WO2009018764A1 - An absorbable modified starch hemostatic material and perparation thereof - Google Patents

Abstract

An absorbable modified starch hemostatic material and preparation thereof, wherein the hemostatic material is etherified starch, or a mixture of one or more etherified starches, crosslinked starches. The modified starch has a molecular weight of 15,000 - 10,000,000, a particle size of 10 - 1000µm, and a water absorption rate of 1 - 100. The biocompatible hemostatic material can directly effect on the wound with blood, concentrate the blood quickly to congulate blood; moreover, the gelatiniform mixture formed with blood has high viscosity, which can plug damaged tissue and blood vessel. The biocompatible hemostatic material is easy to swell in the water and easy to be washed so that the residue can be reduced; it is stable, not easy to decompose, and has long shelf life and storage advantage. The biocompatible hemostatic material can also be used as absorbable surgical antisticking material, promoting tissue healing material, surgical sealant and wound no-joint tissue adhesive.

Description

 Modified starch absorbable hemostatic material and preparation method thereof

 The invention relates to a modified starch absorbable hemostatic material and a preparation method thereof, in particular to a modified starch hemostatic material which is directly sprayed on a blood wound surface of a human or a mammal for hemostasis and can be absorbed by the human body. The modified starch absorbable hemostatic material is biocompatible and can further be used as one of a surgical anti-adhesion material, a tissue healing material, a surgical sealant, and a wound-free tissue glue. Background technique

 Surgery and trauma usually cause bloody wounds, causing a large amount of blood loss, and timely use of hemostasis. Several commonly used surgical absorbable hemostatic materials are provided below.

 1. Absorbable gelatin sponge and collagen sponge

 Gelatin sponge is derived from the extract of animal tissues, and its main component is animal collagen. Its hydrophilic and porous structure absorbs moisture from the blood and concentrates the blood to achieve hemostasis. However, gelatin is a collagen extract derived from animals, containing heterologous proteins, which may cause allergic reactions, and may cause symptoms such as fever in patients. At the same time, the absorption of gelatin sponge by the human body is slow, generally about 4 weeks, so it will increase. The infection rate of the wound.

 Collagen sponges are also derived from animal collagen extracts. In addition to concentrating blood by absorbing water from the blood, it is also possible to promote coagulation by activating endogenous coagulation mechanisms.

 Like the gelatin sponge, the collagen sponge is derived from animals and is a heterologous protein; and the human body absorbs it slowly, clinically manifested as a complication of the patient's allergic reaction and wound infection, so the clinical use is greatly limited.

2, Oxidized Cel lulose ^ Oxidized regenerated cel lulose Oxidized cellulose is one type of cellulose derivative. The hemostasis mechanism concentrates the blood by the characteristic of water absorption of the material and initiates the blood coagulation mechanism. At the same time, the acidic carboxyl group combines with hemoglobin Fe to produce acidic methemoglobin in the blood, forming a brown rubber block, sealing the end of the capillary and stopping bleeding. Oxidized regenerated cellulose has the same hemostatic mechanism as oxidized cellulose.

 The oxidized cellulose is artificially synthesized. Normal humans are relatively slow to absorb this type of product due to the lack of enzymes that metabolize cellulose oxide, typically 3 to 6 weeks. It can cause local infection and affect local tissue healing. The experimental results by Nagamatsu suggest that the acidity of oxidized cellulose may cause nerve fiber variability, and the large amount of oxidized cellulose used for peripheral nerves should be avoided. Oxidized cellulose has a strong water absorption. In the bone cavity and the skull, due to the absorption of blood, volume expansion can cause nerve compression symptoms, and clinical application is also limited.

 3, Fibrin glue

 Fibrin glue is composed of fibrinogen, thrombin, aprotinin and calcium chloride. Hemostasis is mainly caused by thrombin-activated fibrinogen replication in the third phase of coagulation. In recent years, the fibrin sealant is a widely used clinical application, and it is a spray device for fibrinogen binding to thrombin. Before use, a nurse needs to dissolve fibrinogen and thrombin separately under the surgery table. It takes about several minutes. When it is difficult to dissolve the product, it needs to be heated in a water bath. After the dissolution, the spray device should be assembled. It takes time and effort, and cannot be used in a timely manner in the case of sudden emergency surgery. In addition, because thrombin in fibrin glue is derived from human or animal, it is limited because of its limited source and high cost. However, fibrin derived from human, bovine or pig is easily caused by foreign body/species protein. Allergic reactions and the occurrence of animal-borne infections. Moreover, the adhesion of fibrin glue to wet tissue wounds is weak, and active bleeding cannot be effectively controlled.

 4, natural biopolysaccharide products

 In recent years, natural biopolysaccharide products have developed rapidly and received attention. The natural biopolysaccharide products currently used for hemostasis are plant polysaccharides and chitosan. They are biocompatible, non-toxic, non-irritating, and are not susceptible to allergic reactions in the body, and they do not cause infections of animal-borne diseases.

(1) Chitosan/chitin products The chitosan/chitin product is representative of a high-expansion chitosan sponge, which is made from natural marine biological extract chitosan and advanced bioengineering technology. Chitosan has good water absorption, can initiate and accelerate the initiation of its own coagulation mechanism and promote coagulation, so it can be used as a topical hemostatic agent. However, due to the lack of enzymes in the human body that rapidly and efficiently degrade it, it is not yet available for use in surgery. At present, there is no report at home and abroad that it is used as a class III hemostatic material for hemostasis in clinical surgery. Patent Application No. 200480023477. 6 (International Application No. PCT/US2004/019043) provides a hemostatic material formed by depositing microporous polysaccharide microspheres onto chitosan, both of which are hydrophilic and biodegradable. It has similar biocompatibility and hemostatic mechanism, and combines to produce a hemostatic material that is superior to chitosan itself. However, this method cannot be realized in the body or deep in the body cavity because it is subjected to chitosan as a fiber, a puff, a non-woven fabric or the like.

 (2) Microporous polysaccharide-Ari staTM

 In 2002, Medaf or Company of the United States developed an absorbable hemostatic material called Ari staTM (US Patent US6060461), whose active ingredient is microporous polysaccharides, including dextran. The Microporous Polysaccharide Hemospheres (MPH) polysaccharide is a powdery, biocompatible granule prepared from purified natural plant starch and does not contain any animal or human-derived ingredients. Avoid the risk of allergies. MPH particles have the function of a hydrophilic molecular sieve to accelerate the formation of a gelatinous mixture around the particles by accumulating solid components in the blood, such as platelets, red blood cells, albumin, thrombin and fibrinogen. The natural coagulation process. MK1 produces a fast and powerful blood clot by shrinking the blood. Significantly reduce the time spent on bleeding during surgery. Because it can be catabolized by amylase in the human body, it will be completely decomposed in 7-14 days after surgery, and will not cause complications in the surgical area. Ari staTM absorbable hemostatic material is prepared by reacting starch with epichlorohydrin. The hydroxyl group-containing epichlorohydrin reacts with starch molecules to form ethyl glycerol, which can crosslink starch molecules into a three-dimensional network structure.

Ari staTM hemostatic material is arguably one of the most effective hemostatic powders available today, but it still has some problems. First of all, from the application side, this hemostatic material is mainly limited to the skin or soft group. Hemostasis of woven wounds, hemostasis in the deep tissues of the body cavity, especially endoscopic hemostasis (such as gastroscope, colonoscopy and laparoscopy), there is still no effective means; Second, from the preparation method, Epichlorohydrin is a colorless oily liquid with irritating odors like ether and chloroform. It is toxic and narcotic, so it is unfavorable to environmental protection and has high production cost. Third, its hemostatic effect from hemostasis effect. Not strong enough, low water absorption ratio, and slower water absorption, especially for active bleeding and hemostasis. Fourth, its viscosity is low, and the gel formed after water absorption is poorly viscous. Therefore, the adhesion between the clot formed by blood and the tissue is poor, and it is not effective to block the damaged tissue and blood vessels, thereby affecting hemostasis. Effect.

