Starch-based medical adhesive as well as preparation method and application thereof

Abstract

The invention discloses a starch-based medical adhesive as well as a preparation method and application thereof, and particularly relates to the technical field of biomedical materials. The method comprises the following steps: firstly, adding modified starch 1 into water, and heating, stirring and gelatinizing in an oil bath pan to obtain a modified starch 1 solution; adding the modified starch 2 into water, and heating, stirring and gelatinizing in an oil bath pan to obtain a modified starch 2 solution; mixing the modified starch 1 solution and the modified starch 2 solution, and uniformly stirring to obtain a modified starch compound; and finally, performing low-temperature freezing treatment on the modified starch compound, performing freeze-drying treatment, and crushing the freeze-dried modified starch compound to obtain the starch-based medical adhesive. The medical adhesive disclosed by the invention has good biocompatibility, can be degraded into a non-toxic and harmless product in an organism, has relatively strong wet tissue adhesion strength and good tissue compliance, is simple in process, can directly act on skin wounds, deep wounds and wounds which are difficult to reach by an operation, and is simple and convenient to use.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and particularly relates to a starch-based medical adhesive and its preparation method and application. Background Art

[0002] As the largest organ of the human body, the integrity of the skin's barrier function plays an irreplaceable role in resisting pathogen invasion, regulating water balance, and maintaining the homeostasis of the internal environment. However, mechanical trauma, thermal injury, etc. often lead to skin barrier damage and cause local or systemic complications. Traditional wound closure techniques such as sutures and staplers can provide mechanical support, but there are risks of causing secondary injuries and stress concentration at the perforation site leading to scar formation. Moreover, such closure techniques are difficult to completely close the wound, easily causing tissue fluid leakage and pathogen invasion, thus triggering an inflammatory response and hindering wound healing.

[0003] Currently, the medical adhesives used clinically mainly include cyanoacrylate adhesives and fibrin glue. Chinese patents CN112266337A, CN116392627A, etc. are all cyanoacrylate adhesives. Although cyanoacrylate adhesives can achieve rapid wound closure, due to defects such as non-degradability, heat release during polymerization, and poor tissue compliance, they are prone to cause foreign body reactions or chronic inflammation; Chinese patents CN110711264A, CN109529098A, etc. are all adhesives adding fibrin-related substances. Although fibrin glue has good biocompatibility, its adhesion and mechanical strength are insufficient, and some of its internal components may cause allergic reactions in organisms.

[0004] An ideal medical adhesive should simultaneously meet the following properties: 1. Good biocompatibility (avoiding foreign body or allergic reactions); 2. Degradability and non-toxic degradation by-products; 3. Good wet tissue adhesion (able to overcome the influence of interfacial water on adhesion); 4. Good tissue compliance (adapting to tissue deformation and avoiding stress concentration).

[0005] Starch is a natural high-molecular polysaccharide formed by the polymerization of D-glucose through α-glycosidic bonds, and its molecular structure has significant heterogeneity: Amylose linearly connects glucose units through α-1,4-glycosidic bonds to form an unbranched chain structure; amylopectin presents a highly branched topological structure, with its main chain composed of α-1,4-glycosidic bonds, and side chains branch out every 24-30 glucose residues through α-1,6-glycosidic bonds. Moreover, these branch points are not randomly distributed but show a clustered periodic arrangement, and short side chains orderly aggregate along the main chain at nanoscale intervals to form a clustered supramolecular assembly. This unique clustered topological structure endows starch granules with the characteristics of high-density packing and forms locally ordered semi-crystalline regions through hydrogen bonding between molecular chains, which is also the core feature that differentiates starch from other polysaccharides. The aggregated structure of starch molecules has a decisive influence on its physical and chemical properties. In natural starch granules, amylose molecules are mainly distributed in the amorphous region, while the clustered branches of amylopectin molecules form a double-helix structure and are orderly arranged to form crystalline regions. This semi-ordered structure makes starch granules insoluble in water at room temperature, but gelatinization occurs in high-temperature aqueous solutions, that is, when the temperature exceeds the initial gelatinization temperature, water molecules will penetrate into the interior of the granules, destroying the crystalline structure and stretching the molecular chains.

