U.S. patent application number 14/479649 was filed with the patent office on 2015-05-14 for hemostatic sponge.
The applicant listed for this patent is Baxter Healthcare S.A., Baxter International Inc.. Invention is credited to Hans Christian Hedrich, Joris Hoefinghoff.
Application Number | 20150132362 14/479649 |
Document ID | / |
Family ID | 42731904 |
Filed Date | 2015-05-14 |
United States Patent
Application |
20150132362 |
Kind Code |
A1 |
Hoefinghoff; Joris ; et
al. |
May 14, 2015 |
HEMOSTATIC SPONGE
Abstract
The present invention provides a hemostatic porous sponge
comprising a matrix of a fibrous biomaterial and particles of a
fluid absorbing, particulate material adhered to said matrix
material, a method of producing these sponges and their use for
wound healing.
Inventors: |
Hoefinghoff; Joris; (Vienna,
AT) ; Hedrich; Hans Christian; (Vienna, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Baxter International Inc.
Baxter Healthcare S.A. |
Deerfield
Glattpark (Opfikon) |
IL |
US
CH |
|
|
Family ID: |
42731904 |
Appl. No.: |
14/479649 |
Filed: |
September 8, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12816645 |
Jun 16, 2010 |
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14479649 |
|
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61187576 |
Jun 16, 2009 |
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Current U.S.
Class: |
424/444 ;
424/443; 514/13.5; 514/13.6 |
Current CPC
Class: |
A61L 15/425 20130101;
A61L 15/64 20130101; A61L 2300/418 20130101; A61L 15/325 20130101;
A61L 15/26 20130101; A61L 15/58 20130101; A61L 15/32 20130101; A61L
2400/04 20130101; A61L 15/44 20130101 |
Class at
Publication: |
424/444 ;
514/13.5; 514/13.6; 424/443 |
International
Class: |
A61L 15/42 20060101
A61L015/42; A61L 15/26 20060101 A61L015/26; A61L 15/58 20060101
A61L015/58; A61L 15/64 20060101 A61L015/64; A61L 15/32 20060101
A61L015/32; A61L 15/44 20060101 A61L015/44 |
Claims
1. A hemostatic porous sponge comprising a matrix of a fibrous
biomaterial and particles of a fluid absorbing particulate material
adhered to said matrix material.
2. The sponge according to claim 1, wherein said fibrous
biomaterial comprises collagen.
3. The sponge according to claim 1, wherein said particulate
material is a hemostatic material.
4. The sponge according to claim 3, wherein said particulate
material is a cross-linked polymer.
5. The sponge according to claim 3, wherein said particulate
material comprises gelatin, fibrin, collagen or any mixture
thereof.
6. The sponge according to claim 1 further comprising thrombin or a
precursor of thrombin.
7. The sponge according to claim 1 further comprising an adhesive
layer.
8. The sponge according to claim 7, wherein said adhesive layer
comprises a bioresorbable polymer.
9. The sponge according to claim 7, wherein the adhesive comprises
a first cross-linkable component, a second cross-linkable component
that cross-links with the first cross-linkable component under
reaction enabling conditions.
10. The sponge according to claim 9, wherein said first and/or
second cross-linkable component comprise PEG or a derivative
thereof.
11. The sponge according to claim 7, wherein said adhesive
comprises succinimidyl or maleimidyl and thiol or amino groups.
12. The sponge according to claim 7, wherein said adhesive layer is
discontinuously coated on at least one side of the sponge.
13. The sponge according to claim 1 being freeze-dried or
air-dried.
14. The sponge according to claim 1 comprising a supporting layer
with greater tensile strength than the matrix material.
15. The sponge according to claim 14, wherein said supporting layer
comprises a bioresorbable polymer.
16. The sponge according to claim 14, wherein said supporting layer
comprises has a greater density than the matrix material.
17. A method of manufacturing a hemostatic porous sponge comprising
providing a fluid of a fibrous biomaterial and suspended particles
of a fluid absorbing, particulate material, and drying said fluid
with the suspended particles, thereby obtaining a hemostatic porous
sponge comprising a matrix of a fibrous biomaterial and particles
of a fluid absorbing, particulate material adhered to said matrix
material.
