the cartridge, at least two toothed
rams, wherein each toothed ram is at least partially within a
cylinder bore, a trigger connected to the housing, wherein the
trigger includes a toothed drive rack, a toothed wheel assembly
that cooperates with the toothed drive rack and with the toothed
rams.
23. The method of claim 22, wherein the cartridge is a separate
component from the housing that is inserted into the housing
further comprising providing a pressure monometer operably
connected to measure the pressure in at least one cylinder; wherein
the plungers are attached to the rams; wherein the wheel assembly
includes an inner toothed wheel sandwiched between two outer
toothed wheels each of smaller diameter than the inner wheel;
wherein the drive rack engages the wheel assembly upon manual
pressure to the trigger and wherein the drive rack disengages the
wheel assembly upon release of pressure on the trigger, and falls
away; further comprising providing a fill manifold for introducing
fluids into the cylinder, wherein the fill manifold comprises a
fill manifold adaptor that couples to the adaptor of the delivery
device wherein the adaptor includes at least two exit ports that
each couple to the at least two exit ports of the housing adaptor,
at least two syringes, at least two conduits wherein one end of the
conduit connects to the syringe and a second end of the conduit
connects to an exit port of the fill manifold adaptor; further
comprising providing a delivery manifold for delivering the fluids,
comprising a delivery adaptor that includes at least two exit ports
that each couple to the at least two exit ports of the housing
adaptor, at least two conduits having two ends wherein a first end
of each of the conduits connects to an exit port of the delivery
manifold, and wherein a second end of each of the conduits connects
to a duel port luer fittings, wherein the luer fitting is
configured to delivery fluid from one conduit to an inner needle
and wherein the luer fitting is configured to delivery fluid from
the second conduit to a space defined by the exterior of the inner
needle and by a second larger diameter needle that connects to the
luer fitting with the inner needle being within the insider of the
larger diameter needle; and wherein the inner needle does not
extend past a distal tip of the second needle.
24. A method of treating a disc that is leaking nucleus pulposus
through at least one defect in the annulus fibrosus, comprising:
injecting a fibrin sealant into the disc to reduce at least a
portion of the at least one defect, wherein the fibrin sealant
injected into the disc comprises fibrinogen and thrombin, wherein
the fibrin sealant is injected using a delivery device that
comprises: a cartridge having at least two cylinder bores for
fluids to be delivered, wherein each cylinder includes an exit port
for a fluid, a plunger within each cylinder for pushing the fluids
out of the cylinder, a housing adapted to receive the cartridge,
wherein the housing or cartridge includes an adaptor to receive and
lock a manifold that operably connects to the exit ports of the
cartridge, at least two toothed rams, wherein each toothed ram is
at least partially within a cylinder bore, a trigger connected to
the housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
25. The method of claim 24, wherein the cartridge is a separate
component from the housing that is inserted into the housing;
further comprising providing a pressure monometer operably
connected to measure the pressure in at least one cylinder; wherein
the plungers are attached to the rams; wherein the wheel assembly
includes an inner toothed wheel sandwiched between two outer
toothed wheels each of smaller diameter than the inner wheel;
wherein the drive rack engages the wheel assembly upon manual
pressure to the trigger and wherein the drive rack disengages the
wheel assembly upon release of pressure on the trigger, and falls
away; further comprising providing a fill manifold for introducing
fluids into the cylinder, wherein the fill manifold comprises a
fill manifold adaptor that couples to the adaptor of the delivery
device wherein the adaptor includes at least two exit ports that
each couple to the at least two exit ports of the housing adaptor,
at least two syringes, at least two conduits wherein one end of the
conduit connects to the syringe and a second end of the conduit
connects to an exit port of the fill manifold adaptor; further
comprising providing a delivery manifold for delivering the fluids,
comprising a delivery adaptor that includes at least two exit ports
that each couple to the at least two exit ports of the housing
adaptor, at least two conduits having two ends wherein a first end
of each of the conduits connects to an exit port of the delivery
manifold, and wherein a second end of each of the conduits connects
to a duel port luer fittings, wherein the luer fitting is
configured to delivery fluid from one conduit to an inner needle
and wherein the luer fitting is configured to delivery fluid from
the second conduit to a space defined by the exterior of the inner
needle and by a second larger diameter needle that connects to the
luer fitting with the inner needle being within the insider of the
larger diameter needle; and wherein the inner needle does not
extend past a distal tip of the second needle.
Description
[0001] This application claims priority to U.S. provisional
application No. 60/854,413, filed Oct. 24, 2006, to U.S.
provisional application No. 60/623,600, filed Oct. 29, 2004 and is
a continuation-in-part of U.S. application Ser. No. 11/205,760,
filed Aug. 17, 2005, of U.S. application Ser. No. 11/205,784, filed
Aug. 17, 2005, and of U.S. application Ser. No. 11/205,775, filed
Aug. 17, 2005, and this application claims priority to U.S.
provisional application No. 60/764,019, filed Feb. 1, 2006, and
this application claims priority to U.S. provisional application
No. 60/764,020, filed Feb. 1, 2006, all of which are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The disclosure herein generally relates to an apparatus and
method for the delivery of a biologic sealant such as fibrin
sealant.
BACKGROUND OF THE INVENTION
[0003] Fibrin sealants, and glues, are well known and are used
extensively in various clinical settings. Such sealants are
indicated as adjuncts to hemostasis in surgeries when control of
bleeding by conventional surgical techniques, including suture,
ligature, and cautery is ineffective or impractical. In these
cases, the sealant was applied topically. Delivery devices have
been developed for these uses. Typical fibrin sealant devices are
adapted to spray the fibrin sealant.
[0004] More recently, fibrin sealant has been used to treat
degenerative disc disease that leads to discogenic pain. In this
regard, U.S. Pat. No. 6,468,527 (Austin) discloses the injection of
a fibrin sealant into the intra-discal space. This patent discloses
use of a dual syringe system wherein thrombin and fibrinogen
initially mix in a Y-connector that attaches to a needle and to the
two syringes. The fibrin sealant immediately begins clotting upon
contact of the fibrinogen and the thrombin. The components continue
to mix and clot as they-travel down the spinal needle toward the
tip of the needle that is in the disc.
[0005] However, the inventors herein have recognized that the prior
delivery device shown in U.S. Pat. No. 6,468,527 is prone to
clogging due to clotting of the components within the needle. In
addition, the inventors have recognized that it would be desirable
for a surgeon administering the sealant to know the pressure of the
components being delivered so that the surgeon does not
over-pressurize the disc and/or so that the surgeon can use the
delivery device as a diagnostic tool to ascertain the extent of
damage to the disc.
SUMMARY OF THE INVENTION
[0006] This invention provides a solution to one or more of the
disadvantages and desired capabilities described above.
[0007] In the practice of the present invention, a biologic sealant
such as fibrin sealant can be introduced into, for example, the
spinal area of a human being. Fibrin sealant comprises fibrinogen
and thrombin, which form fibrin when mixed. Calcium chloride may be
included in the fibrin sealant. The fibrin may optionally include
one or more additives, such as various biological and
non-biological agents.
