U.S. patent application number 13/122723 was filed with the patent office on 2011-11-10 for chitosan foam medical devices and methods.
This patent application is currently assigned to PROVIDENCE HEALTH SYSTEM - OREGON. Invention is credited to Kenton W. Gregory, Jian Xin Guo.
Application Number | 20110274726 13/122723 |
Document ID | / |
Family ID | 42100930 |
Filed Date | 2011-11-10 |
United States Patent
Application |
20110274726 |
Kind Code |
A1 |
Guo; Jian Xin ; et
al. |
November 10, 2011 |
CHITOSAN FOAM MEDICAL DEVICES AND METHODS
Abstract
The invention provides a solid foam wound dressing useful for
hemorrhage control and wound repair, as well as methods for making
such a wound dressing.
Inventors: |
Guo; Jian Xin; (Portland,
OR) ; Gregory; Kenton W.; (Portland, OR) |
Assignee: |
PROVIDENCE HEALTH SYSTEM -
OREGON
Portland
OR
|
Family ID: |
42100930 |
Appl. No.: |
13/122723 |
Filed: |
October 6, 2009 |
PCT Filed: |
October 6, 2009 |
PCT NO: |
PCT/US09/59726 |
371 Date: |
June 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61103067 |
Oct 6, 2008 |
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13122723 |
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Current U.S.
Class: |
424/400 ; 264/28;
514/55 |
Current CPC
Class: |
A61F 13/00063 20130101;
A61F 2013/0071 20130101; B29K 2105/045 20130101; A61F 2013/0091
20130101; A61F 2013/00931 20130101; A61L 15/28 20130101; A61P 7/04
20180101; A61L 2300/412 20130101; A61F 13/00991 20130101; B29L
2031/753 20130101; A61L 2430/34 20130101; A61F 13/15577 20130101;
B29K 2005/00 20130101; A61L 2300/404 20130101; A61L 2400/04
20130101; A61F 13/00012 20130101; A61L 2300/418 20130101; A61F
2013/00314 20130101; A61L 15/44 20130101; A61L 15/28 20130101; A61P
31/04 20180101; A61P 31/12 20180101; A61F 13/00987 20130101; A61L
2300/408 20130101; B29K 2995/0037 20130101; A61F 2013/00106
20130101; A61F 2013/00757 20130101; B29C 44/005 20130101; A61F
2013/0074 20130101; A61P 17/02 20180101; A61F 2013/00472 20130101;
A61L 15/425 20130101; A61F 2013/0054 20130101; A61F 2013/00719
20130101; C08L 5/08 20130101 |
Class at
Publication: |
424/400 ; 514/55;
264/28 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61P 17/02 20060101 A61P017/02; B29C 35/16 20060101
B29C035/16; A61P 31/12 20060101 A61P031/12; A61P 7/04 20060101
A61P007/04; A61K 31/722 20060101 A61K031/722; A61P 31/04 20060101
A61P031/04 |
Claims
1. A method of making a solid foam wound dressing, comprising: I.
introducing gas bubbles into the aqueous solution to form an
aqueous foam, wherein the aqueous solution comprises chitosan, at
least one protic acid and at least one surface active agent; II.
freezing the aqueous foam; and III. dehydrating the aqueous foam to
form a solid foam.
2. The method of claim 1, wherein said dehydrating the aqueous foam
comprises freeze drying the aqueous foam.
3. The method of claim 1, further comprising freezing the foam in a
reduced pressure environment to expand the gas bubbles in the
aqueous foam.
4. (canceled)
5. The method of claim 1, further comprising compressing the solid
foam.
6. (canceled)
7. (canceled)
8. The method of claim 1, wherein the protic acid is a hydrogen
donator acid.
9. (canceled)
10. The method of claim 1, wherein the surface-active agent is
anionic, cationic, non-ionic, or amphoteric.
11. (canceled)
12. (canceled)
13. The method of claim 1, wherein the gas is selected from the
group consisting of air, nitrogen, helium, hydrogen, argon, and
carbon dioxide.
