U.S. patent application number 09/283535 was filed with the patent office on 2002-03-14 for compositions, systems, and methods for arresting or controlling bleeding or fluid leakage in body tissue.
Invention is credited to CRUISE, GREGORY M., HNOJEWYJ, OLEXANDER.
Application Number | 20020032463 09/283535 |
Document ID | / |
Family ID | 56289900 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020032463 |
Kind Code |
A1 |
CRUISE, GREGORY M. ; et
al. |
March 14, 2002 |
COMPOSITIONS, SYSTEMS, AND METHODS FOR ARRESTING OR CONTROLLING
BLEEDING OR FLUID LEAKAGE IN BODY TISSUE
Abstract
A biocompatible and biodegradable hydrogel compound, which is
free of a hemostatic agent, is applied to arrest the flow of blood
or fluid from body tissue. 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.
P.O. BOX 26618
MILWAUKEE
WI
53226-0618
US
|
Family ID: |
56289900 |
Appl. No.: |
09/283535 |
Filed: |
April 1, 1999 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09283535 |
Apr 1, 1999 |
|
|
|
09188083 |
Nov 6, 1998 |
|
|
|
Current U.S.
Class: |
606/214 |
Current CPC
Class: |
A61B 17/3415 20130101;
B01F 33/50112 20220101; A61B 18/1487 20130101; A61B 17/0057
20130101; B01F 25/4233 20220101; A61M 25/0662 20130101; A61B
2090/064 20160201; A61P 7/04 20180101; A61B 18/1482 20130101; A61B
2017/00637 20130101; A61B 2017/0065 20130101; A61B 2017/00084
20130101; A61B 2017/00495 20130101; A61B 2017/005 20130101; A61B
2017/3492 20130101; B01F 25/4231 20220101; A61B 17/00491
20130101 |
Class at
Publication: |
606/214 |
International
Class: |
A61D 001/00; A61B
017/08 |
Claims
We claim:
1. A biocompatible and biodegradable material applied to arrest the
flow of blood or fluid from body tissue comprising a hydrogel
compound free of a hemostatic agent.
2. A material according to claim 1 wherein the hydrogel compound
includes a protein.
3. A material according to claim 2 wherein the protein includes
recombinant or natural serum albumin.
4. A material according to claim 1 wherein the compound includes a
polymer.
5. A material according to claim 4 wherein the polymer includes
poly(ethylene) glycol (PEG).
6. A material according to claim 5 wherein the PEG comprises a
multi-armed polymer.
7. A biocompatible and biodegradable material applied to arrest
diffuse bleeding comprising a hydrogel compound free of a
hemostatic agent.
8. A material according to claim 7 wherein the hydrogel compound
includes a protein.
9. A material according to claim 8 wherein the protein includes
recombinant or natural serum albumin.
10. A material according to claim 7 wherein the compound includes a
polymer.
11. A material according to claim 10 wherein the polymer includes
poly(ethylene) glycol (PEG).
12. A material according to claim 11 wherein the PEG comprises a
multi-armed polymer.
13. A biocompatible and biodegradable material applied to arrest
the flow of blood or to seal tissue comprising a mixture of 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 covering structure.
14. A material according to claim 13, wherein the protein solution
comprises a hydrophilic protein selected from a group consisting
essentially of albumin, gelatin, antibodies, serum fractions, or
serum.
15. A material according to claim 13, wherein the protein solution
comprises a water soluble derivative of a hydrophobic protein
selected from a group consisting essentially of collagen,
fibrinogen, elastin, chitosan, or hyaluronic acid.
16. A material according to claim 13, wherein the protein solution
comprises recombinant or natural human serum albumin.
17. A material according to claim 16, wherein the human serum
albumin is at a concentration of about 25% or less.
18. A material according to claim 13, wherein the protein solution
includes a buffer.
19. A material according to claim 18, wherein the buffer includes
carbonate or phosphate.
20. A material according to claim 18, wherein the buffer has a
concentration of about 0.3 M to about 0.4 M.
21. A material according to claim 20, wherein the buffer comprises
carbonate at a concentration of about 0.3 M and a pH value of about
8 to about 10.
22. A material according to claim 13, wherein the protein solution
has a pH value of between about 7 to about 10.
23. A material according to claim 22, wherein the pH value is about
8 to about 10.
24. A material according to claim 13, wherein the polymer is
electrophilically derivatized.
25. A material according to claim 13, wherein the polymer solution
includes a derivative of a polymer selected from a group consisting
essentially of poly(ethylene glycol), poly(ethylene oxide),
poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline),
poly(ethylene glycol)-co-poly(propylene glycol) block copolymers,
or electrophilically derivatized polysaccharides, carbohydrates, or
proteins.
26. A material according to claim 13, wherein the polymer is
comprised of poly(ethylene glycol)(PEG).
27. A material according to claim 26, wherein the PEG has a
molecular weight of between about 1,000 and about 30,000
g/mole.
28. A material according to claim 27, wherein the PEG has a
molecular weight of between about 2,000 and about 15,000
g/mole.