18. A hemostatic porous sponge obtainable by a method according to
claim 17.
19. Method of treating an injury comprising administering a
hemostatic porous sponge comprising a matrix of a fibrous
biomaterial and a fluid absorbing, particulate material adhered to
said matrix material to the site of injury.
20. The method according to claim 19, wherein said injury comprises
a wound, a hemorrhage, damaged tissue and/or bleeding tissue.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of and claims priority to
U.S. patent application Ser. No. 12/816,645 filed Jun. 16, 2010,
which claims the benefit of Provisional Application No. 61/187,576
filed Jun. 16, 2009, the entire contents of both of which are
hereby incorporated by reference for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of hemostatic
sponges, a method of producing said sponges and their uses in
hemostasis.
BACKGROUND OF THE INVENTION
[0003] Biological glues based on coagulation factors of human or
animal origin have long been known. A method for producing tissue
adhesives based on fibrinogen and factor XIII has been described in
U.S. Pat. No. 4,362,567, U.S. Pat. No. 4,298,598 and U.S. Pat. No.
4,377,572. The tissue adhesives are usually applied together with a
separate component containing thrombin, which is enzymatically
acting on fibrinogen to form fibrin, and on factor XIII to form the
active factor XIIIa, which cross-links the fibrin to obtain a
stable fibrin clot.
[0004] Collagen pads have been used for many years to improve wound
healing or to stop bleeding. Their mechanism of action in
hemostasis is based on platelets aggregation and activation, the
formation of thrombin on the surface of activated platelets and the
formation of a hemostatic fibrin clot by the catalytic action of
thrombin on fibrinogen. To improve the hemostatic action of
collagen pads or sheets it has been suggested to include factors of
hemostasis within such pads.
[0005] In U.S. Pat. No. 4,600,574 a tissue adhesive based on
collagen combined with fibrinogen and factor XIII is described.
This material is provided in the lyophilized form, ready for use.
The fibrinogen and factor XIII are combined with the collagen by
impregnating the collageneous flat material with a solution
comprising fibrinogen and factor XIII, and lyophilizing said
material.
[0006] The WO 97/37694 discloses a hemostatic sponge based on
collagen and an activator or proactivator of blood coagulation
homogeneously distributed therein. This sponge is provided in a dry
form, which could be air-dried or lyophilized. However, it still
contains a water content of at least 2%.
[0007] U.S. Pat. No. 5,614,587 discusses bioadhesive compositions
comprising collagen cross-linked using a multifunctionally
activated synthetic hydrophilic polymer, as well as methods of
using such compositions to effect adhesion between a first surface
and a second surface, wherein at least one of the first and second
surfaces can be a native tissue surface.
[0008] Collagen-containing compositions which have been
mechanically disrupted to alter their physical properties are
described in U.S. Pat. No. 5,428,024, U.S. Pat. No. 5,352,715, and
U.S. Pat. No. 5,204,382. These patents generally relate to
fibrillar and insoluble collagens. An injectable collagen
composition is described in U.S. Pat. No. 4,803,075. An injectable
bone/cartilage composition is described in U.S. Pat. No. 5,516,532.
A collagen-based delivery matrix comprising dry particles in the
size range from 5 .mu.m to 850 .mu.m which may be suspended in
water and which has a particular surface charge density is
described in WO 96/39159. A collagen preparation having a particle
size from 1 .mu.m to 50 .mu.m useful as an aerosol spray to form a
wound dressing is described in U.S. Pat. No. 5,196,185. Other
patents describing collagen compositions include U.S. Pat. No.
5,672,336 and U.S. Pat. No. 5,356,614.
SUMMARY OF THE INVENTION
[0009] The subject of the invention is a hemostatic porous sponge
comprising a matrix of a fibrous biomaterial and particles of a
fluid absorbing particulate material adhered to said matrix
material. It has been found that previous pads of fibrous
biomaterials, in particular collagen pads, for wound healing failed
to induce hemostasis at conditions with impaired hemostasis (e.g.
after heparinization). The inventive use of a particulate material
within a matrix of collagen improves hemostasis in comparison to
hemostasis without fluid absorbing particulate material. Without
being limited to a certain theory, it appears that when using
particles with a high capability to absorb liquids, a high
concentration of clotting factors present in blood can be achieved
which favors hemostasis. It is difficult to apply such particles
directly onto the bleeding wound because the particles tend to flow
away with the bloodstream. The incorporation of such particles in a
hemostatic sponge allows a local fixation of such particles and
further improves the hemostatic action of the sponge.