14. The method of claim 1, wherein the gas bubbles are introduced
by mixing, beating, agitating, aerating, whipping, or injecting the
gas into the aqueous solution.
15. The method of claim 1, wherein the wound dressing is capable of
promoting at least one of hemostasis, wound healing, and adherence
to wet tissues.
16. (canceled)
17. The method of claim 1, wherein the wound dressing is
antimicrobial and antiviral.
18. (canceled)
19. (canceled)
20. The method of claim 1, wherein the solid foam comprises at
least one of an open-cell structure and a lamella structure.
21. (canceled)
22. A solid foam wound dressing comprising chitosan, at least one
protic acid and at least one surface active agent wherein said
wound dressing has a porous structure that is mechanically flexible
and adhesive when in contact with physiological fluids or
moisture.
23. The wound dressing according to claim 22, wherein the
physiological fluid is blood.
24. The wound dressing of claim 22, wherein the solid foam wound
dressing is a compressed solid foam wound dressing.
25. (canceled)
26. The wound dressing of claim 22, wherein the protic acid is a
hydrogen donator acid.
27. (canceled)
28. The wound dressing of claim 22, wherein the surface-active
agent is anionic, cationic, non-ionic, or amphoteric.
29. (canceled)
30. The wound dressing of claim 22, wherein the surface-active
agent is antimicrobial and antiviral.
31. The wound dressing of claim 22, wherein the wound dressing is
capable of promoting at least one of hemostasis, wound healing, and
adherence to wet tissues.
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. The wound dressing of claim 22, wherein the solid porous
material comprises at least one of an open-cell structure and a
lamella structure.
37. (canceled)
38. A method of treating a wound, comprising applying the wound
dressing according to claim 22 to the wound.
Description
TECHNICAL FIELD
[0001] Embodiments of the present invention relate to methods and
devices for controlling bleeding and treating wounds.
BACKGROUND
[0002] Excessive blood loss is one of the leading causes of death
following severe injury in the battlefield or civilian world.
Timely and effective hemorrhage control can not only save victim's
lives but also prevent them from post-injury complications and
facilitate their wound healing process. Direct pressure at sites of
injury by clamping, tourniquet or manual compression in conjunction
with medical gauze, has been long used for standard treatment of
bleeding wounds on the battlefield. Though many topical hemostatic
dressings based on gelatin, collagen and oxidized cellulose have
been long used for surgical procedures, they haven't been deployed
in the field because of their limited effectiveness in controlling
high pressure bleeding. Recently, several new advanced topical
hemostats have been developed to treat severe bleeding and deployed
for military and civilian emergency use. These include
chitosan-based wound dressings.
[0003] Chitosan is a derivative of chitin, a naturally occurring
biomaterial. There are several advantages by utilizing chitosan as
wound dressing material due to its biodegradability,
biocompatibility, antibacterial activity, hemostatic activity and
bioadhesive property. Chitosan-based wound dressing can be made in
a form of powder, film, sheet, patch, sponge, non-woven pad,
fabric, mesh, or the like.
[0004] Currently there are two physical forms of chitosan-based
hemostatic dressings (CELOX.TM. granules and chitosan bandages)
that are commercially available and approved by Food and Drug
Administration for temporary hemorrhage control. CELOX.TM. is
lightweight chitosan powder manufactured by MedTrade Products Ltd.
The CELOX.TM. achieves hemostasis by interacting with blood to form
a barrier clot at the bleeding site. However, because CELOX.TM., by
nature, has no physical integrity, the powder may be flushed away
by ongoing high volume and high pressure bleeding before forming
clots. Another disadvantage of CELOX.TM. is that the manual
compression necessary for slowing down blood flow cannot be applied
if powder dressing is used alone. Chitosan bandages are a rigid,
crystalline chitosan matrix. A combination of its strong adhesive
properties and ability to promote clotting makes the bandage
effective in controlling severe bleeding when the wounds are open
and accessible. However, if the bleeding is from a narrow and deep
injury, hemorrhage control by a chitosan bandage may not be
effective either because of a difficulty applying the bandage or
because of a poor conformity to the injury cavity due to its
physical stiffness. Therefore, there is a need to improve the
flexibility of chitosan bandages while maintaining or further
improving its adhesive properties and hemostatic activity.