 Starch is a kind of dextran, generally insoluble in water, does not absorb water or absorb water at normal temperature, natural starch is in

In hot water above 60 °C, it will swell and become a viscous translucent colloidal solution. The original starch is processed to treat the molecules to be isomerized, and new chemical and physical properties are obtained, which become modified starch. The starch is classified according to the source, including potato starch, corn starch, etc., and contains amylose and amylopectin, and has a particle size of 1 to 100 Mm and an average diameter of 15 to 30 Mm.

 The natural raw starch is in the form of powder. Due to the small particles and light particles, it is often floating on the surface of the bleeding blood when sprayed on the bleeding wound surface. In the case of blood, the modified starch self-agglomerates and is not easy to penetrate into the bleeding site, especially for the activity. Bleeding, it is difficult to achieve the purpose of stopping bleeding. Summary of the invention

 The technical problem to be solved by the invention is to provide a modified starch absorbable hemostatic material, which directly acts on a blood wound, including hemostasis on tissues, organs in the body surface, body and body cavity, rapid hemostasis, absorption for the human body, and Has a sticky plugging effect.

 A further technical problem to be solved by the present invention is to provide a modified starch absorbable hemostatic material which is also useful as a biocompatible anti-tissue tissue adhesion material, a tissue healing material, a surgical sealant and a wound-free tissue glue.

A further technical problem to be solved by the present invention is to achieve the above object by selecting different denaturation methods and processes for starch. The technical solution adopted by the present invention to solve the above technical problems is: a modified starch absorbable hemostatic material, wherein the hemostatic material is etherified modified starch, or combined denaturation of etherification and crosslinking, etherification and esterification Starch, molecular weight is 15,000~2,000,000, particle size is 10~1000Mm, 37 °C, 6.67% starch solution viscosity is 30~557. 9mPa · s, when the modified starch is saturated with water at room temperature The viscous work is 60 to 100 g · mm.

 The modified starch granules preferably have a particle diameter of 30 to 500 Mm, and the starch granules having a particle diameter of 30 to 500 Mm account for not less than 95% of the total starch granules.

 The modified starch granules are further preferably 50 to 250 Mm in particle diameter.

 Under the premise of ensuring easy absorption in the body, the modified starch granules of the above-mentioned particle size range of the present invention have a high penetration rate and an increased water absorption rate when applied to a bleeding wound, and the hemostatic effect is remarkably improved, especially in the case of active bleeding.

 The modified starch comprises carboxymethyl starch, which is a linear structural polymer, and has the following structural formula:

OCH ₂ COONa

根据国家变性淀粉分类， 所述的羧甲基淀粉为醚化变性淀粉。

According to the National Modified Starch Classification, the carboxymethyl starch is an etherified modified starch.

 The modified starch comprises hydroxyethyl starch and is a linear structural polymer.

 The hydroxyethyl starch is an etherified modified starch.

Both carboxymethyl starch and hydroxyethyl starch are clinically widely used plasma substitutes with good biocompatibility and safety. And the hemostatic material of the present invention can be broadened to other plasma substitutes, Known properties make a safe and reliable hemostatic material.

 The modified starch hemostatic material is a blood cell or a hemostatic powder.

 The invention provides a preparation method of the modified starch absorbable hemostatic material, wherein the modified starch is made from an etherified modified starch raw material, or a composite modified starch raw material which is etherified and crosslinked, etherified and esterified. After condensing, pelletizing, sieving, the molecular weight is 15,000~2, 000, 000, the particle size is 10~100OMm, 37 °C, 6.67% starch solution viscosity is 30~557. 9mPa · s The viscosity work when the modified starch is saturated with water at room temperature is 60~100g · Let.

 The agglomeration and pelletization are carried out by placing the modified starch raw material in a boiling machine, adding steamed water, and forming the pellet at 40 to 50 °C. For the physical process, the specific process is as follows: The raw material is in an annular fluidized state in the container, and is preheated and mixed by the purified heated air, and the steamed water is atomized and sprayed, so that several particles are accumulated into a pellet containing steamed water. As the hot air continuously dries the material, the water in the pellets evaporates and solidifies. This process is repeated to form ideal, uniform spherical particles.

 The granules are formed into a film or layer and attached to the fiber fabric.

 The modified starch of the present invention may have various hemostasis modes, and the powder may be sprayed directly on the blood wound surface, and may be sprayed on the blood wound surface or formed into a film-like or layered product. In the fiber fabric, as the inner surface of the band-aid, direct compression on the blood-stained surface to stop bleeding.

 The invention provides a use of the modified starch absorbable hemostatic material for hemostasis of blood wounds of humans, mammals, birds and reptiles.

 The invention is further applied to the human body surface, the tissues and organs in the body and the blood tissue wounds in the tissues or organs in the body cavity, or used for surgery, trauma first aid, laryngoscope, endoscope, endoscopic hemostasis.

 The etherified modified starch hemostatic material also includes cationic starch.

 The etherified, crosslinked composite modified starch hemostatic material comprises cross-linked carboxymethyl starch.

The invention further provides a modified starch biocompatible hemostatic material, wherein the hemostatic material is etherified modified starch, or etherified, crosslinked composite modified starch, or compound denaturation of etherification, cross-linking, esterification One or two or more compositions of starch having a molecular weight of 15,000 to 10, 000, 000, granules The particle size is 10 to 1000 Mm, and the water absorption ratio of the modified starch hemostatic material is 1 to 100 times.

 The so-called absorbable hemostatic material is a biocompatible hemostatic material that can be absorbed by body tissues. In the present invention, specifically, when the modified starch absorbable hemostatic material is in contact with a blood-stained surface, the enzyme in the blood-scarred tissue cells, including amylase and carbohydrase, is degraded and converted into a small molecule compound. , such as monosaccharide, absorbed by the body.

 The absorbable hemostatic material is a kind of biocompatible hemostatic material, which is used in the surgical wounds of human body after being disinfected, and the Chinese Food and Drug Administration classifies it as an I I class medical device. Biocompatibility is generally considered to be a local compatibility between the material and the tissue, ie the material does not cause local tissue reactions. Biocompatible hemostatic material means that the hemostatic material used for blood wounds does not cause local tissue reaction, including non-toxicity, no mucosal irritation, no genotoxicity, no allergic or other immune reaction, no damage to blood cells, etc. . In the present invention, human or other mammals are mainly studied.

 The modified starch biocompatible hemostatic material preferably has a particle size of 30 to 500 Mffl, and the starch granules having a particle diameter of 30 to 500 Mm account for not less than 95% of the total starch granules. More preferably, it is 50 to 500 Mm.

 The etherified modified starch comprises at least one of carboxymethyl starch, hydroxyethyl starch, and cationic starch.

 Carboxymethyl starch and hydroxyethyl starch are clinically widely used plasma substitutes with good biocompatibility and safety. Moreover, the hemostatic material of the present invention can be broadened to other plasma substitutes to produce a safe and reliable hemostatic material using its generally known properties.