[0010] A further aspect relates to a method of manufacturing a
hemostatic porous sponge comprising providing a fluid of a fibrous
biomaterial and suspended particles of a fluid absorbing,
particulate material, and drying said fluid with the suspended
particles, thereby obtaining a hemostatic porous sponge comprising
a matrix of a fibrous biomaterial and particles of a fluid
absorbing, particulate material adhered to said matrix material. A
hemostatic porous sponge obtainable by this method is comprised by
the present invention. The term "fluid" according to the present
invention includes a solution, a suspension or a gel.
[0011] Also provided is a kit for preparing a wound coverage,
comprising a sponge as herein disclosed and pharmaceutically active
substances. This kit and its components are in particular for the
manufacture of a medical sponge for the treatment of an injury.
[0012] The person skilled in the art will readily understand that
all preferred embodiments disclosed in the following are examples
of specific embodiments, but are not necessarily limiting the
general inventive concept. Furthermore, all special embodiments can
be read on all inventive aspects and embodiments in any
combination, if not mutually exclusive. All equivalents or obvious
alterations or modifications as recognized by the skilled person
are included by the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The object of the invention is a hemostatic sponge based on
a fibrous biomaterial with improved hemostatic properties. This
goal is achieved by providing a fluid absorbing, particulate
material adhered to the sponge. The fibrous biomaterial may support
any hemostatic or blood clotting actions. This effect can be
strengthened by the inventive particulate material. These particles
are adhered to the fibrous biomaterial to provide a sufficiently
strong fixation of the particles, increasing shelf life and
increasing durability during usage, in particular as wound coverage
where mechanic tensions can lead to unwanted detachment of the
particles. The term "adhered" according to the present invention
means that the particles are distributed within or embedded in or
entrapped in the fibrous biomaterial. The particles may be held in
the matrix material in any ordered or disordered state, preferably
being homogeneously distributed therein. The sponge is a porous
network of a fibrous biomaterial able to absorb body fluids when
applied on an injury. Furthermore, the sponge is usually flexible
and suitable to apply on diverse tissues and locations with various
shapes.
[0014] The terms "sponge" and "pad" are used interchangeably within
the meaning of the present invention.
[0015] Preferably the fibrous biomaterial is collagen, a protein, a
biopolymer, or a polysaccharide.
[0016] The collagen used for the present invention can be from any
collagen suitable to form a gel, including a material from liquid,
pasty, fibrous or powdery collagenous materials that can be
processed to a porous or fibrous matrix. The preparation of a
collagen gel for the production of a sponge is e.g. described in
the EP 0891193 (incorporated herein by reference) and may include
acidification until gel formation occurs and subsequent pH
neutralisation. To improve gel forming capabilities or solubility
the collagen may be (partially) hydrolyzed or modified, as long as
the property to form a stable sponge when dried is not
diminished.
[0017] The collagen or gelatin of the sponge matrix is preferably
of animal origin, preferably bovine or equine. However, also human
collagen might be used in case of a hypersensitivity of the patient
towards xenogenic proteins. The further components of the sponge
are preferably of human origin, which makes the sponge suitable
especially for the application to a human.
[0018] In a preferred embodiment the matrix material of the fibrous
biocompatible polymer which forms the porous network of the sponge
constitutes of between 1-50%, 1-10%, or about 3% of the dried
porous sponge (w/w-%).
[0019] The particulate material in general is not soluble, in
particular not water-soluble. It remains particulate in water.
However the particles may be porous and/or hygroscopic and are
allowed to swell. "Fluid absorbing" shall be considered as the
physical process to hold fluids upon contacting which may or may
not provoke swelling of the particles. Preferably the particles can
hold an amount of a fluid, in particular blood, of at least 1 time,
at least 2 times, at least 4 times or at least 10 times and/or up
to 100 times, up to 20 times or up to 10 of the dry weight of the
sponge. The particulate material according to the present invention
can take up fluids even under pressure. To improve stability and
adjust the swelling properties,the particulate material can be
cross-linked.