29. A material according to claim 27, wherein the PEG has a
molecular weight of between about 10,000 and 15,000 g/mole.
30. A material according to claim 26, wherein the PEG comprises a
multi-armed polymer structure.
31. A material according to claim 13, wherein the polymer comprises
a compound of the formula PEG-(DCR-CG).sub.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.
32. A material according to claim 31, wherein the compound
comprises a multi-armed polymer structure.
33. A material according to claim 31, wherein the degradation
control region (DCR) comprises a hydrolytically degradable
moiety.
34. A material according to claim 33, wherein the hydrolytically
degradable moiety includes 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), or
poly(phosphoesters).
35. A material according to claim 31, wherein the degradation
control region (DCR) comprises an enzymatically degradable
region.
36. A barrier according to claim 35, wherein the enzymatically
degradable region includes Leu-Glyc-Pro-Ala (collagenes sensitive
linkage) or Gly-Pro-Lys (plasmin sensitive linkage).
37. A material according to claim 31, wherein the degradable
control region (DGR) includes ester containing linkages.
38. A material according to claim 37, wherein the degradable
control region (GCR) includes succinic acid or glutaric acid.
39. A material according to claim 31, wherein the cross-linking
group (CG) includes an active ester.
40. A material according to claim 39, wherein the active ester
includes an ester of N-hydroxysuccinimide.
41. A material according to claim 31, wherein the cross-linking
group (CG) selectively reacts with sulfhydryl groups.
42. A material according to claim 41, wherein the cross-linking
group (CG) includes vinyl sulfone, N-ethyl maleimide,
iodoacetamide, or orthopyridyl disulfide.
43. A material according to claim 31, wherein the cross-linking
group (CG) selectively reacts with amino groups.
44. A material according to claim 43, wherein the cross-linking
group (CG) includes aldehydes.
45. A material according to claim 31, wherein the cross-linking
group (CG) reacts with sulfhydryl, primary amino, and secondary
amino groups.
46. A material according to claim 31, wherein the cross-linking
group (CG) include active esters, epoxides, carbonylimidazole,
nitrophenyl carbonates, tresylate, mesylate, tosylate, or
isocyanate.
47. A material according to claim 31, wherein the cross-linking
group (CG) is present in a concentration of less than about 5% of
total mass of the compound.
48. A material according to claim 31, wherein the cross-linking
group (CG) is present in a concentration of about 1% or less of
total mass of the compound.
49. A material according to claim 31, wherein the PEG comprises a
4-arm PEG, the degradation control region comprises glutaric acid,
and the cross-linking group includes a N-hydroxysuccinimide
ester.
50. A material according to claim 47, wherein the 4-arm PEG has a
molecular weight of about 10,000 g/mole.
51. A material according to claim 31, wherein the compound
comprises poly(ethylene glycol) tetra-succinimidyl glutarate.
52. A material according to claim 31, wherein the compound
comprises poly(ethylene glycol)tetra-succinimidyl succinate.
53. A material according to claim 49 or 51 or 52, wherein the
protein solution includes recombinant or natural human serum
albumin.
54. A material according to claim 53, wherein the human serum
albumin is present in a concentration of about 25% or less.
55. A material according to claim 13, wherein the polymer solution
includes poly(ethylene glycol)tetra-succinimidyl glutarate.
56. A material according to claim 55, wherein the polymer solution
includes water.
57. A material according to claim 55, wherein the protein solution
includes recombinant or natural human serum albumin.
58. A material according to claim 57, wherein the human serum
albumin is present in a concentration of about 25% or less.
59. A material according to claim 13, wherein the polymer has a
functionality of four.
60. A material according to claim 13, wherein the polymer solution
includes poly(ethylene glycol)tetra-succinimidyl succinate.
61. A material according to claim 13, wherein the polymer solution
has a concentration that ranged from about 5% to about 35% w/w.
62. A system to arrest the flow of blood or fluid from body tissue
comprising a first dispenser containing a first liquid component, a
second dispenser containing a second liquid component, a mixer
coupled to the first and second dispensers for mixing the first and
second liquid components to form the material as defined in claim 1
or 7.
63. A system according to claim 62 wherein the mixer includes a
spray head.
64. A system according to claim 62 wherein the mixer includes a
cannula.
65. A system to arrest the flow of blood or to seal tissue
comprising a first dispenser containing a first liquid component
comprising a protein solution, a second dispenser containing a
second liquid component comprising a polymer solution including a
derivative of a hydrophilic polymer with a functionality of at
least three, a mixer coupled to the first and second dispensers for
mixing the first and second liquid components, wherein, upon
mixing, the protein solution and the polymer solution cross-link to
form a mechanical non-liquid tissue covering structure.
66. A system according to claim 65 wherein the mixer includes a
spray head.
67. A system according to claim 65 wherein the mixer includes a
cannula.
68. A method for arresting the flow of blood or fluid from body
tissue comprising the step of dispersing on the body tissue a
biocompatible and biodegradable material comprising a hydrogel
compound free of a hemostatic agent.