 Cationic starch in modified starch is used as a hemostatic material. In addition to its water absorption, it is used to attract negatively charged red blood cells to interact with it, thereby accelerating the process of coagulation. The positively charged modified starch adheres tightly to the tissue after contact with the blood, and closes the wound, thereby quickly stopping bleeding. The cationic starch can be used alone as a hemostatic material, or it can be mixed with other modified starches as a hemostatic material.

 The etherified, crosslinked composite modified starch comprises crosslinked carboxymethyl starch.

The modified starch biocompatible hemostatic material may comprise two or more modified starches, according to The requirements for the physical and chemical properties of the hemostatic material may be 99:1 to 1:99 by weight of the two modified starches. These may include: 95: 5, 90: 10, 85: 15, 80: 20, 75: 25, 70: 30, 65: 35, 60: 40, 55: 45, 50: 50.

 Modified starch biocompatible hemostatic material products, including modified starch hemostatic powder, modified starch hemostatic granules, modified starch hemostatic cells, modified starch hemostatic aerosols and aerosols.

 The modified starch biocompatible hemostatic material is prepared from a modified starch raw material, or an etherified and crosslinked composite modified starch raw material by coagulation, pelletizing and sieving, and has a molecular weight of 15,000 to 10,000,000. The particle size is from 10 to 1000 Mm.

 In view of the use of the above-described modified starch biocompatible hemostatic material product, the modified starch granules are formed into a film or layer and adhered to the fiber fabric.

 The use of the above-mentioned modified starch absorbable hemostatic material is a hemostatic material for hemostasis of blood wounds in humans, mammals, birds, and reptiles.

 Specifically, hemostasis materials for hemostasis of human body surface, tissues and organs or organs in the body cavity, or for surgery, trauma, first aid, endoscopy, including nose, laryngoscope, gastroscope, colonoscopy, abdominal cavity Hemostasis material for hemostasis under mirror and thoracoscopic surgery.

 Experiments have shown that, in addition to hemostasis, the modified starch biocompatible hemostatic material of the present invention has an effect of preventing postoperative tissue adhesion and promoting wound tissue healing. With this property, the modified starch hemostatic material of the present invention can also be used as Biocompatible anti-adhesion materials after surgery, promote the use of tissue healing materials. In addition, by utilizing the high viscosity characteristic of the modified starch of the present invention after water absorption, the modified starch hemostatic material of the invention is used as a biocompatible surgical sealant and a wound-free tissue glue for treatment in surgery, trauma, first aid, etc. Both are of great significance.

Surgical sealant refers to a biological material used to prevent leakage of gas or liquid after surgery in the lungs, liver, brain, gastrointestinal tract, and cardiovascular surgery. The leakage of liquid and gas after surgery is a common complication after surgery, and the modified starch of the present invention is used as a surgical sealant in the tissue around the surgical suture and the retention tube, which can form a mechanical barrier to "plug" the wound, reducing Or prevent leakage of gas or liquid. When organized After healing, the sealant is gradually absorbed and absorbed by the body.

 The method for using the modified starch biocompatible hemostatic material described above is used for human body surface, tissues and organs or tissues or organs in the body cavity, including skin, subcutaneous soft tissue, muscle tissue, bone tissue, brain tissue, nerve tissue, liver, One or more combinations of organ tissues such as kidneys, spleen, or anti-adhesion materials for surgery, tissue healing materials, surgical sealants, and wound-free tissue glue.

 The modified starch biocompatible hemostatic material according to the present invention is a composite modified starch which is obtained by denaturation of the original starch into etherified starch, or etherification and crosslinking, and the denaturation method includes one or more chemical denaturation, enzyme treatment One of denaturation, one of natural denaturation, or multiple denaturation of one method, or a composite denaturation of at least two methods.

 The denaturation mechanism of the modified starch is: The starch molecular chain is cut, rearranged or introduced into other chemical groups to change its structure, and the denatured starch has superior performance to the original starch.

 A modified starch absorbable hemostatic material of the present invention, which is used as a hemostatic material, comprises: The modified starch is a modified starch which is denatured to dissolve or swell in water to form a viscous gel or viscous liquid.

 The mechanism further includes: the modified starch is a modified starch having a hydrophilic group which is denatured.

 When the water-absorbing, water-absorbing and highly viscous modified starch acts on the bleeding wound, it can quickly absorb the moisture in the blood and concentrate the blood. At the same time, the gelled mixture formed with blood and plasma adheres to the bleeding wound, mechanically sealed. Block damaged blood vessels and wounds to achieve hemostasis.

 In the above denaturation method, the chemical denaturation is at least one chemical denaturation by a chemical reagent, including esterification, etherification, and cross-linking denaturation.

 By reacting the functional group of the starch glucose unit with a chemical reagent, for example, by carboxylation modification, hydroxylation modification, the starch has a hydrophilic group, and the biogenic or polyfunctional reagent can form an original starch macromolecule. The crosslinked body, or, by grafting, obtains a hydrophilic group of a macromolecule, thereby increasing the water absorption property of the starch and increasing the viscosity. The viscosity of the modified starch is related to the type of the original starch, the degree of substitution, and the functional groups on the cross-linking or grafting.

The water absorption of the modified starch and the viscosity after water absorption make the starch-coagulation mixture formed after contact with blood. The composition "has a high viscosity, or the formed clotting mixture acts on the functional groups of the tissue protein to cause the "starch-coagulation mixture" to adhere to the damaged wound tissue to achieve hemostasis and blocking.

 The modified starch biocompatible hemostatic material of the present invention can be used for hemostasis in surgery or bone tissue damage caused by trauma, particularly hemostasis in the cancellous part of the bone. In some patients, such as children, the elderly, osteoporosis patients, open thoracic, craniotomy, bleeding in the sternum and skull section is difficult to control, clinically used bone wax (B0NEWAX) on the sternum, skull section, but bone Wax is not easy to absorb, and it is easy to cause complications such as nonunion and infection.

 The modified starch biocompatible hemostatic material of the invention can replace the bone wax, and utilizes the characteristics of water absorption, good viscosity and good shape to perform hemostasis and mechanical closure and sealing of the fracture or the bone section formed by the operation. After that, it can be quickly metabolized and degraded, avoiding the medical problem of using bone wax to cause complications such as nonunion and infection.

 The mechanism of action of the present invention as a material for absorbable tissue adhesion prevention can be achieved by reducing local bleeding, exudation, and mechanically isolating wounds or wounds from adjacent tissue organs such as the peritoneum to prevent wound tissue or The purpose of adhesion of organs to other tissues or organs around them.

 The mechanism of action of the present invention as a material for promoting tissue healing is: by adopting an appropriate operation method and applying an appropriate amount to an organ such as skin, subcutaneous soft tissue, muscle tissue, bone tissue, brain tissue, nerve tissue, liver, kidney, spleen, etc. Damaged tissue can have a role in promoting healing. For example, the wound in a large area burn patient can be used as a "stent" for skin tissue growth to promote the healing of skin tissue; bone growth and crawling can be used as a bone defect caused by trauma, bone tumor resection, etc. The "scaffold" helps the bone tissue to heal and grow; it can be used as a "stent" for brain tissue growth and crawling in the brain tissue caused by brain trauma and brain tumor resection, and help the brain tissue cells to grow.

The mechanism of action of the present invention as a biocompatible surgical sealant is that a protective colloid or membrane can be formed on the wound or wound surface to seal blood, tissue fluid, lymph fluid, cerebrospinal fluid, bile, gastric juice caused by surgery, trauma, and the like. , the exudation of intestinal fluid, thereby preventing lymphatic fistula, biliary fistula, pleural effusion, intestinal fistula, cerebrospinal fluid spasm, vasospasm and the like. The mechanism of action of the present invention as a biocompatible wound-free tissue glue is that the damaged nerve tissue, muscle tissue, bone tissue, skin, subcutaneous tissue, organ, etc. can be bonded, repaired, repaired, or It is bonded to his medical materials in tissues, organs and their wounds that need to be repaired.