[0006] Due to the unique molecular and aggregated structure of starch, it has good biocompatibility and biodegradability, and is a medical adhesive material with great potential. For example, in Chinese patents CN101497670A, CN108753202A, etc. However, such starch adhesives mainly have a hemostatic function, and adhesion is an auxiliary function, and the strength for adhesion alone is insufficient. After adhesion, movement will cause cracking or peeling, and the effect is not good; Chinese patent CN119552532A discloses a preparation method of a starch adhesive for corrugated paper. Although the starch adhesive in this patent is also modified starch, its modification uses aldehyde group modification. Although it has high adhesive ability, its toxicity after aldehyde group modification limits its application in medical adhesives. Summary of the Invention

[0007] Therefore, the present invention provides a starch-based medical adhesive, its preparation method and application to solve the problems in the prior art.

[0008] Natural starch itself has two problems. One is that there are lack of functional groups (only hydroxyl groups) in its molecular chain structure. The other is that natural starch granules are semi-crystalline structures, and these crystal regions limit the dissolution of starch granules like cross-linking points. The limitations in these two aspects make it difficult for natural starch granules to be used as bioadhesives. Therefore, starting from these two aspects, the present invention introduces functional groups through chemical modification, and then destroys its crystal structure through a gelatinization process to enhance the molecular diffusion effect. By using both methods simultaneously, the adhesion strength of the material of the present invention to wet tissues has been greatly improved. For a single modified starch, its crystal structure is not destroyed, still limiting the solubility of the material, resulting in a very low bonding strength between the two modified starches (low bulk strength), and also a low bonding strength between the material and tissues (low interfacial adhesion strength).

[0009] To achieve the above object, the present invention provides the following technical solutions: A preparation method of a starch-based medical adhesive according to the first aspect of the present invention, the method comprising: Step 1, pretreatment of modified starch Add modified starch 1 into water, heat and stir for gelatinization in an oil bath to obtain a modified starch 1 solution; add modified starch 2 into water, heat and stir for gelatinization in an oil bath to obtain a modified starch 2 solution; Step 2, mixing Mix the modified starch 1 solution and the modified starch 2 solution, stir evenly to obtain a modified starch complex; Step 3, freezing, drying and pulverizing First, subject the modified starch complex to cryogenic freezing treatment, then perform freeze-drying treatment, and pulverize the freeze-dried modified starch complex to obtain a starch-based medical adhesive.

[0010] Further, the modified starch 1 is one or more of carboxymethylated starch, carboxyethylated starch, carboxypropylated starch, phosphated starch, xanthated starch, citrated starch, acetylated starch, acetylated diphosphate starch.

[0011] Preparation method of modified starch 1: Add NaOH into deionized water, stir to dissolve and then add isopropanol, stir and heat to 40 °C. Subsequently, add starch, and introduce nitrogen gas. After stirring for 1 h, add sodium chloroacetate / ethylene oxide / propylene oxide / phosphate / citrate / xanthate / acetic anhydride, and react for 3 h. After the reaction is completed, filter the obtained slurry, and wash the obtained product 5 times with an 85% ethanol solution. Then wash with absolute ethanol, filter and dry to obtain a modified starch 1 sample.

[0012] Furthermore, the modified starch 2 is starch modified with a quaternary ammonium salt and / or starch modified with a tertiary aminoalkyl group.

[0013] Preparation method of modified starch 2: First, sodium hydroxide was dissolved in deionized water and stirred magnetically until the solution was clear; at the same time, 2,3-epoxypropyltrimethylammonium chloride / 2,3-epoxypropyl-N,N-dialkylamine was dispersed in deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, starch was evenly dispersed in deionized water, and the above NaOH / EPTAC (or NaOH / DAEPA) mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction was completed, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally modified starch 2 was obtained by freeze drying and crushing and sieving.

[0014] The modified starch 1 and modified starch 2 selected by the present invention have wet tissue adhesion, while other modified starches (such as N,N-dimethyldecylamine modified) or some modified starches that also carry positive and negative charge groups are insufficient in solubility and adhesion strength.

[0015] Furthermore, the starch is one or more of bean starch, potato starch, sweet potato starch, potato starch, cereal starch, wheat starch, water chestnut starch, lotus root starch, and corn starch.