BRIEF SUMMARY OF EMBODIMENTS OF THE INVENTION
[0005] It is the objective of the present invention to provide a
new bioadhesive solid foam wound dressing useful for hemorrhage
control and wound repair, as well as methods for making such a
wound dressing.
[0006] In one aspect the invention provides a superporous matrix in
a form of solid foam. In an embodiment of this aspect of the
invention, the solid foam is a chitosan-based foam. The resulting
foam is mechanically flexible without compromised physical
integrity, is adhesive when in contact with physiological fluid or
moisture, and is medically useful for hemorrhage control and/or to
promote wound healing.
[0007] In another aspect, the invention provides a method of making
a solid foam wound dressing. In one embodiment of this aspect the
method comprises aerating an aqueous chitosan solution comprising
at least one protic acid and at least one surface active ingredient
to form an aqueous foam, freezing the aqueous foam, dehydrating the
aqueous foam to form a solid foam. Embodiments of this aspect may
further comprise compressing the solid foam to form a compressed,
flexible, solid foam wound dressing. Embodiments of this aspect may
further include imprinting a pattern or texture on the surface of
the compressed foam to retain a microporous matrix substantially on
the surface of the compressed foam.
[0008] In another aspect, the invention provides a method of
treating a wound. In one embodiment of this aspect the method
comprises applying a solid foam wound dressing according to the
invention to a wound.
BRIEF DESCRIPTION OF THE FIGURES
[0009] Embodiments of the present invention will be readily
understood by the following detailed description in conjunction
with the accompanying figures.
[0010] FIG. 1. A scanning electron micrograph at 500.times. of
cross-section of chitosan foam produced in accordance with the
present invention
[0011] FIG. 2. A scanning electron micrograph at 500.times. of base
surface of chitosan foam produced in accordance with the present
invention.
[0012] FIG. 3. A photograph of three chitosan foams produced in
accordance with the present invention (1) freeze-dried chitosan
sponge produced in the absence of surface-active agent (foam
density: 0.0370 g/cm.sup.3) (2) freeze-dried chitosan foam produced
at normal atmosphere during freezing phase (foam density: 0.0211
g/cm.sup.3) (3) freeze-dried chitosan foam produced at a reduced
pressure (foam density: 0.0124 g/cm.sup.3)
[0013] FIG. 4. Effect of chitosan concentration on the density of
chitosan aqueous foam in accordance with the present invention.
[0014] FIG. 5. Effect of mixing time in the preparation of chitosan
aqueous foam (1.75% w/w) in accordance with the present
invention.
[0015] FIG. 6. Effect of cationic surface-active agent on the
density of chitosan aqueous foam (1.75% w/w) in accordance with the
present invention.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0016] In the following detailed description, reference is made to
embodiments in which the invention may be practiced. It is to be
understood that other embodiments may be utilized and structural or
logical changes may be made without departing from the scope of the
present invention. Therefore, the following detailed description is
not to be taken in a limiting sense, and the scope of embodiments
in accordance with the present invention is defined by the appended
claims and their equivalents.
[0017] Various operations may be described as multiple discrete
steps in turn, in a manner that may be helpful in understanding
embodiments of the present invention; however, the order of
description should not be construed to imply that these operations
are order dependent.
[0018] The description may use the phrases "in an embodiment," or
"in embodiments," which may each refer to one or more of the same
or different embodiments. Furthermore, the terms "comprising,"
"including," "having," and the like, as used with respect to
embodiments of the present invention, are synonymous.
