U.S. patent application number 12/228029 was filed with the patent office on 2009-03-05 for modified starch material of biocompatible hemostasis.
This patent application is currently assigned to Xin Ji. Invention is credited to Jianping Chen, Xin Ji, Xueshen Shi, Cheng Xing.
Application Number | 20090062233 12/228029 |
Document ID | / |
Family ID | 40408454 |
Filed Date | 2009-03-05 |
United States Patent
Application |
20090062233 |
Kind Code |
A1 |
Ji; Xin ; et al. |
March 5, 2009 |
Modified starch material of biocompatible hemostasis
Abstract
A modified starch material for biocompatible hemostasis,
biocompatible adhesion prevention, tissue healing promotion,
absorbable surgical wound sealing and tissue bonding, when applied
as a biocompatible modified starch to the tissue of animals. The
modified starch material produces hemostasis, reduces bleeding of
the wound, extravasation of blood and tissue exudation, preserves
the wound surface or the wound in relative wetness or dryness,
inhibits the growth of bacteria and inflammatory response,
minimizes tissue inflammation, and relieves patient pain. Any
excess modified starch not involved in hemostatic activity is
readily dissolved and rinsed away through saline irrigation during
operation. After treatment of surgical wounds, combat wounds,
trauma and emergency wounds, the modified starch hemostatic
material is rapidly absorbed by the body without the complications
associated with gauze and bandage removal.
Inventors: |
Ji; Xin; (Shanghai, CN)
; Xing; Cheng; (Shanghai, CN) ; Shi; Xueshen;
(Shanghai, CN) ; Chen; Jianping; (Shanghai,
CN) |
Correspondence
Address: |
DAVID AND RAYMOND PATENT FIRM
108 N. YNEZ AVE., SUITE 128
MONTEREY PARK
CA
91754
US
|
Assignee: |
Xin Ji
|
Family ID: |
40408454 |
Appl. No.: |
12/228029 |
Filed: |
August 8, 2008 |
Current U.S.
Class: |
514/60 |
Current CPC
Class: |
A61L 2300/406 20130101;
A61L 26/0085 20130101; Y10T 428/2982 20150115; A61L 24/08 20130101;
C08B 33/06 20130101; A61L 24/0036 20130101; A61K 45/06 20130101;
C08B 33/04 20130101; A61L 31/045 20130101; C08B 31/04 20130101;
C08B 31/02 20130101; C08B 35/06 20130101; A61K 9/0014 20130101;
A61K 31/738 20130101; A61L 31/042 20130101; C08L 3/04 20130101;
A61L 24/0015 20130101; C08B 31/18 20130101; A61K 9/14 20130101;
C08B 30/00 20130101; C08B 31/08 20130101; A61P 17/02 20180101; C08B
35/02 20130101; C08L 89/06 20130101; C08L 89/06 20130101; A61L
24/104 20130101; C08L 3/04 20130101; C08L 3/04 20130101; C08B 31/12
20130101; A61K 31/718 20130101; A61L 26/0023 20130101; A61L 31/125
20130101; A61L 24/0073 20130101; A61L 2400/04 20130101; A61K 9/19
20130101; C08B 31/003 20130101; C08B 31/10 20130101; C08B 35/04
20130101; C08L 3/18 20130101; C08L 3/18 20130101; A61L 24/08
20130101; C08B 31/00 20130101; C08B 33/02 20130101; A61L 26/0023
20130101; C08B 30/20 20130101; A61L 2430/34 20130101; C08B 31/16
20130101 |
Class at
Publication: |
514/60 |
International
Class: |
A61K 31/718 20060101
A61K031/718; A61P 17/02 20060101 A61P017/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 9, 2007 |
CN |
200710141944.0 |
Jan 14, 2008 |
CN |
200810032631.6 |
Claims
1. A method of treating a tissue of an animal, comprising a step of
applying a biocompatible modified starch to the tissue of the
animal, wherein the modified starch has a molecular weight 15,000
daltons or more and a grain diameter of 1 to 1000 .mu.m.
2. The method, as recited in claim 1, further comprising a step of
applying the biocompatible modified starch to a wound surface of
the tissue for hemostasis.
3. The method, as recited in claim 1, further comprising a step of
applying the biocompatible modified starch to a wound surface of
the tissue for adhesion prevention and promoting tissue
healing.
4. The method, as recited in claim 1, further comprising a step of
applying the biocompatible modified starch to a wound surface of
the tissue to prevent bleeding and fluid exudation from the
tissue.
5. The method, as recited in claim 2, further comprising a step of
degrading the biocompatible modified starch with amylase and
carbohydrase in the wound surface and transforming into
monosaccharides for absorption.
6. The method, as recited in claim 2, further comprising a step of
promoting bacteriostatic and anti-inflammatory effects on the wound
surface.
7. The method, as recited in claim 2, wherein the modified starch
has water absorbency capacity of 1 to 100 times.
8. The method, as recited in claim 1, wherein the animal is
selected from a group consisting of mammal, birds, and reptile.
9. The method, as recited in claim 1, wherein the tissue of the
animal is a tissue of skin surface or internal organs, wherein the
biocompatible modified starch is able to be used for hemostasis,
adhesion prevention, tissue healing promotion, wound sealing, and
wounded tissue bonding in surgical operation and trauma treatment
including surgical treatment under laryngoscope, endoscope, and
laparoscope.
10. The method, as recited in claim 2, wherein said modified starch
is a synthetic modified starch product made into hemostatic power
form, hemostatic spherical form, or hemostatic aerosol form.
11. The method, as recited in claim 1, further comprising a step
of: making the modified starch into a modified starch product by
particle agglomerating and pellet processing, wherein the modified
starch product is in form of hemostatic powder which has starch
grains with grain diameter of 10.about.1000 .mu.m containing at
least 95% starch grains with a diameter of 30.about.500 .mu.m in
total, to provide effects of hemostasis, adhesion prevention,
tissue healing promotion, sealing, adhesive plugging, and bonding
to a bleeding wound surface.
12. The method, as recited in claim 1, further comprising the steps
of: applying the modified starch to a bleeding wound surface;
degrading the modified starch with amylase and carbohydrase in the
bleeding wound surface, further transforming the modified starch
into monosaccharides in the body; allowing the modified starch to
be absorbed by the body; allowing the modified starch to promote
bacteriostatic and anti-inflammatory effect on the bleeding wound
surface; and allowing the modified starch to dissolve or suspend in
water after contacting with the water so as to irrigate the
remaining excess modified starch after hemostasis achieved.
13. The method, as recited in claim 11, wherein the tissue of the
animal is a tissue of skin surface or internal organs, wherein said
biocompatible modified starch is able to be used for hemostasis,
adhesion prevention, tissue healing promotion, wound sealing, and
wounded tissue bonding in surgical operation and trauma treatment
including the surgical treatment under laryngoscope, endoscope, and
laparoscope.
14. The method, as recited in claim 12, wherein the biocompatible
modified starch is hemostatic powder having hemostatic grains with
a grain diameter of 10.about.1000 .mu.m.
15. The method, as recited in claim 2, wherein the biocompatible
modified starch is a synthetic modified starch hemostatic product
made into hemostatic sponge, hemostatic foam, hemostatic film or
hemostatic plaster in form of columnar, sheet, massive, flocculent,
and membranous.
16. The method, as recited in claim 2, wherein the biocompatible
modified starch is a synthetic modified starch hemostatic product,
which is a hemostatic sponge, wherein the modified starch comprises
an etherified starch which comprises at least one of carboxymethyl
starch, hydroxyethyl starch and cationic starch.
17. The method, as recited in claim 2, wherein the biocompatible
modified starch is a synthetic modified starch hemostatic product,
which a hemostatic sponge, wherein the modified starch comprises a
cross-linked starch which comprises at least a cross-linked
carboxymethyl starch.
18. The method, as recited in claim 2, wherein the biocompatible
modified starch is a synthetic modified starch hemostatic product,
which is a hemostatic sponge, wherein the modified starch comprises
a composite modified starch which comprises at least a
pre-gelatinized hydroxypropyl distarch phosphate.
19. The method, as recited in claim 2, wherein the biocompatible
modified starch is a synthetic modified starch hemostatic product,
which is a hemostatic film, wherein the modified starch comprises
at least one of a carboxymethyl starch, a hydroxyethyl starch, a
cationic starch, a cross-linked carboxymethyl starch, a
pre-gelatinized hydroxypropyl distarch phosphate, and a grafting
starch.
20. The method, as recited in claim 1, wherein the biocompatible
modified starch is a modified starch hemostatic product produced by
the steps of: (a) dissolving or swelling the modified starch into
modified starch solution or suspension with liquid; and (b) making
the modified starch hemostatic product by vacuum freeze drying or
vacuum drying the modified starch solution or suspension; wherein
the modified starch hemostatic product is in form of hemostatic
sponge, hemostatic film, and hemostatic plaster and the bleeding
wound surface is a wound surface of skin surface or internal
organs, wherein the modified starch is able to be used for
hemostasis, adhesion prevention, tissue healing promotion, wound
sealing, and wounded tissue bonding in surgical operation and
trauma treatment including the surgical treatment under
laryngoscope, endoscope, and laparoscope.
21. The method, as recited in claim 20, wherein the modified starch
is mixed, diluted and vacuum freeze dried with at least a material
selected from the group consisting of biocompatible gelatin and
collagen to produce a composite modified starch hemostatic
material.
22. The method, as recited in claim 20, wherein the modified starch
is mixed, diluted and vacuum freeze dried with at least a material
selected from the group consisting of blood coagulation factor,
fibrin, calcium agent, protamine, polypeptide, peptide, and amino
acid to produce a modified starch hemostatic material that contains
coagulant.
23. The method, as recited in claim 20, wherein said modified
starch hemostatic product is made by a process comprising the steps
of mixing, diluting and vacuum freeze drying a modified starch with
at least a material selected from the group consisting of glycerol,
kaolin, sorbitol, ethanol, ammonia, and polyethylene glycol to
produce a modified starch hemostatic material that contains
plasticizing agent.
24. The method, as recited in claim 20, wherein the modified starch
is mixed, diluted and vacuum freeze dried with at least a material
selected from the group consisting of biocompatible oxidized
cellulose, carboxymethyl cellulose, chitosan, hyaluronic acid, and
sodium alginate to produce a composite modified starch hemostatic
material.
25. A method of producing a biocompatible modified starch,
comprising steps of: (a) modifying a biocompatible starch; and (b)
producing a modified starch, wherein the modified starch has a
molecular weight 15,000 daltons or more and a grain diameter of
1.about.1000 .mu.m.
26. The method, as recited in claim 25, wherein the modified starch
provides effects of hemostasis, preventing postoperative adhesions,
promoting tissue healing, sealing blood vessels, sealing wounds,
and adhering wounds to a bleeding wound surface, and a
bacteriostatic and anti-inflammatory effect to the bleeding wound
surface, wherein the bleeding wound surface is a tissue of skin
surface or internal organs, wherein the modified starch is able to
be used for hemostasis, adhesion prevention, tissue healing
promotion, wound sealing, and wounded tissue bonding in surgical
operations and trauma treatments including the surgical treatment
via laryngoscope, endoscope, and laparoscope.
27. The method, as recited in claim 25, wherein the molecular
weight of the modified starch is 15,000.about.2,000,000
daltons,
28. The method, as recited in claim 25, wherein the modified starch
has a water absorbency of 1.about.500 times its particle
weight.
29. The method, as recited in claim 25, wherein the modified starch
is a modified starch containing hydrophilic group.
30. The method, as recited in claim 25, wherein the modified starch
dissolves or swells in water and forms adhesive gel or adhesive
liquid.
31. The method, as recited in claim 27, wherein the modifying
process of the biocompatible starch is selected from a group
consisting of physical modifying process, chemical modifying
process, enzymatical modifying process, and natural modifying
process.
32. The method, as recited in claim 31, wherein the physical
modifying process includes irradiating, mechanical and damp-heat
treatments.
33. The method, as recited in claim 31, wherein the chemical
modifying process includes at least a chemical modifying treatment
with a chemical reagent, which comprises a process selected from a
group consisting of acidolysis, oxidation, esterification,
etherification, cross-linking, and grafting modifying
treatments.
34. The method, as recited in claim 27, wherein the modified starch
comprises at least one of a pre-gelatinized starch, an acid
modified starch, a dextrin, an oxidized starch, an esterified
starch, an etherified starch, a grafting starch, a cross-linked
starch, and a composite modified starch.
35. The method, as recited in claim 34, wherein a preparation
process of the pre-gelatinized starch is modified by a dry process,
including extrusion process and roller drying process.
36. The method, as recited in claim 34, wherein a preparation
process of the pre-gelatinized starch is modified by a wet process,
including spray drying process.
37. The method, as recited in claim 34, wherein the etherified
starch comprises at least one of a carboxymethyl starch, a
hydroxyethyl starch, and a cationic starch.
38. The method, as recited in claim 34, wherein the esterified
starch comprises a hydroxypropyl distarch phosphate.
39. The method, as recited in claim 34, wherein the cross-linked
starch comprises at least a cross-linked carboxymethyl starch.
40. The method, as recited in claim 34, wherein the grafting starch
comprises at least a crylic acid-carboxymethyl starch grafting
copolymer and a propylene ester-carboxymethyl starch grafting
copolymer, wherein the grafting starch has a molecular weight of
50,000.about.2,000,000 daltons.
41. The method, as recited in claim 34, wherein the esterified
starch comprises at least a hydroxypropyl distarch phosphate,
wherein the cross-linked starch comprises at least a cross-linked
carboxymethyl starch, wherein the grafting starch comprises at
least a crylic acid-carboxymethyl starch grafting copolymer and a
propylene ester-carboxymethyl starch grafting copolymer, wherein
the modified starch has a volume of water absorbency not lower than
1 time its own particle weight.
42. The method, as recited in claim 34, wherein the modified starch
has a volume of water absorbency not lower than 1 time its own
particles weight.