[0008] In one broad respect, this invention is an apparatus for
delivery of a biologic sealant. This device comprises a cartridge
having at least two cylinder bores for fluids to be delivered,
wherein each cylinder includes an exit port for a fluid, a plunger
within each cylinder for pushing the fluids out of the cylinder, a
housing adapted to receive the cartridge, wherein the housing or
cartridge includes an adaptor to receive and lock a manifold that
operably connects to the exit ports of the cartridge, at least two
toothed rams, wherein each toothed ram is at least partially within
a cylinder bore, a trigger connected to the housing, wherein the
trigger includes a toothed drive rack, a toothed wheel assembly
that cooperates with the toothed drive rack and with the toothed
rams.
[0009] In another broad respect, this invention is a method of
making a device for delivery of biologic materials, comprising:
providing a cartridge having at least two cylinder bores for fluids
to be delivered, wherein each cylinder includes an exit port for a
fluid, providing a plunger within each cylinder for pushing the
fluids out of the cylinder, providing a housing adapted to receive
the cartridge, wherein the housing or cartridge includes an adaptor
to receive and lock a manifold that operably connects to the exit
ports of the cartridge, providing at least two toothed rams,
wherein each toothed ram is at least partially within a cylinder
bore, providing a trigger connected to the housing, wherein the
trigger includes a toothed drive rack, providing a toothed wheel
assembly that cooperates with the toothed drive rack and with the
toothed rams.
[0010] In another broad respect, this invention is a kit for
treating a disc, comprising: fibrinogen, thrombin, and a device for
delivery of biologic materials, wherein the device comprises: a
cartridge having at least two cylinder bores for fluids to be
delivered, wherein each cylinder includes an exit port for a fluid,
a plunger within each cylinder for pushing the fluids out of the
cylinder, a housing adapted to receive the cartridge, wherein the
housing or cartridge includes an adaptor to receive and lock a
manifold that operably connects to the exit ports of the cartridge,
at least two toothed rams, wherein each toothed ram is at least
partially within a cylinder bore, a trigger connected to the
housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
[0011] In another broad respect, this invention is a method of
making a kit, comprising providing fibrinogen, providing thrombin,
and providing a device for delivery of biologic materials, wherein
the device comprises: a cartridge having at least two cylinder
bores for fluids to be delivered, wherein each cylinder includes an
exit port for a fluid, a plunger within each cylinder for pushing
the fluids out of the cylinder, a housing adapted to receive the
cartridge, wherein the housing or cartridge includes an adaptor to
receive and lock a manifold that operably connects to the exit
ports of the cartridge, at least two toothed rams, wherein each
toothed ram is at least partially within a cylinder bore, a trigger
connected to the housing, wherein the trigger includes a toothed
drive rack, a toothed wheel assembly that cooperates with the
toothed drive rack and with the toothed rams.
[0012] In another broad respect, this invention is a method of
treating a disc that is leaking nucleus pulposus through at least
one defect in the annulus fibrosus, comprising: injecting a fibrin
sealant or other biologic sealant into the disc to reduce at least
a portion of the at least one defect, wherein the fibrin sealant
injected into the disc comprises fibrinogen and thrombin, wherein
the fibrin sealant is injected using a delivery device that
comprises: a cartridge having at least two cylinder bores for
fluids to be delivered, wherein each cylinder includes an exit port
for a fluid, a plunger within each cylinder for pushing the fluids
out of the cylinder, a housing adapted to receive the cartridge,
wherein the housing or cartridge includes an adaptor to receive and
lock a manifold that operably connects to the exit ports of the
cartridge, at least two toothed rams, wherein each toothed ram is
at least partially within a cylinder bore, a trigger connected to
the housing, wherein the trigger includes a toothed drive, rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams. The defect can be a tear of the annulus
fibrosus, a fissure in the annulus fibrosus, and the like.
Advantageously, injection of the fibrin sealant can also serve to
restore normal hydrostatic pressure, a key component to disc
health.
[0013] In certain embodiments of the device, kit, and methods of
this invention, the housing and the cartridge are together
monolithic; the cartridge is a separate component from the housing
that is inserted into the housing; the device includes a pressure
monometer operably connected to measure the pressure in at least
one cylinder; wherein the plungers are attached to the rams; the
wheel assembly includes an inner toothed wheel sandwiched between
two outer toothed wheels each of smaller diameter than the inner
wheel; the drive rack engages the wheel assembly upon manual
pressure to the trigger and wherein the drive rack disengages the
wheel assembly upon release of pressure on the trigger, and falls
away; the device includes a fill manifold for introducing fluids
into the cylinder, wherein the fill manifold comprises a fill
manifold adaptor that couples to the adaptor of the delivery device
wherein the adaptor includes at least two exit ports that each
couple to the at least two exit ports of the housing adaptor, at
least two syringes, at least two conduits wherein one end of the
conduit connects to the syringe and a second end of the conduit
connects to an exit port of the fill manifold adaptor; the device
includes a delivery manifold for delivering the fluids, comprising
a delivery adaptor that includes at least two exit ports that each
couple to the at least two exit ports of the housing adaptor, at
least two conduits having two ends wherein a first end of each of
the conduits connects to an exit port of the delivery manifold, and
wherein a second end of each of the conduits connects to a duel
port luer fitting; the luer fitting is configured to deliver fluid
from one conduit to an inner needle and wherein the luer fitting is
configured to deliver fluid from the second conduit to a space
defined by the exterior of the inner needle and by a second larger
diameter needle that connects to the luer fitting with the inner
needle being within the inside of the larger diameter needle,
especially where the tip of the inner needle extends up from about
1.5 inch to about 0.5 inch from the distal tip of the outer needle
and in one embodiment is from about 0.75 inch to about 1 inch from
the distal tip, especially where the inner needle is an 18 gauge
needle and the outer needle is a 22 gauge needle; and combinations
thereof.
[0014] In one embodiment, in the practice of this invention the
nucleus pulposus has not been removed by surgery, such as in the
case of a total or partial discectomy or by nucleoplasty for a
herniated disc.
[0015] This invention also includes a kit including the delivery
device of this invention and the components used to inject the
fibrin sealant. The components may comprise fibrinogen, such as
freeze-dried fibrinogen, thrombin such as freeze-dried thrombin,
and the delivery device. The kit can optionally include CaCl,
contrast agent and other additives.