 The modified starch hemostatic material of the invention reduces wound bleeding, oozing blood, exudation of tissue fluid and keeping the wound or wound relatively moist or dry during hemostasis, thereby inhibiting bacterial growth and inflammatory reaction, and contributing to local anti-inflammatory of wound , reduce the pain of the patient. In addition, in order to enhance the anti-inflammatory effect, when the modified starch hemostatic powder is produced, a known antibiotic or other anti-inflammatory agent may be added to the material to prepare an anti-inflammatory hemostatic composite material for body surface use and body use.

 In order to further enhance the safety of the modified starch directly used in wounds, tissues and the like, the modified starch material of the present invention may be sterilized after packaging, and the sterilization methods include, but are not limited to, Y-ray irradiation sterilization, ethylene oxide sterilization, and ozone sterilization.

 The difference between the present invention and existing hemostatic materials is:

 Compared with U.S. Patent No. 6060461-Microporous Polysaccharide, it is also a biocompatible hemostatic material which can be formed by cross-linking of starch with epichlorohydrin and can be absorbed in vivo. The mechanism is: Since the hemostatic material has micropores on the surface or inside, the micropores act as molecular sieves, and the size of the pores can determine that small molecules such as water molecules can enter the interior of the particles, and macromolecules such as red blood cells, platelets, and fibrin. It is then blocked on the surface of the particles to promote coagulation.

 The microporous polysaccharides of this patent are made by a special process and are not disclosed in the patent. For ordinary modified starches, including cross-linked modified starch, in most cases, this is not the case. Microporous structure. In the present invention, it is not necessary to utilize the microporous property of the modified starch as the molecular sieve to achieve the purpose of hemostasis. The present invention has a hydrophilic group by denaturation of the original starch, and directly hydrates with the water molecule, thereby achieving concentration. The effect of blood, promoting blood clotting, rather than the presence or absence of micropores on the surface of the modified starch.

In addition, the present invention improves the water absorption of the starch and the viscosity after water absorption by selecting or changing the degree of substitution, selecting the ratio of amylopectin to amylose content, and changing the functional group, so that the modified starch forms a starch after contact with blood. - a "viscous gel" of the blood mixture that adheres to the tissue and mechanically blocks the blood Tube breaks and wounds, which are not mentioned in the microporous polysaccharides of the US6060461 patent, are also a major feature of the present invention over conventional hemostatic materials. It is irrelevant whether the modified starch is made into a hemostatic powder, and the hemostatic particles have a microporous structure on the surface of the starch, and the hemostatic effect of the hemostatic material is related to the characteristics of the modified starch from which they are made.

 The beneficial effects of the invention are:

 The absorbable modified starch of the invention directly acts on the blood wound surface, can be directly sprayed or formed into a film-like external application to the blood wound surface, and immediately stops bleeding, and the water absorption rate is several times that of the existing hemostatic material AristaTM, and the speed of water absorption Also significantly improved. In addition, the modified starch of the present invention has greater viscosity and stronger viscosity than the similar products, and can further block the damaged tissue and blood vessels while stopping bleeding, thereby significantly improving the hemostatic effect. In addition, the selected carboxymethyl starch and hydroxyethyl starch raw materials are widely used in the medical industry at home and abroad, with high safety and good biocompatibility. Therefore, the products have reliable safety and clinical promotion value.

 Another advantage of the present invention is that: since the modified starch material of the present invention is easily swelled or dissolved in water, the wound can be washed with a liquid such as physiological saline after the purpose of hemostasis, and the modified starch hemostatic material which is not involved in hemostasis can be easily used. It is washed away by water, sucked away by suction device or wiped off with auxiliary materials to reduce residual in the body, facilitate rapid metabolism and absorption, reduce foreign body reaction and facilitate wound healing. When debridement treatment is carried out after war wounds, self-rescue, and emergency treatment, the hemostatic agent can be easily removed, even if a small amount of modified starch hemostatic material remains, it can be absorbed by the body, avoiding the damage caused to the patient and the wounded by tearing gauze and bandage. pain.

The modified starch hemostatic material is also stable, not easy to decompose, has a long shelf life, is easy to store, is resistant to high pressure, low pressure, high temperature resistance (up to 60 ° C or higher), low temperature resistance (up to -40 ° C or less), and is not easy to change physical and chemical properties. It can be used as an army, firefighters, ambulances, and homes, especially as a hemostatic material in extreme conditions such as cold, hot areas and deserts, Antarctica, Arctic, high mountains, space, and underwater. DRAWINGS

Figure 1 is a comparison of the water absorption ratios of 66# and Ari staTM.

Figure 2 is a comparison of the water absorption speed of 66# and Ari staTM.

Figure 3 is a comparison of the water saturation ratio of 66# and Ari staTM.

Figure 4 is a comparison of the viscous work of 66#, 88# and Ari staTM.

Figure 5 is a comparison of the viscosity of 66#, 88# and Ari staTM.

Figure 6 is a graph showing the hemostatic effect of a rabbit liver hemorrhage positive control group (Ari staTM).

Figure 7 is a graph showing the hemostatic effect of the rabbit liver hemorrhage 66# product group.

Figure 8 is a graph showing the hemostatic effect of a rabbit liver hepatic negative control group (original starch).

Figure 9 is a graph showing the intra-abdominal adhesion of mice in 24 hours.

Figure 10 is a graph showing the intraperitoneal degradation of mice in 24 hours.

Figure 11 is a graph showing the subcutaneous degradation of the 66# product group in 12 hours.

Figure 12 is a graph showing the subcutaneous degradation of the rats in the positive control group (Ari staTM) for 12 hours.

Figure 13 is a graph showing the subcutaneous degradation of the negative control group (original starch) in 12 hours.

Figure 14 is a graph showing the subcutaneous degradation of the negative control group (original starch) in 24 hours.

Figure 15 is a graph showing the adhesion effect of a rat intestinal adhesion control group.

Figure 16 is a graph showing the effect of rat intestinal adhesion 66# anti-adhesion.

Figure 17 is a graph showing the anti-adhesion effect of rat intestinal adhesion sodium hyaluronate. detailed description

Example 1

A modified starch absorbable hemostatic material, comprising carboxymethyl starch, which is obtained by etherification denaturation of original starch (potato starch) into a carboxymethyl starch, and the carboxymethyl starch raw material is placed in a boiling machine at 40 to 50 ° C Next, steamed water was added, and the hemostatic material 66# was prepared by coagulation, pelleting, and sieving (manufacturer Starch Medical Inc. batch number 070717, degree of substitution 2 to 4). The molecular weight of the carboxymethyl starch 66# product is 15,000~ 2, 000, 000, particle size is 10~1000Mm, wherein the starch granules with a particle size of 30~500Mm account for not less than 95% of the total starch granules, further preferably the particle size is 50~250Mm, 37 °C, 6 The viscous work of the modified starch at room temperature is 68. lg · let.

Example 2

 A modified starch absorbable hemostatic material, comprising hydroxyethyl starch, which is obtained by etherification and denaturation of raw starch (potato starch) into hydroxyethyl starch, and the hydroxyethyl starch raw material is placed in a boiling machine at 40 to 50 ° C Add steamed water, polymerize, pelletize, and sieve to make hemostatic material 88# (manufacturer Starch Medical Inc. batch number 071122). The hydroxyethyl starch 88# product has a molecular weight of 15,000 to 2,000,000, and a particle size of 10 to 1000 Mm, wherein the starch granules having a particle diameter of 50 to 500 Mm account for not less than 95% of the total starch granules. 2g · mm。 The viscosity of the modified starch is 75. 2g · mm when the temperature is saturated with water at 30 ° C.