69. A method according to claim 68 wherein the dispersing step
includes spraying the material on the body tissue.
70. A method according to claim 68 wherein the dispersing step
includes flowing the material on the body tissue through a
cannula.
71. A method for arresting diffuse bleeding comprising the step of
dispersing on the body tissue a biocompatible and biodegradable
material comprising a hydrogel compound free of a hemostatic
agent.
72. A method according to claim 71 wherein the dispersing step
includes spraying the material on the body tissue.
73. A method according to claim 71 wherein the dispersing step
includes flowing the material on the body tissue through a
cannula.
74. A method for arresting the flow of blood or to seal tissue
comprising the step of dispersing on the body tissue a
biocompatible and biodegradable material comprising a mixture of 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 covering structure.
75. A method according to claim 74 wherein the dispersing step
includes spraying the mixture on the body tissue.
76. A method according to claim 68 wherein the dispersing step
includes flowing the mixture on the body tissue through a cannula.
Description
RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/188,083, filed Nov. 6, 1998 and entitled
"Compositions, Systems, and Methods for Creating in Situ,
Chemically Cross-linked, Mechanical Barriers."
FIELD OF THE INVENTION
[0002] The invention generally relates systems and methods for
arresting or controlling the bleeding or leakage of fluid in body
tissues, e.g., diffuse organ bleeding, lung punctures, anastomotic
leakage, and the like.
BACKGROUND OF THE INVENTION
[0003] Hemostatic barriers are routinely called upon to control
bleeding. The bleeding may be caused by trauma, e.g. splenic,
kidney, and liver lacerations, or may be caused during surgery,
e.g. tumor removal or bone bleeding.
[0004] Bleeding is conventionally controlled by the application of
solid sheets of material, e.g. gauze, Gelfoam.TM. material, or
Surgicel.TM. material. These materials can be soaked with a
hemostatic agent, such as thrombin or epinephrine, or sprayable
formulations such as fibrin glue.
[0005] Conventional treatment modalities require the use of these
hemostatic agents in conjunction with pressure to achieve
hemostasis. The various hemostatic agents can include coagulation
factors (e.g. thrombin), platelet activators (e.g. collagen),
vasoconstrictors (epinephrine), or fibrinolytic inhibitors.
[0006] In some instances, conventional treatments achieve
hemostasis in a clinically acceptable time. Still, there are a
number of drawbacks.
[0007] For example, many treatment modalities consist of bovine
collagen and bovine thrombin to cause the desired clotting action.
These products have the potential for the transmission to humans of
bovine spongiform encephalopathy (also called "Mad Cow Disease").
Regardless, the bovine thrombin marketed today is relatively
impure, and these impurities can lead to complications in certain
patient populations. Furthermore, fibrin glue, generally composed
of purified fibrinogen and thrombin from pooled human blood, has
safety and efficacy concerns as well. Additionally, many products
do not achieve hemostasis in a clinically acceptable period,
particularly in cases of brisk bleeding.
[0008] In addition to hemostatic agents, surgical sealants are also
commonly used to control bleeding or fluid leakage along
anastomoses formed by suture or staple lines, e.g., between blood
vessels, bowel, or lung tissue. In cases of blood leakage, fibrin
glue can be utilized to seal an anastomosis. Still, fibrin glue's
lack of adhesion to moist tissue, safety concerns, and cost
precludes its widespread use as a surgical sealant for blood vessel
anastomoses.
[0009] Conventional hemostatic agents and surgical sealants for
blood vessel anastomoses achieve hemostasis using the application
of pressure and by activating the coagulation pathway of the blood.
Yet, many of the surgeries where hemostatic barriers and surgical
sealants are required also require the administration of
anti-coagulation therapies, such as heparin. The hemostatic barrier
or surgical sealant, which is promoting coagulation, is hindered by
the effect of the heparin, which is preventing coagulation.
[0010] Despite conventional treatment modalities for hemostatic
barriers and surgical sealants, there is a need for a biomaterial
that safely, quickly, and reliably arrests or controls fluid
leakage in body tissues through the application of pressure and
without interaction with the patient's coagulation pathways.
SUMMARY OF THE INVENTION
[0011] The invention provides compositions, instruments, systems,
and methods, which arrest or control bleeding or leakage of fluid
in body tissue.
[0012] According to one aspect of the invention, a biocompatible
and biodegradable material is provided which comprises a hydrogel
compound free of a hemostatic agent and which, when applied by
instruments, systems, and methods that embody the invention,
arrests the flow of blood or fluid from body tissue.
[0013] According to another aspect of the invention, a
biocompatible and biodegradable material is provided which
comprises a hydrogel compound free of a hemostatic agent and which,
when applied by instruments, systems, and methods that embody the
invention, arrests organ diffuse bleeding.
[0014] According to another aspect of the invention, a
biocompatible and biodegradable material is provided which
comprises a protein solution and a polymer solution including a
derivative of a hydrophilic polymer with a functionality of at
least three, which, when mixed by instruments, systems, and methods
that embody the invention, form a mechanical non-liquid covering
structure that arrests the flow of blood or seals tissue.