43. The method, as recited in claim 41, wherein the modified starch
has a water absorbency of 2.about.500 times its own particle
weight.
44. The method, as recited in claim 33, wherein the step (a)
comprises a step of making a pre-gelatinized hydroxypropyl distarch
phosphate into a composite modified starch hemostatic material.
45. The method, as recited in claim 42, wherein the step (a)
comprises a step of making a pre-gelatinized hydroxypropyl distarch
phosphate into a composite modified starch hemostatic material,
wherein the modified starch has a water absorbency of 2.about.50
times its particle weight.
46. The method, as recited in claim 33, wherein the step (a)
comprises a step of grafting a carboxymethyl starch with a crylic
acid and a propylene ester to make grafting starch hemostatic
materials of crylic acid-carboxymethyl starch grafting copolymer
and propylene ester-carboxymethyl starch grafting copolymer.
47. The method, as recited in claim 42, wherein the step (a)
comprises a step of grafting a carboxymethyl starch with a crylic
acid and a propylene ester to make a grafting starch hemostatic
materials of crylic acid-carboxymethyl starch grafting copolymer
and propylene ester-carboxymethyl starch grafting copolymer,
wherein the modified starch has a water absorbency of 20.about.500
times its particle weight.
48. A preparation method of a biocompatible modified starch for
treating a tissue of an animal as claimed in claim 1, wherein the
method comprises the steps of: (a) adding a starch material into a
boiler under 40.about.50.degree. C.; and (b) adding a distilled
water, and making a finished product of modified starch material by
agglomeration and pelletion; wherein the modified starch material
has a molecular weight of 15,000 daltons or more, and a grain
diameter of 1.about.1000 .mu.m containing at least 95% starch
grains with a diameter of 30.about.500 .mu.m in total; wherein the
modified starch provides the effects of hemostasis, preventing
adhesion, promoting tissue healing, sealing, plugging, and adhering
to a bleeding wound surface, and a bacteriostatic and
anti-inflammatory effect to the bleeding wound surface, wherein the
bleeding wound surface is a wound surface of skin surface or
internal organs, wherein the modified starch is able to be used for
hemostasis, adhesion prevention, tissue healing promotion, wound
sealing, and wounded tissue bonding in surgical operation and
trauma treatment including the surgical treatment under
laryngoscope, endoscope, and laparoscope.
49. The method, as recited in claim 48, wherein the biocompatible
starch material is a carboxymethyl starch material, a finished
product of the modified starch material is a carboxymethyl starch
(66#) whose suspension of 6.67% has a viscosity not lower than 30
mPas under 37.degree. C., and an adhesion Work Index of the
modified starch at maximum water absorption under room temperature
exceeds 40 gsec (100% saturation).
50. The method, as recited in claim 48, wherein the starch material
is a hydroxyethyl starch material, a finished product of the
modified starch material is hydroxyethyl starch material (88#), and
adhesion Work Index of the modified starch at maximum water
absorption under room temperature exceeds 60 gsec (100%
saturation).
51. The method, as recited in claim 48, wherein the starch material
is a cross-linked carboxymethyl starch material, a finished product
of the modified starch material is cross-linked carboxymethyl
starch whose suspension of 6.67% has viscosity not lower than 30
mPas under 37.degree. C., and adhesion work index of the modified
starch at maximum water absorption under room temperature exceeds
40 gsec (100% saturation).
52. A preparation method of a modified starch for treating a tissue
of an animal as claimed in claim 1, comprising the steps of: a)
providing a biocompatible modified starch material having a
molecular weight of 15,000 daltons or more and a grain diameter of
1.about.1000 .mu.m; b) adding water, agitating, and inducing
sufficient swelling of the starch grains and dispersing them into
water to form uniform emulsion; c) freeze for 22 hours under
-40.degree. C.; d) placing into a refrigerant drying apparatus,
freeze drying for 20 hours under -40.about.-50.degree. C. and
vacuum less than 20 Pa; and e) obtaining a modified starch
hemostatic sponge/foam; wherein the modified starch provides
effects of hemostasis, preventing adhesion, promoting tissue
healing, sealing, adhesive plugging, and adhering, to a bleeding
wound surface, and a bacteriostatic and anti-inflammatory effect to
the bleeding wound surface.
53. The method, as recited in claim 52, further comprising the
steps of adding a forming agent into the modified starch material
of the step (a), mixing uniformly, and obtaining a modified starch
sponge/foam containing the forming agent, which is applied to the
bleeding wound surface of skin surface or internal organs, wherein
the modified starch provides the effects of hemostasis, adhesion
prevention, tissue healing promotion, wound sealing and wounded
tissue bonding, wherein the forming agent comprises at least a
material selected from a group of gelatin, collagen, oxidized
cellulose, carboxymethyl cellulose, chitosan, hyaluronic acid,
sodium alginate, glycerol, kaolin, sorbitol, ethanol, ammonia, and
polyethylene glycol.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention relates to a modified starch material
of biocompatible hemostasis, biocompatible adhesion prevention,
tissue healing promotion, absorbable surgical sealing and tissue
bonding, and more particularly to a modified starch material, which
is absorbable by human beings and animals, and applied directly to
wound surface of humans and mammals, including wound surface with
blood or extravasate, to stanch blood, prevent adhesion, promote
tissue healing, seal section of wound tissue, prevent bleeding and
exudation of tissue fluid, bond tissue and organ wounded by trauma
or operation, help repairing tissue, and avoid or reduce surgical
suture.
[0003] 2. Description of Related Arts
[0004] Surgical operations and trauma may create bleeding wounds,
which can produce a risk of excess blood loss. Therefore, hemostats
to control bleeding should be applied in a timely manner. It is a
common to apply biocompatible, absorbable hemostatic agents to
bleeding wound sites to achieve hemostasis (cessation of bleeding)
in surgical procedures, trauma treatment and home self rescue.
There is clinical benefit to provide patients a hemostatic agent
which is safe, efficacious, easy to use, and cost effective.
[0005] Prior absorbable hemostats consist of the following classes
of materials:
[0006] Hemostatic sponge class: gelatin sponge, collagen sponge,
chitosan sponge, carboxymethyl cellulose sponge, thrombin and
fibrin sponges;
[0007] Hemostatic gauze/hemostatic film class: oxidized cellulose
gauze, oxidized regenerated cellulose gauze, oxidized cellulose
gauze with carboxymethyl cellulose;
[0008] Hemostatic glue class: fibrin glue, synthetic glue;
[0009] Polysaccharide hemostatic powder class: microporous
polysaccharide powder, chitosan powder, algae powder.
[0010] A detailed analysis of absorbable hemostats in common use is
stated below:
[0011] 1. Absorbable Gelatin Sponges and Collagen Sponges:
[0012] The gelatin sponge is extracted from animal tissue, and the
main component of the gelatin sponge is animal collagen. The
gelatin sponge has a hydrophilic and multi-porous structure to
concentrate blood components by absorbing water in the blood to
arrest bleeding. However, gelatin is a collagen-based material from
animal extract and contains heterogenetic protein which may cause
anaphylaxis, resulting in feverish symptoms in patients. Further,
the human body absorbs the gelatin material very slowly, and on
average requires more than four weeks to fully dissolve. Foreign
agents with slow absorption times can be sites for infection,
tissue inflammation, and wound healing retardation.
[0013] Collagen sponges, which are also extracted from animal
tissue, promote blood coagulation by activating the endogenous
coagulation cascade while also concentrating blood components by
absorbing water in the blood.
[0014] Like the gelatin sponges, collagen sponges are also sourced
from animal collagen and contain heterogenetic protein, which is
slow to absorb in the human body. The collagen sponge may produce
complications of anaphylaxis, slow healing and infections. Due to
these clinical risks, applications of collagen sponges may be
limited in the future.
[0015] 2. Oxidized Cellulose Hemostatic Gauze and Oxidized
Regenerated Cellulose Hemostatic Gauze:
[0016] Oxidized cellulose is a cellulose derivative. The hemostatic
mechanism of oxidized cellulose is the concentration of blood
components through the hygroscopic activity of oxidized cellulose,
which stimulates blood coagulation as the carboxyl material
combines with haemoglobin Fe to produce acidic hematin in the
blood. The resulting brown gel seals capillary vessels and promotes
hemostasis. Oxidized regenerated cellulose has the same mode of
action as oxidized cellulose.
[0017] Oxidized cellulose is synthetic. Normal human tissue
degrades oxidized cellulose slowly by metabolizing enzymes. This
process generally require 3-6 weeks depending on the dosage and the
tissue location in the body. Oxidized cellulose may cause local
infection and adversely affect local tissue healing. Patent
application, China publication number CN1533751A, discloses a
hemostatic wound dressing with a trade name of SURGICEL. SURGICEL
includes a cellulose fabric and a multi-porous polymer substrate on
the fabric surface which contacts the wound. The substrate contains
biocompatible, water-soluble polymers. The fabric fibers are
oxidized regenerated cellulose and the biocompatible, water-soluble
polymers are polysaccharides. This hemostatic wound dressing
consists primarily of oxidized cellulose, a slowly absorbing
material in the human body.
[0018] 3. Fibrin Glues:
[0019] Fibrin glues consist of fibrinogen, thrombin, aprotinin and
calcium chloride. The hemostatic action relies mainly on the
activation of fibrinogen by the thrombin to promote coagulation
cascade. Fibrin sealants are a mixture of fibrinogen and thrombin
and have been widely used in recent years. The thrombin and fibrin
in fibrin glues are sourced from either animal or human blood
components and therefore create the risk of anaphylaxis and viral
infections such as hepatitis, AIDS, and BSE. Fibrin glues
demonstrate weak adhesion when applied to wet, bleeding tissue and
may be ineffective in the presence of active bleeding. Further,
fibrin glues require special mixing, timing and storage
condition.
[0020] 4. Natural Biological Polysaccharide Products:
[0021] In recent years, natural, biological polysaccharide-based
products have focused much attention. The natural biological
polysaccharide products are derived from plant material and
chitosans and usually presented in powder form. These products have
good biocompatibility, no toxicity, no tissue irritation, and no
risk of anaphylaxis or viral infection from animal or human
components contained in other hemostats.
[0022] Chitosan/Chitin Products:
[0023] Chitosan products are typically available in high swelling
and non-absorbable sponges. Chitosan is made from the crushed
shells of crustaceans. Chitosan has rapid hydrophilic capability
and can activate the blood coagulation mechanism through its strong
ionic charge. However, due to a lack of human enzymes to degrade
chitosan, chitosan-derived products will be confined to topical
applications. There is no evidence that chitosan products have been
used in clinic as absorbable surgical hemostats.
[0024] Microporous Polysaccharide Hemospheres (MPH):
[0025] In 2002, MEDAFOR, INC. in the USA developed an absorbable
hemostatic material called Arista.TM. (U.S. Pat. No. 6,060,461),
which consists of microporous polysaccharid particles (MPH). The
microporous polysaccharide particles are made through the reaction
of purified starch and epichlorohydrin, wherein the epichlorohydrin
reacts with starch molecules. This reaction results in the
formation of ethyl propanetriol which creates a glucose molecule
crosslink to the 3D network structure.
[0026] There are a few disadvantages of the MPH hemostatic powder.
Firstly, the delivery of MPH mainly focuses on local,
easy-to-access wound sites but presents some difficulties for
effective applications for deep, tortuous wounds, in particular the
endoscopic procedures (such as minimally invasive surgery via
endoscope and laparoscope). Secondly, during the production
process, epichlorohydrin, a colourless, oily and toxic chemical, is
employed to produce a required reaction. This production process is
not environment friendly. The cost of production is relatively
expensive. Thirdly, the hemostatic efficacy of MPH is not
satisfactory in particular for profuse bleeding due to its low
hydrophilic capacity and slow water absorption characteristic.
Fourthly, the adhesiveness of the MPH to tissue is low following
contacting with blood. The low viscosity, low adhesiveness of MPH
following water absorption may reduce the hemostatic efficacy of
MPH due to its weak sealing capability to wounded tissues and
broken vessels. Fifthly, in the presence of active bleeding, the
MPH powder can be easily washed away by blood flow if not
compressed with a gauze on the top of powder. This gauze
compression requirement adds an additional step in the hemostatic
powder application technique and may risk re-bleeding when the
gauze is removed. Therefore, MPH may have an unsatisfactory
hemostatic efficacy for active bleeding.
SUMMARY OF THE INVENTION
[0027] An object of the present invention is to provide a
biocompatible, modified starch composition and new uses of the
modified starch in humans and/or animals as a topical and surgical
hemostat. Hemostasis occurs immediately and effectively when the
said hemostat contacts blood on wound sites.
[0028] Another object of the present invention is to provide a
modified starch composition as an agent for anti-adhesion therapy,
for promoting tissue healing, for sealing wounds and bleeding
vessels, for adhesive sealing and tissue bonding, and for promoting
bacteriostatic and anti-inflammatory effects on bleeding wound
sites. In addition to its hemostatic performance, the application
of the invention will support anti-adhesions, tissue healing,
surgical sealing and tissue bonding and reinforcement when the
bleeding wound is on the skin surface or in the internal organs and
whether the application is in an open surgical operation, trauma
treatment, or delivered under laryngoscope, endoscope, and
laparoscope.
[0029] Another object of the present invention is to provide
methods of producing the modified starch hemostatic composition and
the technological formula to manufacture the modified starch in the
following formats: powder, sponge, foam, gel, film and others.
These formats do fulfill dynamic surgical hemostatic requirements,
and are easy to use.
[0030] Another object of the present invention is to provide the
methods, process and techniques to modify the starch composition to
satisfy important physical and chemical properties and
characteristics, technical parameters and technical indices
required for a hemostat, surgical sealant, an agent for
anti-adhesion, tissue healing, tissue adhesive sealing and tissue
bonding. The modified starch hemostatic composition is absorbed by
humans and animals, is safe and effective, and can be degraded
rapidly.
[0031] In addition, the modified starch in the present invention
can be used as a biocompatible, an anti-adhesion material, a tissue
healing agent, a surgical sealant, and a tissue
bonding/reinforcement substance for tissue repair.