[0016] Advantageously, the device, methods, and kit of this
invention facilitate extended pain relief for patients with
discogenic pain, wherein for example nucleus pulposus leaks out of
the disc through defects (e.g. tears or fissures) in the annulus
fibrosus. Surprisingly, it has been found that the device of this
invention which employs an outer introducer needle and an inner
needle within the introducer needle, wherein the tip of the inner
needle does not protrude past the distal tip of the outer
introducer needle, and in one embodiment is approximately one inch
from the distal tip of the outer introducer needle, provides a
final fibrin sealant clot with surprising properties. This needle
configuration facilitates mixing of the components of the fibrin
sealant (or other biologic sealant) to provide improved set-up time
(or "work time"), less viscosity with slower set up to afford
easier use in practice and higher penetration of sealant into
tears, fissures, and so forth, enhanced mechanical properties of
the final sealant including greater elasticity (easier to deform)
with slightly less failure load (i.e., the force required to make a
permanent rupture), approximately a 200% improvement in fracture
toughness (i.e., need twice as much energy to break the sealant as
compared to a clot made using a standard device), extended
solidification time of about twice as long to reach 10,000 poise
viscosity, with the ultimate sealant having sufficient mechanical
properties to be useful for intradiscal injections. Likewise, the
device of this invention advantageously allows a practitioner to
reuse the delivery gun in a sterile environment for multiple
injections for a patient by removing the injection manifold,
loading the cartridges with fresh sealant components, attaching the
same or new injection manifold, inserting a second or the same
introducer needle intradiscally, inserting the inner needle within
the introducer needle, and applying pressure to the trigger to
inject sealant. The device should be primed with sealant components
prior to insertion of the inner needle. Likewise, by use of the
device of this invention, where the inner needle does not extend
past the distal tip of the outer needle, and where the tip of the
inner needle is within an inch or two inches from the distal tip of
the longer outer needle, it has been found that partially set up
sealant within the needles can be readily pushed out of the needles
to thereby advantageously clear (unclog) the needles for delivery
of additional sealant, which begins mixing at the tip of the inner
needle.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 shows a semi-exploded view of one embodiment of the
device of this invention.
[0018] FIG. 2 shows a semi-exploded view of components of one
embodiment of the device of this invention.
[0019] FIG. 3 shows a device of this invention, including exit
ports 38, 38' of the cartridge 30.
[0020] FIG. 4 shows a perspective view of the device of this
invention.
[0021] FIG. 5 shows a wheel assembly used in one embodiment of the
device of this invention.
[0022] FIGS. 6-8 show one embodiment of the needle assembly of this
invention.
[0023] FIGS. 9A, 9B, and 9C show representative cross-sectional
views of multi-lumen catheters.
[0024] FIG. 10 shows the device of this invention with a delivery
manifold operably attached to the device.
[0025] FIG. 11 shows the device of this invention with a fill
manifold operably attached to the device.
[0026] FIG. 12 shows the device of this invention from a
cross-sectional view.
[0027] FIG. 13 shows a graph of dynamic setting viscosity profiles
for fibrin delivered from a DUPLOJECT device and from a device of
this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The delivery device of this invention is illustrated in the
figures. In general, the device of this invention comprises: a
cartridge having at least two cylinder bores for fluids to be
delivered, wherein each cylinder includes an exit port for fluid, a
plunger within each cylinder for pushing fluids out of the
cylinder, a housing adapted to receive the cartridge, wherein the
housing or cartridge includes an adaptor to receive and lock a
manifold that operably connects to the exit ports of the cartridge,
at least two toothed rams, wherein each toothed ram is at least
partially within a cylinder bore, a trigger connected to the
housing, wherein the trigger includes a toothed drive rack, a
toothed wheel assembly that cooperates with the toothed drive rack
and with the toothed rams.
[0029] Referring now to FIG. 1, a representative delivery device of
this invention is depicted. The device 10 includes a housing 20
that holds or is connected to some of the device's other parts. The
housing can be made from a variety of materials, but is typically
made from one or more plastic materials. The housing can generally
be referred to as being in the shape of a pistol or gun, including
a handle 21 and barrel 22. A cartridge 30 is positioned within the
barrel 22. The housing is adapted to receive and house the
cartridge. The cartridge 30 is thus positioned within the barrel
22. The housing can be a multi-piece component, such as a two piece
housing that is assembled using screws, or configured using snap-in
type functionality. The specific design shown in FIG. 1 is merely
representative and not intended to limit the types of housings
employed in the practice of this invention.
[0030] In addition, a trigger 40 is operably connected to and
situated within the housing so that the trigger 40 can slide from a
first position into the housing to a second position as pressure is
applied by the operator to the trigger 30. The housing 20 can
include an internal stop, not shown, for the travel of the trigger
30.
[0031] The cartridge 30 is depicted in greater detail in FIG. 2.
Thus, the cartridge 30 includes two cylinders 31, 31' that each has
a bore 32, 32' for receipt of a fluid. Each cylinder 31, 31'
defines a generally straight tube having the same diameter for the
length of the bores 32, 32'. The cartridge 30 may include one or
more fittings, slots, or the like that serve to secure the
cartridge 30 within the housing. For example in FIG. 2 the housing
includes a fitting 53 that is configured to fit within slot 37 of
the cartridge to thereby secure cartridge 30 from lateral movement.
It should be appreciated that the cartridge 30 does not move upon
application of pressure to the trigger 40. Rather, application of
pressure to the trigger 40 engages the rack 42, wheel assembly 50,
and rams 34, 34' to push the plungers 36, 36' toward the exit ports
38, 38' (see FIG. 3) of the cartridge 30. In FIG. 2, the extended
gear ends 51, 51' of the wheel assembly 50 fit into bore 33 of the
cartridge 30 (see also FIG. 4). It should be appreciated that the
cartridge 30 can be integral with the housing 20. That is, the
cartridge 30 need not be a separate and/or detachable component
that is placed within the housing but instead can be formed as part
of the housing during fabrication of the housing. Likewise, the
cartridge can be of one-piece or multi-piece construction. In the
figures the cartridge 30 is one-piece.
[0032] It should be appreciated that the wheel assembly 50 can be a
single piece or can be assembled from multiple parts to form the
assembly. Thus, for example, with respect to a multiple-part
assembly, as depicted in FIG. 5, a toothed internal gear 52 having
extended gear ends 51, 51' is inserted into internal bore 53 of
wheel 50. The gear 52 is adapted to engage the wheel 50, such as by
interdigitating teeth, so that the assembly would move as a single
part during use of the device 10. In this embodiment, the inner
toothed gear 52 can be seen to be sandwiched between the extended
gear ends 51, 51. Alternatively, the wheel assembly can be cast,
forged, milled, or otherwise formed to manufacture a single
monolithic wheel assembly. Alternatively to teeth, the wheel
assembly 50, rack 42, and rams can be made of materials that engage
with sufficient friction to provide the desired movement, using for
example tacky rubber materials, materials have a grainy surface
(e.g., with a sand-paper like finish), and so on.
[0033] Referring again to FIG. 2, there is shown a pressure
read-out display 60 that provides the surgeon with a pressure
reading within one of the bores 32, 32' of the cartridge 30. A
transducer, not shown, is configured to measure pressure within a
bore and a line, not shown, from the transducer to the display 70
provides a signal to electronic circuitry that processes the signal
and provides a reading to display 70. Thus, the pressure monitor
couples to the delivery device through a line connected to a
transducer in, for example, one of the syringes. Alternatively, the
transducer can be located within the connector, or anywhere else
where the transducer can be introduced within the device such that
pressure of within the device can be measured. Preferably, the
transducer is in the bore. The display can be but is not limited to
an LCD.