[0019] In various embodiments of the invention, methods and devices
for treating wounds are provided. Although certain embodiments have
been described herein for purposes of description of the preferred
embodiment, it will be appreciated by those of ordinary skill in
the art that a wide variety of alternate and/or equivalent
embodiments or implementations calculated to achieve the same
purposes may be substituted for the embodiments shown and described
without departing from the scope of the present invention. Those
with skill in the art will readily appreciate that embodiments in
accordance with the present invention may be implemented in a very
wide variety of ways. This application is intended to cover any
adaptations or variations of the embodiments discussed herein.
Therefore, it is manifestly intended that embodiments in accordance
with the present invention be limited only by the claims and the
equivalents thereof.
[0020] In one aspect the invention provides a solid foam wound
dressing to control severe bleeding, not only in open and easily
accessible injured areas but also at narrow and deep wound cavities
where an application of current commercially available wound
dressing may be limited. Embodiments of this aspect of the present
invention include a solid foam wound dressing that is mechanically
flexible without compromised physical integrity, capable of
interacting with body fluid, having conformity with live tissues,
resistant to dissolution, is adhesive when in contact with
physiological fluid or moisture, and is medically useful for
hemorrhage control and/or to promote wound healing.
[0021] Embodiments of this aspect of the invention include a
hydrophilic polymer-based foam wound dressing. In some embodiments
the hydrophobic polymer is a polysaccharide. The term
polysaccharide is intended to include, but is not limited to,
chitin, chitosan, starch, cellulose, dextran, alginate,
hyaluronate, guar gum, xanthan gum, carrageenan, and their
derivatives. In a preferred embodiment, the polysaccharide is
chitosan. The term "chitosan" generally refers to a deacetylated
derivative of chitin. In various embodiments, the present invention
may include one or more derivatives of chitosan. In embodiments of
this aspect the wound dressing may further comprise at least one
protic acid and/or at least one surface-active agent.
[0022] In embodiments of this aspect of the present invention the
solid foam comprises lamella and/or open-cell pore structures in
which the pores are substantially uniformly distributed and
interconnected within the foam. In some embodiments, the solid foam
may further comprise microporous imprints on the surfaces of the
foam. Thereby providing a solid foam having significantly high
surface areas on the surfaces, as well as inside the foam.
[0023] Embodiments of this aspect of the present invention may
provide one or more advantages over current wound dressings. For
example, the solid foam is soft and flexible and can be bent,
twisted, folded and rolled; lacks of stiff crust layer on the top
surface; comprises a uniform porous structures from bottom to top
as well as side to side; has large surface areas; is applicable to
narrow-entry and deep wound cavities; quickly interacts with body
fluid to form adhesive layer and clot bleeding site; can conform to
irregular wound surfaces and cavities, capable of controlling high
volume and high pressure bleeding rapidly and effectively; can seal
bleeding site and prevent rebleeding; is easy to remove; has
enhanced infection protection when surface-active ingredient has
inherent antimicrobial properties in addition to foaming ability;
and can facilitate wound healing by allowing cells to penetrate and
grow through the porous matrix.
[0024] In another aspect, the invention provides a method of making
a wound dressing. In one embodiment of this aspect the method
comprises aerating an aqueous solution comprising a polysaccharide
and at least one protic acid and at least one surface active
ingredient to form an aqueous foam, freezing the foam, and
dehydrating the aqueous foam to form a solid foam. Embodiments of
this aspect may further comprise compressing the solid foam to form
a compressed, flexible, solid foam wound dressing. Embodiments of
this aspect may further include imprinting a pattern or texture on
the surface of the compressed foam to retain a microporous matrix
substantially on the surface of the compressed foam. In preferred
embodiments, the aqueous foam is a chitosan-based foam. The ability
to form a solid foam from an aqueous solution is related to the
apparent density of the aqueous foam after formation. The lower
aqueous foam density, the better solid-foaming ability of the
aqueous solution.
[0025] In various embodiments, the aqueous foam may be formed by
introducing gas bubbles into the aqueous solution through mixing,
beating, agitating, aerating, whipping, injecting or other
mechanical actions. For such embodiments, the gas may include, but
not limited to, air, nitrogen, helium, hydrogen, argon, carbon
dioxide or other inert gas. Severity of mechanical actions such as
mixing time, speed and temperature may be adjusted depending on
foam density and the foam stability desirable for the process, and
the softness, flexibility and adhesiveness of final product
desirable for medical treatment.