[0015] 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
[0016] FIG. 1 is a plan view of a system for arresting or
controlling bleeding or leakage of fluid in body tissue, showing
the components of the system prepackaged in sterile kits;
[0017] FIG. 2 is a diagrammatic view of a compromised tissue
region, upon which a covering structure that embodies the features
of the invention has been dispersed to arrest or control
bleeding;
[0018] FIG. 3 is a side view of the covering structure shown in
FIG. 2, taken generally along line 3-3 in FIG. 2;
[0019] FIG. 4 is a side view of an introducer/mixer, with the
syringes containing a liquid albumin solution and a liquid PEG
solution mounted and ready for use, the introducer mixer having an
attached mixing spray head to disperse the solutions to form the
covering structure shown in FIGS. 2 and 3;
[0020] FIG. 5 is a side view of an introducer/mixer, with the
syringes containing a liquid albumin solution and a liquid PEG
solution mounted and ready for use, the introducer mixer having an
attached cannula to disperse the solutions to form the covering
structure shown in FIGS. 2 and 3;
[0021] FIG. 6A is an exploded, perspective view of the kit shown in
FIG. 1 that contains the liquid and solid components and syringe
dispensers for the covering structure;
[0022] FIG. 6B is an exploded, perspective view of the kit shown in
FIG. 1 that contains the introducer/mixer shown in FIGS. 4 and 5,
which receives the syringes shown in FIG. 6A during use;
[0023] FIGS. 7A, 7B, and 7C illustrate use of the system shown in
FIG. 1 to control or arrest diffuse organ bleeding;
[0024] FIGS. 8A, 8B, and 8C demonstrate use of the system shown in
FIG. 1 to seal a puncture site in a lung;
[0025] FIGS. 9A, 9B, and 9C illustrate use of the system shown in
FIG. 1 to control or arrest bleeding through an anastomosis;
and
[0026] FIGS. 10A to 10D are perspective views showing the
manipulation of syringes contained in the kit shown in FIG. 6A, to
create a liquid PEG solution for use with the system shown in FIG.
1.
[0027] 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
[0028] FIG. 1 shows a system 10 of functional instruments for
arresting or controlling the loss of blood or other fluids in body
tissue.
[0029] During use, the instruments of the system 10 are brought to
a compromised tissue region (shown as an incision INC in FIGS. 2
and 3), where bleeding or loss of another body fluid is occurring,
e.g., due to diffuse bleeding or anastomosis. The parts of the
system 10 are manipulated by a physician or medical support
personnel to create a liquid material, which is immediately
dispersed as a spray directly onto the surface of the compromised
tissue region. The liquid material transforms as it is being
dispersed as a result of cross-linking into an in situ-formed
non-liquid covering structure. The covering structure intimately
adheres and conforms to the surface the compromised tissue region,
as FIG. 3 best shows.
[0030] Due to the physical characteristics of the covering
structure and the speed at which it forms in situ, the presence of
the covering structure mechanically arrests or blocks further blood
or fluid loss from the compromised tissue region, without need for
a hemostatic agent. The covering structure exists long enough to
prevent blood or fluid leakage while the compromised tissue region
heals by natural processes. The covering structure is, over time,
degraded by hydrolysis by in the host body and cleared by the
kidneys from the blood stream and removed in the urine.
[0031] In the illustrated embodiment (see FIG. 1), the system 10 is
consolidated in two functional kits 12 and 14.
[0032] The kit 12 houses the component assembly 18, which contains
the formative components from which the covering structure is
created. The kit 12 holds the components in an unmixed condition
until the instant of use.
[0033] The kit 14 contains a dispersing assembly 16. The dispersing
assembly 16 brings the components in the assembly 18, while in
liquid form, into intimate mixing contact. At the same time, the
assembly 16 disperses the liquid mixture onto the surface of the
compromised tissue region, to ultimately form the in situ covering
structure.
[0034] I. The Covering Structure
[0035] The covering structure comprises a material that is
chemically cross-linked, to form a non-liquid mechanical matrix or
barrier.
[0036] In a preferred embodiment, the material of the covering
structure is a protein/polymer composite hydrogel. The 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 material is nontoxic,
biodegradable, and possesses mechanical properties such as cohesive
strength, adhesive strength, and elasticity sufficient to block or
arrest diffuse organ bleeding, or to block or arrest seepage as a
result of anastomosis, or to seal lung punctures.
[0037] The material also permits the rate of cross-linking and
gelation to 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.
[0038] A. Material Components
[0039] In the illustrated embodiment (see FIG. 1), the component
assembly 18 includes first and second dispensing syringes 60 and
62, in which the formative components of the covering structure are
stored prior to use.
[0040] (i) Natural Plasma-based Protein 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.
[0041] Suitable proteins for incorporation into 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.
[0042] The preferred protein solution is 25% human serum albumin,
USP. Human serum albumin is preferred due to its biocompatibility
and its ready availability.