 The water absorption performance of the invention is measured by a capillary method measuring device, and water is injected into the acid burette so that the zero-scale liquid surface of the acid burette is flush with the lower end of the core funnel filter plate. The filter paper was cut at a radius of 2.25 cm, weighed, placed in a sand core funnel, and completely in contact with the filter plate. Open the piston until the filter paper is completely absorbent. Adjust the acid burette to zero scale, weigh 0. lg powder, spread evenly on the filter paper, put it into the sand core funnel, start from the liquid level, every 20s, 40s, 60s, observe the liquid level drop distance, calculate the sample Water absorption speed and water absorption saturation per unit time.

 The water absorption properties of carboxymethyl starch 66# and Ari staTM (medafor, USA) in Example 1 of the present invention are shown in Table 1.

 Table 1

吸水饱和率（％) (60s) 50. 00 94. 74

Water absorption saturation rate (%) (60s) 50. 00 94. 74

 The water absorption ratio refers to the maximum amount of water that can be absorbed by the lg sample.

 Water absorption ratio (ml/g) = water absorption (ml) / sample amount (g).

 Please refer to FIG. 1 for the comparison of the water absorption ratio of 66# and AristaTM, and it can be seen from Table 1 that the carboxymethyl starch 66# of the present invention has a significant increase in water absorption ratio relative to Ari staTM, which is about Ari staTM. 3 times; the maximum water absorption rate within 10s of water absorption is nearly 4 times that of Ari staTM.

The water absorption speed is the average speed of water absorption in the first, second and third 20 seconds, respectively, V ₂ . _s = water absorption (ml) / 20 (s) in 20 seconds.

 Please refer to Figure 2 for the comparison of the water absorption speed of 66# and AristaTM. As can be seen from Table 1, the water absorption speed of 66# of the present invention is greater than that of AristaTM in three 20 seconds respectively, indicating that 66# absorbs water more than AristaTM. Faster and more effective.

 The water absorption saturation ratio refers to the ratio of the water absorption of the sample to its maximum water absorption capacity (ie, the absolute value of the water absorption ratio) for a certain period of time. It can also reflect the water absorption speed of the sample from one side.

 Please refer to Figure 3 for the comparison of the water absorption ratio of 66# and Ari staTM. As can be seen from Table 1, the water absorption saturation of 66# at 20 seconds, 40 seconds, and 60 seconds is greater than AristaTM, indicating that at the same time. 66# is faster than AristaTM to achieve saturation; 66# has reached 58% of total water absorption in 20 seconds, nearly 95% of total water absorption in 1 minute, and it absorbs water faster than AristaTM.

 The test method for the viscous property of the present invention employs a viscous work test using a texture analyzer (physical property tester), manufactured by Stable Micro System, and the product model is TA-XT plus. Experimental probes: A/BE (anti-extrusion probe) and P36R (cylindrical probe).

 The test condition is: at room temperature, the speed before the test: 0. 5mm / sec; the test speed: lmm / sec; the speed after the test is 10. Omm / sec; the stress: 100g; the return distance is 5.0 mm; the contact time is 10. Osec; Type: Automatic one 5g.

 The viscous properties of carboxymethyl starch 66#, hydroxyethyl starch 88# and Ari staTM in Examples 1 and 2 of the present invention are shown in Table 2.

Table 2 88# 66# Ari staTM viscous work (g · mm) (25% saturation) 420. 9 15. 0 0. 7 viscous work (g · mm) (50% saturation) 307. 4 78. 9 4. 0 viscous work (g · mm) (100% saturation) 75. 2 68. 1 17. 0 viscous work means that the probe will be subjected to a sample adhesion to it while doing the return movement, and the probe is completely When it is separated from the experimental sample, it must do work. The work done during this period is the viscous work, which reflects the bonding strength (firmness) of the viscous agent and the probe surface.

 The viscous properties measured by the texture analyzer are also characterized by using a viscous work index, which is expressed as: viscous work (g * mm) = viscous work index (g ' sec ) X test speed (mm/sec) in this embodiment In the test speed of 1 mm/sec, the viscous work index is consistent with the value of the viscous work. The viscous work index at 75 % saturation is 75. 2g sec, and the viscous work is 75. 2 g · mm.

 The 25 % saturation represents the saturation of the sample at a maximum water absorption of 1/4.

 The 50% saturation represents the saturation of the sample at a maximum water absorption capacity of 1/2.

 100% saturation represents the saturation of the sample at maximum water absorption capacity.

 Please refer to Figure 4 for the comparison of 66#, 88# and Ari staTM viscous work. As can be seen from Table 2, the viscous performance of Ari staTM is far less than that of 66# and 88#, 88#. When the saturation is low, the viscosity of 88# is particularly high, and the viscosity of 66# is gradually increased, and the viscous work of both water absorption is significantly higher than that of Ari staTM. In the process of hemostasis, it can better function as a plugging.

 The viscosity performance test method of the present invention employs a viscometer (brookfi led Dv-2), rotor No. 3; a rotational speed of 60 rpm; a denatured starch solution concentration of 6.67 %, and a temperature of 37 °C.

 The viscosity properties of the carboxymethyl starch 66# and Ari staTM of the present invention are shown in Table 3.

table 3

See FIG. 5 is a # 66, # 88 compared with FIG Ari sta ™ viscosity, it can be seen by Table 3, # 66, # 88 a viscosity substantially greater than Ari sta ^TM.

Example 3

 A biocompatible modified starch for hemostasis, comprising cross-linked carboxymethyl starch, which is obtained by etherification and cross-linking of original starch (potato starch) to form cross-linked carboxymethyl starch, cross-linked carboxymethyl starch raw material The mixture was placed in a boiling machine at 40 to 50 ° C, distilled water was added, and the mixture was subjected to polymerization, pelleting, and sieving to prepare a cross-linked carboxymethyl starch hemostatic material 66#+ (manufacturer Starch Medical Inc. batch number 071108). The crosslinked carboxymethyl starch 66#+ product has a molecular weight of 15,000 to 2,000,000 and a particle size of 10 to 1000 Mm, wherein the starch granules having a particle diameter of 50 to 500 Mm are not low in total starch granules. At 95%.

 The water-repellent ratios of the modified starches and AristaTM hemostatic powders (medafor, USA) in Examples 1, 2, and 3 of the present invention were measured by centrifugation, and the results are shown in Table 4:

 Table 4

 The water absorption ratio refers to the maximum amount of water that can be absorbed by the lg sample.

 Water absorption ratio (ml/g) = water absorption (ml) / sample amount (g).

 As can be seen from Table 4, both the prepared carboxymethyl starch 66# and the crosslinked carboxymethyl starch 66#+ modified starch have a preferred water absorption ratio.

Example 4

A biocompatible modified starch for hemostasis, comprising cationic starch, which is made into a cationic starch by etherification and denaturation of a raw starch, and the cationic starch raw material is placed in a boiling machine at 40 to 50 ° C, and steamed water is added. Polymerization, pelleting, sieving to form a cationic starch hemostatic material. The molecular weight of the cationic starch product is 15, 000~10, 000, 000, particle size is 10~1000Mm, wherein the starch granules with a particle size of 50~500Mm account for not less than 95% of the total starch granules.