[0034] Pressure monitors are available commercially. For example, a
suitable pressure monitor is currently available from Merit Medical
Systems, Inc. (Utah, US) sold as a Meritrans.TM. transducer. Other
representative pressure monitors are disclosed in, for example,
U.S. patent application number 2005/0004518, incorporated herein by
reference. In the device disclosed in 2005/0004518, a pressure
transducer is integrally mounted in the plunger of a syringe under
the plunger tip such that the force applied by the plunger to the
fluid in the syringe is transmitted to the transducer and the
resulting electronic signal is converted to a display value, aiding
the physician in diagnosing diseased disks in the back. The
transducer of the pressure monitor can be positioned in the barrel
of a syringe or, alternatively, in the connector (or "hub").
[0035] A dispenser manifold 60 is shown in FIGS. 1 and 2. The
dispenser manifold 60 includes dispenser manifold inlet ports 61,
61' that sealably align and couple with the exit ports 38, 38' of
the cartridge 30. The dispenser manifold 60 is adapted to couple to
the manifold coupling portion 39 of the cartridge using, for
example, fittings 62, 63 that engage complimentary slots 39' so as
to lock in the dispenser manifold 60 to the coupling portion 39. In
the embodiment depicted in the FIGS, the exit ports 38, 38' are
embodied within manifold coupling portion 39. The coupling portion
39 may alternatively be formed into the housing 20, though
typically is part of the cartridge 30. The dispenser manifold 60
depicted in FIGS. 1, 2, and 3 also includes an optional hood 64.
The dispenser manifold 60 includes fluid tubes 65, 66 that receive
and transfer fluid from the cartridge 30 to the needle assembly 80
which is depicted for example in FIGS. 6-9. The tubes 65, 66 can be
made of a variety of materials, but in general are made of flexible
materials to facilitate improved usage by the surgeon. Typically
the tubes 65, 66 are made of polymeric materials, especially
medical grade materials. Alternatively, the tubes can be made of
soft metals or other materials that permit the tubes to flex. Thus
the delivery manifold for delivering the fluids can include a
delivery adapter that includes at least two exit ports that each
couple to the at least two exit ports of the housing adaptor, at
least two conduits having two ends wherein a first end of each of
the conduits connects to an exit port of the delivery manifold, and
wherein a second end of each of the conduits connects to a duel
port luer fittings, wherein the luer fitting is configured to
delivery fluid from one conduit to an inner needle and wherein the
luer fitting is configured to delivery fluid from the second
conduit to a space defined by the exterior of the inner needle and
by a second larger diameter needle that connects to the luer
fitting with the inner needle being within the insider of the
larger diameter needle. FIG. 10 illustrates the device 10 where the
manifold 60 has been operably connected to the cartridge 30 so that
the inlet ports of the manifold 60 align with the exit ports of the
cartridge 30.
[0036] Instead of the dispenser manifold 60, a fluid fill manifold
90 as depicted in FIG. 11 can be used to load fluids into the
cylinders 31, 31' of the cartridge 30. Like the dispenser manifold
60, the fill manifold 90 includes inlet ports (not shown) that
sealably align and couple with exit ports 38, 38'. The fill
manifold 90 includes fittings 92, 93, and an optional hood 64.
However, the fill manifold 90 includes tubes 95, 96 that couple to
syringes 97, 98 that are filled with the fluids to be introduced
into the cylinders 31, 31'. The syringes 97, 98 connect via luer
fittings 99, 99' to the tubes. Thus during use the syringes 97, 98
are filled with fluids (e.g. a thrombin solution and a fibrinogen
solution) to be introduced into the cylinders 31, 31'. The syringes
are locked into place using the luer fittings, and then the fluids
are injected into the cylinders at which time the plungers 36,
36'are driven back. Next, the fill manifold 90 is removed and
replaced with the dispenser manifold 60, which also has fitting to
lock the fill manifold in, after which time the surgeon primes the
device for use, inserts and locks the inner needle within the outer
needle, and injects the biologic sealant of choice into a desired
location, such as a disc, in the body. Thus, the fill manifold for
introducing fluids into the cylinder includes a fill manifold
adaptor that couples to the adaptor of the delivery device wherein
the adaptor includes at least two exit ports that each couple to
the at least two exit ports of the housing adaptor, at least two
syringes, at least two conduits wherein one end of the conduit
connects to the syringe and a second end of the conduit connects to
an exit port of the fill manifold adaptor. It should be appreciated
that the fill manifold 90 can be alternatively connected to a wide
variety of refilling parts other than the syringes 97, 98. Thus,
the fluid fill manifold 90 can use, for example, pressurized
containers, automated injection devices, fluid bags that are
manually or automatically squeezed to effect refilling into the
cylinders, fluid ampoules that are punctured with needles to access
the fluids using pressurized gas to force the fluids into the
cylinders, and so on.
[0037] The needle assembly 80 is depicted in FIGS. 6-8. The needle
assembly may include two coaxial needles, or an outer needle and an
inner polymeric catheter. In FIG. 6, the outer needle 81, which is
inserted directly into the patient to be treated, is connected via
luer fittings 82, 82' with the outer needle 81 surrounding an inner
needle 82 (see FIG. 7). The outer needle is typically an 18-22
gauge spinal needle that includes a bent portion 81' to assist the
surgeon in navigating the body during insertion of the spinal
needle. The inner needle can be of any size such that fluids may
flow in the gap between the needles. In certain embodiments, the
inner needle 83 may include ports near the tip 83' to facilitate
potentially improved mixing of the fluids. Likewise, the tip 83'
may be capped. FIGS. 9A-9C illustrate cross-sectional views of
needles and catheters that may be employed in the practice of this
invention. If a multi-lumen catheter or needle is employed, then
the luer fitting would be adapted to delivery each fluid to a
respective lumen. Referring again to FIGS. 6-8, the inner needle 83
can be of any length but typically is sized so that when the inner
and outer needles are coupled together the tip 83' of the inner
needle 83 extends to within between 1 mm and 50 mm of the tip 81'
of the outer needle 81, in other embodiments is from about 0.5 inch
to about 1.5 inch from the tip of the outer needle, and in one
embodiment is from about 3/4 inch to about 1 inch from the distal
tip of the outer needle. In one embodiment, a fibrinogen solution
is provided to the inner needle 83 while a thrombin solution is
provided to the outer needle 81. Fluid mixing is initiated at the
tip 83' of inner needle 83.
[0038] FIGS. 9A and 9B show representative cross-sectional views of
multi-lumen catheters. FIG. 9A shows a bitumen catheter 200 wherein
the lumen are in side-by-side arrangement and in which fibrinogen
would be injected through lumen 201 and the activating compound
through lumen 202. In FIG. 9B a trilumen catheter 210 is depicted
wherein a first lumen 211 may carry one fluid, second lumen 212
carries a second fluid, and a third lumen 213 may carry and
additive or have a wire inserted through the lumen 213 to improve
the physical integrity and rigidity of a polymeric catheter. FIG.