[0043] 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 0.03 M to
about 0.4 M, and the preferred range of pH is from about 7.0 to
about 10.0. A preferred buffer system for the covering structure is
carbonate buffer at a concentration of 0.315 M at a pH value of
about 9 to about 10. As will be described later, there is a
relationship between pH and the time for cross-linking (also called
"gelation").
[0044] (ii) Electrophilic Water Soluble Polymer
[0045] 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 the mechanical covering structure. The
covering structure adheres and conforms to the surface of the
tissue region on which it is dispensed. The covering structure is,
over time, resorbed.
[0046] 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.
[0047] 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.
[0048] The preferred polymer can be generally expressed as
compounds of the formula:
PEG-(DCR-CG).sub.n
[0049] where:
[0050] DCR is a degradation control region.
[0051] CG in a cross-linking group.
[0052] n.gtoreq.3
[0053] 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
covering structure 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 material) (a preferred gelation time is
under three seconds), and (ii) the mechanical properties of the
covering structure 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.
[0054] 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.
[0055] 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 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.
[0056] In the illustrated embodiment, the polymer 102 is initially
packaged prior to use in the second dispensing syringe 62 in an
inert atmosphere (e.g., argon) in a stable, powder form. In this
arrangement, the 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.
[0057] 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 62 prior to use.
[0058] (a) Selection of the Degradation Control Region DCR
[0059] 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,
[0060] 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).
[0061] Examples of enzymatically degradable regions include
Leu-Glyc-Pro-Ala (collagenase sensitive linkage) and Gly-Pro-Lys
(plasmin sensitive linkage).
[0062] The preferred degradable control regions for degradable
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 materials
are ether containing linkages. The material can also be created
without the introduction of a degradation control region.
[0063] (b) Selection of the Cross-linking Group CG
[0064] 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.
[0065] 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.
[0066] (c) Preferred Multiple Arm PEG Polymer
[0067] 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.
[0068] 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 covering structure.
With these material formulations, it is possible to intimately mix
the water soluble polymer with the albumin protein using, e.g.,
atomization, or static mixing, or in-line channel mixing.
[0069] 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 covering
structure 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.
[0070] The resulting nonfluent material created by mixing 25%
albumin and 4-PEG-SG is approximately 80% water, 13% albumin, and
7% PEG. The material is well tolerated by the body, without
invoking a severe foreign body response. Over a controlled period
of time, the 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 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 material loses its physical
strength during the first twenty days, and total resorption occurs
in about 4 weeks.
[0071] The following Examples demonstrate the superior features of
the material of the invention.
EXAMPLE 1
[0072] Preparation of Cross-linked Networks
[0073] Cross-linked covering structure 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.
[0074] 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 covering
structure network formed at room temperature in about 90
seconds.
EXAMPLE 2
[0075] Control of the Rate of Gelation
[0076] The rate of formation of the cross-linked covering structure
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.
[0077] 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 100mM 9 10 sec 50 mM 9 20 sec 0 mM 7 90 sec
[0078] II. The Dispersing assembly
[0079] As FIG. 4 shows, the dispersing assembly 16 comprises a
material introducer/mixer 22. The material introducer/mixer 22
receives the two dispensing syringes 60 and 62. The material
introducer/mixer 22 allows the physician to uniformly dispense the
two components in a liquid state from the dispensing syringes 60
and 62.
[0080] The material introducer/mixer 22 also mixes the components
while flowing in the liquid state from the dispensing syringes 60
and 62.
[0081] To accomplish these functions (see FIG. 4), the material
introducer/mixer 22 includes syringe support 64. The support 64
includes side-by-side channels 66 (see FIG. 1, too). The channel 66
accommodates in a snap-friction-fit the barrels of the syringes 60
and 62.
[0082] The material introducer/mixer 22 also includes a syringe
clip 68. The syringe clip 68 includes spaced apart walls 70 forming
an interior race 72. The race 72 receives in a sliding friction fit
the thumb rests 74 of the pistons 76 of the dispensing syringes 60
and 62, in axial alignment with the syringe barrels 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.
[0083] To faciliate handling, 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.
[0084] The 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.
[0085] 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.
[0086] 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.
[0087] The material introducer/mixer 22 further includes a mixing
spray head 94, which, in use, is coupled to the single outlet port
92. In FIG. 1, the kit 14 contains several interchangeable mixing
spray heads 94, in case one mixing spray head 94 becomes clogged
during use.
[0088] The mixing spray head 94 may be variously constructed. It
may, for example, comprise a spray head manufactured and sold by
Hemaedics.
[0089] Alternatively, the material introducer/mixer 22 can include
a cannula 152, which, in use, can be coupled to the outlet port 92
instead of the mixing spray head (see FIG. 5).
[0090] 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 either in the mixing spray head 94
or the cannula 152. Atomization of the two components occurs as
they are dispersed through the mixing spray head 94 under pressure
from operation of the mechanically linked dispensing syringes 60
and 62. Passage of the liquid components through the cannula 152
will channel-mix the materials. Either by atomization or channel
mixing, the liquid components are sufficiently mixed to immediately
initiate the cross-linking reaction.