[0020] The particulate material may be a hemostatic material and
provide for the hemostatic action of the sponge alone or in
combination with the sponge matrix. Hemostasis or any other
clotting activity can be induced by activating the hemostatic
system in a subject. The hemostatic sponge can increase the rate of
hemostatic reactions as compared to hemostasis without treatment.
This activation can be based on a multitude of reactions but
usually includes catalytic processes of blood or serum proteins or
oxidative processes. After initiation, the subject's hemostatic
system usually proceeds with a strong enzymatic cascade leading to
clotting. Such a catalysis or any other hemostatic activity can be
initiated by the matrix material or the particulate material. Of
course it is also possible to provided additional reactants or
catalysts with the inventive sponge, such as an activator or
proactivator of blood coagulation, including fibrinogen, thrombin
or a thrombin precursor.
[0021] In preferred embodiments, particulate material is a polymer
and/or a biomaterial, in particular a biopolymer. In order to
facilitate recovery of the injury (in particular in the case of
internal surgery where removal of any remaining foreign material
may require addition surgery) it is preferred to use a
bioresorbable particulate material.
[0022] The particulate material, the matrix material or the sponge
as a whole can be biodegradable, being suitable for biological
decomposition in vivo, or bioresorbable, i.e. able to be resorbed
in vivo. Full resorption means that no significant extracellular
fragments remain. A biodegradable material differs from a
non-biodegradable material in that a biodegradable material can be
biologically decomposed into units which may either be removed from
the biological system and/or chemically incorporated into the
biological system. In a preferred embodiment the particular
material, the matrix material or sponge as a whole can be degraded
by a subject, in particular a human subject, in less than 6 month,
less than 3 month, less than 1 month, less than 2 weeks.
[0023] The particles can, e.g., be gelatin, gelatin derivatives,
chemically derivatized gelatin, collagen, fibrin, proteins,
polysaccharides or any mixture thereof, but other kinds of organic
material can be used as well. Preferably, it is water-insoluble,
biodegradeable and bioresorbable. Natural gelatin is cheap and
broadly available and can be obtained from many sources. Gelatin is
a hydrolysate of collagen. Convenient animal sources of gelatin and
collagen include chicken, turkey, bovine, porcine, equine, or human
sources. The collagen can also be artificial or recombinant
collagen. Preferably, the gelatin is cross-linked to prevent
complete solubility. Cross-linking may be achieved by incomplete
hydrolysation of collagen or chemical cross-linking using
cross-linking reagents such as formaldehyde or divalent
aldehydes.
[0024] The particles according to the present invention are
preferably microparticles being in the size range of micrometers.
In preferred embodiments the particle size (average diameter in dry
state) is 2000 .mu.m or below. Even smaller particles may be used,
e.g. of an average size below 1000 .mu.m, or below 100 nm. Also
possible is any size range within these borders, e.g. an average
diameter of from 100 nm to 2000 .mu.m in dry state.
[0025] Examples of such particles are e.g. described in U.S. Pat.
No. 6,063,061 and U.S. Pat. No. 6,066,325 (both incorporated herein
by reference).
[0026] After drying, the sponge may have a water content of at
least 0.5 (percentages given in w/w here). In certain embodiments
the sponge can be freeze-dried or air-dried.
[0027] Preferably, the sponge comprises an activator or
proactivator of blood coagulation, including fibrinogen, thrombin
or a thrombin precursor, as e.g. disclosed in U.S. Pat. No.
5,714,370 (incorporated herein by reference). Thrombin or the
precursor of thrombin is understood as a protein that has thrombin
activity and that induces thrombin activity when it is contacted
with blood or after application to the patient, respectively. Its
activity is expressed as thrombin activity (NIH-Unit) or thrombin
equivalent activity developing the corresponding NIH-Unit. The
activity in the sponge can be 500-5.000. In the following thrombin
activity is understood to comprise both, the activity of thrombin
or any equivalent activity. A protein with thrombin activity might
be selected from the group consisting of alpha-thrombin,
meizothrombin, a thrombin derivative or a recombinant thrombin. A
suitable precursor is possibly selected from the group consisting
of: prothrombin, factor Xa optionally together with phospholipids,
factor IXa, activated prothrombin complex, FEIBA, any activator or
a proactivator of the intrinsic or extrinsic coagulation, or
mixtures thereof.