9C depicts a trilumen catheter 230 wherein the lumen 231, 232, and
233 are arranged in sequence (in side-by-side relationship). A
multi-lumen catheter can be used in this invention. A multi-lumen
catheter can have a number of cross-sectional structures. The
catheter can also have more than three lumen.
[0039] FIG. 8 shows a detailed embodiment of the luer fitting 82'.
Thus, fibrinogen tube 65 feeds fibrinogen solution directly into a
port 84 that couples to the inner needle 83. By contrast, tube 64
feeds thrombin solution, for example, into the hub (the void space)
85 of the luer fitting 82' whereby when the outer needle 81 is
connected via luer fitting 82 the thrombin solution flows into the
hub and into needle 81. The two fluids do not commingle until one
of the solutions exits the inner needle 83.
[0040] The trigger 40 is depicted in greater detail in FIG. 2. The
trigger includes a toothed rack 42. Upon application of pressure by
the surgeon to the trigger 40, the trigger 40 and rack 42 move
backwards in the direction of the handle 21. The rack 42 then
engages the wheel assembly 50, which rotates as the rack 42 moves
backward. The wheel assembly 50 thereby drives rams 34, 34' which
move plungers 36, 36' forward toward the exit ports 38, 38'. In one
embodiment, the trigger is configured such that the teeth of rack
42 engage the teeth of the wheel assembly 50 when pressure is
applied to the trigger 40, and configured such that the rack 42
drops away when pressure is released so that the respective teeth
no longer engage. This configuration can be provided, for example,
by adapting the housing 20 and trigger 40 such that the backward
motion of the trigger raises the rack 42 such as, for example, in
FIG. 12. In FIG. 12, the trigger 40 includes a guide bore 44
wherein a guide post 28 attached to the housing glides through the
guide bore 44 upon application of pressure to the trigger 40. Upon
release of pressure, spring 45 returns the trigger 40 to its
original position. As the trigger 40 slides towards side A of the
handle 21, a pin 48 that is mounted or integral with the rack 42
slides in the slot 29 to force the rack 42 up or down depending on
the angle of the slot 29 to thereby engage the wheel assembly 50 as
pressure is applied to the trigger 40. In this configuration, the
slot 29 is a part of and integral with the housing 20.
Alternatively, the rack 42 may include a slot with a pin being
mounted within the housing 20, such that the pin glides in the slot
to force the rack 42 to engage the wheel assembly 50.
[0041] The delivery device of this invention can be used to deliver
a wide variety of biologic materials such as but not limited to
fibrin sealant, synthetic polymers such as but not limited to
polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid,
polyethoxazoline, polyhydroxyethyl acrylate, polyhydroxyethyl
methacrylate, polysaccharides, polypeptides, polymers made from
polyethylene glycol, materials disclosed in U.S. Pat. No. 6,428,576
(Haldimann) which is incorporated herein by reference, and so on,
with or without additives. Fibrin sealant is preferred in the
practice of this invention. Fibrin sealant comprises a fibrinogen
component and a thrombin component that converts fibrinogen to
fibrin. The sealant may contain one or more other components. The
fibrin sealant is injected into, for example, the disc to seal
fissures and tears in the annulus fibrosus. Defects in the annulus
fibrosus are commonly diagnosed, currently, using MRI scans and
discograms. This can treat both discogenic low back pain and
radiculopathy leg pain when injected into the lumbar intervertebral
disc.
[0042] The fibrinogen used in the practice of this invention
includes any fibrinogen that will form fibrin in a human body.
Fibrinogen is frequently available in freeze-dried form, and must
be reconstituted prior to use. The fibrinogen can also be frozen or
fresh. The fibrinogen can be autologous (from the patient to be
treated), human including pooled human fibrinogen, recombinant, and
bovine or other non-human source such as fish (e.g., salmon and sea
trout). The fibrinogen is used in an amount suitable for the given
treatment, patient, and so on. The freeze-dried fibrinogen can be
reconstituted using, for example, saline, a saline solution
containing aprotinin, a saline solution containing calcium
chloride, a saline solution containing one or more other additives
such as a local anesthetic, or a solution containing combinations
of additives.
[0043] Thrombin is typically the enzyme used which serves to change
fibrinogen to fibrin. However, other enzymes can be used such as
those derived from snake venom (e.g., batroxobin), or spider venom
as is known in the art. Thrombin is available commercially,
typically in its freeze-dried form. Freeze-dried thrombin must be
reconstituted prior to use. The thrombin can also be frozen or
fresh. Thrombin can be autologous, from a human or pooled human
supply, bovine, or other non-human source such as various arachnids
and other venomous species. The thrombin is used in any amount
which facilitates changing the fibrinogen to fibrin, as is known to
one of skill in the art. The thrombin can be reconstituted using
saline, a saline solution containing calcium chloride, a saline
solution containing one or more other additives such as a local
anesthetic, or a solution containing calcium chloride and one or
more additives.
[0044] Additional additives may be added to the fibrin sealant such
as, but not limited to: antibiotics; antiproliferative, cytotoxic,
and antitumor drugs including chemotherapeutic drugs; analgesic;
antiangiogen; antibody; antivirals; cytokines; colony stimulating
factors; proteins; chemoattractants; EDTA; histamine;
antihistamine; erythropoietin; antifungals; antiparasitic agents;
non-corticosteroid anti-inflammatory agents; anticoagulants;
anesthetics including local anesthetics such as lidocaine and
bupivicaine; analgesics; oncology agents; cardiovascular drugs;
vitamins and other nutritional supplements; hormones;
glycoproteins; fibronectin; peptides including polypeptides and
proteins; interferons; cartilage inducing factors; protease
inhibitors; vasoconstrictors, vasodilators, demineralized bone or
bone morphogenetic proteins; hormones; lipids; carbohydrates;
proteoglycans such as aggrecan (chondrotin sulfate and deratin
sulfate), versican, decorin, and biglycan; antiangiogenins;
antigens; DBM; hyaluronic acid and salts and derivatives thereof;
polysaccharides; cellulose compounds such as methyl cellulose,
carboxymethyl cellulose, and hydroxy-propylmethyl cellulose and
derivatives thereof; antibodies; gene therapy reagents; genetically
altered cells, stem cells including mesenchymal stem cells with
transforming growth factor, and/or other cells; cell growth factors
to promote rehabilitation of damaged tissue and/or growth of new,
healthy tissue such as BMP7 and BMP2; type II collagen; elastin;
sulfated glycosaminoglycan (sGAG), glucosamine sulfate; pH
modifiers; methylsulfonylmethane (MSM); osteogenic compounds;
osteoconductive compounds; plasminogen; nucleotides;
oligonucleotides; polynucleotides; polymers; osteogenic protein 1
(OP-1 including recombinant OP-1); LMP-1 (Lim Mineralization
Protein-1); cartilage including autologous cartilage;
oxygen-containing components; enzymes such as, for example,
peroxidase, which mediate the release of oxygen from such
components; melatonin; vitamins; and nutrients such as, for
example, glucose. However, it is foreseeable that any of these
additives may be added to the fibrin sealant separately or in
combination. One or more of these additives can be injected with
the fibrinogen and thrombin, or alternatively one or more of these
components can be injected separately, either before or after the
fibrin sealant has been injected. For solutions containing an
incompletely water-soluble additive(s), an anti-caking agent such
as, for example, polysorbate, may be added to facilitate suspension
of this component. Glycol may be inappropriate for use as an
anti-caking agent in the instant invention.
