CN114533943A - Quick-acting hemostatic sponge and preparation method thereof - Google Patents
Quick-acting hemostatic sponge and preparation method thereof Download PDFInfo
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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Abstract
The invention discloses a quick-acting hemostatic sponge and a preparation method thereof, wherein polysaccharide-based hemostatic sponge comprises gelatin, polysaccharide conjugate and a cross-linking agent, and the polysaccharide conjugate is prepared by a hydrophilic-hydrophobic co-grafting process. Compared with a mixing scheme of a hydrophilic modified polysaccharide conjugate and a hydrophobic modified polysaccharide conjugate, the group distribution is more uniform, and the property is more stable; the physical and chemical effects can be generated between the hydrophilic and hydrophobic synergistic effects and the whole blood components, so that the whole blood components are promoted to be quickly gelled within 10-30s, and the hemostatic effect of the sponge is greatly enhanced; in the process, the polysaccharide conjugate and the gelatin are uniformly mixed in a mixing and freeze-drying mode, so that the technical problem of nonuniform release caused by easy infiltration of chitosan in the existing chitosan gelatin foam is solved; the cross-linking agent adopts tannic acid, can play a role in diminishing inflammation on the premise of ensuring the biological safety of the sponge, can play a role in synergy with the hemostatic function of chitosan, and has better effect compared with the common chitosan gelatin sponge.
Description
Technical Field
The invention relates to a medical consumable, in particular to a quick-acting hemostatic sponge and a preparation method thereof.
Background
Uncontrollable blood loss is an important cause of death, and excessive blood loss of a wounded person can cause serious consequences, such as hypothermia, blood coagulation abnormality, inflammatory infection, organ failure and the like, and can cause permanent damage to an organism and even endanger life, so that the development of an effective hemostasis means and a hemostasis material is particularly important.
In 1964, Davie and Ratnoff et al proposed the theory of blood coagulation cascade, which divides the blood coagulation process into three stages of prothrombin activator formation, thrombin formation and fibrin formation, and generally thinks that when a body is injured, it stimulates the damaged blood vessel wall to activate the blood coagulation system, and in the presence of platelets, the blood coagulation protein and thrombin are sequentially activated and act, and the fibrinogen is converted into fibrin, and the fibrin monomers are crosslinked, so that blood cells in blood are aggregated and coated, and finally blood clots are formed to realize hemostasis. In summary, the key to achieving rapid hemostasis is to shorten the specific time of the three stages of the blood coagulation process and accelerate the formation of blood clots.
The conventional hemostatic materials include gelatin products, oxidized cellulose or oxidized regenerated cellulose, microfibrillar collagen, fibrin glue, thrombin, mineral products and the like, and the surfaces of the hemostatic materials generally have negative charges and are in contact with platelets to activate human prothrombin, so that the hemostatic materials play a blood coagulation role. Wherein, the pure gelatin product can absorb a large amount of blood and improve the concentration of platelets, thereby shortening the time for forming blood clots and having limited effect; oxidized cellulose or oxidized regenerated cellulose is acidic, and the use of the material at a bleeding part can cause inflammation of surrounding tissues; the raw material for preparing the microfibril collagen is cow leather, so that the risk of causing organism allergy is high; the fibrin is very harsh in use condition, and the body temperature of 37 ℃ needs to be maintained and the fibrin is continuously pressed for 3-5 min to prevent the fibrin from being washed away by blood; the cost of thrombin is too high; mineral products such as porous zeolite, etc. need to absorb a large amount of moisture for reaction, and generate a large amount of heat during use, which may cause local tissue damage. These blood clotting materials all have a common deficiency: it mainly depends on the reaction with blood platelet in blood in the hemostasis process, shortens the prothrombin activation time to promote the formation of blood clot, has limited action range, and is not suitable for the occasion of blood platelet deletion.
Multiple studies show that polysaccharide conjugates can be loaded with positive charges and negative charges on the surface, and have effects on blood components such as platelets, erythrocytes, complement systems and the like: in addition to interacting with platelets, the acetic acid solution can cause negatively charged red blood cells to aggregate by ionic forces; and the hemostatic material can adsorb a large amount of fibrin and other plasma proteins in blood, can realize blood coagulation without activating blood coagulation factors and endogenous blood coagulation pathways in the hemostatic process, and has better effect compared with the common hemostatic material.