Example 5

 A modified starch absorbable hemostatic material, including carboxymethyl starch, which is obtained by etherification and denaturation of raw starch (potato starch) into a carboxymethyl starch raw material (Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.), which is a raw material of carboxymethyl starch The mixture was placed in a boiling machine at 40 to 50 ° C, steamed water was added, and the mixture was condensed, pelletized, and sieved to prepare a carboxymethyl starch hemostatic material (manufacturer Starch Medical Inc. batch number 080118). The carboxymethyl starch hemostatic material has a molecular weight of 15,000 to 2,000,000 and a particle size of 10 to 1000 Mm. The viscosity is measured by a NH79 rotary viscometer, a No. 3 rotor, and a rotational speed of 60, 37 ° C. The 2% starch solution has a viscosity of about 1800 cps (mPa · s). Control experiment 1

Effect of hemostatic effect test on New Zealand rabbit hepatic hemorrhage model

Test purposes:

Observe the hemostatic effect of 66# product on New Zealand rabbit hepatic hemorrhage model.

Test drug:

Name: 66# product

Animals: New Zealand White Rabbit, provided by the Animal Experimental Center of the Second Military Medical University.

Animal Certificate No.: SCKK (Shanghai) 2002-0006

5 animals in each group, a total of 15 animals, weighing 2. 0 ± 0. 3kg.

Test method: 15 New Zealand white rabbits were randomly divided into 5 groups, which were divided into 66# product group (supplied by American SMI company), positive control group (Ari staTM) (medafor company, USA) and negative control group ( Raw starch - commercially available powder). The New Zealand white rabbits were anesthetized with pentobarbital sodium ear veins (40 mg * kg-; after the fixed position, the hair was removed, disinfected, and the abdominal cavity was opened layer by layer, and the liver was fully exposed. The diameter of each liver surface was made by a puncher. , a wound of 0.3 cm depth, immediately spray the hemostatic material to stop bleeding, pressure For 20 seconds, observe the hemostatic effect of each group of animals. Ari staTM and native starch were administered to the positive control group and the negative control material group, respectively. The test animals were given free access to water and diet after surgery. Each group of the test materials was anesthetized for one hour, one day, two days, three days, and seven days after the operation, and the liver wounds were stained with iodine to observe the degradation of the hemostatic material. The wound tissue of the liver was removed, fixed with 10% formaldehyde, and tissue sections were taken to observe the degradation of the hemostatic material.

Dose setting: 50mg / wound

Route of administration: Spray administration.

Number of doses: 1 time / wound

Observation index and observation time: Observe the hemostasis of the drug sprayed on the wound surface, the absorption and degradation of the drug on the liver of the animal, and the recovery of the wound. The observation time was half an hour, one day, two days, three days, seven days after surgery.

test results:

 1. Effect on hemostasis

 The positive control group (Ari staTM) stopped bleeding immediately after spraying the hemostatic material; 66# product group stopped bleeding immediately after spraying the hemostatic material; the original starch sprayed the hemostatic material and could not stop bleeding after giving certain pressure. (See Figures 6 to 8)

 2. Degradation in the body

 In the positive control group (Ari staTM) and the 66# sample group, there was no color reaction after iodine staining for half an hour; the negative control group had a color reaction after 1/2 hour of iodine staining, and no color reaction after 24 hours. Note 66# and Ari staTM have no residual after operation and are quickly absorbed and metabolized by the animal body.

Control experiment 2

Degradation in the peritoneal cavity of mice

Objective: To observe the adhesion and degradation of 66# product in the peritoneal cavity of mice.

Test drug:

Name: 66# product Animals: ICR mice, provided by the Second Military Medical University Animal Center.

Animal Certificate No.: SCXK (Shanghai) 2002— 0006

10 animals per group, 30 in total, weighing 18~23g, male and female

Test method: 66# product (supplied by SMI, USA), positive control Ari staTM (medafor, USA) and negative control raw starch were formulated with normal saline to form a solution of 0.1 g/ml. Thirty ICR mice were randomly divided into a product group of 66, a positive control group (Ari staTM) and a negative control group (original starch - commercially available glutinous rice flour). Each intraperitoneal injection of 1 ml of the corresponding solution, 24 hours later open the abdominal cavity, drip iodine, observe color changes and adhesions in the abdominal cavity. Ari staTM and native starch were administered to the positive control group and the negative control material group, respectively.

Dose setting: 1ml / only

Route of administration: intraperitoneal injection

Number of doses: 1 time / only

Observation index and observation time: After 24 hours, the abdominal cavity was opened, and the adhesion and degradation of the organs in the abdominal cavity of the mice were observed.

test results:

 1, adhesion in the body

 There was no adhesion in the peritoneal organs of the mice in each group of the abdominal cavity for 24 hours. (See Figure 9)

 2. Degradation in the body

 The abdominal cavity of each group of mice in the peritoneal cavity was opened for 24 hours, and stained by iodine staining, and no color reaction was observed. (See Figure 10) Conclusion: The experimental group 66# does not cause adhesion in the abdominal cavity of mice. Within 24 hours, the carboxymethyl starch 66# injected into the peritoneal cavity of human mice has been metabolically absorbed by the mouse.

Control experiment 3

Subcutaneous degradation in rats

Objective: To observe the subcutaneous adhesion and degradation of 66# rats.

Test drug: Name: 66# product (provided by SMI, USA)

Animals: Sprague-Dawley rats, provided by the Second Military Medical University Animal Center.

Animal Certificate No.: SCXK (Shanghai) 2002— 0006

There were 8 animals in each group, 24 in total, weighing 230 ± 10g, half male and half female.

Test method: SD rats were randomly divided into 66# product group, positive control group (Ari _S t _a TM) (med _a f ₀ r company, USA) and negative control group (original starch - commercially available glutinous rice flour). Anesthetized with pentobarbital sodium (30 mg/kg), the skin was cut in the back and extremities of the animal, and the test material was sutured. Four rats were anesthetized to open the wound after 12 hours and 24 hours, and the adhesion was observed. The degradation of the hemostatic material was observed by iodine staining and photographed. Ari staTM and native starch were administered to the positive control group and the negative control material group, respectively.

Dose setting: 50mg / wound

Route of administration: Subcutaneous implantation

Number of doses: 1 time

Observation index and observation time: The skin was opened after 12 hours and 24 hours, and the adhesion and degradation were observed. test results:

 1. Degradation in the body

After 12 hours of subcutaneous implantation, the 66# product group and the positive control group were detected by iodine staining, and no color reaction occurred. After 24 hours of subcutaneous implantation, the color reaction of the negative control group disappeared. (See Figures 11 to 14)

 2, adhesion in the body

After 12 hours of subcutaneous implantation, the 66# product group, the positive control group and the negative control group had no adhesion. Control experiment 4

Degradation in vitro

Test purpose: Observe the degradation of 66# product in vitro.

Test drug:

Name: 66# product Instrument: Screen master 3000 semi-automatic biochemical analyzer (BPC, Italy); DK-80 electric thermostatic sink (Shanghai Yiheng Technology Co., Ltd.)

Test method: Positive material Ari staTM (medafor, USA), 66# product (supplied by American SMI company) and negative control (original starch - commercially available tantalum powder), each weighing 100 mg into a test tube, adding 37U _a -amylase And 240U saccharification enzyme, add physiological saline to 10ml, 37. 5 ° C water bath, respectively, at each time point with glucose kit (Shanghai Fosun Long March Medical Science Co., Ltd., batch number: P070321) test the glucose content in the tube.