[0032] The technical formulas in the present invention fulfill the
foregoing performance requirements with modified starch
applications as a biocompatible hemostatic material with mechanisms
that include dissolving or swelling in water and the subsequent
formation of adhesive glue or adhesive gel.
[0033] The mechanism further includes a modified starch acquisition
of hydrophilic groups in its molecular chains through the
modification process.
[0034] When the hydrophilic and enhanced adhesive modified starch
according to the present invention is applied to bleeding wound
sites, it rapidly absorbs water in the blood and concentrates blood
components. Meanwhile, this interaction creates an adhesive matrix
formed with the blood and plasma which adheres to the bleeding
wound, mechanically seals the broken blood vessels and stops
bleeding.
[0035] The modified starch material according to the present
invention includes starch modified physically, chemically,
naturally, or enzymatically, and starch modified repeatedly with at
least one of the above methods or a combination of two or more of
the above methods.
[0036] The physical modifying process according to the present
invention comprises irradiation, mechanical, and steam
treatment.
[0037] Physically modified starch, for example, a pre-gelatinized
starch treated solely with spray drying or irradiation process, is
remarkably safe as a bio-absorbable, hemostatic material since it
is not treated with any chemical agents.
[0038] The starch can be pre-gelatinized by the following physical
modifying processes: a) dry-process, such as an extrusion process
and a roller process; b) wet-process, such as a spray drying
process.
[0039] Specifically, after heating the raw starch with a measured
amount of water, starch granules swell to a pasty substance,
regularly arranged micelle of starch are broken, crystallites
disappear, and the resulting composition is easily degraded under
the process of amylase. The pre-gelatinized starch is able to swell
and/or dissolve in cold or room temperature water and form an
adhesive paste whose retrogradation is lower than that of raw
starch, affording easier handling during the production
process.
[0040] Raw starch can be pre-gelatinized through solely a physical
modification process without adding any chemical agents and becomes
a hemostatic material with enhanced hydrophilic and adhesive
properties.
[0041] The pre-gelatinized starch of the present invention is safe,
non-toxic, and has no adverse side effects. The pre-gelatinized
starch is readily degraded and metabolized by enzymes in the body.
The pre-gelatinized material of the present invention is safe and
biocompatible.
[0042] The chemical modifying according to the present invention
includes acidolysis, oxidation, esterification, etherification,
cross-linking, chemical agent grafting, or multiple modifying
processes including at least two of the above processes, or one of
the above modifying processes performed at least twice.
[0043] In the present invention, by adding the functional group on
the raw starch glucose units with chemical agents, e.g. by
carboxylation modification, or hydroxylation modification, the
starch captures hydrophilic groups in its molecular structure and
obtains hydrophilic properties. By using bifunctional or
polyfunctional chemical agents to cross-link the raw starch
macromolecules or grafting external macromolecular hydrophilic
groups to the raw starch, the starch acquires enhanced hydrophilic
properties and viscosity/adhesiveness in a water solution. The
viscosity of modified starch relates to the raw starch origin and
the degree of substitution of external and cross-linked or grafted
functional groups, etc. When contacting blood, the hydrophilic and
adhesive properties of the modified starch of the present invention
produce a "starch-blood coagulation matrix" with strong adhesive
characteristics which can seal wounded tissue and stop bleeding. In
addition, the interaction between the formed blood coagulation
matrix and the functional groups of tissue proteins causes the
"starch-blood coagulation matrix" to adhere to and seal the wounded
tissue, resulting in hemostasis.
[0044] Specifically, the described modified starch contains one or
more groups of pre-gelatinized starch, acid modified starch,
dextrin, oxidized starch, esterified starch, etherified starch, and
cross-linked starch.
[0045] The described hemostatic composition comprises two or more
modified starches to satisfy the physical and chemical properties
of a hemostatic agent, where the weight ratio of the two modified
starch groups can be 99:1.about.1:99.
[0046] Specifically, the weight ratio of the two modified starch
groups can be: 95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35,
60:40, 55:45, or 50:50.
[0047] The main physical parameters of the modified starch,
according to the present invention, are provided below:
[0048] The modified starch of the present invention has a molecular
weight over 15,000 daltons (for instance, 15,000.about.2,000,000
daltons).
[0049] The modified starch of the present invention has a water
absorbency capacity not lower than one time its weight (i.e. 1 gram
of described modified starch can absorb 1 gram or more of water);
whereas it can be 1.about.500 times generally and 2.about.100 times
preferably.
[0050] The modified starch composition of the present invention
includes, but not limited to, at least one carboxymethyl starch,
hydroxyethyl starch, and cationic starch.
[0051] For example, the carboxymethyl starch is a polymer of linear
structure as expressed in the following formula:
##STR00001##
[0052] Modified starches such as carboxymethyl starch (CMS) and
hydroxyethyl starch are known clinically as plasma substitutes.
These modified starches exhibit biocompatibility and safety with no
toxic side effects when employed in the human circulatory system.
The hemostatic composition, according to the present invention, can
further include other plasma substitutes by means of well-known
pharmacokinetics approaches and specified physical/chemical
properties to produce safe and reliable hemostatic agents.
[0053] When cationic starch of the modified starches is selected as
a hemostatic material, the surface positive charge of the cationic
starch attracts and interacts with electronegative blood
erythrocytes, accelerating the blood coagulation process.
Furthermore, when contacting blood, the positively charged modified
starch adheres tightly to tissue, seals the wound, and rapidly
stops bleeding. The cationic starch can be used independently as a
hemostatic material or mixed with other modified starches as a
composite hemostatic material.
[0054] Composite modified starch comprises, but is not limited to,
at least pre-gelatinized hydroxypropyl distarch phosphate.
Specifically, the hydroxypropyl distarch phosphate is produced by
cross-linking and etherifying the starch with propylene oxide and
phosphoric acid, followed by pre-gelatinization modification
through a spray drying process. The hydroxypropyl distarch
phosphate of the present invention has high adhesiveness, strong
water absorbency and robust hemostatic effects. It is stable in
acidic or alkali environments and can be used as a biocompatible,
hemostatic material, a surgical sealant, a tissue healing
composition, an anti-adhesion agent, and a tissue repair
material.
[0055] The cross-linked starch of the present invention includes,
but is not limited to, at least one of epichlorohydrin cross-linked
starch and cross-linked carboxymethyl starch.
[0056] The grafted starches of the present invention includes at
least a propylene ester-carboxymethyl starch grafted copolymer and
a crylic acid-carboxymethyl starch grafted copolymer. Grafted
starch has both enhanced water absorption capability and high
viscosity/adhesiveness. Therefore, it has a profound effect on
hemostasis when applied to wound surfaces, especially combat
wounds, traumatic wounds, and profuse bleeding from large arteries
and large veins due to aneurysms or large phlebangioma
ruptures.
[0057] The modified starch, according to the present invention, can
be made in powder form, spherical form or aerosol form to be
delivered directly to the bleeding wound surface.
[0058] As to the wound surface of large burn areas, adopting
inhalator or aerosol can stanch blood at the wound surface, reduce
tissue fluid exudation, and keep the wound surface moist to aid
tissue healing.
[0059] In addition, the hemostatic material of the present
invention can be made into hemostatic sponge, foam, film, and
plaster, which can be applied to a bleeding wound site to stanch
blood directly, wherein the hemostatic sponge, foam, the hemostatic
film, and the hemostatic plaster can be made into a film or an
attaching layer to the inside or surface of a fiber fabric, such as
a bandage, band-aid; etc. Such hemostatic sponge, foam, hemostatic
film, and hemostatic plaster can be columnar, sheet, massive,
flocculent, or membranous.
[0060] The modified starch hemostatic foam of the present invention
is easy to apply to active bleeding sites and achieves an optimal
hemostatic outcome. The hemostatic foam of the present invention
can be made from one or more varieties of modified starch processed
by vacuum freeze drying. The hemostatic foam of the present
invention can be a composite hemostatic foam made from one or more
varieties of modified starches and other biocompatible hemostatic
materials processed by vacuum freeze drying or other drying
processes.
[0061] Wherein, according to the present invention, other
biocompatible hemostatic materials other than the modified starches
can comprise one or more of the groups of gelatin, collagen,
carboxymethyl cellulose, oxidized cellulose, oxidized regenerated
cellulose, and chitosan.
[0062] In order to solve the challenge of molding modified starch
into sponges and foam, the present invention combines other known
bioabsorbable hemostatic materials with strong biocompatibility and
clinically acceptable qualities with the modified starch of the
present invention to produce composite hemostatic sponges and
foams. Whereas other known bioabsorbable hemostatic materials can
be of one or more components, the modified starches can also be of
one or more components, such as modified starch+gelatin, modified
starch+collagen, modified starch+thrombin, modified
starch+chitosan, modified starch+carboxymethyl cellulose, and
modified starch+hyaluronic acid. These combinations can be molded
into sponge and foam forms to satisfy clinical requirements.
[0063] Weight proportions between the biocompatible modified starch
and other biocompatible hemostatic materials can be
99.9:0.1.about.1:99.
[0064] Specifically, the weight ratio between the modified starch
and other biocompatible hemostatic materials preferably is: 95:5,
90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, 50:50,
45:55, 40:60, 35:65, 30:70, 25:75, or 20:80.
[0065] This additional coagulant material may be added to the
described modified starch hemostatic sponge or foam directly during
the vacuum freeze drying production process to produce a composite
hemostatic sponge or composite hemostatic foam. The production
process may involve, but is not limited to, pre-mixing the
coagulant material with the modified starch directly before vacuum
freeze drying process.
[0066] Accordingly, the coagulant of the present invention
comprises one or more combinations of the following group of blood
coagulation factors: thrombin, fibrin, calcium agent, polypeptide,
peptide, amino acid, and protamine.
[0067] The modified starch sponge and foam of the present invention
can be manufactured into hemostatic sponges and foam formed by a
vacuum freeze drying process utilizing a forming agent or a
plasticizing agent.
[0068] Whereas the forming agents of the present invention
comprises, but not limited to, organic forming agents, inorganic
forming agents, natural forming agents, and man-made plasticizing
agents, which may include, but not limited to, one or more
combinations of glycerol, kaolin, sorbitol, ethanol, ammonia, and
polyethylene glycol.
[0069] Specifically, the vacuum freeze drying process is a drying
method that freezes wet material or solutions to a solid state
under low temperatures (-10.about.-50.degree. C.) and then converts
the solid material into a gas and then, in a vacuum (1.3-1.5 Pa),
back to a solid material without an intermediate liquid phase
(sublimination). As the vacuum freeze drying is processed under low
temperature and low pressure, the moisture sublimes directly to
produce a substance with numerous special properties. The basic
parameters of the vacuum freeze drying process specify both
physical parameters and process parameters. The physical parameters
include thermal conductivity, transfer coefficient, etc. The
process parameters include freezing, heating, state of the
material, etc. Continued research on this freezing process involves
experiments to identify the optimal freezing curve. As the
described biocompatible, modified starch hemostatic material can be
made into a hemostatic glue, the physical form can be colloidal,
dissolved colloidal, thawed colloidal, semi-liquid or gelatinous,
etc. The hemostatic glue can be produced by adding other liquids,
not limited to water, to the modified starch by diluting, swelling,
or dissolving the liquids in certain proportions.
[0070] According to the present invention, the topical application
of modified starch can be used as a hemostatic agent to manage and
control bleeding wound surfaces in humans, mammals, birds, or
reptiles, and the internal application for hemostasis of bleeding
wound surfaces within human bodies, tissues and organs following
surgical operations and trauma treatments, under open surgery or
nasoscope, laryngoscope, endoscope and laparoscope.
[0071] The modified starch hemostatic composition, according to the
present invention, can be applied for hemostasis on bleeding bone
tissue caused by surgery or trauma, particularly for hemostasis in
spongy bone tissue. In thoracic or neurological operations
involving some patients, such as children, elderly people, and
patients with osteoporosis, sternal bleeding and skull bleeding is
difficult to control. It is common to apply bonewax to the sternum
or skull, however, bonewax is slow to absorb and may cause
complications such as non-union or infection. The modified starch
composition, according to the present invention, is a biocompatible
substitute for bonewax to control bone bleeding and mechanically
seal the wound caused by surgery or trauma with its robust
hydrophilic properties, strong adhesiveness and ease of molding.
The modified starch hemostatic material degrades rapidly after
surgery and avoids the complicating issues of non-union and
infection associated with bonewax. When the modified starch is
applied as a hemostatic material, other biological benefits of the
described modified starch are worthy of attention. It is essential
to evaluate the described modified starch composition as having
further positive effects on wound inflammation, tissue adhesion and
tissue healing while acting as a hemostat.
[0072] It is proven that the modified starch hemostatic material,
according to the present invention, has further application as an
absorbable, postoperative tissue adhesion barrier. The adhesion
barrier of the modified starch, according to the present invention,
prevents wounded tissue or organs from adhering to other tissue or
organs in the vicinity, thereby reducing local bleeding and
exudation, by mechanically isolating the wound or wound surface
from adjacent tissue and surrounding organs, such as the
peritoneum.
[0073] The modified starch, according to the present invention, can
promote tissue healing, including skin, subcutaneous soft tissue,
musculature, bone tissue, neurological tissue, nerve tissue, and
wounded tissue of the liver, kidney, spleen, etc., through proper
dosage and application. The modified starch can be a "scaffold" for
skin tissue cells to promote healing and the growth of skin tissue
from large wound surfaces due to burns, a "scaffold" for osteocyte
growth and propagation in bone defects from trauma, bone tumor
resection, etc., and a "scaffold" for neurological tissue cell
growth and propagation when applied to injured neurological tissue
caused by brain trauma, brain tumor resection, etc. The modified
starch, according to the present invention, has further
applications as a biocompatible surgical sealant, capable of
forming a protective layer of colloid or film on the wound surface
to seal and prevent drainage of blood, tissue fluids, lymph fluid,
cerebrospinal fluid, bile, gastric fluid, and other intestinal
fluids resulting from surgery and trauma treatment. This sealing
effect will prevent lymph fistula leakage, bile flaccidity, pleural
flaccidity, intestinal flaccidity, cerebrospinal flaccidity, and
vascular flaccidity.