The currently used medical sponge is generally gelatin sponge, part of the medical sponge is added with polysaccharide conjugate to improve the hemostatic effect, but the medical sponge is generally added in an infiltration-drying mode in the process, the medical sponge is easy to leach out once after being soaked by blood, the slow release effect cannot be realized, the polysaccharide polymer component is generally single hydrophilic or single hydrophobic, only can interact with part of components in the blood, and the hemostatic effect is not ideal.
Disclosure of Invention
In order to solve the technical problems of non-uniformity and non-ideal hemostatic effect of the polysaccharide conjugate added in the medical sponge, the invention aims to provide a quick-acting hemostatic sponge.
The technical scheme for realizing the purpose of the invention is as follows:
a quick-acting hemostatic sponge comprises gelatin, polysaccharide conjugate and cross-linking agent, wherein the polysaccharide conjugate is hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
In the scheme, the polysaccharide conjugate is directly put into the gelatin solution, and under the action of the cross-linking agent, the polysaccharide conjugate and the gelatin solution are mixed more uniformly, so that a certain degree of cross-linking reaction can be generated under the action of the cross-linking agent, the combination is more stable, the phenomenon that the polysaccharide conjugate is directly infiltrated and separated in the use process can not occur, and the slow release effect can be achieved; compared with the common polysaccharide conjugate sponge on the market, the polysaccharide conjugate has more sufficient action with components in blood and can effectively shorten the blood coagulation time.
Further, the gelatin: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1-700: 100: 1.
in order to improve the safety and obtain the anti-inflammatory effect, the cross-linking agent in the quick-acting hemostatic sponge can be selected from tannic acid.
Wherein the preparation of the polysaccharide conjugate comprises the following steps:
a1, adding a hydrophobic functional substance and EDC/NHS into a water-soluble polysaccharide solution, grafting the hydrophobic functional substance on a polysaccharide macromolecular main chain through a coupling reaction, and preparing the hydrophobically modified polysaccharide material through precipitation, washing and vacuum drying.
A2, adding a hydrophilic functional substance and EDC/NHS into the hydrophobically modified polysaccharide material prepared in A1, grafting the hydrophilic functional substance on the hydrophobically modified polysaccharide macromolecular main chain through a coupling reaction, and dialyzing and freeze-drying to prepare the hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
Further, the water-soluble polysaccharide in the steps A1 and A2 is one or more of chitosan, hydroxymethyl chitosan, carboxypropyl chitosan, chitosan oligosaccharide, sodium alginate, hyaluronic acid and aminodextran; the concentration of the polysaccharides in A1 and A2 is 10-50 mg/mL.
Further, in the preparation step of the polysaccharide conjugate: the hydrophilic functional substance in A1 comprises one or more of 3, 4-dihydroxyphenyl propionic acid, 3,4, 5-trihydroxybenzoic acid, 4-carboxyphenylboronic acid, dopamine hydrochloride and 3-aminophenylboronic acid hydrochloride;
the hydrophobic functional substance in A2 comprises one or more of n-octanoic acid, dodecanoic acid, hexadecanoic acid, caprylic anhydride, dodecanoic anhydride, hexadecanoic anhydride, n-octylamine, n-dodecylamine, n-hexadecylamine and n-octadecylamine.
Further, the molar ratio of the polysaccharide dissolved in the step A1 to the added hydrophobic multifunctional substance is 5: 1-20: 1, the molar ratio of the polysaccharide dissolved in the step A2 to the added hydrophilic multifunctional substance is 1: 0.5-1: 2, the molar ratio of the polysaccharide dissolved in A2 to the coupling reaction activator EDC/NHS added was 1: 2: 2.
the preparation method of the quick-acting hemostatic sponge comprises the following steps:
s1, dissolving the cross-linking agent in water, adding gelatin under stirring to perform cross-linking reaction to obtain gelatin solution A;
s2, dissolving the polysaccharide conjugate in dilute acid solution to obtain polysaccharide solution B;
s3, mixing A and B under stirring, foaming and pre-freezing to obtain precursor;
and S4, carrying out vacuum freeze drying treatment on the precursor obtained by solidifying in the S3 to obtain the sponge.