 Dose setting: lOOmg

 Observation index and observation time: glucose content at 0, 12, 18, 24, 48, 96h

 test results:

 Degradation in vitro

 Table 5 Degradation of test samples to glucose (mol/L) in vitro at different times

 Conclusion: The carboxymethyl starch of experimental group 66# can be metabolized to glucose by α-amylase and glucoamylase. Control experiment 5

 Hemostatic observation of canine femoral artery injury model

 Test purpose: To observe the hemostatic effect of 66# and 88# products under severe trauma, and to test the hemostatic effects of modified physical starches 66# and 88# and Ari staTM with different physical characteristics.

 Test animals: Test dogs.

 There are 5 animals in each group, 20 in total, weighing 20~25kg, male.

Test method: Dogs were randomly divided into control group (gauze press), 66# product group, 88# product group and Ari staTM group. Expose the femoral artery, use a 18-gauge needle to pierce the exposed femoral artery, see arterial blood self-piercing The hole is ejected, allowing it to bleed freely for 2 seconds. The femoral artery injury model was established, and immediately sprayed at the bleeding point with Ali staTM, 66# and 88# of lg, and manually pressed, and the control group was pressed with gauze. Then, the hemostasis was observed at 60 seconds, 90 seconds, 120 seconds, and 180 seconds after the compression, and the bleeding was stopped after the bleeding was stopped by the fistula, and the number of successful hemostasis was recorded.

 Table 6 Hemostasis of test animals under different hemostatic conditions

 Test Conclusions

 The hemostasis of the femoral artery hemorrhage in the 66# group, 88# group and Ari staTM group was significantly hemostatic compared with the control group. The 66# group and the 88# group had better sealing effect on the femoral artery than the AristaTM group, and the hemostasis time was significantly shortened. Further, the viscous 88# group has an improved sealing effect on the femoral artery through the mouth of the 66# group, and the hemostasis time is shortened.

 Control experiment 6

 To observe the effect of carboxymethyl starch 66# on preventing postoperative intestinal adhesion in rats

 Test drug:

 Name: 66# product (supplied by SMI, USA), commercially available sodium hyaluronate. Laboratory animals and grouping

 34 SD male rats, weighing 200-250 g, were provided by the Experimental Animal Center of the Fourth Military Medical University. They were randomly divided into a blank control group, group 66#, and medical sodium hyaluronate (SH) group, with 11 or 12 groups in each group. Preparation of rat intestinal adhesion model

All animals in each group were fasted for 12 h, and anesthetized by intramuscular injection of 30 mg/kg body weight with 3% sodium pentobarbital solution. Remove the median incision of the abdomen about 2cm, put the cecum, gently scrape the serosa serosa, until oozing, then add absolute ethanol to the wound surface, and then clamp the cecal mesenteric artery with the five-toothed sac for about 2min, causing temporary local Ischemia. After the above treatment, the 66i^P SH group completely covered the wound with the corresponding drug; the blank control group did not give any drug. After the drug was returned to the abdominal cavity, the hemorrhage clamp was used to pinch the corresponding abdominal wall, and the abdominal cavity was closed with a 1-0 silk thread. Intramuscular injection of gentamicin 4U daily for 3 days after surgery to prevent infection. After 14 days, the same anesthesia method was used for open examination and sampling.

Related measurement

 1) General Record the survival of the postoperative rats.

 2) Intestinal adhesions: In the abdominal incision, the abdominal incision was used to cut the abdominal cavity with a bottom-down "U"-shaped incision, and then the abdominal wall flap was lifted up to expose the abdominal cavity, and the end of the cecum and the wound of the abdominal wall were observed. The adhesion situation. The degree of intestinal adhesion refers to the Nair grade 5 classification criteria: grade 0, no adhesion at all; grade 1, between the visceral or abdominal wall; grade 2, between the internal organs or between the visceral and abdominal wall; grade 3, more than two adhesions, The viscera does not directly adhere to the abdominal wall; at level 4, the viscera directly adheres to the abdominal wall, regardless of the adhesion zone. Table 7 Results of intestinal adhesion assessment in each group

 *Compared with the blank control group P<0.05.

 Please refer to Figure 15 for the adhesion effect of the rat intestinal adhesion control group, Figure 16 is the anti-adhesion effect diagram of the rat intestinal adhesion 66#, and Figure 17 is the anti-adhesion effect diagram of the rat intestinal adhesion sodium hyaluronate. 7 results show that sodium hyaluronate, carboxymethyl starch 66 # can significantly reduce the degree of postoperative intestinal adhesion in rats.

Control experiment Effect of Carboxymethyl Starch 66# on Rabbit Bone Healing

Main test material

 Carboxymethyl starch 66# (supplied by SMI, USA), Arista hemostasis (medafor, USA), commercially available bone wax.

Experimental animal

 Adult New Zealand rabbits 32, female, 2. 0~2. 5 kg, provided by the Experimental Animal Center of the Fourth Military Medical University. Each of the two defect cavities can be drilled and randomly divided into blank control group, 66# group, Arista group and bone wax group 4 groups, 8 in each group.

experimental method

 Anesthetized with a 3% pentobarbital sodium solution at 30 mg/kg body weight, and placed prone on the surgery table. A sagittal incision with a length of about 4 cm in the center of the head exposes the skull and completely exfoliates the epithelium. Two circular defect holes were drilled on both sides of the midsole of the skull with a 6 mm diameter drill bit. The defect penetrated the whole layer of the parietal bone (the thickness of the parietal bone was basically the same), and did not cross the middle seam. The defect was randomly assigned to cover one of 66#, Arista or bone wax, and the control group did not use any material. The periosteum and scalp were sutured with a 4-0 absorbable thread, aseptically wrapped and returned to the cage for 6 weeks. Intramuscular injection of gentamicin 40U daily for 3 days after surgery to prevent infection. Observe the general situation of animals every day.

 7 days before sacrifice, the animal's ear vein was injected with calcein 20 mg/kg (Calcein, Sigma, 2% sodium bicarbonate); 1 day before sacrifice, the other side of the ear was injected with tetracycline 30 mg/kg.

 (Tetracycl ine, Sigma, double distilled water dissolved). Calcein and tetracycline are deposited on the mineralization front of the newly formed bone matrix, so it can be used as a marker to detect the growth range during the 6-day period of bone.

Material and bone healing evaluation method

 1. Materials After 6 weeks of surgery, the animals were sacrificed by intravenous injection of excess pentobarbital, and the skull with a margin of at least 1.5 cm extending from the original defect was included, including the connected periosteum and dura mater. The skull specimen was fixed with 70% alcohol.

2. Bone healing score Healing scores for bone healing in all defects. Healing scores: 0 = no visible defects; 1 = less visible defects; 2 = moderate visible defects; 3 = extensive visible defects. 3. Pathological and immunohistochemical fixed skull specimens were embedded in paraffin, routinely sectioned, and photographed under fluorescent light under ultraviolet light. Two fluorescent markers of calcein and tetracycline bind to bone and anterior bone of new bone

At the junction (unmineralized bone), linear fluorescence is present, so the distance between the two fluorescent markers indicates the rate of mineral deposition during the 6-day period, reflecting the activity of the osteoblasts, ie the rate of osteogenesis.