[0074] The modified starch, according to the present invention, has
further application as a biocompatible tissue adhesive, capable of
adhering, repairing, and bonding wounded nerve tissue, musculature,
and tissues of the bone, skin, viscera, and subcutaneous tissue. It
can also bond other curative materials to wounded tissue and organs
for tissue repair.
[0075] In addition to the above advantages, the modified starch of
the present invention has a bacteriostatic and anti-inflammatory
effect on bleeding wound surfaces. The modified starch hemostatic
material, according to the present invention, has a hemostatic
effect which controls bleeding, reduces blood and tissue fluid
exudation, and maintains a moist wound surface. As a result, it
suppresses the growth of bacteria and reduces the inflammatory
response, diminishing local irritation and relieving pain.
Furthermore, to strengthen the anti-inflammatory response, known
antibiotic or other anti-pyrotic agents can be added to the
modified starch during the manufacturing process to produce
hemostatic powder, sponges and foams, hemostatic glues and gels,
etc., all of which are suitable for topical and internal clinical
applications.
[0076] Another advantage of the modified starch hemostatic material
of the present invention is the rapid particle dissolution in
water, facilitating the easy removal of excess modified starch
particles from the wound by simple saline irrigation. The residual
modified starch not actively involved in hemostasis can be rinsed
away by irrigation. In the treatment of battle wounds, self rescue,
or first aid, the hemostatic material remaining in small amounts
will be absorbed by the body and the irritation of wound
debridement or gauze removal is avoided.
[0077] The modified starch hemostatic material has properties of
stability, extended shelf life, resistance to high and low
pressure, resistance to high temperature (up to 60.degree. C.) and
low temperature (down to 40.degree. C.), convenient storage, and
physical stability. Therefore, it may also be employed as a
hemostatic material for the military, emergency, and first-aid
uses. Particularly, it can be adapted for extreme environmental
conditions such as desert areas, polar regions, alpine areas, outer
space, and underwater probes.
[0078] The modified starch sponge and foam has physical properties
of pliability, flexibility, moldability, and curling. It can be
adapted for wound surfaces with various shapes, sizes, and
features, such as deep and irregular anatomical wounds, organ
physiologies, both inside and outside the lacuna surface, and
applied under endoscope, laparoscope or open surgery.
[0079] To enhance the safety of applying the modified starch to
wound surfaces, tissue, etc., the modified starch material,
according to the present invention, can be packaged and sterilized
with, but not limited to, gamma irradiation, oxirane, and ozone
sterilization.
[0080] At least a production process of a biocompatible modified
starch material according to the present invention, comprising the
steps of:
[0081] providing a modified hygroscopic biocompatible starch
material and adding into a agglomerator under 40.about.50.degree.
C.; and
[0082] adding distilled water and producing a modified starch
finished product material by particle agglomerating and pellet
processing;
[0083] wherein the modified starch finished product has a molecular
weight over 15,000 daltons (for instance, 15,000.about.2,000,000
daltons) and a grain diameter of 10.about.1000 .mu.m, wherein
starch grains with diameters of 30.about.500 .mu.m represent no
less than 95% of the total amount of starch grains, wherein the
modified starch finished product can provide effects of hemostasis,
adhesion prevention, tissue healing promotion, sealing, adhesive
plugging, bonding to a bleeding wound surface, and bacteriostatic
and anti-inflammatory effect on the bleeding wound surface of
either external or internal bleeding tissue and organs. The
modified starch finished product can be applied for topical use,
for surgical use, or via laryngoscope, endoscope and
laparoscope.
BRIEF DESCRIPTION OF THE DRAWINGS
[0084] FIG. 1 illustrates hemostatic effects of Arista.TM. in a
rabbit liver bleeding model.
[0085] FIG. 2 illustrates hemostatic effects of a modified starch
carboxymethyl-starch 66# in a rabbit liver bleeding model.
[0086] FIG. 3 illustrates hemostatic effects of raw starch in a
rabbit liver bleeding model.
[0087] FIG. 4 illustrates adhesion in abdominal cavity in the
experimental group (carboxymethyl starch 66#) 24 hours after the
establishment of the mouse model.
[0088] FIG. 5 illustrates degradation in abdominal cavity in the
experimental group (carboxymethyl starch 66#) 24 hours after the
establishment of the mouse model.
[0089] FIG. 6 illustrates intestinal adhesion in the control rat
group (blank).
[0090] FIG. 7 illustrates preventive effects of modified
starch-carboxymethyl starch 66# on intestinal adhesion in rats.
[0091] FIG. 8 illustrates preventive effects of sodium hyaluronate
(positive control) on intestinal adhesion in rats.
[0092] FIG. 9 illustrates a comparison of bone healing indexes in
rabbits.
[0093] FIG. 10 illustrates a representative scanning electron
microscope photo of section of pre-gelatinized hydroxypropyl
distarch phosphate (51#) hemostatic sponge A.
[0094] FIG. 11 illustrates a representative scanning electron
microscope photo of section of pre-gelatinized hydroxypropyl
distarch phosphate (51 #) hemostatic sponge B.
[0095] Table 1 illustrates a comparison of water absorption ability
between carboxymethyl starch 66# and Arista.TM..
[0096] Table 2 illustrates a comparison of work of adhesion among
carboxymethyl starch 66#, hydroxyethyl starch 88#, and
Arista.TM..
[0097] Table 3 illustrates a comparison of viscosity between
carboxymethyl starch 66#, according to the present invention, and
Arista.TM..
[0098] Table 4 illustrates water absorbency of various modified
starch by the method of centrifugation.
[0099] Table 5 illustrates hemostatic effects of the materials on
experimental animals under different hemostatic conditions.
[0100] Table 6 illustrates grades of intestinal adhesion in
different rat groups.
[0101] Table 7 illustrates results of seven bone healing indexes in
rabbit groups.
[0102] Table 8 illustrates a comparison of physical and chemical
properties among the above-mentioned hemostatic sponges and other
hemostatic sponges
[0103] Table 9 illustrates water absorption ability of composite
hemostatic sponges.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0104] The present invention provides a modified starch material
with the biocompatible properties of hemostasis, adhesion
prevention, tissue healing, absorbable tissue sealing and tissue
bonding. More specifically, the modified starch material, which is
rapidly degraded by humans and animals when applied directly to the
wound surface of humans and mammals, including a bleeding or
exudating wound surface, is able to stop bleeding, prevent
adhesions, promote tissue healing, seal wounded tissue, prevent
bleeding and fluid exudation from tissue, bond and repair tissue or
organs injured during trauma or surgery, and avoid or minimize
surgical sutures.
[0105] Starch is a glucosan. At room temperature, raw starch is
generally not soluble in water, nor does it readily absorb water.
Raw starch normally absorbs water at temperatures above 60.degree.
C. and swells to an adhesive, translucent and colloidal solution.
The modified starch is raw starch processed through physical and
chemical modifications, resulting in physical and chemical changes
which make its characteristics and properties suitable for
applications in various industries. Starch is generally classified
by its origin, such as potato starch or corn starch, etc. There are
two types of glucose chains in starch, including a simple chain
called amylose and a complex branched form called amylopectin. The
diameter range of starch grains is normally between 1.about.100
.mu.m and the average diameter is from 15 to 30 .mu.m.
[0106] Natural raw starch has minimal hemostatic characteristics
because starch grains are small and light and the hydrophilic
properties are unsatisfactory at room temperature.
[0107] The modified starch acquires certain chemical and physical
characteristics by cutting, rearranging, or adding other chemical
groups that change the structure of the raw starch molecular chain.
The modified starch can be categorized primarily into physically
modified starch, chemically modified starch, enzymatically modified
starch, and naturally modified starch, according to the performed
modification process.
[0108] Physical modification is the process which produces modified
starch, with the desired properties and functions, by physically
changing the microcrystalline starch structure through heating,
extrusion, and irradiation. Specifically, physically modified
starch includes of pre-gelatinized starch (a-starch), .gamma.-ray,
microwave or high frequency radiation starch, mechanically milled
starch, and steam treated starch, etc.
[0109] Chemically modified starch is produced by processing the raw
starch with chemical agents and changing the molecular structure to
achieve the desired modified starch properties. Specifically, the
chemically modified starch is categorized primarily as acid
modified starch, oxidized starch, baking dextrin, esterified
starch, etherified starch, grafting starch, etc.
[0110] Enzymatically modified starch is produced by processing the
raw starch with enzymes, such as .alpha.-cyclic dextrin,
.beta.-cyclic dextrin, .gamma.-cyclic dextrin, malto-dextrin and
amylopectin.
[0111] Naturally modified starch may possess the same properties as
chemically modified starch by changing the structure of natural raw
starch with a variety breeding and genetic techniques.
[0112] The modified starches generally require multi-modification
of the raw starch to achieve the desired properties. In another
words, it is the modification with two or more modifying methods
that produces the final, composite, modified starch. Most of the
widely used modified starches are composite modified starches that
have been modified several times.
[0113] The modified starch material according to the present
invention can be applied to a bleeding wound surface in humans and
animals as a hemostatic agent for topical and surgical use. The
modified starch material according to the present invention can be
used on soft tissue and organs to rapidly and effectively control
bleeding.
[0114] The present invention provides methods and technological
approaches of producing the hemostatic modified starch material,
which produce the modified starch in form of powder, sponge, foam,
colloid, film, and other forms that satisfy various surgical
hemostatic requirements, including ease of use.
[0115] The present invention provides biocompatible modified starch
material which can be produced by various methods and processes to
achieve essential physical and chemical properties,
characteristics, technical parameters, and technical indices
required for hemostasis, adhesion prevention, sealing, adhesive
gluing, promotion of healing, and tissue bonding within the
application environment. The modified starch hemostatic material is
safe, reliable, absorbable, and rapidly degradable by humans and
animals.
[0116] Additionally, the modified starch material of the present
invention can be used as a biocompatible anti-adhesion agent, a
tissue healing promotion material, a surgical sealant, and a tissue
bonding composition for tissue repair.
[0117] The technical formulas of the present invention fulfill the
foregoing performance requirements with modified starch
applications as a biocompatible hemostatic material with
characteristics that include dissolving or swelling in water and
the subsequent formation of an adhesive glue or adhesive gel.
[0118] The characteristics of the modified starch of the present
invention further include the acquisition of hydrophilic groups in
its molecular chains through the described modification
process.
[0119] When the hydrophilic and enhanced adhesive modified starch
is applied to bleeding wound sites, it rapidly absorbs water in the
blood and concentrates blood components. Concurrently, this
interaction creates an adhesive matrix formed with the blood and
plasma which adheres to the bleeding wound, mechanically seals
broken blood vessels and stops bleeding.
[0120] The modified starch material according to the present
invention includes starch modified physically, chemically,
naturally, or enzymatically, and starch modified repeatedly with at
least one of the above methods or a combination of two or more of
the above methods.
[0121] The physical modifying process according to the present
invention employs irradiation, mechanical, and steam
modification.
[0122] Physically modified starch, for example, a pre-gelatinized
starch treated solely with spray drying or irradiation process, is
remarkably safe as a bio-absorbable, hemostatic material since it
is not treated with any chemical agents.
[0123] Pre-gelatinized starch can be modified by an extrusion
process, roller drying, and a spray drying process.
[0124] Specifically, after heating the raw starch with a measured
amount of water, starch granules swell to a pasty substance,
regularly arranged micelle of starch are broken, crystallites
disappear, and the resulting composition is easily degraded under
the process of amylase. Pre-gelatinized starch is able to swell
and/or dissolve in cold or room temperature water and form an
adhesive paste whose retrogradation is lower than that of raw
starch, affording easier handling during the production process.
Raw starch can be pre-gelatinized through solely a physical
modification process without adding any chemical agents and becomes
a hemostatic material with enhanced hydrophilic and adhesive
properties.
[0125] The pre-gelatinized starch of the invention is safe,
non-toxic, and has no adverse side effects. The pre-gelatinized
starch is readily degraded and metabolized by enzymes in the body.
The described pre-gelatinized material is safe and
biocompatible.
[0126] The chemical modifying as described above includes
acidolysis, oxidation, esterification, etherification,
cross-linking, chemical agent grafting. Alternatively, multiple
modifying processes comprises at least two of the above processes,
or one of the above modifying processes performed at least
twice.
[0127] According to the present invention, by adding the functional
group on the raw starch glucose units with chemical agents, e.g. by
carboxylation modification, or hydroxylation modification, the
starch captures hydrophilic groups in its molecular structure and
obtains hydrophilic properties. By using bifunctional or
polyfunctional chemical agents to cross-link the raw starch
macromolecules or grafting external macromolecular hydrophilic
groups to the raw starch, the starch acquires enhanced hydrophilic
properties and viscosity/adhesiveness in a water solution. The
viscosity of modified starch relates to the raw starch origin and
the degree of substitution of external and the cross-linked or
grafted functional groups, etc. When contacting blood, the
hydrophic and adhesive properties of the prescribed modified starch
will produce a "starch-blood coagulation matrix" with strong
adhesive characteristics which can seal wounded tissue and stop
bleeding. In addition, the interaction between the formed blood
coagulation matrix and the functional groups of tissue proteins
will cause the "starch-blood coagulation matrix" to adhere to and
seal the wounded tissue, resulting in hemostasis.
[0128] An advantage of the present invention is that the modified
starch compositions are easily swollen and/or dissolved in water,
allowing the formed adhesive gel at the wound site to be irrigated
and dissolved by normal saline rinse after hemostasis. Since the
residual modified starch particles not in contact with blood can be
easily washed away with water, absorbed by an aspirator, or wiped
away with gauze materials, it will minimize the residual particles
in the wound and the risk of tissue inflammation.
[0129] Specifically, the modified starch of the present invention
contains one or more groups of pre-gelatinized starch, acid
modified starch, dextrin, oxidized starch, esterified starch,
etherified starch, or cross-linked starch.