[0028] The hemostatic sponge according to the invention might be
used together with further physiologic substances. For example, the
sponge preferably further comprises pharmacologically active
substances, among them antifibrinolytics, such as a
plasminogen-activator-inhibitor or a plasmin inhibitor or an
inactivator of fibrinolytics. A preferred antifibrinolytic is
selected from the group consisting of aprotinin or an aprotinin
derivative, alpha2-macroglobulin, an inhibitor or inactivator of
protein C or activated protein C, a substrate mimic binding to
plasmin that acts competitively with natural substrates, and an
antibody inhibiting fibrinolytic activity.
[0029] As a further pharmacologically active substance an
antibiotic, such as an antibacterial or antimycotic might be used
together with the sponge according to the invention, preferably as
a component homogeneously distributed in the sponge. Further
bioactive substances such as growth factors and/or pain killers may
be also present in the inventive sponge. Such a sponge might be
useful in e.g. wound healing.
Further combinations are preferred with specific enzymes or enzyme
inhibitors, which may regulate, i.e. accelerate or inhibit, the
resorption of the sponge. Among those are collagenase, its
enhancers or inhibitors. Also, a suitable preservative may be used
together with the sponge or may be contained in the sponge.
[0030] Although a preferred embodiment relates to the use of the
hemostatic sponge which contains the activator or proactivator of
blood coagulation as the only active component, further substances
that influence the velocity of blood coagulation, hemostasis and
quality of the sealing, such as tensile strength, strength of the
product to tissue, and durability might be comprised.
[0031] Procoagulants that enhance or improve the intrinsic or
extrinsic coagulation, such as factors or cofactors of blood
coagulation, factor XIII, tissue factor, prothrombin complex,
activated prothrombin complex, or parts of the complexes, a
prothrombinase complex, phospholipids and calcium ions, might be
used. In case of a surgical procedure where a precise sealing is
needed, it might be preferable to prolong the working period after
the hemostatic sponge is applied to the patient and before clotting
is effected. The prolongation of the clotting reaction will be
ensured, if the sponge according to the invention further comprises
inhibitors of blood coagulation in appropriate amounts. Inhibitors,
such as antithrombin III optionally together with heparin, or any
other serine protease inhibitor, are preferred.
[0032] It is also preferred to have such additives, in particular
the thrombin or a precursor of thrombin evenly distributed in the
material in order to prevent local instability or
hypercoagulability of the material. Even with a certain water
content the thrombin activity is surprisingly stable, probably
because of the intimate contact of thrombin and collagen in the
homogeneous mixture. Nevertheless, thrombin stabilizers preferably
selected from the group consisting of a polyol, a polysaccharide, a
polyalkylene glycol, amino acids or mixtures thereof might be used
according to the invention. The exemplary use of sorbitol,
glycerol, polyethylene glycol, polypropylene glycol, mono- or
disaccharides such as glucose or saccharose or any sugar or
sulfonated amino acid capable of stabilizing thrombin activity is
preferred.
[0033] According to a further embodiment of the present invention
an adhesive layer is attached to the inventive sponge in order to
improve adherence of the sponge to a tissue or wound. Such adhesive
materials suitable for a sponge for use as a hemostat are e.g.
disclosed in the WO2008/016983 (incorporated herein by reference in
its entirety). Preferred adhesives mediate adjunctive hemostasis by
themselves, and can be suitable to mechanically seal areas of
leakage. Such adhesives are for example bioresorbable polymers, in
particular polymers that cross-link and solidify upon exposure to
body fluids. In further embodiments the adhesive is resorbable
and/or biocompatible and can be degraded by a subject, in
particular a human subject, in less than 6 months, less than 3
months, less than 1 month or less than 2 weeks.
[0034] "Adhesive" should be understood in the sense that it adheres
or binds to a biological tissue and may or may not bind to other
materials. A special adhesive layer may comprise a first
cross-linkable component, a second cross-linkable component that
cross-links with the first cross-linkable component under reaction
enabling conditions, wherein the first and second cross-linkable
component cross-link to form a porous matrix having interstices.