In the preparation process, the density of the foam can be adjusted by adjusting the component proportion, the inflation pressure and the pressure retention time.
The quick-acting hemostatic sponge can be matched with a fixing bandage to be used as an arterial tourniquet.
By adopting the technical scheme, the invention has the following beneficial effects:
(1) the polysaccharide conjugate and the gelatin are effectively mixed by adopting a mode of mixing and freeze-drying after cross-linking the polysaccharide conjugate and the gelatin, so that the technical problems of easiness in infiltration and uneven release caused by mechanical addition of chitosan in the existing chitosan gelatin foam are solved;
(2) the tannin is used as a cross-linking agent, has an anti-inflammatory effect on the premise of ensuring the biological safety of the sponge, and can play a synergistic effect with the hemostatic function of the chitosan, so that the wound healing can be accelerated.
(3) The polysaccharide conjugates in the components are prepared by a hydrophilic-hydrophobic co-grafting process, and compared with a scheme of physically mixing a hydrophilic modified polysaccharide conjugate and a hydrophobic modified polysaccharide conjugate, the polysaccharide conjugates are more uniform in group distribution and more stable in property; because the hemostatic material has the hydrophilic group and the hydrophobic group, the hemostatic material can generate physicochemical action with the whole blood component through the hydrophilic-hydrophobic synergistic action, so that the whole blood component is promoted to be quickly gelled within 10-30s, and the hemostatic effect is greatly improved.
Detailed Description
In order to better understand the technical scheme, the technical scheme is described in detail in the following with reference to specific embodiments of the specification.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. Thus, the detailed description of the embodiments of the present invention provided below is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Example 1
In this example, the quick-acting hemostatic sponge comprises gelatin, a polysaccharide conjugate that is an amphiphilic co-grafted polysaccharide conjugate, and a cross-linking agent.
Wherein, the weight ratio of gelatin: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1.
the polysaccharide conjugate in the quick-acting hemostatic sponge comprises the following steps:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid and 100mL of ethanol was added followed by 364uL of caprylic anhydride and 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an lyophilic-hydrophobic co-grafted chitosan conjugate.
The preparation method of the quick-acting hemostatic sponge comprises the following steps:
s1, dissolving 2g of tannic acid in water, adding 30g of gelatin with jelly strength of 300Bloom under stirring, and heating to perform crosslinking reaction to obtain a gelatin solution A;
s2, dissolving 10g of polysaccharide conjugate in dilute acid solution to obtain polysaccharide solution B;
s3, mixing A and B under stirring, introducing nitrogen into the solution to make the pressure in the container reach 2.5 atmospheres, and maintaining the pressure for 3 hours; cooling to-75 deg.C at a speed of 15 deg.C/h, and pre-freezing to form the mixed solution;
and S4, performing vacuum freeze drying treatment on the precursor obtained by solidifying in the S3 to obtain the sponge.
Example 2
This example is the same as example 1 except that the hydrophilic-hydrophobic co-grafted chitosan conjugate was prepared by the following steps:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 45 deg.C, followed by the addition of 0.2g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an lyophilic-hydrophobic co-grafted chitosan conjugate.
Example 3
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an lyophilic-hydrophobic co-grafted chitosan conjugate.
Example 4
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an amphiphilic co-grafted chitosan conjugate.
Example 5
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by 0.154g of dodecanoic anhydride, and 2.38g of EDC and 1.43g of NHS were added. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 4 to 5.0, followed by the sequential addition of 1.03g of 4-carboxyphenylboronic acid, 2.38g of EDC and 1.43g of NHS, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an amphiphilic co-grafted chitosan conjugate.
Example 6
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
2g of hydrophobically modified chitosan was dissolved in 100mL of 0.2M acetic acid, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an amphiphilic co-grafted chitosan conjugate.