[0130] The hemostatic composition of the present invention
comprises two or more modified starches to satisfy the physical and
chemical properties of a hemostatic agent, where the weight ratio
of the two modified starch groups can be 99:1.about.1:99.
[0131] Specifically, the weight ratio of the two modified starch
groups can be: 95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35,
60:40, 55:45, or 50:50.
[0132] The main physical parameters of the modified starch,
according to the present invention, are provided below:
[0133] The modified starch of the present invention has a molecular
weight over 15,000 daltons (for instance, 15,000.about.5,000,000
daltons).
[0134] The modified starch of the present invention has a water
absorbency capacity not lower than one time its weight (i.e. 1 gram
of described modified starch can absorb 1 gram or more of water);
whereas it can be 1500 times generally and 2.about.100 times
preferably.
[0135] The modified starch composition of the present invention
comprises, but is not limited to, at least one carboxymethyl
starch, hydroxyethyl starch, and cationic starch.
[0136] For example, the carboxymethyl starch is a polymer of linear
structure as expressed in the following formula:
##STR00002##
[0137] The modified starches such as carboxymethyl starch (CMS) and
hydroxyethyl starch are known clinically as plasma substitutes.
These modified starches exhibit biocompatibility and safety with no
toxic side effects when employed in the human circulatory system.
The hemostatic composition, according to the present invention, can
also include other plasma substitutes by means of well-known
pharmacokinetics approaches and specified physical/chemical
properties to produce safe and reliable hemostatic agents.
[0138] When cationic starch of the modified starches is used as a
hemostatic material, the surface positive charge of the cationic
starch can attract and interact with electronegative blood
erythrocytes, accelerating the blood coagulation process.
Furthermore, when contacting blood, the positively charged modified
starch adheres tightly to tissue, seals the wound, and rapidly
stops bleeding. The cationic starch can be used independently as a
hemostatic material, or mixed with other modified starches as a
composite hemostatic material.
[0139] The composite modified starch comprises, but not limited to,
at least pre-gelatinized hydroxypropyl distarch phosphate.
Specifically, the hydroxypropyl distarch phosphate is produced by
cross-linking and etherifying the starch with propylene oxide and
phosphoric acid, followed by pre-gelatinization modification
through a spray drying process. The hydroxypropyl distarch
phosphate has high adhesiveness, strong water absorbency and robust
hemostatic effects. It is stable in acidic or alkali environments
and can be used as a biocompatible, hemostatic material, a surgical
sealant, a tissue healing composition, an anti-adhesion agent, and
a tissue repair material.
[0140] The cross-linked starch of the present invention comprises,
but is not limited to, at least one epichlorohydrin cross-linked
starch and one cross-linked carboxymethyl starch.
[0141] The grafted starches of the present invention comprises at
least a propylene ester-carboxymethyl starch grafted copolymer and
a crylic acid-carboxymethyl starch grafted copolymer. Grafted
starch has both enhanced water absorption capability and high
viscosity/adhesiveness. Accordingly, it has a profound effect on
hemostasis when applied to wound surfaces, especially combat
wounds, traumatic wounds, and profuse bleeding from large arteries
and large veins due to aneurysms or large phlebangioma
ruptures.
[0142] The modified starch, according to the present invention, can
be made into powder form, spherical form or aerosol form to be
delivered directly to the bleeding wound surface.
[0143] For large wound surfaces from burns, selecting an aerosol
sprayed modified starch hemostatic powder in combination with a
modified starch sponge or film can achieve not only hemostasis but
also reduce tissue fluid exudation. This combined application
preserves a moist wound surface and develops a "scaffold" for fiber
cell growth and propagation through the healing tissue.
[0144] Specifically, the hemostatic powder of the present invention
is made by an agglomeration process and pellet fabrication.
Normally, modified starch grain dimensions are relatively small and
light and may need to agglomerate into larger sizes and heavier
weights which can readily disperse into the excess blood and
generate coagulation close to the broken vessels to achieve an
optimal hemostatic outcome. The agglomeration process may not be
necessary for large sized modified starch particles such as grafted
starch or cross-linked starch.
[0145] The modified starch particles of the present invention have
a diameter range of 10.about.1000 .mu.m, preferrably 30.about.500
.mu.m. Starch particles with diameters of 30.about.500 .mu.m
represent no less than 95% of the total starch particles in the
preferred embodiment. The measured, optical diameter of the starch
particles is between 50.about.250 .mu.m.
[0146] Specifically, because pre-agglomerated modified starch
particles are small and lightweight, they readily form a colloid on
the particle surface with the moisture in blood. In this case, it
affects the hemostatic outcome by preventing water molecules from
further dispersing to other starch particles. The present invention
accepts and adopts agglomeration processing technologies in the
food and pharmaceutical industries to accumulate microscopic
modified starch particles in the general 5.about.50 .mu.m diameter
range, creating clinically applicable particles with a diameter
range of 30.about.500 .mu.m. Modified starch particles produced by
the process disclosed above exhibit rapid water absorption, strong
hydrophilic properties and rapid dispersion in blood to achieve
improved hemostatic outcomes, while not readily forming a colloidal
protecting layer which may disrupt the hemostatic effect.
[0147] To fulfill the requirements of clinical operations, the
present invention provides various methods and processes to produce
hemostatic compositions with acceptable properties that assist
doctors with hemostatic therapy during surgery. The powder form
modified starch hemostat readily adapts to diffuse oozing of blood
on large surface areas, and the hemostatic powder can be delivered
to a bleeding wound surface under celioscope, nasoscope,
laparoscope or endoscope. The powder will have a sealing effect on
postoperative biliary fistulas, thoracic cavity fistulas, lymph
fistulas, intestinal fistulas, and wound tissue exudation. Excess,
residual powder can be rinsed away with normal saline to reduce the
risk of inflammation and infection.
[0148] The hemostatic material of the present invention can be a
hemostatic sponge, a hemostatic foam, a hemostatic film, or a
hemostatic bandage, which can be applied directly to a wound
surface to stop bleeding, wherein the hemostatic sponge/foam, the
hemostatic film, and the hemostatic bandage can be made into a pad
or patch by attaching a backing layer or substrate of fiber
fabric.
[0149] The hemostatic sponge, hemostatic foam, hemostatic film, and
hemostatic bandage according to the present invention can be
produced into, but not limited to, the following forms: columnar,
sheet, flocculent, or membranous.
[0150] Concerning active bleeding and high pressure arterial
bleeding, surgeons or emergency responders must apply pressure to
the wound to stop bleeding. In this circumstance, the hemostatic
powder and the clot formed can be easily washed away by the high
pressure blood flow resulting in a failure of hemostasis. In
addition, by compressing the hemostatic powder on the bleeding
wound, the clotting action forms an adhesive gel which easily
sticks and adheres to surgical gloves, instruments, and gauze. As a
result, upon removal of gloves, instruments or gauze from the
coagulated wound, re-bleeding may occur. The present invention
provides a modified starch sponge or foam which can be applied and
remain directly on the wound, thereby solving the above problem of
re-bleeding. The modified starch hemostatic sponge or foam is
absorbable, easy to use and may remain directly on the wound for a
satisfactory effect.
[0151] The hemostatic sponge and foam of the present invention can
be made from one or more, but not limited to, modified starch
processes such as vacuum freeze drying.
[0152] The hemostatic sponge and foam of the present invention can
be a composite hemostatic sponge and a composite hemostatic foam
made from one or more compositions of modified starch and other
biocompatible hemostatic materials through, but not limited to, the
vacuum freeze drying process.
[0153] Whereas, the biocompatible hemostatic materials described
above comprise, but not limited to, one or more groups of gelatin,
thrombin, collagen, carboxymethyl cellulose, oxidized cellulose,
oxidized regenerated cellulose, chitosan, or sodium alginate.
[0154] To solve the challenge of molding modified starch into
sponges and foam, the present invention combines other known
bio-absorbable hemostatic materials with strong biocompatibility
and clinically acceptable qualities with the modified starch to
produce composite hemostatic sponges and foams. Whereas other known
bioabsorbable hemostatic materials can be of one or more
components, modified starches can also comprise one or more
components, such as modified starch+gelatin, modified
starch+collagen, modified starch+thrombin, modified
starch+chitosan, modified starch+carboxymethyl cellulose, and
modified starch+hyaluronic acid. These combinations can be molded
into sponge and foam form to satisfy clinical requirements.
[0155] Weight proportion between the biocompatible modified starch
and other biocompatible hemostatic materials can be
99.9:0.1.about.1:99.
[0156] Specifically, the weight ratio between the modified starch
and other biocompatible hemostatic materials can preferably be:
95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45,
50:50, 45:55, 40:60, 35:65, 30:70, 25:75, or 20:80.
[0157] This additional coagulant material can be added to the
modified starch hemostatic sponge or foam of the present invention
directly during the vacuum freeze drying production process to
produce a composite hemostatic sponge or composite hemostatic foam
The production process can, but not limited to, pre-mixing the
coagulant material with the modified starch directly before vacuum
freeze drying process.
[0158] Whereas the coagulant of the present invention comprises,
but not limited to, one or more combinations of the following blood
coagulation factors: thrombin, fibrin, calcium agent, polypeptide,
peptide, amino acid, and protamine.
[0159] The modified starch sponge and foam of the present invention
can be manufactured into hemostatic sponge and foam form by a
vacuum freeze drying process utilizing a forming agent or a
plasticizing agent.
[0160] Whereas the forming agents as described above comprise, but
not limited to, organic forming agents, inorganic forming agents,
natural forming agents, and man-made plasticizing agents, which can
include, but not limited to, one or more combinations of glycerol,
kaolin, sorbitol, ethanol, ammonia, and polyethylene glycol.
[0161] Specifically, vacuum freeze drying process is a drying
method that freezes wet material or solutions to a solid state
under low temperatures (-10.about.-50.degree. C.) and then converts
the solid material into a gas and then, in a vacuum (1.3-1.5 Pa),
back to a solid material without an intermediate liquid phase
(sublimination). As the vacuum freeze drying is processed under low
temperature and low pressure, the moisture sublimes directly to
produce a substance with numerous special properties.
[0162] The basic parameters of the vacuum freeze drying process
specify both physical parameters and process parameters. The
physical parameters include thermal conductivity, transfer
coefficient, etc. The process parameters include freezing, heating,
state of the material, etc. Continued research on this freezing
process involves experiments to identify the optimal freezing
curve.
[0163] As the described biocompatible, modified starch hemostatic
material can be made into a hemostatic glue, the physical form can
be colloidal, dissolved colloidal, thawed colloidal, semi-liquid or
gelatinous, etc.
[0164] The hemostatic glue can be produced by adding other liquids,
not limited to water, to the modified starch by diluting, swelling,
or dissolving the liquids in certain proportions.
[0165] The present invention discloses the topical application of
modified starch as a hemostatic agent to manage and control
bleeding wound surfaces in humans, mammals, birds, or reptiles, and
the internal application for hemostasis of bleeding wound surfaces
within human bodies, tissues and organs following surgical
operations and trauma treatments, under open surgery or nasoscope,
laryngoscope, endoscope and laparoscope.
[0166] It is important to note that the modified starch hemostatic
composition, according to the present invention, can be applied for
hemostasis on bleeding bone tissue caused by surgery or trauma,
particularly for hemostasis in spongy bone tissue. In thoracic or
neurological operations involving some patients, such as children,
elderly people, and patients with osteoporosis, sternal bleeding
and skull bleeding is difficult to control. It is common to apply
bonewax to the sternum or skull, however, bonewax is slow to absorb
and may cause complications such as non-union or infection. The
modified starch composition, according to the present invention, is
a biocompatible substitute for bonewax to control bone bleeding and
mechanically seal the wound caused by surgery or trauma with robust
hydrophilic properties, strong adhesiveness and ease of molding.
The modified starch hemostatic material degrades rapidly after
surgery and avoids the complicating issues of non-union and
infection associated with bonewax.
[0167] As the modified starch is applied as hemostatic material,
other biological benefits of the modified starch are worthy of
attention. It is essential to evaluate the modified starch
composition for its positive, additional effects on wound
inflammation, tissue adhesion and tissue healing while it functions
as a hemostat.
[0168] Through research and experimentation, it is proven this
modified starch hemostatic material, according to the present
invention, has further application as an absorbable, postoperative
tissue adhesion barrier. The adhesion barrier of the modified
starch, according to the present invention, prevents wounded tissue
or organs from adhering to other tissue or organs in the vicinity,
thereby reducing local bleeding and exudation, by mechanically
isolating the wound or wound surface from adjacent tissue and
surrounding organs, such as the peritoneum.
[0169] The modified starch, according to the present invention, can
promote tissue healing, including skin, subcutaneous soft tissue,
musculature, bone tissue, neurological tissue, nerve tissue, and
wounded tissue of the liver, kidney, spleen, etc. through proper
dosage and application. The modified starch can create a "scaffold"
for skin tissue cell healing and growth of skin tissue from large
wound surfaces due to burns, and a "scaffold" for osteocyte growth
and propagation in bone defects from trauma, bone tumor resection,
etc.; and a "scaffold" for neurological tissue cell growth and
propagation when applied to injured neurological tissue caused by
brain trauma, brain tumor resection, etc.
[0170] The mechanism for promoting tissue healing is the "glue"
formation after modified starch contacts blood and establishes the
"scaffold" on the wound surface which facilitates the adherence,
growth, connection and propagation of tissue cells such as
osteoblasts or fibroblasts. In addition, local blood platelets are
increasingly concentrated on the wound and, when activated, release
tissue factors which promote healing.
[0171] The modified starch, according to the present invention, has
further applications as a biocompatible surgical sealant, capable
of forming a protective layer of colloid or film on the wound
surface to seal and prevent drainage of blood, tissue fluids, lymph
fluid, cerebrospinal fluid, bile, gastric fluid, or and other
intestinal fluids resulting from surgery and trauma treatment. This
sealing effect will prevent lymph fistula leakage, bile flaccidity,
pleural flaccidity, intestinal flaccidity, cerebrospinal
flaccidity, and vascular flaccidity.