[0045] The biologic sealant including fibrinogen and thrombin
(fibrin sealant) are injected in amounts effective to seal a given
defect of the disc, as is apparent to one of skill in the art. The
amount of thrombin can be varied to reduce or lengthen the time to
complete fibrin formation. In general, the higher level of thrombin
per unit amount of fibrinogen, the faster fibrin formation occurs.
If slower fibrin formation is desired, then less thrombin is used
per unit fibrinogen. The use of calcium chloride in one or both of
the component solutions will affect the strength of the fibrin so
formed, with increasing amount of calcium chloride increasing the
strength of the fibrin clot. Generally, for a composition
comprising fibrinogen that is an aqueous solution, it is believed
that from about 3 mL to about 5 mL of such composition is
sufficient to be an effective fibrin sealant. However, depending on
the use of the composition, the dosage can range from about 0.05 mL
to about 40 mL.
[0046] Fibrin sealants mimic the final stage of the natural
clotting mechanism. Typically, such sealants entail the mixing of a
fibrinogen component with an activating enzyme such as thrombin.
Thrombin is an enzyme that exists in blood plasma which causes the
clotting of blood by converting fibrinogen into fibrin. In normal
practice, the components of the fibrin sealant are reconstituted
separately, from a freeze-dried state, prior to use. However, the
use of samples prepared from a frozen state or a fresh state is
also acceptable. To increase biocompatibility of the sealant with
host tissue, various components may be supplied endogenously from
host body fluids. Combining the reconstituted components produces a
viscous solution that quickly sets into an elastic coagulum. A
method of preparing a conventional fibrin sealant is described by
J. Rousou, et al. in Journal of Thoracic and Cardiovascular
Surgery, vol. 97, no. 2, pp 194-203, February 1989. Cryoprecipitate
derived from source plasma is washed, dissolved in buffer solution,
filtered and freeze-dried. The freeze-dried fibrinogen is
reconstituted in a fibrinolysis inhibitor solution containing, for
example 3000 KIU/ml of aprotinin (a polyvalent protease inhibitor
which prevents premature degradation of the formed fibrin). The
solution is stirred and heated to a temperature of about 37.degree.
C. Each solution (the thrombin and fibrinogen solutions) is drawn
up in a dual barrel syringe and mounted on a Y-connector to which a
needle is attached for delivery of the combined solution. (See,
e.g. the DUPLOJECT.RTM. device, from ImmunoAG, Vienna, Austria).
Thus, mixing of the components only occurs during the delivery
process which facilitates clot formation at the desired site of
application only.
[0047] It should be appreciated that fibrin formation begins
immediately on contact of the fibrinogen and thrombin. The term
"injecting" of fibrin sealant or other biologic sealant thus
encompasses any injection of components that form sealant in the
disc, including circumstances where a portion of the components
react to form sealant due to mixing prior to contact with or actual
introduction into the disc (i.e., within the needle assembly).
[0048] It should also be appreciated that the point, or points, of
injection (e.g., at the tip of a spinal needle) can be within the
annulus fibrosus or in the nucleus pulposus. If the injection
occurs in the nucleus pulposus, the injected components may form a
patch at the interface between the nucleus pulposus and the annulus
fibrosus, or, more commonly, the components flow into the defect(s)
(e.g., fissures) of the annulus fibrosus and potentially
"overflowing" into the interdiscal space. In practice,
over-pressurizing the disc by injecting the components into the
disc should be avoided.
[0049] In one embodiment, about 75-105 mg/mL of freeze-dried
fibrinogen is reconstituted according to conventional methods, and
about 45-55 mg/mL thrombin component is reconstituted separately
from a freeze-dried state according to the methods and compositions
of the present invention. Freeze-dried fibrinogen and freeze-dried
thrombin are available in kit-form from such manufacturers as
Baxter under names such as TISEEL.RTM.. These two fibrin sealant
components can be prepared for example in about 2 mL samples each
to yield approximately 4 mL of total sealant (reconstituted
fibrinogen plus reconstituted thrombin).
[0050] While several methods and compositions may be used for
preparing the freeze-dried thrombin for use in the invented fibrin
sealant, one method is providing about 45-55 mg/mL of freeze-dried
thrombin and mixing it with a reconstituting solution. The
reconstituting solution may optionally further comprise about
0.1-100 milligrams of another additive described herein (e.g.,
local anesthetic) and/or calcium chloride. The calcium chloride
concentration can be, for example, 1-100 millimoles/mL, and in one
embodiment 4-40 millimoles/mL. If employed, the calcium chloride
concentration should be sufficient to further the polymerization
reaction that forms a durable fibrin sealant clot. A
preservative-free reconstituting solution may be desirable, but is
not required.
[0051] A contrast agent may be used in conjunction with the
injection of the fibrin sealant. The contrast agent may be injected
prior to injection of the fibrin sealant. Alternatively, the
contrast agent is included in the fibrinogen component or thrombin
component that is injected into the disc. Contrast agents and their
use are well known to one of skill in the art.
[0052] Alternative amounts and concentrations of fibrinogen and
thrombin may be used to form the desired fibrin sealant clot in the
body. For example, as discussed above, varying the fibrinogen
and/or thrombin amount/concentration may be done to vary the
viscosity and the "setting time" of the combined fibrinogen and
thrombin components. Likewise, varying fibrinogen may change the
density of the combined components, which may be important for
controlling flow through a long conduit such as a catheter into the
body. Varying thrombin may vary the polymerization time of the
components, which may be important for controlling the time at
which the clot forms for ensuring the components set-up at the
proper site and time in the body rather than setting-up
prematurely.
[0053] When acquired in freeze-dried form, the thrombin and
fibrinogen need to be reconstituted for use. The thrombin
reconstituting solution (e.g., a saline based solution), optionally
containing one or more additives, can be prepared in a single vial
prior to mixing with the freeze-dried thrombin. This component of
the fibrin sealant may then be provided to users in a reconstituted
state, or in two uncombined vials containing freeze-dried thrombin
and a premixed reconstitution solution. Mixing of the contents of
the two vials may be performed at any point up to, and including,
the time at which the fibrin sealant is injected into the patient.