The adhesive layer may further comprise a hydrogel-forming
component, which is capable of being hydrated to form a hydrogel to
fill at least some of the interstices. Such an adhesive material is
disclosed in the WO 2008/016983 (incorporated herein by reference).
The first cross-linkable component can include multiple
nucleophilic groups and the second cross-linkable component can
include multiple electrophilic groups. Upon contact with a
biological fluid, or in other reaction enabling conditions, the
cross-linkable first and second components cross- link to form a
porous matrix having interstices. The hydrogel-forming component
can be e.g. a polymer, in particular a biopolymer including
polysaccharides or proteins. The hydrogel-forming component is
preferably selected from material as being capable of being
hydrated to form a biocompatible hydrogel that comprises gelatine
and will absorb water when delivered to a moist tissue target side.
Such a hydrogel forming component is e.g. the particulate material
of the sponge. In some aspects, the first cross-linkable component
of the adhesive includes a multi-nucleophilic polyalkylene oxide
having m nucleophilic groups, and the second cross-linkable
component includes a multi-electrophilic polyalkylene oxide. The
multi-nucleophilic polylkylene oxide can include two or more
nucleophilic groups, for example NH.sub.2, --SH, --H, --PH.sub.2,
and/or --CO--NH--NH.sub.2. In some cases, the multi-nucleophilic
polyalkylene oxide includes two or more primary amino groups. In
some cases, the multi-nucleophilic polyalkylene oxide includes two
or more thiol groups. The multi-nucleophilic polyalkylene oxide can
be polyethylene glycol or a derivative thereof. In some cases, the
polyethylene glycol includes two or more nucleophilic groups, which
may include a primary amino group and/or a thiol group. The
multi-electrophilic polyalkylene oxide can include two or more
electrophilic groups such as CO.sub.2N(COCH.sub.2).sub.2,
--CO.sub.2H, --CHO, --CHOCH.sub.2, --N.dbd.C.dbd.O,
--SO.sub.2CH.dbd.CH.sub.2, N(COCH).sub.2, and/or
--S--S--(C.sub.5H.sub.4N). The multi-electrophilic polyalkylene
oxide may include two or more succinimidyl groups. The
multi-electrophilic polyalkylene oxide may include two or more
maleimidyl groups. In some cases, the multi-electrophilic
polyalkylene oxide can be a polyethylene glycol or a derivative
thereof.
[0035] In special embodiments the first and/or second
cross-linkable component is/are synthetic polymers, preferably
comprising polyethyleneglycols (PEG) or derivatives thereof. The
polymer can be a derivative of PEG comprising active side groups
suitable for cross-linking and adherence to a tissue. Preferably,
the adhesive comprises succinimidyl, maleimidyl and/or thiol
groups. In a two polymer set-up, one polymer may have succinyl or
maleimidyl groups and a second polymer may have thiol groups which
can attach to the groups of the first polymer. These or additional
groups of the adhesive may facilitate the adherence to a
tissue.
[0036] The adhesive layer can be continuously or discontinuously
coated on at least one side of the sponge. However, to allow
contact of any body fluids at an injury with the main sponge
material, i.e. the fibrous biomaterial and the particulate material
it is preferred to place the adhesive layer onto the sponge in a
discontinuous manner, e.g. it is possible to place a grid or any
other mask onto the sponge and only fill the interstices with the
adhesive material and subsequently remove the grid, leaving
accessible areas to the collagen sponge matrix. Continuous coatings
can be preferable for administration in low bleeding
conditions.
[0037] In a further aspect of the invention it is also possible to
provide a supporting layer with greater tensile strength than the
matrix material on at least one side of the sponge. Preferably, the
supporting layer is on the opposite side from the adhesive layer.
When used, the supporting layer does not face the injury and may or
may not be an active hemostatic layer. In principle, it can be of
any material providing physical resistance to the sponge. It can be
selected from similar materials as the matrix material or the
particulate material. Nevertheless, it may be beneficial if the
supporting layer comprises a bioresorbable polymer, as with any
other layer, in particular if the complete sponge should be
bioresorbable.