Example 7
The gelatin of this example: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran was dissolved in 50mL of deionized water and 50mL of ethanol was added, the pH was adjusted to 5.0, followed by 364uL of caprylic anhydride and 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic-co-grafted aminodextran conjugate.
Example 8
The gelatin of this example: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified annual glucan;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic-co-grafted aminodextran conjugate.
Example 9
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 65 ℃ and the pH is adjusted to 5.0, followed by the addition of 0.154g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran 5 sugar;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic-co-grafted aminodextran conjugate.
Example 10
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic-and-hydrophobic co-grafted aminodextran conjugate.
Example 11
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran are dissolved in 50mL of deionised water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.02g of 4-carboxyphenylboronic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give an amphiphilic co-grafted aminodextran conjugate.
Example 12
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 65 ℃ and the pH is adjusted to 5.0, followed by the addition of 0.154g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
2g of hydrophobically modified aminodextran was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, then 1.19g of 3, 4-dihydroxyphenylpropionic acid, 2.38g of EDC and 1.43g of NHS were added in sequence, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic-co-grafted aminodextran conjugate.
Example 13
The gelatin of this example: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of hyaluronic acid was dissolved in 50mL of deionized water and 50mL of ethanol was added to adjust the pH to 5.0, followed by 219uL of n-octylamine and 1.02g of EDC and 0.61g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
dissolving 2g of hydrophobically modified hyaluronic acid in 50mL of deionized water, aerating nitrogen for 10 minutes, adjusting the pH to 5.0, subsequently adding 0.5g of dopamine hydrochloride, 1.02g of EDC and 0.61g of NHS in sequence, reacting overnight, dialyzing against acidified deionized water for 3 days, and lyophilizing to obtain the hydrophilic-hydrophobic co-grafted hyaluronic acid conjugate.
Example 14
The gelatin of this example: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of hyaluronic acid was dissolved in 50mL of deionized water and 50mL of ethanol was added to adjust the pH to 5.0, followed by 219uL of n-octylamine and 1.02g of EDC and 0.61g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
2g of hydrophobically modified hyaluronic acid was dissolved in 50mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, followed by the sequential addition of 0.46g of 3-aminophenylboronic acid hydrochloride, 1.02g of EDC and 0.61g of NHS, reaction overnight, dialysis against acidified deionized water for 3 days, and lyophilization to give the hydrophobically cografted hyaluronic acid conjugate.
Example 15
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of hyaluronic acid was dissolved in 50mL of deionized water and 50mL of ethanol was added to adjust the pH to 5.0, followed by 219uL of n-octylamine and 1.02g of EDC and 0.61g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
dissolving 1g of hydrophobically modified hyaluronic acid in 50mL of deionized water, aerating nitrogen for 10 minutes, adjusting the pH to 5.0, subsequently adding 0.5g of dopamine hydrochloride, 1.02g of EDC and 0.61g of NHS in sequence, reacting overnight, dialyzing against acidified deionized water for 3 days, and lyophilizing to obtain the hydrophilic-hydrophobic co-grafted hyaluronic acid conjugate.
Example 16
The gelatin of this example: polysaccharide conjugates: crosslinking agent 500: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS were added. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
dissolving 1g of hydrophobically modified sodium alginate in 100mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then adding 0.96g of dopamine hydrochloride, 1.94g of EDC and 1.16g of NHS in sequence, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted sodium alginate conjugate.
Example 17
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS were added. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
1g of hydrophobically modified sodium alginate was dissolved in 100mL of deionized water, purged with nitrogen for 10 minutes, the pH was adjusted to 5.0, followed by the sequential addition of 0.88g of 3-aminophenylboronic acid hydrochloride, 1.94g of EDC and 1.16g of NHS, reacted overnight, dialyzed against acidified deionized water for 3 days, and lyophilized to give the lyophilic co-grafted sodium alginate conjugate.
Example 18
The gelatin of this example: polysaccharide conjugates: the crosslinker is 700: 100: 1; further, unlike example 1, the procedure for preparing the polysaccharide conjugate was:
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS were added. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
dissolving 2g of hydrophobically modified sodium alginate in 100mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then adding 0.96g of dopamine hydrochloride, 1.94g of EDC and 1.16g of NHS in sequence, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted sodium alginate conjugate.