Reconstitution of the fibrinogen solution can be accomplished
according to conventional methods. For example, the fibrinogen
component may be reconstituted in an aprotinin saline solution
which optionally contains additives such as, for example, a local
anesthetic. If desired, the thrombin or the fibrinogen or both can
be reconstituted using a saline solution that contains one or more
additives. All solutions are brought to a temperature of about
37.degree. C. Preferably, the thrombin is combined with the
fibrinogen solution using the dual-syringe injection procedure
described herein to form a single sealant composition which is
injected into a patient. The instant invention provides a vehicle
for the delivery of the sealant that conveys the sealant to the
precise area of the back, seals any annular fissures, and holds the
fibrin in place via the elastic coagulum. In addition, the
biodegradable nature of the formed fibrin clot minimizes or
eliminates the need for invasive surgical removal following the
effective period of use. Therefore, an advantage of the sealant and
method of application is the ability to provide a minimally
invasive means of accomplishing localized, prolonged sealing of
defects (e.g., fissures) in the annulus fibrosus, and if an
additive is in the sealant, time-released additive delivery.
[0054] The fibrin sealant may be injected into the disc or other
body area using procedures well known to one of skill in the art.
In general, the fibrin sealant of this invention is injected into
the disc, the epidural space, the zygaphysical (2-joint) joint, the
vertebral canal, and/or thecal sac. With respect to an injection of
fibrin sealant into a disc (an intra-discal injection) serves to
create a fibrin matrix which seals the disc from leaking material
from the nucleus into the area outside the disc. For example, the
fibrin sealant can be delivered by fluoroscopic transforaminal
lumber epidural or intra-discal injection, such as described in
U.S. Pat. No. 6,468,527, incorporated herein by reference. For the
treatment of back injuries such as these, the fibrin sealant is
injected into the nucleus pulposus to fill any fissures or voids of
the annulus fibrosus, to seal the bone end plates to the disc,
increase pressure of the disc, and to increase the height of the
disc space. The injection may also serve to coat areas adjacent to
the disc, directly on the nerve roots and surrounding areas which
serve to protect those areas from the effects of the leaking
nucleus material. Sealing the fissures and bone end plates halts
the leakage of harmful chemicals into the disc environment and
prevents the initiation of foreign-body reactions towards the
damaged disc by the immune system. Increasing the disc space
relieves pressure from the nerve root. That is, as a result of the
injection, an increase of the disc height occurs, which' increases
the spacing between lamina, and which in turn relieves pressure on
the nerve roots on the lamina. For this application,
supplementation of the fibrin sealant with growth factors may
promote rehabilitation of the damaged tissues or the gradual
replacement of the fibrin sealant with healthy tissue.
[0055] Use of the improved fibrin sealant composition may be better
understood by reference to the following examples. These examples
are representative and should not be construed to limit the scope
of this invention or claims hereof. Unless otherwise indicated
(example 3), corticosteroid is absent from the fibrin sealant being
used in these examples and the procedures were conducted in the
absence of a heating step of the nucleus fibrosus and annulus
fibrosus.
EXAMPLE 1
Fluoroscopic Transforaminal Epidural Injection
[0056] With a patient in the prone position on the imaging table, a
fluoroscope is positioned and adjusted to locate the intervertebral
foramen of the affected nerve root. A curved 22 ga..times.3.5''
needle is introduced after anesthetizing the skin and deep tissue.
The needle is advanced under direct fluoroscopic vision to a
position in the anterior epidural space. Positioning of the needle
is verified by a lateral fluoroscopic view and by injecting
contrast medium through the needle. Such positioning may or may not
require further adjustment. If adjusted, location of the needle is
once again verified. Advancement of the needle into the correct
region may stimulate pain in a manner consistent with the initial
complaint. Therefore, needle placement may also be verified by the
patient's pain recognition. The epidural space is anesthetized with
injectable anesthetic. The fibrin sealant of fibrinogen and
thrombin (prior to clotting) is then introduced using the device of
this invention such as shown in the FIGS. until the volumes of the
dual syringe system are sufficiently depleted. The fibrin sealant
then coats the nerve root and annulus and the needle is withdrawn.
Patient observation and vital signs monitoring is performed for
about 20-30 minutes following the procedure.
[0057] For this procedure, a sufficient volume of the fibrin
sealant is injected to effectively hydro-dissect the area around
the targeted nerve root. It is believed that due to the avascular
nature of the epidural space, the absorption/degradation period is
typically longer than that observed for open applications in
regions with greater vascularity and exposure to room air at the
time of application.
[0058] The ability of the fibrin sealant to seal annular fissures
related to disc herniation offers a therapeutic benefit to
patients. Chemical radiculitis, or inflammation of the nerve root,
is known to be quite painful in some instances. It is believed that
use of the fibrin sealant in the above described manner not only
coats the nerve root, but also seals annular fissures surrounding
the herniated disk. As a result of the hydro-dissection of the area
around the affected nerve root, the sealant also seals annular
fissures from outside the annulus.
EXAMPLE 2
Fluoroscopic Guided Intra-Discal Injection
[0059] After sterile preparation, an introducer needle is advanced
in oblique projection to a superior articular process. A curved
spinal needle is advanced through the introducer needle into the
disc. Both anterior-posterior and lateral fluoroscopic projections
are used to confirm proper needle placement. If the needle
placement needs to be adjusted, placement is again confirmed
fluoroscopically. A contrast agent is injected to confirm needle
placement. In patients with chemical radiculitis, the contrast
agent can be observed to be leaking through the annular fissures
and/or intra-discal pathology can be identified. Once the needle is
properly positioned in the intra-discal space, the fibrin sealant
is injected using the delivery device of this invention such as
shown in the FIGS. The fibrin sealant is observed to force the
contrast agent from the intra-discal space as it seals the annual
fissures. Alternatively, the contrast agent is injected with the
sealant. Alternatively, no contrast agent is used. The procedure
seals the defects/fissures of the annulus fibrosus and stops the
chemical leakage and facilitates regeneration within the disc.
EXAMPLE 3
Comparative Assessment of the Physical Property of Clots
[0060] TISSEEL VH S/D fibrin sealant was prepared according to
manufacturer guidelines. The reactive components were mixed and
delivered using a DUPLOJECT delivery device or the deliver device
of this invention as shown in FIGS. 1-8 and 9-12.
[0061] In the device of this invention used in this example, the
tip of the inner needle was approximately one inch short of the
distal tip of the introducer needle. The inner needle was a 22
gauge needle and the outer needle was an 18 gauge needle. As used
herein including Table 1, "Biostat" refers to the device used in
the tests constructed according to this invention.
[0062] A DUPLOJECT delivery device is the standard device used
currently for mixing and providing fibrin sealant. The DUPLOJECT
device includes dual syringes that feed fibrinogen solution and
thrombin solution into a Y-connector where mixing of the solutions
is initiated. The DUPLOJECT device is equipped with a standard one
inch length 18 gauge needle, which is the needle provided with the
DUPLOJECT delivery device. In use, solutions are placed in two
syringes, the syringes are loaded into the dual syringe clip of the
DUPLOJECT device, the mixing chamber is attached to the tips of the
syringes and fastened to the dual syringe clip using the retaining
strap, and the needle is then attached to the mixing chamber. The
DUPLOJECT delivery device has been approved for use with fibrin
sealant by the US Food and Drug Administration, and is mentioned in
U.S. Pat. No. 6,468,527 for use in injecting fibrin sealant and
corticosteroid into a disc.