 Twisted fluorescent line spacing (μ πι)

 Mineral deposition rate =

 Number of days between two doses (d)

 The sections were dewaxed, dehydrated, and transparent. Using Goldner-Mason-Trichrome and Ponceau staining, the bone-like and mineralized bone areas could be displayed in color, optical microscopy, photographing, and image analysis software to measure the area of each stained part. Defective bone type bone area

 Bone-like area ratio

 Total area of defected hole

 Mineralized bone area rate

 Total area of the defect hole

 Lack of area ratio

 Total area of the defect hole

Statistical processing

The data were processed by SPSS 11. 0 statistical software, and the data between groups were compared using AN0VA analysis of variance _c . Survival of animals

 One rabbit did not wake up from anesthesia after the operation and died the next day; 5 patients were slow to respond, did not enter the water, and eventually died. The time distribution was 3 to 18 days after surgery, and all groups were distributed, so the rabbit died after surgery. There is no time and grouping rules that can rule out infection or drug. The remaining 34 were awake, responsive, and normal.

Bone healing indicators measurement results

 The indicators of bone healing are shown in Table 8.

 Table 8 Results of bone healing index of rabbits in each group

Blank control group 2.14±0.84 2.02±0.34 12.02±4.32 6.23±2.34 76.21±19.35 66# 1.23±0.45* 3.86±1.19* 35.02±9.85* 28.25±9.35: 43.12±11.87* Arista 1.44±0.23* 3.62±0.98* 28.02 ±8.57* 32.23±9.30 ^: 38.34±14.32* bone wax 1.86±0.65 2.87±0.84* 22.02±6.32 16.23±6.86: 58.34±17.64

* Compared with blank control group P<0. 05

 According to Table 8, the healing scores of the rabbit skull defects were observed 6 weeks after surgery, and the 66# and Arista groups were significantly lower than the control group, while the bone wax group was no different from the control group.

 Mineral deposition rate, osteogenic area ratio, and mineralized bone area rate indicators are presented as 66# and Arista

The group was significantly higher than the blank control group; the absent area ratio 66# and Arista group were significantly lower than the blank control group.

 The results suggest that both 66# and Arista have the effect of promoting the healing of rabbit skull. There is no difference between the absolute value and the statistical comparison. The bone wax reflects from some indicators, and also has the effect of promoting bone healing. Further observation.

Claims

Claim A modified starch absorbable hemostatic material, characterized in that: the hemostatic material is etherified modified starch, or etherified and crosslinked, esterified composite modified starch, molecular weight of 15,000~2, 000 , 000, particle size of 10~1000Mm, 37 °C, 6. 67% starch solution viscosity is 30~557. 9mPa · s, the viscosity of the modified starch at room temperature is 60~100g when saturated with water.  2. The modified starch absorbable hemostatic material according to claim 1, wherein: the modified starch granules preferably have a particle size of 30 to 500 Mm, and the starch granules having a particle diameter of 30 to 500 Mm are not low in total starch granules. At 95%.  The modified starch absorbable hemostatic material according to claim 2, wherein the modified starch particle diameter is more preferably 50 to 250 Mm.  The modified starch absorbable hemostatic material according to claim 1 or 2 or 3, wherein the etherified modified starch comprises carboxymethyl starch.  The modified starch absorbable hemostatic material according to claim 1 or 2 or 3, wherein the etherified modified starch comprises hydroxyethyl starch.  The modified starch absorbable hemostatic material according to claim 1, wherein the modified starch hemostatic material is a blood cell or a hemostatic powder.  The method for preparing a modified starch absorbable hemostatic material according to claim 1, wherein the modified starch is composed of an etherified modified starch raw material, or an etherified and crosslinked, esterified composite modified starch raw material. After condensing, pelletizing, sieving, the molecular weight is 15,000~2, 000, 000, the particle size is 10~1000Mm, 37 °C, 6.67% starch solution viscosity is 30~557. 9mPa · s The viscosity work when the modified starch is saturated with water at room temperature is 60 to 100 g * mm. The method for preparing a modified starch absorbable hemostatic material according to claim 7, wherein: the agglomerating and pelletizing comprises placing the modified starch raw material in a boiling machine, adding steamed water, in 40~ 50 °C Under, made into granules.  The method for preparing a modified starch absorbable hemostatic material according to claim 8, wherein the particles are attached to the fiber fabric in a film form or in a layer form.  The use of the modified starch absorbable hemostatic material according to claim 1, which is useful for hemostasis of blood wounds in humans, mammals, birds and reptiles.  11. Use of a modified starch absorbable hemostatic material according to claim 10 for use in bloody wounds of human body surface, tissues and organs or organs in body cavities, or for surgery, trauma, first aid, endoscopic Microscopically, including nose, laryngoscope, gastroscope, colonoscopy, laparoscopic and thoracoscopic hemostasis.  The modified starch absorbable hemostatic material according to claim 1 or 2 or 3, wherein the etherified modified starch further comprises a cationic starch.  The modified starch absorbable hemostatic material according to claim 1 or 2 or 3, wherein the etherified, crosslinked complex modified starch comprises crosslinked carboxymethyl starch.  14. The use of the modified starch absorbable hemostatic material according to claim 1, and also for use in a postoperative anti-adhesion material, a tissue healing material, a surgical sealant, a wound-free tissue glue, or a The combination above.  15. A modified starch biocompatible hemostatic material, characterized in that: the hemostatic material is one or two or more combinations of etherified modified starch or etherified or crosslinked composite modified starch. The molecular weight is 15,000~10, 000, 000, the particle size is 10~1000Mm, and the water absorption ratio is 1~100 times. The modified starch biocompatible hemostatic material according to claim 15, wherein: the modified starch granules preferably have a particle diameter of 30 to 500 Mm, and the starch granules having a particle diameter of 30 to 500 MF1 do not occupy the total starch granules. Less than 95%.  The modified starch biocompatible hemostatic material according to claim 15 or 16, wherein the etherified modified starch comprises at least one of carboxymethyl starch, hydroxyethyl starch, and cationic starch. The modified starch biocompatible hemostatic material according to claim 15 or 16, wherein the etherified and crosslinked composite modified starch comprises crosslinked carboxymethyl starch. 19. The modified starch biocompatible hemostatic material product according to claim 15, wherein: the modified starch hemostatic material comprises modified starch hemostatic powder, modified starch hemostatic granule, modified starch hemostatic globule, modified starch hemostatic gas Aerosols and aerosols.  The method for preparing a modified starch biocompatible hemostatic material according to claim 19, wherein: the modified starch is condensed by an etherified modified starch raw material, or an etherified or crosslinked composite modified starch raw material. , pelletized, sieved, molecular weight of 15,000~10,000,000, particle size of 10~1000Mm.  The method of using a modified starch biocompatible hemostatic material according to claim 15, wherein the modified starch granules are formed into a film or layer and adhered to the fiber fabric.  22. Use of the modified starch biocompatible hemostatic material according to claim 15, which is a hemostatic material for hemostasis of blood wounds in humans, mammals, birds and reptiles.  23. The use of the modified starch biocompatible hemostatic material according to claim 22, for hemostasis of human body surface, tissues and organs or organs in a body cavity, or for surgery, trauma, first aid, endoscopy , including nose, laryngoscope, gastroscope, colonoscopy, laparoscopic and thoracoscopic hemostasis.  24. The use of the modified starch biocompatible hemostatic material of claim 15 as one of an absorbable surgical anti-adhesion material, a tissue healing material, a surgical sealant, a wound-free tissue glue or More than one combination.  25. A method of using a modified starch biocompatible hemostatic material for use according to claim 24, for use in human body surfaces, tissues and organs or tissues or organs in the body cavity, including skin, subcutaneous soft tissue, muscle tissue, bone tissue, brain Tissue, nerve tissue, liver, kidney, spleen organ tissue, or one or more combinations of anti-adhesion materials for use after surgery, tissue healing materials, surgical sealants, wound-free tissue glue.