[0026] In embodiments according to this aspect of the invention,
dehydrating the aqueous foam may include, but not limited to,
freeze-drying or lyophilization or other methods known in the art.
In embodiments of this aspect, the aqueous foam may be solidified
before the gas bubbles trapped in the foam collapse or coalesce. In
embodiments of this aspect, the freezing temperature may be
controlled in such a way that lamella ice crystals are formed and
the trapped gas bubbles are uniformly distributed in the frozen
foam before drying. In various embodiments, the freeze temperature
may be in the range 0.degree. C. to -200.degree. C., or in the
range -10.degree. C. to -80.degree. C. Once the foam is frozen,
water and acid in the foam may be removed though sublimation and
desorption after a freeze-drying cycle (lyophilization). The final
solid foam may be sponge-like and have both lamella and/or
open-cell pore structures.
[0027] Embodiments of this aspect of the invention may include
freezing the foam at a reduced pressure to further expand the gas
bubbles trapped in the aqueous foam, prior to a collapse and/or
coalescence. In embodiments of this aspect, the reduced pressure
environment may be maintained until the expanded gas bubbles are
substantially frozen. In such embodiments, the reduced pressure
environment may be in the range from 100 mTorr to 750 Torr
depending on the freezing temperature, and the desired softness,
flexibility and adhesiveness of the final product.
[0028] In accordance with various embodiments, the aqueous foam can
be made to conform to a desirable shape by transferring the aqueous
foam to a heat-conducting container, such as aluminum mold, prior
to dehydrating the aqueous foam.
[0029] In embodiments of this aspect of the invention, the solid
foam may be compressed, for example, between two flat heated
platens or rollers under pressure. The solid foam may be compressed
to the thickness from 1 to 30 times thinner than uncompressed foam,
depending on the density of the uncompressed foam. Preferably, the
solid foam may be compressed 2 to 20 times thinner compared to the
thickness of uncompressed foam.
[0030] In embodiments of this aspect of the invention, the solid
foam may be further imprinted with patterns or textures during or
after the compression of the solid foam in order to improve
coherent strength and flexibility, prevent rapid dissolution and
enhance adhesiveness while substantially preserving unique
microporous structures on the surfaces. Such imprinting can be
achieved by using platens or rollers having patterns or textures or
by using soft substrates with patterns or textures loaded between
the platens or rollers during compression of the foam. In such
embodiments, the temperature of the platens and rollers, with or
without the soft substrates, may be controlled at a range from
40.degree. C. to 100.degree. C., preferably from 50.degree. C. to
80.degree. C., depending on the mass of the foam, compression speed
and the desirable thickness of the densified matrix.
[0031] In an embodiment of the present invention, the soft
substrates may comprise a polymeric sheet, mat, and mesh, or
knitted or woven fabric having patterns or textures on the
surfaces. Preferred soft substrate may include, but not limited to,
twill fabrics that have distinct diagonal wale weaving pattern as a
result of passing the weft threads over one warp thread and then
under two or more warp threads, and may be soft but firm enough to
able to densify the solid foam under heating and pressure
conditions to form a compressed foam with imprinted surfaces.
Compressed foam having imprinted surfaces may comprise a
combination of high density and low density matrixes as a result of
the soft and patterned twill fabric.
[0032] In embodiments of the invention, the twill fabric may be 1/2
twill, 2/1 twill, 2/2 twill, 2/1 herringbone twill, 2/2 herringbone
twill, 2/1 diamond twill or 2/2 diamond twill, 3/1 twill, 3/2
twill, 4/1 twill, 4/2, 5/1 twill, 5/2 twill, or the like. Preferred
twill fabric may include, but not limited to, 2/1 twill, 2/2 twill,
3/1 twill.
[0033] In embodiments of the invention, the twill fabric may be
made from lint-free synthetic and natural polymers materials. It is
preferable the materials are medically acceptable fabrics.