[0091] The parts of the introducer/mixer 22 are made, e.g., by
molding medical grade plastic materials, such as polycarbonate and
acrylic.
[0092] III. The Kits
[0093] As FIGS. 6A and 6B 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.
[0094] The component assembly 18 is carried by the tray 112 in the
kit 12 (see FIG. 6A). The dispersing assembly 16 is carried by the
tray 112 in the kit 14 (see FIG. 6B).
[0095] As shown in FIG. 6B, the kit 14 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 sterile environment.
[0096] The kit 14 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.
[0097] 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.
[0098] As shown in FIG. 6A, kit 12 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.
[0099] 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.
[0100] 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.
[0101] 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. 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.
[0102] IV. Using the System
[0103] A. Controlling or Arresting Diffuse Organ Bleeding
[0104] In this embodiment, exemplary directions 122 are described,
which instruct the physician how to use of the system 10 to arrest
diffuse bleeding of an injured or compromised body organ. In the
illustrated embodiment (see FIG. 7A), diffuse bleeding is shown to
occur diagrammatically through an incision in the organ.
[0105] The system 10 is applicable for use to control or arrest
diffuse bleeding in diverse types of organs, e.g., the liver,
spleen, kidney, or bone. The cause of diffuse bleeding that the
system 10 controls or arrests can also vary. The diffuse bleeding
can occur as a result of trauma or accidental injury. The diffuse
bleeding can also occur during normal surgical intervention, e.g.,
by organ resection, or tumor excision, or (in the case of bone) by
sternotomy, orthopedic procedure, or craniotomy. The diffuse
bleeding can also occur through needle tracks formed during tissue
biopsy, or by capillary bed bleeding, as a result of saphenous vein
harvesting, adhesiolysis, or tumor removal. It should be
appreciated that the effectiveness of the system 10 does not depend
upon where the diffuse bleeding is occuring or its underlying
cause.
[0106] 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. The
physician opens the inner wrap 118 of the kit 12 to gain access the
first, second, and third syringes 60, 62, and 104.
[0107] The directions 122 for use instruct the physician to remove
from the 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 kit 12 the third syringe
104, which contains sterile water 106 (e.g., about 2 cc). Both are
contained in the polymer package 138.
[0108] As FIG. 10A 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. 10B) and transfers water from the water syringe 104 into the
powder 100 in the second dispensing syringe 62 (see FIG. 10C). 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.
[0109] 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.
[0110] According to the directions 122, the physician now closes
the stopcock valve 108 (as FIG. 10D 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 two hours after mixing, it should be discarded.
[0111] 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.
[0112] The physician now, or at a previous time, opens the outer
wrap 118 of the kit 14 to gain access to the material
introducer/mixer 22. 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.
[0113] Following the directions 122, 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 spray
head 94.
[0114] As FIG. 7B shows, the physician is instructed to position
the mixing spray head 94 in a close relationship with the exposed
site of diffuse bleeding on the organ. The physician applies manual
pressure to the dispensing syringes 60 and 62. Albumin 100 from the
first dispensing syringe 60 contacts the PEG solution 136 from the
second dispensing syringe 62 in the mixing spray head 94.
Atomization of the liquid components occurs through the mixing
spray head 94 under pressure from operation of the mechanically
linked dispensing syringes 60 and 62. The mixed liquids initiate
the cross-linking reaction as they are dispersed onto the organ
surface. Within seconds (as determined by the gel time), the liquid
material transforms by in situ cross-linking into a non-liquid
structure covering the diffuse bleeding site. As FIG. 7C shows, the
covering structure adheres and conforms to the organ surface,
including entry into any incision, blunt penetration, or other
surface irregularity from which the diffuse bleeding emanates. Due
to speed of cross-linking and the physical properties of the
covering structure, diffuse bleeding does not wash away or dilute
the liquid material as it transforms into the covering
structure.
[0115] As cross linking rapidly occurs at the surface of the organ,
the covering structure entraps diffused blood. Diffuse bleeding
just as rapidly stops as the structure forms in situ, without need
of any hemostatic agent. The covering structure forms an in situ
barrier against further bleeding on the surface of the organ. The
covering structure exists long enough to prevent further blood or
fluid leakage while the compromised organ heals by natural
processes.
EXAMPLE 3
[0116] Control of Bleeding from a Kidney Incision
[0117] 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
consisted of 25% human serum albumin, USP (Plasbumin-25, Bayer
Corporation), buffered with 195 mM sodium carbonate and 120 mM
sodium bicarbonate. Syringes containing 2.0 mL of the polymer
solution and 2.0 mL of the albumin solution were connected to a
joiner and sprayhead (DuoFlow, Hemaedics, Brentwood, Calif.).
[0118] The kidney of a sedated pig was exposed. An incision
approximately an inch long and a quarter inch deep was made on the
surface of the kidney. The continual flow of blood was temporarily
collected with gauze. The gauze was then removed and the sprayable
hemostatic solution, consisting of the polymer and albumin
syringes, was applied using digital pressure.