[0038] The supporting layer may comprise collagen or gelatin, in
particular cross-linked gelatin or collagen. In order to improve
tensile strength and mechanical support of the sponge matrix it is
preferred that the supporting layer is of greater density than the
matrix material.
[0039] The present invention also provides a wound coverage
comprising a sponge according to the invention. The sponge and all
additional layers can be provided in a ready to use wound coverage
in suitable dimensions. The sponge and/or the coverage preferably
has a thickness of at least 1 mm or at least 3 mm or at least 5 mm
and/or up to 20 mm, depending on the indication. When the
relatively thick flexible sponge is applied to a wound it is
important that blood and fibrinogen can be absorbed throughout the
sponge before fibrin is formed that might act as a barrier for the
absorption of further wound secret.
[0040] Another aspect of the invention relates to a method of
manufacturing a hemostatic porous sponge comprising providing a
fluid of a fibrous biomaterial and suspended particles of a fluid
absorbing, particulate material, and drying said fluid with the
suspended particles, thereby obtaining a hemostatic porous sponge
comprising a matrix fibrous biomaterial and particles of a fluid
absorbing, particulate material adhered to said matrix material.
Drying may include freeze drying or air drying and comprises
removing volatile components of the fluid.
[0041] The pH of the fluid, in particular in the case of aqueous
solutions may be at least 6, up to 9. Preferred pH ranges are
neutral, preferably between 6 and 9 or between 7 and 8. Likewise,
it is preferred if the particulate material reacts pH neutral in
contact with an aqueous solvent.
[0042] One advantage of the inventive particles is that, after
being formed from pH neutral solutions, a sponge material will also
react in a pH neutral manner in contact with an aqueous solvent.
"pH neutral" is considered to increase, or alternatively also
decrease, the pH by not more than 1, preferably not more than 0.5
For such a test e.g. equal amounts (mass) of particles and water,
preferably without buffer substances, can be used.
[0043] In preferred embodiments the solvent is aqueous, i.e.
containing water, or pure water, i.e. no other liquid solvent is
present. Solvents may comprise water, alcohol, including methanol,
ethanol, propanol, butanol, isopropanol, ketones, such as acetone,
DMSO, etc. The solvent may or may not further comprise further
compounds such as additives, emulsifiers, detergents and wetting
agents. If such compounds are used, it is preferred that they are
water removable and do not form stable and remaining complexes with
the fibrous sponge matrix or the particulate material. The
additional compounds may be acidic, preferably neutral or
basic.
[0044] The preparation of the suspension and/or the fibrous
biomaterial (e.g. a collagen gel) can be carried out at room
temperature but also at lower (close to 0.degree. C.) or higher
temperatures (close to 40.degree. C.) and any temperature range in
between as well as even lower or higher temperatures. Thus, in
preferred embodiments any one of the method steps is performed
between 0.degree. C. and 40.degree. C. or between 15.degree. C. and
30.degree. C.
[0045] Any additional layer, e.g. the adhesive layer or the
supportive layer can be attached to the dried matrix. However it is
also possible to co-dry the additional layer and thus obtain a
composite sponge, e.g. if the supportive layer can be constituted
from a fluid or gel of a polymer, e.g. a fibrous biomaterial like
collagen similar to the matrix material. The matrix of the sponge
with the suspended particles can be placed onto said supportive
material fluid (or vice versa) and both fluids can be dried in one
step. If the concentration of the polymer in the fluid for the
supportive material is greater than for the fibrous matrix, usually
a layer with greater density may be obtained. Preferably, the
collagen fluid for the sponge matrix has a concentration of from
0.1% to 5% (w/w-%), preferably between 0.1% to 1%, most preferably
about 0.2%.
The concentration of the polymer, in particular collagen, for the
supportive layer may be e.g. of from 0.5% to 5% (w/w-%), preferably
0.5% to 2%, most preferred between 15 to 2%. In order to keep these
layers separate it is possible to first apply a first fluid into a
suitable container, freeze said fluid and apply a second fluid,
etc. Such a container can then be freeze-dried to obtain the solid
sponge.
[0046] In a further aspect the present invention provides a
hemostatic porous sponge obtainable by the method according to the
invention described above. All preferred embodiments mentioned
above for a hemostatic sponge can also be read to this obtainable
sponge.