[0034] In embodiments of the invention, the soft substrates for the
compression in the present invention may have internal heating
wires connected to external temperature controller so that platens
or rollers are not needed to be heated separately.
[0035] In embodiments of the present invention, the concentration
of chitosan in the aqueous solution may be in the range from 0.1%
to 20% by weight, or in the range of 0.5% to 10% by weight,
depending on the molecular weight of the chitosan, foam density and
stability desirable for the process, and the softness, flexibility
and adhesiveness of final product desirable for medical
treatment.
[0036] In embodiments of the present invention, the molecular
weight of chitosan used in the aqueous solution may be varied from
1 k Dalton to 2000 k Dalton, or from 10 k to 1000 k Dalton,
depending on the foam density and stability desirable for the
process, and the softness, flexibility and adhesiveness of final
product desirable for medical treatment.
[0037] In embodiments of the present invention, the protic acid
used in the aqueous solution may be a proton donor acid that
facilitates dissolving chitosan and stabilizes foam formed during
the process. For example, the acid may include, but not limit to,
formic acid, acetic acid, propionic acid, lactic acid, succinic
acid, glutamic acid, tartaric acid, citric acid, hydrochloric acid,
nitric acid, phosphoric acid, and the like. The concentration of
acid in the aqueous solution may be in the range from 0.01% to 10%
by weight, or from 0.1% to 5% by weight, depending on the stability
of foam during the process, and the softness, flexibility and
adhesiveness of final product desirable for medical treatment.
[0038] In various embodiments, the surface-active agent to aid foam
formation and stabilize the foam during the process may be an
anionic surface-active agent, cationic surface-active agent,
non-ionic surface-active agent, or amphoteric surface-active agent.
For example, the anionic surface-active agent may include, but not
limit to, sodium or ammonium dodecyl sulfate or caboxylate or
phosphate, sodium laureth sulfate, alky benzene sulfonates, sodium
carboxyl methylcellulose, sodium stearate, fatty acid sodium salts,
phosphatidic acid salt or the like. The cationic surface-active
agent may include, but not limit to, fatty amine halides, cetyl
trimethylammonium halides, cetylpyrindium halides, benzalkonium
halides, benzethonium halides, polyethoxylated tallow amine, or the
like. The non-ionic surface active agents may include, but not
limit to, methylcellulose, hydroxylethyl cellulose, hydroxyl
methypropylcellulose, alky poly(ethylene oxide), octyl glucoside,
decyl maltoside, cetyl alcohol, .degree. leyl alcohol, pluronics,
tween 20, tween 60, tween 80, or the like. The amphoteric
surface-active agents may include, but not limited to, gelatin,
white egg, dodecyl betaine, lysozyme, plant proteins, serum
albumins, blood plasma, dodecyl dimethylamine oxide, cocamidopropyl
betaine, coco ampho glycinate, or the like. Preferred
surface-active agent for the aqueous solution is water and/or acid
soluble cationic, nonionic and amphoteric agents, preferably
quaternary ammonium based cationic surface-active agents
functioning as both a foaming agent and an antimicrobial and/or
antiviral agent, e.g. benzethonium halides, cetyl trimethylammonium
halides and the like, can be used for the aqueous solution. The
amount of surface-active agent may be varied from 0.001% to 50% by
weight, or from 0.01% to 25% by weight, depending on the type of
surface-active agent, foam density and stability desirable for the
process, and the softness, flexibility and adhesiveness of final
product desirable for medical treatment.
[0039] In accordance with various embodiments, plasticizers may be
optionally used to further improve mechanical and physical
properties of the foam. The plasticizers in the aqueous solution
may include, but not limit to, glycerol, sorbitol, Tween 60, Tween
80, polyglycol and its derivatives, and the like.
[0040] In another aspect, the invention provides a method of
treating a wound. In one embodiment of this aspect the method
comprises applying a solid foam wound dressing as disclosed
herein.