[0172] The modified starch, according to the present invention, has
further applications as a biocompatible tissue adhesive, capable of
adhering, repairing, and bonding wounded nerve tissue, musculature,
and tissues of the bone, skin, viscera, and subcutaneous tissue. It
will also bond other curative materials to wounded tissue and
organs.
[0173] The differences between the present invention and prior
hemostatic materials are:
[0174] In contrast, the microporous polysaccharide hemospheres of
U.S. Pat. No. 6,060,461, an absorbable, biocompatible hemostatic
material, are formed by cross-linking starch with epichlorohydrin.
The mechanism of the microporous polysaccharide hemospheres
involves the molecular sieving of blood components based on their
molecular weight. This microporous hemostat allows water molecules
and other lower weight molecules into its particles and
concentrates heavier molecules, such as erythrocytes, platelets,
and fibrinogen, on the surface of the particles to promote blood
coagulation.
[0175] The microporous polysaccharide hemospheres of U.S. Pat. No.
6,060,461 are produced under a proprietary process not disclosed in
the patent. However, normal modified starches, including
cross-linked modified starch, do not necessarily possess the
microporous structure of the microporous polysaccharide hemospheres
as described in U.S. Pat. No. 6,060,461. By contrast, the present
invention does not employ the microporous properties of a molecular
sieve in modified starch to achieve hemostasis. Rather, the present
invention adopts other technical processes to import hydrophilic
groups to raw starch molecules which enable the modified starch to
directly interact with water molecules under hydration, resulting
in rapid dehydration of blood and concentration of blood clotting
components. This action does not relate to whether or not the
modified starch has a microporous surface.
[0176] In addition, by means of changing the degree of
substitution, selecting proportional ratios of amylopectin and
amylose, adding functional groups to starch molecular or modifying
the functional groups in starch chains, etc, the present invention
is able to increase the hydrophilic property and viscosity of the
modified starch, which produces an "adhesive gel" that adheres
strongly to tissue and mechanically seals broken blood vessels
after contact with blood. The above properties were not identified
in the microporous polysaccharide hemospheres of U.S. Pat. No.
6,060,461 and these described properties in present invention have
advantages over prior hemostatic materials. The modified starch in
this invention can be made into hemostatic powder, hemostatic
sponges and foam, hemostatic glue and gel, independent of whether
or not the modified starch has a microporous structure on the
surface. On the contrary, the hemostatic effect of the powder, the
sponge, the foam, the glue and the gel relates to the induced
physical and chemical properties of the modified starch under which
the invention is synthesized.
[0177] When compared with Chinese publication patent number
CN1533751A, hemostatic dressings consist of two necessary
components: fabric and a multi-porous polymer substrate attached to
the fabric, which then forms a composite structure. The fabric is
made from the oxidized regenerated cellulose described previously.
Since human physiology lacks sufficient degrading enzymes for
oxidized regenerated cellulose, this hemostatic material is slow to
absorb in the human body, thus risking local infections and
compromising tissue healing In the description of the substrate,
the patent identifies dextran and carboxymethyl cellulose as
derivatives of dextran. Cellulose and starch are two large classes
of dextran with distinctly different properties, though both are
polysaccharide dehydrating and poly-condensing from glucose
monomers. Firstly, the polymerization degree of starch is generally
from hundreds to thousands, and the molecular weight of starch is
from tens of thousands of Daltons to hundreds of thousands of
Daltons. The polymerization degree of cellulose is generally
thousands and the molecular weight of cellulose is from hundreds of
thousands of Daltons to millions of Daltons. Secondly, all
repeating glucose chains in starch are arranged in the same
direction, while repeating cellulose chains connect to each other
by rotating 180.degree. along the axial direction, which produces
the different glucose and cellulose structures. Further, starch is
easily degraded and metabolized by amylase and carbohydrase,
enzymes abundant in the human body. Conversely, cellulose is slow
to metabolize and absorb since the human body lacks sufficient
amounts of the requisite degrading enzymes.
[0178] Consequently, when producing biocompatible, absorbable
materials employed for hemostasis, the properties of starch are
superior to those of cellulose since modified starch is readily
degraded into glucose by the abundant amount of amylase in the
human body and absorbed rapidly. The biocompatibility advantage of
starch over cellulose is apparent. Furthermore, the oxidized
regenerated cellulose dressing has weak adhesion to tissue,
requires compression to maintain contact with tissue, and therefore
can not effectively seal blood vessels in the wounded surface,
limiting its clinical applications.
[0179] In addition to the above different properties, the modified
starch described in the present invention has a bacterio-static and
anti-inflammatory effect on bleeding wound surfaces. The modified
starch hemostatic material, according to the present invention, has
a hemostatic effect which controls bleeding, reduces blood and
tissue fluid exudation, and maintains a moist wound surface. As a
result, it suppresses the growth of bacteria and reduces the
inflammatory response, diminishing local irritation and relieving
pain. Furthermore, to strengthen the anti-inflammatory response,
known antibiotic or other anti-pyrotic agents can be added to the
modified starch during the manufacturing process to produce
hemostatic powder, sponges and foams, hemostatic glues and gels,
etc., all of which are suitable for topical and internal clinical
applications.
[0180] Another advantage of the modified starch hemostatic material
according to the present invention is the rapid particle
dissolution in water, facilitating the easy removal of excess
modified starch particles from the wound by simple saline
irrigation. The residual modified starch not actively involved in
hemostasis can be rinsed away by irrigation. In the treatment of
battle wounds, self rescue, or first aid, the hemostatic material
remaining in small amounts will be absorbed by the body and the
irritation wound debridement or gauze removal is avoided.
[0181] The modified hemostatic starch material has properties of
stability, extended shelf life, resistance to high and low
pressure, resistance to high (up to 60.degree. C.) and low (down to
-40.degree. C.) temperatures, storage convenience, and physical
stability. Therefore, it can be employed as a hemostatic material
for military, emergency, and first-aid uses. Particularly, it can
be adapted in extreme environmental conditions such as desert
areas, polar regions, alpine areas, outer space, and underwater
probes. The modified starch sponge has the physical properties of
pliability, flexibility, moldability, and curling. It can be
adapted for wound surfaces with various shapes, sizes, and
features, such as deep and irregular anatomical wounds and organs,
both inside and outside the lacuna surfaces, and may be applied via
endoscope, laparoscope or open surgery.
[0182] To enhance the safety of applying the modified starch to
wound surfaces, tissue, etc., the modified starch material,
according to the present invention, can be packaged and sterilized
with, but not limited to, gamma irradiation, oxirane, and ozone
sterilization.
[0183] However, adopting alcohol sterilization, autoclave or steam
sterilization is not recommended as it may change the physical and
chemical properties of the modified starch and compromise its
hemostatic effect.
[0184] A. Preparation of Modified Starch Powder
Preferred Embodiment 1
[0185] A biocompatible modified starch material for use as
hemostatic material. It includes carboxymethyl starch (66#).
Carboxymethyl starch material is added into an agglomerator at
40.about.50.degree. C. Distilled water is added. The processes
include particles coagulation (agglomeration) and pellet making.
Molecule weight of the carboxymethyl starch (66#) is
15,000.about.2,000,000 dalton. Diameter of the particles is
10.about.1000 .mu.m. Particle diameter is between 30 and 500 .mu.m
in no less than 95% of the particles. Viscosity of a 6.67%
suspension at 37.degree. C. is 557.9 mPas. Work of adhesion under
room temperature is 68.1 gsec when the modified starch is saturated
with water.
Preferred Embodiment 2
[0186] A modified starch absorbable hemostatic material includes
hydroxyethyl starch (88#). Hydroxyethyl starch material and
distilled water are added into an agglomeratorat
40.about.50.degree. C. The processes include particles coagulation
(agglomeration) and pellet making Molecule weight of the
hydroxyethyl starch (88#) is 15,000.about.1,000,000 dalton.
Diameter of hydroxyethyl starch (88#) particles is 10.about.1000
.mu.m. Particle diameter is between 50 and 500 .mu.m in no less
than 95% of the particles. Work of adhesion under room temperature
is 420.9 gsec when the modified starch is saturated with water.
[0187] The water absorption ability of this invention is measured
by a capillary method. Water is added into an acid burette so that
the liquid level at zero graduation of the acid burette equals to
the bottom of the filter plate of a sand core funnel. Filter paper
is trimmed into a disc with a 2.25 cm radius, weighed, and put into
the sand core funnel until it fully touches the filter plate. The
piston is opened until the filter paper is fully absorbed with
water. The acid burette is adjusted to zero graduation. 0.1 g
sample powder is weighed, scattered evenly on the filter paper, and
placed in the sand core funnel. Starting from the time when liquid
begins to fall, liquid level is recorded every 20 s, 40 s and 60 s.
Water absorption speed and water absorption saturation per unit
time are calculated.
[0188] A comparison of water absorption ability between
carboxymethyl starch 66# and Arista.TM. groups is illustrated in
Table 1.
[0189] As illustrated in Table 1, the water absorption speed of
carboxymethyl starch 66# within all three 20 s intervals are
greater than that of Arista.TM., indicating that 66# absorbs water
faster than Arista.TM. and is more effective. The capacity of water
absorption of 66# is almost 5 times as that of Arista.TM. in the
first 20 s interval.
[0190] The water absorption speed refers to the average water
absorption speed in the first 20 s, the second 20 s, and the third
30 s intervals. V20 s=water absorbed in 20 s(ml)/20 (s).
[0191] Saturation rate of water absorption refers to the amount of
water absorbed by the sample in a certain period of time divided by
its maximal water absorption capacity (i.e. the absolute value of
water absorbency). This measure reflects the water absorption speed
of the same sample from another angle.
[0192] As illustrated in Table 1, 66# has a higher saturation rate
of water absorption than Arista.TM. at the 20 s, 40 s, and 60 s
intervals, indicating that 66# absorbs more water than Arista.TM.
in a same period of time. For 66#, 58 percent of total water
absorbency is achieved in 20 s; nearly 95% is achieved in one
minute. The water absorption speed of 66# is greater than that of
Arista.TM..
[0193] The stickiness of the present invention is measured as the
work of adhesion using a texture analyzer (physical property
analyzer; Stable Micro System, Model TA-XT plus). Probes used in
the experiment includes A/BE (backward extrusion probe) and P36R
(cylindrical probe).
[0194] Experiment conditions are: pre-experimental speed: 0.5
mm/sec; experimental speed: 10.0 mm/sec; stress: 100 g; retrieval
distance: 5.0 mm; contact time: 10.0 sec; trigger: automatic, 5
g.
[0195] A comparison of work of adhesion among carboxymethyl starch
66# (according to the present invention), hydroxyethyl starch 88#,
and Arista.TM. is illustrated in Table 2.
[0196] When the probe moves back, it will encounter the adhesive
force produced by the sample. For the probe to separate completely
from the sample, it must do work. The work done during this period
is referred to as the work of adhesion and can be used to measure
the adhesive strength (degree of firmness) between the adhesive
agent and probe surface.
[0197] 25% saturation rate refers to the saturation at 1/4 maximal
water absorption capacity.
[0198] 50% saturation rate refers to the saturation at 1/2 maximal
water absorption capacity.
[0199] 100% saturation rate refers to the saturation at maximal
water absorption ability.
[0200] As illustrated in table 2, the adhesiveness (stickiness) of
Arista.TM. is much lower than that of 66# and 88#. The work of
adhesion of 88# decreases with increasing saturation rate, and has
particularly high adhesiveness (stickiness) and at lower saturation
rate. Adhesiveness (stickiness) of 66# increases gradually. At
maximal saturation, both materials have significantly higher
stickiness than Arista.TM., and produce better effects of adhesive
plugging.
[0201] Viscosity of the present invention is measured by a
viscometer (brookfiled Dv-2). Test conditions are: Rotor 3;
rotating speed: 60; concentration of modified starch solution:
6.67%; temperature: 37.degree. C.
[0202] A comparison of viscosity between carboxymethyl starch 66#
in the present invention and Arista.TM. is illustrated in Table
3.
[0203] As illustrated in Table 3, the viscosity of 66# is
significantly higher than that of Arista.TM..
Preferred Embodiment 3
[0204] A biocompatible modified starch material for use as
hemostatic material. It includes pre-gelatinized hydroxypropyl
distarch phosphate (51#). Its molecule weight is over 15,000 dalton
(15,000.about.2,000,000 dalton). Diameter of its particles is
10.about.1000 .mu.m. Particle diameter is between 50 and 500 .mu.m
in no less than 95% of the particles.
Preferred Embodiment 4
[0205] A biocompatible modified starch applied in hemostasis
includes crosslinked carboxymethyl starch (66#+). Its molecule
weight is over 15,000 dalton (15,000.about.2,000,000 dalton) and
the diameter of particles is 10.about.1000 .mu.m; among them, those
with diameters between 50 and 500 .mu.m take no less than 95% of
total amount of starch particles.
Preferred Embodiment 5
[0206] A biocompatible modified starch for use as hemostatic
material. It includes pre-gelatinized starch prepared using a spray
drying process. Its molecule weight is over 15,000 dalton
(15,000.about.2,000,000 dalton). Diameter of particles is
10.about.1000 .mu.m, Particle diameter is between 50 and 500 .mu.m
in no less than 95% of the particles.
[0207] The water absorbency of various modified starch is
determined by centrifugation and the results are illustrated in
Table 4:
[0208] Water absorbency refers to the maximal water that 1 g sample
can absorb.
[0209] Water absorbency (ml/g)=amount of absorbed water (ml)/amount
of sample (g).
[0210] As illustrated in table 4, all prepared modified starches
have better water absorbency.
[0211] Control Experiment 1
[0212] Hemostatic effects in a liver bleeding model in New Zealand
rabbits.
[0213] Objective: To investigate the hemostatic effects of 66#
products in a liver bleeding model in New Zealand rabbits.