And (3) testing the hemostatic effect:
after the rabbit is successfully anesthetized by intravenous injection of 25% urethane anesthetic (1g/kg) at the ear margin, the abdominal cavity of the rabbit is opened, and the liver of the rabbit is fully exposed. A wound surface of 0.5cm length by 0.5cm depth was prepared with a sharp knife at a distance of about 1cm from the edge of the lobe of the liver. Recording the hemostasis time(s), calculating the bleeding quality of the wound surface (m2-m1)
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A quick-acting hemostatic sponge is characterized in that: the components of the conjugate comprise gelatin, polysaccharide conjugate and a cross-linking agent, wherein the polysaccharide conjugate is hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
2. The quick-acting hemostatic sponge according to claim 1, wherein: the gelatin is as follows: polysaccharide conjugates: 300 parts of a crosslinking agent: 100: 1-700: 100: 1.
3. the quick-acting hemostatic sponge according to claim 1, wherein: the cross-linking agent is tannic acid.
4. The quick-acting hemostatic sponge according to claim 1, wherein: the preparation of the polysaccharide conjugate comprises the following steps:
a1, adding a hydrophobic functional substance and EDC/NHS into a water-soluble polysaccharide solution, grafting the hydrophobic functional substance on a polysaccharide macromolecular main chain through a coupling reaction, and preparing a hydrophobically modified polysaccharide material through precipitation, washing and vacuum drying;
a2, adding a hydrophilic functional substance and EDC/NHS into the hydrophobically modified polysaccharide material prepared in A1, grafting the hydrophilic functional substance on the hydrophobically modified polysaccharide macromolecular main chain through a coupling reaction, and dialyzing and freeze-drying to prepare the hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
5. The quick-acting hemostatic sponge according to claim 4, wherein the polysaccharide conjugate is prepared by the steps of: the water-soluble polysaccharide in A1 and A2 is one or more of chitosan, hydroxymethyl chitosan, carboxypropyl chitosan, chitosan oligosaccharide, sodium alginate, hyaluronic acid and aminodextran; the concentration of the polysaccharide is 10-50 mg/mL.
6. The quick-acting hemostatic sponge according to claim 4, wherein the polysaccharide conjugate is prepared by the steps of:
the hydrophilic functional substance in A1 comprises one or more of 3, 4-dihydroxyphenyl propionic acid, 3,4, 5-trihydroxybenzoic acid, 4-carboxyphenylboronic acid, dopamine hydrochloride and 3-aminophenylboronic acid hydrochloride;
the hydrophobic functional substance in A2 comprises one or more of n-octanoic acid, dodecanoic acid, hexadecanoic acid, caprylic anhydride, dodecanoic anhydride, hexadecanoic anhydride, n-octylamine, n-dodecylamine, n-hexadecylamine and n-octadecylamine.
7. The quick-acting hemostatic sponge according to claim 4, wherein the polysaccharide conjugate is prepared by the steps of: the molar ratio of the polysaccharide dissolved in the step A1 to the added hydrophobic multifunctional substance is 5: 1-20: 1; the molar ratio of the polysaccharide dissolved in the step A2 to the hydrophilic multifunctional substance added is 1: 0.5-1: 2, the molar ratio of the polysaccharide dissolved in A2 to the coupling reaction activator EDC/NHS added was 1: 2: 2.
8. the method for preparing a quick-acting hemostatic sponge according to claim 1, wherein the method comprises the following steps: the method comprises the following steps:
s1, dissolving the cross-linking agent in water, adding gelatin under stirring, heating to make it cross-linking reaction to obtain gelatin solution A;
s2, dissolving the polysaccharide conjugate in dilute acid solution to obtain polysaccharide solution B;
s3, mixing A and B under stirring, foaming and pre-freezing to obtain precursor;
and S4, carrying out vacuum freeze drying treatment on the precursor obtained by solidifying in the S3 to obtain the sponge.
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