[0016] Furthermore, in step 1, the heating temperature is 40-300° C. Below 40° C., it is easy to cause gelatinization failure or incomplete gelatinization, and dissolving or lowering the gelatinization temperature by solvent method involves the following two problems: one is the solubility temperature, and the existing solvents usually have low solubility in dissolving starch at room temperature; the other is the biosafety problem, and the commonly used starch solvents are mostly organic reagents, which have certain toxicity problems, and it is difficult to completely remove the solvent during the preparation process.

[0017] Furthermore, in the step 1, the concentrations of the modified starch 1 solution and the modified starch 2 solution are both 0.1%-10%.

[0018] Furthermore, in the step 2, the mass ratio of the modified starch 1 solution to the modified starch 2 solution is 0.1-0.9:0.9-0.1.

[0019] Furthermore, in step three, the low-temperature freezing temperature is -10 to -270°C.

[0020] According to the second aspect of the present invention, a starch-based medical adhesive is provided, characterized in that the starch-based medical adhesive is prepared by the above-mentioned method for preparing the starch-based medical adhesive.

[0021] Use of a starch-based medical adhesive provided by the third aspect of the present invention in the preparation of materials related to wound closure.

[0022] The present invention has the following advantages: The medical adhesive of the present invention has good biocompatibility, can be degraded in vivo and the degradation products are non-toxic and harmless. It has strong wet tissue adhesion strength and good tissue compliance. The process is simple and it can be directly applied to skin wounds, deep wounds and wounds in areas difficult to reach by surgery, and is simple and convenient to use.

[0023] In the present invention, two kinds of modified starches are gelatinized, which destroys the microcrystalline regions in the structure of the modified starches. The existence of the microcrystalline regions will limit the solubility of the modified starches and the exposure of active groups. After gelatinization, the molecular chains of the modified starches stretch, exposing more active groups, and the molecular chain diffusion ability is enhanced. Compared with the method of directly mixing the two kinds of modified starches, the starch-based medical adhesive in the present invention has a fluffy structure, increasing the hygroscopicity and adhesiveness of the adhesive. Moreover, the cross-linking method of the two kinds of gelatinized modified starches is through positive and negative electrostatic interactions, that is, physical cross-linking, making the material have good self-healing and dynamic adaptability. That is, the starch-based medical adhesive of the present invention can be directly applied to the wound site, quickly absorb tissue exudate, in-situ solidify and form a stable and strong adhesion, thereby achieving rapid wound closure, and forming a strong adhesion with the tissue after use, not easy to peel off, adapting to the dynamic movement of the tissue, and can be applied to the closure of wounds in dynamic movement parts. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only exemplary, and for those of ordinary skill in the art, without creative efforts, other implementation drawings can be obtained according to the provided drawings.

[0025] The structures, ratios, sizes, etc. illustrated in this specification are only used to cooperate with the content disclosed in the specification for those who are familiar with this technology to understand and read, and are not used to limit the limiting conditions under which the present invention can be implemented. Therefore, they do not have technical substance significance. Any modification of the structure, change of the proportional relationship or adjustment of the size, without affecting the effects that the present invention can produce and the purposes that can be achieved, should still fall within the scope that the technical content disclosed by the present invention can cover.

[0026] Figure 1 Tensile test diagram after bonding of the starch-based medical adhesive 1 provided in Experimental Example 4 of the present invention; Figure 2This is a test diagram of tissue compliance after bonding with the starch-based medical adhesive 2 provided in Experimental Example 4 of the present invention; Figure 3 This is a scanning electron microscope image of the cross-linked structure of the starch-based medical adhesive 5 provided in Experimental Example 4 of the present invention; Figure 4 The starch-based medical adhesive 3 provided in Experimental Example 4 of the present invention is a picture of the rat back skin after bonding; Figure 5 This is a diagram showing the cytotoxicity experiment of the starch-based medical adhesive 4 provided in Experimental Example 4 of the present invention; Figure 6 The bursting pressure test diagram of the starch-based medical adhesive 5 obtained in Experimental Example 5 provided in Experimental Example 4 of the present invention and the non-gelatinized starch-based medical adhesive 1 obtained in Comparative Example 1, wherein CMS / QS represents starch-based medical adhesive 5, and CMS / QS-Mix represents non-gelatinized starch-based medical adhesive 1. DETAILED DESCRIPTION