[0214] Test Drugs:
[0215] Name: Product 66# (carboxymethyl starch hemostatic
spheres)
[0216] Animals: New Zealand white rabbits, supplied by Laboratory
Animal Center, the Second Military Medical University.
[0217] Certification Number: SCKK (SH) 2002-0006
[0218] A total of 15 animals were used (n=5 per group). Body
weight: 2.0.+-.0.3 kg.
[0219] Methods:
[0220] 15 New Zealand white rabbits were randomly divided into 3
groups, a product 66# group, a positive control group (Arista.TM.)
and a negative control group (raw starch) (n=5, respectively). The
rabbits were anaesthetized with sodium pentobarbital (40 mg/kg) via
ear vein injection. Rabbits were fixed in a supine position. Hair
was removed. After disinfection, the abdominal cavity was opened
layer by layer to expose the liver sufficiently. A 1 cm diameter
and 0.3 cm deep wound was produced using a puncher on the liver
surface. Hemostatic material was applied immediately. The wound was
pressed for 20 s. Hemostatic effects were observed in each animal
group. The animals received Arista.TM. and raw starch in the
positive control group and the negative control group,
respectively. All the animals received un-restricted food and water
after the surgery. At half an hour, one, two, three and seven days
after surgery, one animal from each group was chosen and received
anesthesia. The hepatic wound surface was stained with iodine to
observe the degradation of the hemostatic materials. The wound
tissue was taken out and fixed with 10% formaldehyde. Tissue
sections were prepared and used to observe the degradation of the
hemostatic materials.
[0221] Dosage: 50 mg/wound surface
[0222] Route: spray applying
[0223] Frequency: once/wound surface
[0224] Outcomes and observation time: hemostatic effect, absorption
and degradation, healing of the wound surface. Observation time
were: half a hour, one day, two days, three days and seven days
after the surgery.
[0225] Results:
[0226] Effects on Hemostasis
[0227] In the positive control group (Arista.TM.), the bleeding was
stopped immediately after the hemostatic material was sprayed on.
In the product 66# group, the bleeding was also stopped
immediately. In the raw starch group, the bleeding could not be
stopped after the hemostatic material was sprayed on even with
wound pressing. (See FIGS. 1 to 3)
[0228] Degradation In Vivo
[0229] There was no iodine color reaction in the positive control
group (Arista.TM.) and product 66# group at half an hour. Color
reaction was positive in the negative control group at half an hour
later, but not 24 hours later.
[0230] Control Experiment 2
[0231] Degradation in Abdominal Cavity of Mice
[0232] Objective: To investigate the adhesion and degradation of
product 66# in abdominal cavity of mice.
[0233] Test Drugs:
[0234] Name: Product 66# (carboxymethyl starch hemostatic
spheres)
[0235] Animal: ICR mouse, supplied by Laboratory Animal Center, the
Second Military Medical University.
[0236] Certification Number of Animals: SCXK (SH) 2002-0006
[0237] A total of 30 animals were used (n=10 per group). Body
weight: 18-23 g. Half were females and half were males.
[0238] Methods: Product 66#, the positive control Arista.TM., and
the negative control raw starch, were prepared into 0.1 g/ml
solutions with normal saline. A total of 30 ICR mice were randomly
divided into three groups, a product 66# group, a positive control
group (Arista.TM.) and a negative control group (raw starch).
Animals received intraperitoneal injection of 1 ml of the
above-mentioned solutions. Twenty-four hours later, abdominal
cavity was opened. Iodine was applied in the abdominal cavity to
observe color change and visceral adhesion. Animals in the positive
control group and the negative control group received Arista.TM.
and raw starch, respectively.
[0239] Dosage: 1 ml/per mouse
[0240] Route: intraperitoneal injection
[0241] Frequency: once/per mouse
[0242] Outcomes and observation time: The abdominal cavity was
opened 24 hours after the administration to observe organ adhesion
and material degradation.
[0243] Results:
[0244] Adhesion In Vivo
[0245] Twenty-four hours later, no organ adhesion was found in the
abdominal cavity in 66# experimental group. (See FIG. 4)
[0246] Degradation In Vivo
[0247] No iodine color reaction was found in 66# experimental group
at twenty-four hours later, indicating that 66# had been degraded
completely within the mice body. (See FIG. 5)
[0248] Control Experiment 3
[0249] An investigation of hemostastic effects of products 66# and
88# in a canine femoral artery bleeding model.
[0250] Objective: To observe the hemostatic effect of product 66#
and 88# in serious trauma, and compare the hemostatic effect of
product 66# and product 88# with Arista.TM..
[0251] Animals: experimental dogs.
[0252] A total of 20 male animals were used (n=5 per group). Body
weight: 20-25 kg.
[0253] Methods: The animals were randomly divided into a control
group (pressing with gauze), a product 66# group, a product 88#
group, and an Arista.TM. group. The femoral artery was exposed and
punctured with a No. 18 needle (diameter: 2 F). Blood was allowed
to flow freely for 2 second. After establishment of the canine
femoral artery injury model, product 66#, 88#, or Arista.TM. (1 g,
respectively) was applied on the bleeding sites and pressed
manually. Animals in the control group received pressing with
gauze. Then, after pressing for 60 s, 90 s, 120 s, and 180 s,
hemostatic effects of the materials were observed. Successful cases
were recorded. Stop of bleeding or blood oozing at the puncturing
was used as a criterion for successful hemostasis. Hemostatic
status of experimental animals under different hemostatic
conditions is shown in Table 5.
CONCLUSION
[0254] Product 66#, 88# and Arista.TM. had significant hemostatic
effects on canine femoral artery bleeding as compared with the
control group. Product 66# and 88# had better sealing effects on
the punctured site at femoral artery and significantly shorter
hemostatic time than Arista.TM.. Furthermore, the more adhesive
product 88# had better sealing effects on the punctured site at
femoral artery and shorter hemostatic time than product 66# and
Arista.TM..
[0255] Control Experiment 4
[0256] An investigation on postoperative intestinal adhesion in
rats.
[0257] A sample of product 66# in the experimental group was
compared with a positive control of sodium hyaluronate on sale for
medical use, and a blank control.
[0258] Experimental Animals and Grouping
[0259] Thirty-four male SD rats weighing 200.about.250 g were
supplied by Laboratory Animal Center, the Fourth Military Medical
University. They were divided into three groups: a blank control
group, a 66# group, and a positive control group of medical sodium
hyaluronate (SH). Each group consisted 11 or 12 rats.
[0260] Preparation of the Rat Intestinal Adhesion Model
[0261] Animals in all groups were fasted but received unrestricted
supply of water 12 hours before the operation. Rats were
anaesthetized with 3% sodium pentobarbital (30 mg/kg;
intramuscular). The cecum was exposed through a 2 cm midline
incision in the lower abdomen. The serosa of the cecum was scraped
until blood oozed. Anhydrous ethanol was applied on the wound
surface. The mesenteric artery of cecum was clamped with a 5-finger
clamp for 2 min to induce temporary ischemia. After these
treatments, the wound surface in the 66# group and SH group were
covered with the corresponding drugs. The blank controls did not
receive any drug. The cecum was placed back into the original
position in the abdominal cavity. The opposing abdominal wall was
damaged with a hemostatic forcep and the abdominal cavity was
closed with No. 1-0 thread layer by layer. Rats received
intramuscular gentamicin injection (4 U) for 3 consecutive days
after the surgery to prevent infection. Fourteen days later, the
same method of anesthesia was used to open the abdominal cavity for
examination and sampling.
[0262] Relevant Measurements
[0263] 1) General Condition: Survival of the rats was recorded
after the operation.
[0264] 2) Intestinal Adhesion: The abdominal cavity was opened
using a U-shaped incision (bottoms down) that included the original
midline incision. The tissue flap was lifted up to expose the
abdominal cavity. Adhesion between the cecum and the abdominal wall
was observed and graded using the Nair 5 Grading System: Grade 0:
no adhesion; Grade 1: one adhesion belt between the viscera or
between different points of the abdominal wall; Grade 2: two
adhesion belts between the viscera or between the viscera and
abdominal wall; Grade 3: two adhesion belts; no direct adhesion of
the viscera to the abdominal wall; Grade 4: the viscera adhere to
the abdominal wall directly, regardless of the number of adhesion
belt.
[0265] Please refer to FIG. 6 for the intestinal adhesion in the
blank control group. FIG. 7 illustrates the effects of 66# in
preventing intestinal adhesion. FIG. 8 illustrates the effects of
sodium hyaluronate in preventing intestinal adhesion. These results
indicated that the sodium hyaluronate and carboxymethyl starch 66#
could significantly reduce postoperative intestinal adhesion in
rats.
[0266] Control Experiment 5
[0267] An investigation on the postoperative bone healing condition
in rabbits
[0268] Experimental Method
[0269] Major Materials
[0270] Carboxymethyl starch 66#, pre-gelatinized hydroxypropyl
distarch phosphate 51#, bone wax, and blank control group.
[0271] Experimental Animals and Grouping
[0272] 32 New Zealand adult female rabbits, 2.0.about.2.5 kg, were
supplied by Laboratory Animal Center of the Fourth Military Medical
University. Two defect pores could be drilled on each animal. The
rabbits were randomly divided into a blank control group, a 66#
group, a 51# group, and a bone wax group (n=8, respectively).
[0273] Operative Method
[0274] Animals were anaesthetized with 3% sodium pentobarbital via
the ear vein injection (30 mg/kg) and fixed on a prone position on
an operative table. A 4 cm sagital incision was made along the
midline to expose the skull. The periosteum was removed completely.
A round defect pores was made on each side of cranial midline with
a 6 mm diameter drill bit (diameter: 6 mm). The defects spanned the
layer of the skull (The thickness of the skull is essentially
uniform in parietal bone). The midline was not crossed. The defects
were covered randomly with one of the aforementioned materials. No
material was applied in the control group. The periosteum and scalp
were sutured with absorbable 4-0 thread. The wound was aseptically
dressed. Animals were placed back to the home cage and raised for 6
weeks. Animals received intramuscular gentamicin injection (4 U) 3
consecutive days after the surgery to prevent infection. The
general situation of the animals was monitored everyday.
[0275] Seven days prior to the sacrifice, animals received calcein
(Sigma, dissolved in 2% sodium bicarbonate) via the ear veins (20
mg/kg). At 1 day to the sacrifice, animals received tetracycline
(30 mg/kg; Sigma, dissolved in double distilled water) via the ear
vein on the other side. Calcein and tetracycline were deposited on
the mineralizing front of newly formed bone matrix, thus could be
used as markers to measure the growth range of the bone during the
six days.
[0276] Sampling and the Assessment for Bone Healing
[0277] 1. Sampling: Six weeks after the operation, the animals were
sacrificed with excessive intravenous pentobarbital injection. The
skull covering at least 1.5 cm from the defect edge was included.
The samples included periosteum and cerebral dura mater. The
samples were fixed with 70% alcohol.
[0278] 2. Bone Healing Score: Bone healing of all defects was
assessed with healing score. The standards were: 0=no visible
defect; 1=a few visible defects; 2=moderate visible defects;
3=extensive visible defects.
[0279] 3. Pathology and Immunohistochemistry: Fixed skull sample
was embedded with paraffin. Sections were prepared using routine
methods, observed and photographed using an ultraviolet fluorescent
microscope. The fluorescent markers, calcein and tetracycline, bind
to the newly formed bone matrix and that not calcified yet,
respectively, thus showing linear fluorescence. The distance
between the two fluorescent labeling lines indicates mineral
apposition rate (MAR) during the 6 days and activity of
osteoblasts, (osteogenetic speed).
MAR = Distance between two fluorescent labeling lines ( m ) Days
between two administrations ##EQU00001##
[0280] Sections were deparaffinated, dehydrated, transparentized
and stained with Goldner-Mason-Trichrome and ponceau. The osteoid
area and mineralization bone area were labeled in different colors,
and were observed under a light microscope, photographed. Areas
stained with different materials were analyzed with an image
analysis software.
Osteoid Rate = Osteoid area of defect pore Area of defect pore
##EQU00002## Mineralization Bone Rate = Mineralization bone area of
defect pore Area of defect pore ##EQU00002.2## Defect Area Rate =
congenital absence area of defect pore Area of defect pore
##EQU00002.3##
[0281] 4. Evaluation Criteria: Bone healing score, mineral
deposition rate, the osteoid area, mineralization bone area, and
congenital absence area.
[0282] 5. Statistical Analysis
[0283] Data were treated with SPSS 11.0 statistical software.
Analysis of variance was employed in the comparison of data among
the groups.
[0284] Experimental Results
[0285] Result
[0286] The healing score of defects in 51# group and 66# group was
significantly lower than that in the blank control group and the
bonewax group at the sixth week after the operation. The mineral
deposition rate, osteoid area, mineralization bone area and other
indexes in 51# group and 66# group were significantly higher than
those in the blank control group, whereas the congenital absence
area in 51# group and 66# group was significantly lower than that
in the blank control group.
[0287] As shown in FIG. 9, a representative photograph for bone
healing indexes in rabbits, 66# and 51 # had remarkable effects in
improving the skull healing in rabbits.
[0288] B. Modified Starch Sponge
Preferred Embodiment 6
[0289] Two gram pre-gelatinized hydroxypropyl distarch phosphate
51# is added into 30 ml water and stirred continuously to make
starch particles swell sufficiently and disperse into a uniform
suspension. Several drops of glycerol are added as a plasticizing
agent (forming agent). The liquid is then put in a container and
pre-cooled at -40.degree. C. for 22 hours. It is then frozen and
dried for 20 hours at -40.degree. C. in a vacuum<20 Pa in a
freezing drier. The final product is modified starch composite
hemostatic sponge A.
Preferred Embodiment 7
[0290] One gram pre-gelatinized hydroxypropyl distarch phosphate
51# is added into 30 ml water and stirred continuously to make
starch particles swell sufficiently and disperse into a uniform
suspension. The liquid is then put in a container and precooled at
-40.degree. C. for 22 hours. It is then frozen and dried for 20
hours at -50.degree. C. in a vacuum<20 Pa in a freezing drier.