[0119] As the two solutions were mixed in the sprayhead, the
crosslinking reaction began. As the atomized, mixed fluid landed on
the surface of the bleeding kidney, the gelation of the solution
occurred. The hydrogel adhered tenaciously to the surface of the
kidney, preventing blood from flowing. The hydrogel also had
sufficient cohesive strength to prevent rupture. Without the use of
a hemostatic agent, hemostasis occurred instantaneously using the
mechanical barrier of the hydrogel.
EXAMPLE 4
[0120] Control of Bleeding from a Spleen Incision
[0121] 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
consisted of 25% human serum albumin, USP (Plasbumin-25, Bayer
Corporation), buffered with 195 mM sodium carbonate and 120 mM
sodium bicarbonate. Syringes containing 2.0 mL of the polymer
solution and 2.0 mL of the albumin solution were connected to a
joiner and sprayhead (DuoFlow, Hemaedics, Brentwood, Calif.).
[0122] The spleen of a sedated pig was exposed. An incision
approximately an inch long and a quarter inch deep was made on the
surface of the spleen. The continual flow of blood was temporarily
collected with gauze. The gauze was then removed and the sprayable
hemostatic solution, consisting of the polymer and albumin
syringes, was applied using digital pressure.
[0123] As the two solutions were mixed in the sprayhead, the
crosslinking reaction began. As the atomized, mixed fluid landed on
the surface of the bleeding spleen, the gelation of the solution
occurred. The hydrogel adhered tenaciously to the surface of the
spleen, preventing blood from flowing. The hydrogel also had
sufficient cohesive strength to prevent rupture. Without the use of
a hemostatic agent, hemostasis occurred instantaneously using the
mechanical barrier of the hydrogel.
EXAMPLE 5
[0124] Control of Bleeding from a Liver Incision
[0125] 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
consisted of 25% human serum albumin, USP (Plasbumin-25, Bayer
Corporation), buffered with 195 mM sodium carbonate and 120 mM
sodium bicarbonate. Syringes containing 2.0 mL of the polymer
solution and 2.0 mL of the albumin solution were connected to a
joiner and sprayhead (DuoFlow, Hemaedics, Brentwood, Calif.).
[0126] The liver of a sedated pig was exposed. An incision
approximately an inch long and a quarter inch deep was made on the
surface of the liver. The continual flow of blood was temporarily
collected with gauze. The gauze was then removed and the sprayable
hemostatic solution, consisting of the polymer and albumin
syringes, was applied using digital pressure.
[0127] As the two solutions were mixed in the sprayhead, the
crosslinking reaction began. As the atomized, mixed fluid landed on
the surface of the bleeding liver, the gelation of the solution
occurred. The hydrogel adhered tenaciously to the surface of the
liver, preventing blood from flowing. The hydrogel also had
sufficient cohesive strength to prevent rupture. Without the use of
a hemostatic agent, hemostasis occurred instantaneously using the
mechanical barrier of the hydrogel.
[0128] B. controlling or Arresting Air Leaks From a Lung
Incision
[0129] The exemplary directions 122 just described can be modified
to instruct the physician how to use of the system 10 to control or
arrest the leakage of air through a perforation or puncture in the
lung caused, e.g., by trauma (see FIG. 8A).
[0130] In this embodiment, the instructions 122 instruct the
physician to prepare the dispensing syringes 60 and 62 and coupled
them to the joiner 84 in the manner previously set forth. The
physician is instructed to attach the mixing spray head 84 and
position the mixing spray head 94 in a close relationship with lung
puncture site. The lung is deflated (see FIG. 8B).
[0131] In the manner previously described, the physician applies
manual pressure to the dispensing syringes 60 and 62 (as FIG. 8B
shows). Albumin 100 from the first dispensing syringe 60 contacts
the PEG solution 136 from the second dispensing syringe 62 in the
mixing spray head 94. Atomization of the liquid components also
occurs through the mixing spray head 94 under pressure from
operation of the mechanically linked dispensing syringes 60 and 62.
The mixed liquids initiate the cross-linking reaction as they are
dispersed into contact with tissue surrounding the the lung
puncture site. Within seconds, the liquid material transforms by in
situ cross-linking into a non-liquid structure covering the
puncture site (see FIG. 8C). Air leaks through the puncture site
stop as the structure forms in situ. The covering structure exists
long enough to prevent further air leaks, while the lung tissue
heals by natural processes.
EXAMPLE 5
[0132] Control of Air Leaks from a Lung Incision
[0133] 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
consisted of 25% human serum albumin, USP (Plasbumin-25, Bayer
Corporation), buffered with 195 mM sodium carbonate and 120 mM
sodium bicarbonate. Syringes containing 2.0 mL of the polymer
solution and 2.0 mL of the albumin solution were connected to a
joiner and sprayhead (DuoFlow, Hemaedics, Brentwood, Calif.).