[0041] In accordance with various embodiments of the present
invention, the wound dressings may help control severe bleeding,
not only in open and easily accessible injured areas but also at
narrow and deep wound cavities where an application of current
commercially available chitosan wound dressing are limited. The new
dressing of the present invention has been tested for hemorrhage
control in a lethal femoral artery injury animal model. The results
shown below demonstrate that the new dressing is very effective at
stopping severe bleeding.
[0042] Embodiments of the present invention may impart cost savings
over prior art methods for producing foam wound dressings. For
example, an expansion of gas bubbles trapped in the aqueous foam
via reducing pressure before or during freezing in the
freeze-drying process may reduce the amount of foaming agent used
while achieving the same or even better physical properties. The
formation of aqueous foam with high surface area may be favorable
for drying during freeze-drying process. Ease of cutting or slicing
a solid chitosan-based foam to a desired shape and size of dressing
sheet compared to prior chitosan-based structures, which are
difficult to cut or slice due to non-uniform crystal structures,
may also provide an opportunity to increase the scale of single
loading during freeze drying process, thus reducing manufacturing
cost.
EXAMPLES
Example 1
[0043] Preparation of a chitosan foam formed with air bubbles.
[0044] A 2% (w/w) chitosan aqueous solution was prepared by
dissolving chitosan in acetic acid solutions (2% w/w) in a plastic
bottle. The bottle was placed on a roller and rolled until the
chitosan was completely dissolved. 900 g of the chitosan solution
and 9 gram of benzalkonium chloride solution (2% w/w) as
surface-active agent were added to a mixing bowl. The solution was
mixed with a mixer (KitchenAid) equipped with a whipping wire to
introduce air bubbles to form the foam. The apparent density of the
foam was 0.67 g/cm.sup.3, determined by weighing 1 L of the foam
and calculated.
[0045] FIGS. 1 and 2 show that open-cell pores ranging from few
micrometers to over hundreds micrometers randomly but substantially
uniformly distributed on the surface of the foam matrix and on each
individual lamella layer of the chitosan. The open-cell pores also
enabled all lamella pores interconnect cross whole chitosan foam
matrix.
Example 2
[0046] Preparation of a chitosan foam formed with carbon dioxide
bubbles.
[0047] A chitosan aqueous solution was prepared by the same
procedure described in Example 1 except 40 g of grounded dried ice
was added into chitosan aqueous solution before agitation. Foam
with a density of 0.69 g/cm.sup.3 was obtained.
Example 3
[0048] Effects of chitosan concentration on chitosan foam
formation.
[0049] A chitosan aqueous solution was prepared by the same
procedure described in Example 1 except the chitosan concentration
in the chitosan solution was varied. A series of chitosan foams
with different foam densities were obtained as shown in FIG. 4.
Example 4
[0050] Effects of mechanical action on chitosan foam formation.
[0051] A chitosan aqueous solution was prepared by the same
procedure described in Example 1 except the mixing time was varied.
A series of chitosan foams with different densities were obtained
as shown on FIG. 5.
Example 5
[0052] Effects of the amount of surface-active agent on chitosan
foam formation.
[0053] A chitosan aqueous solution was prepared by the same
procedure described in Example 1 except the amount of benzalkonium
chloride was varied. A series of chitosan foams with different
densities were obtained as shown on FIG. 6.
Example 6
[0054] Use of an anionic surface-active agent as a foaming agent
for chitosan foam formation.
[0055] A chitosan aqueous solution was prepared by the same
procedure described in Example 1 except benzalkonium chloride was
replaced with sodium laury sulfate. A foam with an apparent density
of 0.68 g/cm.sup.3 was obtained.
Example 7
[0056] Preparation of a chitosan solid foam wound dressing from
aqueous foam through freeze-drying.