[0047] The present invention also provides a method of treating an
injury comprising administering a hemostatic porous sponge
comprising a matrix of fibrous biomaterial and a fluid absorbing,
particulate material adhered to said matrix material to the site of
injury. This treatment is in particular suitable for fluid
containment. The treatment may comprise sealing the injury in order
to prevent further fluid leakage. The injury may comprise a wound,
a hemorrhage, damaged tissue, bleeding tissue and/or a leakage of
body fluids.
[0048] Also provided is a kit for preparing a wound coverage,
comprising a sponge as herein disclosed and pharmaceutically active
substances. This kit and its components are in particular for the
manufacture of a medical sponge for the treatment of an injury as
mentioned above.
[0049] The present invention is further exemplified by the
following examples without being limited thereto.
EXAMPLES
Example 1
Collagen Sponge Containing Cross-Linked Gelatin Particles
[0050] A homogeneous suspension containing 80 mg/ml of cross-linked
gelatin particles and 2.1 mg/ml of collagen is prepared by
stirring. This suspension is filled into a tray (layer thickness
3.5 mm) and freeze-dried. A collagen sponge containing entrapped
cross-linked gelatin particles is obtained.
Example 2
Collagen Sponge Containing Cross-Linked Gelatin Particles
Discontinuously Coated with an Adhesive Layer
[0051] A collagen sponge containing cross-linked gelatin particles
is prepared according to example 1. After freeze-drying a grid is
laid onto the obtained product. 14 mg/cm.sup.2 of a 1:1 (w/w)
powder mixture of two cross-linkable polyethyleneglycol polymers
(PEG-A and PEG-B) are applied over the grid onto the pad. Only the
holes of the grid are covered by the powder mixture. The powder is
fixed on the pad by short (2-5 min) heating at a temperature higher
than the melting point of the PEG components. The grid is removed
and a pad with a discontinuous reactive PEG-coating is obtained.
PEG-A is a PEG-succinimidyl powder, PEG-B is a PEG-thiol
powder.
Example 3
[0052] Hemostatic pad composed of the composition described in
example 2 enforced by an additional supporting collagen layer. A
3.5 mm thickness layer of a 10 mg/ml of collagen suspension is
filled into a tray and frozen at -20.degree. C. for 1 h. The frozen
collagen layer is coated by a 3.5 mm layer of the mixture described
in example 3. The two layers are subsequently freeze-dried and the
upper layer coated discontinuously with cross-linkable PEG
components as described in example 2. The obtained layered pad has
more mechanical robustness than the pads described in examples 1
and 2.
Example 4
Hemostasis with the Product Produced According to Example 1
[0053] A liver surface abrasion model for hemostasis on heparinized
(2.times. ACT) pigs is used in order to test the hemostatic
properties of the pads produced in example 1. With a flat, round,
rotating abrasion tool a circular bleeding wound is created on the
surface of heparinized pigs. A pad (3.times.3 cm) is applied dry
onto the bleeding wound and hold in place by slightly pressing with
saline wetted gauze for 2 min. After 2 min the bleeding is stopped.
Within the next 1 min no rebleeding is observed. Blood coagulation
within the pad is observed. After 3 min the pad is removed from the
site of application with the aid of a forceps. Only a slight
adherence to the site of application is observed.
Example 5
Hemostasis with the Product Produced According to Example 2
[0054] The pad described in example 2 is applied in the same animal
hemostasis model and in the same way as described in example 4,
with the discontinuous reactive PEG-coating facing the wound. 2 and
3 min after application no bleeding is observed. Blood enters the
pad by the non-coated areas and coagulates within the pad. It is
not possible to easily remove the pad 3 min after application from
the site of application without disrupting the hemostatic seal. The
adherence caused by the reactive PEG-coating is stronger than the
internal tensile strength of the pad.
Example 6
Hemostasis with the Product Produced According to Example 3
[0055] The pad described in example 3 is applied in the same animal
hemostasis model and in the same way as described in example 4,
with the discontinuous reactive PEG-coating facing the wound.
Hemostasis is obtained in the same way as described in example 5.
The additional collagen layer covers as a smooth sheet the
hemostatic collagen/cross-linked gelatin layer. Adherence to the
wound surface is similar as in example 5.
* * * * *