[0134] The lung of a euthanized, intubated pig was exposed. An
incision approximately an inch long and a quarter inch deep was
made on the surface of the lung. An air leak was confirmed by
manually inflated the lung and listening for the hissing sound of
air leaks. The lung was deflated and the surgical sealant,
consisting of the polymer and albumin syringes, was applied using
digital pressure.
[0135] As the two solutions were mixed in the sprayhead, the
crosslinking reaction began. As the atomized, mixed fluid landed on
the surface of the lung, the gelation of the solution occurred. The
hydrogel was firmly adherent to the surface of the lung. After
about 10 seconds, the lungs were manually inflated and examined for
the presence of air leaks. The hydrogel remained firmly attached to
the lung tissue, even during and after the expansion of the lungs.
Air leaks were not present after the application of the hydrogel
surgical sealant. The hydrogel showed sufficient adhesion,
cohesion, and elasticity to seal air leaks of lung tissue.
[0136] C. Sealing Anastomosis
[0137] The exemplary directions 122 just described can be modified
to instruct the physician how to use of the system 10 as a surgical
sealant along suture lines or about surgical staples, forming an
anastomosis (see FIG. 9A). The sutures or staples can be used,
e.g., to join blood vessels, bowels, ureter, or bladder. The
sutures or staples can also be used in the course of neurosurgery
or ear-nose-throat surgery.
[0138] In this embodiment, the instructions 122 instruct the
physician to prepare the dispensing syringes 60 and 62 and coupled
them to the joiner 84 in the manner previously set forth. The
physician is instructed to attach the mixing spray head 84 and
position the mixing spray head 94 in a close relationship with the
anastomosis (as FIG. 9B shows).
[0139] In the manner previously described, the physician applies
manual pressure to the dispensing syringes 60 and 62. Albumin 100
from the first dispensing syringe 60 contacts the PEG solution 136
from the second dispensing syringe 62 in the mixing spray head 94.
Atomization of the liquid components also occurs through the mixing
spray head 94 under pressure from operation of the mechanically
linked dispensing syringes 60 and 62. The mixed liquids initiate
the cross-linking reaction as they are dispersed into contact with
tissue along the anastomosis (see FIG. 9B). Within seconds, the
liquid material transforms by in situ cross-linking into a
non-liquid structure covering the anastomosis (see FIG. 9C). Blood
or fluid seepage through the anastomosis stop as the structure
forms in situ. The covering structure exists long enough to prevent
further blood or fluid leaks, while tissue along the anastomsis
heals by natural processes.
[0140] It should be appreciated that the compositions, systems, and
methods described are applicable for use to control or arrest
bleeding or fluid leaks in tissue throughout the body, including by
way of example, the following surgical sites and indications:
[0141] (i) In general surgery, such as in the liver (resection,
tumor excision or trauma); in the spleen (trauma or iatrogenic
capsular avlsion; oncology in general (excision of tumors); or
laporoscopic cholecystectomy (Lapchole) (to control bleeding from
the gall bladder bed);
[0142] (ii) In vascular surgery, such as peripheral vascular
procedures; anastomosis sites (carotid, femoral and popliteal
arteries); or aneurysms;
[0143] (iii) In the head, such as craniotomy (to control bone
bleeding from cut bone edges or bleeding from soft tissue); or
superior sagittal sinus (to control bleeding from damage to thin
wall sinus and access to sinus);
[0144] (iv) To treat arteriovenous malformation (AVM) (to control
blood vessel bleeding from smaller vessels);
[0145] (v) To treat tumor complications, such as tumor bed bleeding
or damage to soft tissue due to excisions;
[0146] (vi) To treat hematomas, such as in the control of bleeding
in soft tissues and adjacent to vessels;
[0147] (vii) In orthopedic applications, such as laminectomy or
discectomy, to control bone bleeding from the vertebrae; or spinal
reconstruction and a fusion, to control epidural vessels and
vertabral bleeders; or in hip and knee replacements, to control of
bleeding in smooth muscle tissue, soft tissue;
[0148] (viii) In cardiovascular and thoracic surgery, such as
control of anastomosis sites in coronary artery bypass graft
(C.A.B.G.); aorta reconstruction and repair, to control bleeding in
surrounding tissue; or chest cavity access through the sternum, to
control bone bleeding or soft tissue bleeding;
[0149] (ix) In urology, such as retropubic prostatectomy, to
control bleeding in soft tissue; or partial nephrectomy, to control
parenchymal bleeding; in bladder substitution, uretero-intestinal
anastomosis; urethral surgery; open urethral surgery; or
vasovasostomy;
[0150] (x) In ear-neck-throat surgery, such as during clearing of
the frontal, thmoid, sphenoid and maxillary sinuses; or in polyp
removal;
[0151] (xi) In plastic and reconstructive surgery, such as face
lifts, rhinoplasty, blepharplasty, or breast surgery;
[0152] (xii) In emergency procedures involving trauma, tissue
fracture, or abrasions.
[0153] The features of the invention are set forth in the following
claims.
* * * * *