[0057] A 4''.times.4'' aluminum mold was filled the chitosan foam
prepared in Example 1. The mold was immediately placed on a
pre-cooled freeze dryer shelf and maintained at -40.degree. C. for
3 hours. After complete freezing, the frozen chitosan foam was
dried through sublimation and desorption with a full freeze-drying
cycle. The final freeze-dried solid foam is soft and flexible. The
density of the solid foam was 0.0211 g/cm.sup.3. The freeze dried
foam was pressed into a thickness of about 1.2 mm on a MTS 858 Mini
Bionix II mechanical tester mounted with two flat 6''.times.6''
heated platens. The pressed foam was conditioned in an oven at
80.degree. C. for 15 minutes and sealed in a foil pouch. The
chitosan foam was sterilized using gamma irradiation before wound
treatment.
Example 8
[0058] Preparation of a chitosan solid foam wound dressing from
aqueous foam frozen at a reduced pressure.
[0059] An aluminum mold was filled with the chitosan foam prepared
in Example 1. The mold was placed on a freezer dryer shelf
pre-cooled to -40.degree. C. and immediately the vacuum in the
freeze dryer were pulled down to 400 mBar. The shelf temperature
was maintained at -40.degree. C. for 3 hours. After complete
freezing, the frozen chitosan foam was dried through sublimation
and desorption with a full freeze-drying cycle. The final
freeze-dried solid foam is softer and more flexible as compared to
the solid foam prepared in Example 7. The density of the solid foam
is 0.0124 g/cm.sup.3. The freeze dried foam was pressed into a
thickness of about 1.2 mm on a MTS 858 Mini Bionix II mechanical
tester mounted with two flat 6''.times.6'' heated platens. The
pressed foam was conditioned in an oven at 80.degree. C. for 15
minutes and sealed in a foil pouch. The chitosan foam was
sterilized using gamma irradiation before wound treatment.
Example 9
[0060] Preparation of chitosan compressed foam wound dressing with
imprinted surfaces.
[0061] The uncompressed freeze dried chitosan foam prepared in
Example 8 was pressed between two sheets of lint free 2/1 twill
fabrics into a thickness of about 1.2 mm on a MTS 858 Mini Bionix
II mechanical tester mounted with two flat 6''.times.6'' heated
platens. The final compressed foam with imprinted surfaces had the
same distinct patterns as the twill fabric used for the pressing.
It is more flexible as compared to the pressed foam with flat and
hard surfaces prepared in Example 8 and behaved as a fabric-like
dressing. The compressed and imprinted foam dressing was
conditioned in an oven at 80.degree. C. for 15 minutes and sealed
in a foil pouch. The chitosan foam dressing was sterilized using
gamma irradiation before for wound treatment.
Example 10
[0062] Hemostatic testing of bioadhesive chitosan foam in femoral
artery injury
[0063] Domestic swine were used for the hemostatic test. An
approximate 10 cm incision was made over the groin through the skin
and subcutaneous tissues. The thin adductor muscle that directly
overlies the femoral canal was excised. At least 5 cm of left
femoral artery was isolated (the overlying muscle was removed) and
the collateral branches were ligated. The vessel was bathed with a
few milliliters of Lidocaine to relax the vasospasm and dilate the
artery. A stabilization period of 10-minute was allowed. To create
the injury, the proximal and distal ends of the femoral artery were
clamped and an arteriotomy was made on the anterior portion of the
femoral artery using a 6.0 mm vascular punch. Caution was taken to
avoid the complete transaction and retraction of the vessel.
[0064] The vessel clamps were released and free bleeding was
allowed for 45 seconds. Blood was allowed to accumulate in the
wound cavity. Blood spilling out of the cavity was suctioned into
canisters. Mean arterial pressure (MAP) dropped to below 40 mmHg. A
strip of sterilized chitosan compressed foam (2.8''.times.14'', 5
grams) was then applied to the wound through a pool of blood. While
the foam was held down, two pieces of laparotomy gauze were placed
over it and compressed for 3 minutes. Hemostasis was checked after
compression time. Success was determined when the dressing achieves
30 minutes of hemostasis. Application of the chitosan foams showed
that the severe bleeding was stopped and the hemostasis maintained
over 30 minutes before testing article was removed. The MAP went
back to normal range (>60 mmHg).
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