[0063] Identical fibrinogen and thrombin solutions (TISSEEL fibrin
sealant components using 500 IU/mL thrombin) were loaded into in
each device. The solutions were then pushed through the devices so
that fibrin sealant was injected from each device. A total of eight
clots were cast from four batches of sealant for each delivery
device. Controlled sample volumes (1.6 mL) were delivered by
extrusion into controlled diameter test tubes (12.times.75 mm).
This sample preparation protocol was designed to ensure the
formation of a level, planar test surface with homogenous product
distribution and controlled surface area and sample height. The
test tubes were sealed and stored in a 37 degree Centigrade water
bath for 90 minutes to allow complete product curing prior to
mechanical testing. The mechanical properties of the resulting
clots were measured, including failure load, elastic stiffness, and
failure deformation. Material toughness was also estimated by
calculating the area under the load-deformation curves.
[0064] A calibrated Texture Analyzer XT was used as a multifunction
tensiometer to measure the forces generated during the controlled
depression (2 mm/min, 10 mm maximum displacement) of a 1/4 inch
cylindrical probe into the surface of the clot. Compression of the
gel yielded a steady linear rise in load until failure,
demonstrated graphically by an abrupt deviation from linearity. As
used herein, failure force refers to the force measured at the
moment of the deviation from linearity. Failure displacement refers
to the distance traveled by the probe until the moment of
deviation, with failure deformation providing an estimate of the
clot ductility. Elastic stiffness refers to the change in force
over change in time (slope) of the linear portion of the
load-deformation graph just preceding failure. Elastic stiffness
provides and assessment of the clot's resistance to deformation,
with higher values representing stiffer materials.
[0065] The following Table 1 provides the results of the mechanical
testing of fibrin sealant clots produced by the DUPLOJECT device
and the device according to this invention.
TABLE-US-00001 TABLE 1 DUPLOJECT DUPLOJECT DUPLOJECT Biostat
Biostat Property N Mean SD Biostat N Mean SD Failure load 7* 386 88
8 300 148 (g) Elastic 8 235 61 8 107 42 Stiffness (g/mm) Failure 7*
2.64 0.35 8 6.56 1.65 Deformation (mm) Fracture 7* 269.8 50.7 8
543.5 244.6 toughness (K.sub.1c) *One aberrant value removed based
on Dean and Dixon outlier detection method. All outliers were from
a single sample.
[0066] As shown in Table 1, the DUPLOJECT device and the Biostat
device produced clots with average elastic stiffness loads of 235
g/mm (+/-61) and 107 g/mm (+/-42), respectively. The difference in
elastic stiffness was statistically significant (t-test, p=0.0004).
On average the clots produced from the Biostat device were reduced
in elastic stiffness by 54% relative to the DUPLOJECT device.
[0067] The DUPLOJECT device and the Biostat device produced clots
that failed after an average deformation of 2.64 mm (+/-0.35) and
6.56 mm (+/-1.65) respectively. The difference in failure
deformation was statistically significant (t-test, p=0.0002). On
average, surprisingly, the clots produced from the Biostat device
withstood 165% more deformation prior to failure relative to the
DUPLOJECT device.
[0068] The DUPLOJECT device and the Biostat device produced clots
with an average material toughness proportional to 269.8 g-mm
(+/-50.7) and 543.5 g-mm (+/-244.6, respectively. The difference in
toughness was statistically significant (t-test, p=0.016). On
average, surprisingly, the clots produced from the Biostat device
could absorb twice as much energy (+101.5%) prior to catastrophic
failure relative to the clots produced by the DUPLOJECT device.
[0069] These tests show that., unexpectedly, the device of this
invention produces clots with significantly superior mechanical
properties than clots made using a standard DUPLOJECT device.
[0070] In addition, proteolytic degradation resistance tests were
conducted on additional fibrin samples. The procedures above were
used to prepare clots from the DUPLOJECT device and Biostat device.
It was found, surprisingly, that clots made using the Biostat
device had increased resistance to fibrinolytic degradation
relative to clots made using the DUPLOJECT device.
[0071] Viscometry profiles were also determined. The procedures
above were used to prepare clots from the DUPLOJECT device and
Biostat device. Reheometric Scientific's SR5 Controlled Stress
Rheometer was used to measure the rheological properties of the
setting fibrin clots at body temperature. A cone and plate
geometric configuration (d.about.25 mm, 4.degree.) was used for
viscosity profile assessment. Standardized test protocols were
utilized. Shear rates ranging from 0.1 to 80 sec.sup.-1 were used.
In the dynamic experiments, an oscillatory shear was applied to the
samples while the corresponding elastic (G') and viscous (G'')
moduli were measured as a function of frequency. Samples were
assessed using frequency ranges from 0.01 rad/s to 100 rad/s.
[0072] For purposes of this example, working time refers to the
duration required for the fibrin solution viscosity to reach 750
poise. At this viscosity, the pressure required for syringe
delivery exceeds a 15 psi threshold for hand delivery. The working
time limit represents the period of time the physician has to
deliver the entire product to the disc. The data shows that the
Biostat device increases working time significantly and provides
significantly improved control for intradiscal delivery. In
addition, the Biostat device provides fibrin sealant that allows
for slow delivery and maximizes the potential for low viscosity
components to permeate into annular disruptions (fissures). In
particular, the Biostat device surprisingly increases work time to
1.75 minute (+/-0.73), an 134% average improvement over fibrin
sealant made using the DUPLOJECT device which had a work time of
0.65 min (+/-0.02). The results are shown in FIG. 13. In FIG. 13 it
can be seen that the fibrin sealant delivered from a DUPLOJECT
device sets up significantly faster than fibrin sealant delivered
from a Biostat device.
[0073] Likewise, the setting or solidification time was arbitrarily
defined as the duration required for the fibrin solution viscosity
to reach 10,000 poise (roughly equivalent to solid vegetable
shortening). The results show that the Biostat device significantly
and surprisingly increased the set time to 5.77 min (+/-1.76) from
the 2.90 min (+/-0.38) from the DUPLOJECT device. This provides a
distinct advantage for the practitioner by allowing the fibrin to
more fully infiltrate annular fissures and so on, and associated
significant performance benefits for intradiscal injection of a
biologic sealant.
[0074] It is envisioned that the present invention may be used to
address various conditions through use of the device of this
invention in a manner similar to that described in the examples
above. Discussion of this invention referenced particular means,
materials and embodiments elaborating limited application of the
claimed invention. The invention is not limited to these
particulars and applies to all equivalents. Although this invention
has been described above with reference to particular means,
materials and embodiments, it is to be understood that the
invention is not limited to these disclosed particulars, but
extends instead to all equivalents within the scope of the
following claims.
* * * * *