The final product is modified starch composite hemostatic sponge
B.
[0291] Referring to FIG. 10, a scanning electron microscope photo
for the section of hemostatic sponge A is illustrated, and
referring to FIG. 11, a scanning electron microscope a photo for
the section of hemostatic sponge B is illustrated. Adding
plasticizing agent during production can reduce sponge pore's
diameters and enhance its density and specific surface area.
Preferred Embodiment 8
[0292] Two gram carboxymethyl starch 66# is added into 30 ml water
and stirred continuously to make starch particles swell
sufficiently and disperse into a uniform suspension. The liquid is
then put in a container and precooled at -40.degree. C. for 22
hours. It is then frozen and dried for 20 hours at -50.degree. C.
in a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge C.
Preferred Embodiment 9
[0293] Three gram crosslinked carboxymethyl starch 66#+ is added
into 30 ml water and stirred continuously to make starch particles
swell sufficiently and disperse into a uniform suspension. The
liquid is then put in a container and precooled at -40.degree. C.
for 22 hours. It is then frozen and dried for 20 hours at
-45.degree. C. in a vacuum<20 Pa in a freezing drier. The final
product is modified starch composite hemostatic sponge D.
Preferred Embodiment 10
[0294] Three gram hydroxyethyl starch 88# is added into 30 ml water
and stirred continuously to make starch particles swell
sufficiently and disperse into a uniform suspension. The liquid is
then put in a container and precooled at -40.degree. C. for 22
hours. It is then frozen and dried for 20 hours at -50.degree. C.
in a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge E.
Preferred Embodiment 11
[0295] A certain amount of medical gelatin (10 g) is added into 100
ml water and heated in a beaker to 60.degree. C. to form a
colloidal solution. Two gram carboxymethyl starch 66# is added into
30 ml water and stirred continuously to make starch particles swell
sufficiently and disperse into a uniform suspension. The two
solutions are mixed together in a container with the mass ratio of
medical gelatin to 66# at 1:1. After precooling at -40.degree. C.
for 22 hours, it is frozen and dried for 20 hours under -45.degree.
C. in a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge F.
Preferred Embodiment 12
[0296] A certain amount of medical gelatin (10 g) is added into 100
ml water and heated in a beaker to 60.degree. C. to form a
colloidal solution. Two gram carboxymethyl starch 66# is added into
30 ml water and stirred continuously to make starch particles swell
sufficiently and disperse into a uniform suspension. The two
solutions are mixed together in a container with the mass ratio of
medical gelatin to 66# at 2:1. After precooling at -40.degree. C.
for 22 hours, it is frozen and dried for 20 hours under -45.degree.
C. in a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge G.
Preferred Embodiment 13
[0297] A certain amount of medical gelatin (10 g) is added into 100
ml water and heated in a beaker to 60.degree. C. to form a
colloidal solution. One gram hydroxypropyl distarch phosphate 51#
is added into 30 ml water, and stirred continuously to make starch
particles swell sufficiently and disperse into a uniform
suspension. The two solutions are mixed together in a container
with the mass ratio of medical gelatin to hydroxypropyl distarch
phosphate 51# at 2:1. After precooling at 40.degree. C. for 22
hours, it is frozen and dried for 20 hours under -45.degree. C. in
a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge H.
Preferred Embodiment 14
[0298] A certain amount of medical gelatin (10 g) is added into 100
ml water and heated in a beaker to 60.degree. C. to form a
colloidal solution. One gram hydroxypropyl distarch phosphate 51#
is added into 30 ml water and stirred continuously to make starch
particles swell sufficiently and disperse into a uniform
suspension. The two solutions are mixed together in a container
with the mass ratio of medical gelatin to hydroxypropyl distarch
phosphate 51# at 1:1. After precooling at -40.degree. C. for 22
hours, it is frozen and dried for 20 hours under -45.degree. C. in
a vacuum<20 Pa in a freezing drier. The final product is
modified starch composite hemostatic sponge I.
[0299] 0.1 g of the above-mentioned sponges is used to compare the
chemical and physical property. Results are shown in Table 8.
[0300] An introduction to the measurement of contact angle
[0301] Apparatus: OCA40Micro video contact angle measuring system
(Dataphysics, Germany)
[0302] Methods: A sessile drop method was used to track and record
water absorbing status of sponges using dynamic recording function
and camera function. Details of the procedure were: a sponge sample
was placed on an object table, and adjusted slowly to make the
object stage appear at the inferior 1/3 portion of the visual
field. a needle filled with deionized water connected an injection
unit was used. A drop of water with a certain volume was suspended
at the tip of the needle using an automatic injection system. The
system was focused so that the image of the sponge sample and water
drop appeared clearly in the visual field. The object table was
raised slowly so that the sponge sample touched the water drop. The
camera function and dynamic recording function were turned on
simultaneously to observe the process of water drop being absorbed
and obtain the dynamic contact angle values.
[0303] The water absorption ability of composite hemostatic sponges
is shown in Table 9.
[0304] Water absorbency of the sponges is determined by
centrifugation. 0.025 g sponge was placed in 2 ml water,
equilibrated for 10 minutes, and centrifuged for 10 minutes at 500
rpm. Sample was taken out, and weighed. The amount of remaining
residual liquid was calculated. Each sample was measured 6 times.
Average values were used.
[0305] Volume density of sponges was measured. A sponge sample was
cut into certain length and width and height, and weighed to
calculate the density.
[0306] Hygroscopicity and water absorbency of the sponges were
observed through the OCA40Micro video contact angle measuring
system of Dataphysics, Germany.
[0307] A comparison of water absorbency between composite
hemostatic sponges and other hemostatic sponges is shown in Table
10.
[0308] As shown in Table 10, composite hemostatic sponge containing
modified starch had significantly higher water absorbency than
gelatin sponge and collagen hemostatic sponge. Composite hemostatic
sponge's maximal water absorbency could reach 2.about.5 times
higher than normal gelatin sponge and collagen hemostatic sponge
could. They absorbed water faster and more efficiently and retained
high water absorbency in the fifth and sixth 20 s.
[0309] Control Experiment 6
[0310] Animal Experiment
[0311] Objective: To observe the hemostatic effect of modified
starch hemostatic sponge in a liver bleeding models.
[0312] Experimental Method:
[0313] An area of 2 cm.times.1 cm was cut off with a scalpel on the
liver surface. Wound depth was 0.3 cm. Hemostatic sponges employed
in the experiment to stop bleeding of the wound were: 51#
hemostatic sponge B, 66# hemostatic sponge C, composite hemostatic
sponge I [51#: medical gelatin (mass ratio): 1:1], composite
hemostatic sponge F [66#: gelatin (mass ratio) 1:1], composite
hemostatic sponge [66#: carboxymethyl cellulose (mass ratio): 1:1],
and composite hemostatic sponge [66#: collagen (mass ratio) 10:1].
Simple gelatin sponge and collagen sponge were used as controls.
When the wound started to bleed, the hemostatic sponges were
immediately placed on the wound. A medical surgical glove or
hemostatic gauze was used to pressed the wound and to stop the
blood stream. 1.about.2 min later, the glove or gauze was released
gently to observe the hemostatic effect and whether the glove or
the gauze had adhered to the sponge or the blot clot. and whether
re-bleeding occurred as the glove or gauze was removed. It was
unnecessary to remove modified starch sponge after the bleeding was
stopped. The wound was gently irrigated with normal saline.
[0314] Results:
[0315] All hemostatic sponges containing modified starch in the
experimental groups had satisfactory hemostatic effect and were
convenient to use. Sponges in the experimental groups can absorb
moisture/blood immediately and form an adhesive sponge-blood
coagulation colloid with the blood. Effective control of the
bleeding from the liver wound was achieved in 1-2 minutes, in
comparison to 3-5 min or more with the gelatin sponge and collagen
sponge. Upon contact with the blood, hemostatic sponges in the
experimental groups can adhere to the liver wound tissue tightly to
promote blood coagulation and seal the bleeding vessels on the
wound surface. The sponges in the experimental groups are elastic
and easy to use. They do not adhere to the glove or gauze that are
used to press the wound, and do not destroy the blood clot when the
glove or gauze is removed, and therefore do not cause re-bleeding.
The gelatin sponge and collagen hemostatic sponge in the control
groups absorbed moisture/blood slowly, and needed to be pressed for
multiple times. They adhered poorly to the tissue of wound surface,
and had poor hemostatic effects.
[0316] One skilled in the art will understand that the embodiments
of present invention, as shown in the drawings and described above
are exemplary only and not intended to be limited.
[0317] It will thus be seen that the objectives of the present
invention have been fully and effectively achieved. The embodiments
have been shown and described for the purposes of illustrating the
functional and structural principles of the present invention and
are subject to change without departure from such principles.
Therefore, this invention includes all modifications encompassed
within the spirit and scope of the following claim.
TABLE-US-00001 TABLE 1 Arista .TM. 66# water absorption ability
(ml/s) (first 20s) 0.011 0.056 water absorption ability (ml/s)
(second 20s) 0.008 0.04 water absorption ability (ml/s) (third 20s)
0.007 0.03 saturation rate of water absorption (%) (20s) 28.21
58.42 saturation rate of water absorption (%) (40s) 41.03 84.74
saturation rate of water absorption (%) (60s) 50 94.74
TABLE-US-00002 TABLE 2 88# 66# Arista .TM. adhesion work index g
sec 420.9 15 0.7 (25% saturation rate) adhesion work index g sec
307.4 78.9 4 (50% saturation rate) adhesion work index g sec 75.2
68.1 17 (100% saturation rate)
TABLE-US-00003 TABLE 3 Arista .TM. 66# Viscosity(mPa s) 2 557.9
TABLE-US-00004 TABLE 4 sample water absorbency 51# 17.5 66# 23
.sup. 66#.sup.+ 23.5 88# 4.4 Arista .TM. 12.8
TABLE-US-00005 TABLE 5 Pressing with gauze Arista .TM. 66# 88#
Samples of successful 0/10 0/10 1/10 4/10 hemostasis after pressing
60s Samples of successful 0/10 2/10 5/10 8/10 hemostasis after
pressing 90s Samples of successful 0/10 3/10 9/10 10/10 hemostasis
after pressing 120s Samples of successful 2/10 9/10 10/10 10/10
hemostasis after pressing 180s
TABLE-US-00006 TABLE 6 Blank control 66# Medical sodium group group
hyaluronate SH group Grade 0 0 2 4 Grade 1 0 7 3 Grade 2 0 1 3
Grade 3 3 0 0 Grade 4 8 2 1 Average 3.72 1.42* 1.18* grade *P <
0.05 vs control group
TABLE-US-00007 TABLE 7 mineral healing apposition osteoid
mineralization congenital group score rate(.mu.m/d) area(%) bone
area(%) absence area(%) control 2.14 .+-. 0.84 2.02 .+-. 0.34 12.02
.+-. 4.32 6.23 .+-. 2.34 76.21 .+-. 19.35 group 66# 1.23 .+-. 0.45*
3.86 .+-. 1.19* 35.02 .+-. 9.85* 28.25 .+-. 9.35* 43.12 .+-. 11.87*
51# 1.14 .+-. 0.43* 4.04 .+-. 1.04* 34.02 .+-. 9.22* 31.23 .+-.
8.45* 40.34 .+-. 12.60* bonewax 1.86 .+-. 0.65 2.87 .+-. 0.84*
22.02 .+-. 6.32 16.23 .+-. 6.86* 58.34 .+-. 17.64 *P < 0.05 vs
blank control group
TABLE-US-00008 TABLE 9 Sample Water Water (g) absorbed (ml)
absorbency composite hemostatic sponge F 0.1 1.73 17.3 composite
hemostatic sponge G 0.1 1.95 19.5 composite hemostatic sponge H 0.1
0.82 8.2 composite hemostatic sponge I 0.1 1.1 11.0
TABLE-US-00009 TABLE 8 volume Water water density absorbency
absorption Experimental sample (g/cm.sup.3) (times) hydrophilicity
ability hemostatic sponge A 0.0679 19.7 Hydrophilic, no Absorbing
equilibrium contact angle instantly hemostatic sponge B 0.0563 21.4
Hydrophilic, no Absorbing equilibrium contact angle instantly
hemostatic sponge C 0.0688 22.8 Hydrophilic, no Absorbing
equilibrium contact angle instantly hemostatic sponge D 0.0983 24.9
Hydrophilic, no Absorbing equilibrium contact angle instantly
hemostatic sponge E 0.11179 7.6 Hydrophilic, no Absorbing
equilibrium contact angle instantly Absorbable gelatin 0.0099 40.6
Hydrophobic, contact Extremely sponge angle is 106.degree. slow
collagen sponge of 0.0235 33.2 Hydrophilic, no slow KROD, ltd,
Beijing equilibrium contact angle SURGICEL of Johnson 0.0288 16.4
Hydrophilic, no Absorbing & Johnson, ltd equilibrium contact
angle instantly (oxidized cellulose hemostatic gauze) chitosan
hemostatic 0.1071 35.3 Hydrophilic, no slow sponge of HEMCON,
equilibrium contact angle ltd, US
TABLE-US-00010 TABLE 10 water absorbency (ml/s) First 20s Second
20s Third 20s Fourth 20s Fifth 20s Sixth 20s composite 0.004 0.0035
0.0025 0.0025 0.0025 0.0025 hemostatic sponge F composite 0.0035
0.0035 0.003 0.0025 0.0025 0.0025 hemostatic sponge G composite
0.003 0.002 0.0007 0.0003 0.0003 0.0003 hemostatic sponge H
composite 0.0008 0.0008 0.0008 0.0005 0.0003 0.0003 hemostatic
sponge I Nanjing 0.0008 0.0008 0.0005 0.0003 0.0003 0.0003
absorbable gelatin sponge collagen 0.0017 0.0008 0.0005 0.0003
0.0003 0.0003 sponge of KROD ltd, Beijing
* * * * *