[0027] The following is a description of the implementation of the present invention by specific embodiments. People familiar with the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Example 1 This embodiment provides a method for preparing a starch-based medical adhesive: Corn starch modified with quaternary ammonium salt: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water and stirred magnetically until the solution was clear; at the same time, 3 g of 2,3-epoxypropyltrimethylammonium chloride was dispersed in 20 mL of deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, 3 g of corn starch was evenly dispersed in 100 mL of deionized water, and the above NaOH / EPTAC mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction was completed, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally the corn starch powder sample modified with quaternary ammonium salt was obtained by freeze drying and crushing and sieving.

[0029] Carboxymethyl-modified corn starch: Add 3 g of NaOH to 8 mL of deionized water. After stirring and dissolving, add 100 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 7.5 g of corn starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of sodium chloroacetate and react for 3 h. After the reaction is completed, filter the resulting slurry, and wash the obtained product 5 times with 85% ethanol solution. Then wash with absolute ethanol, filter and dry to obtain a carboxymethyl-modified starch powder sample.

[0030] S1, Weigh 1 g of quaternary ammonium salt-modified corn starch and add it to 100 mL of deionized water. In an oil bath at 60 °C, stir magnetically at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1. S2, Weigh 5 g of carboxymethyl-modified corn starch and add it to 500 mL of deionized water. In an oil bath at 60 °C, stir magnetically at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2. S3, Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm, and stir for 20 min until the complex is uniform to obtain a modified starch complex. S4, Place the stirred and uniform modified starch complex in a refrigerator at -20 °C and freeze it for 12 h. S5, Lyophilize the frozen modified starch complex in a lyophilizer for 48 h until the modified starch complex is completely dry. S6, Grind the lyophilized modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain starch-based medical adhesive 1.

[0031] Example 2 This example provides a method for preparing a starch-based medical adhesive: Quaternary ammonium salt-modified corn starch: The same as in Example 1.

[0032] Carboxyethyl-modified corn starch: Add 3 g of NaOH to 20 mL of deionized water. After stirring and dissolving, add 100 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 5 g of corn starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of ethylene oxide and react for 3 h. After the reaction is completed, filter the resulting slurry, and wash the obtained product 5 times with 85% ethanol solution. Then wash with absolute ethanol, filter and dry to obtain a carboxyethyl-modified corn starch powder sample.

[0033] S1, Weigh 2 g of quaternary ammonium salt-modified corn starch and add it to 100 mL of deionized water. In an oil bath at 200 °C, stir magnetically at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1. S2. Weigh 8 g of carboxyethyl-modified corn starch and add it to 400 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 200 °C for 3 h until the modified starch is completely gelatinized, obtaining the modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous, obtaining the modified starch complex. S4. Freeze the well-stirred modified starch complex in a refrigerator at -20 °C for 24 h. S5. Lyophilize the frozen modified starch complex in a lyophilizer for 48 h until the modified starch complex is completely dry. S6. Grind the lyophilized modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain the starch-based medical adhesive 2.

[0034] Example 3 This example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified corn starch: The same as in Example 1.

[0035] Carboxypropyl-modified corn starch: Add 3 g of NaOH to 20 mL of deionized water, stir to dissolve it, then add 100 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 5 g of corn starch, and introduce nitrogen. After stirring for 1 h, add 10 g of propylene oxide and react for 3 h. After the reaction is completed, filter the obtained slurry, and wash the product 5 times with an 85% ethanol solution. Then wash it with absolute ethanol, filter and dry it to obtain the carboxypropyl-modified corn starch powder sample.

[0036] S1. Weigh 3 g of quaternary ammonium salt-modified corn starch and add it to 100 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 80 °C for 3 h until the modified starch is completely gelatinized, obtaining the modified starch 1 solution. S2. Weigh 9 g of carboxypropyl-modified corn starch and add it to 300 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 80 °C for 3 h until the modified starch is completely gelatinized, obtaining the modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous, obtaining the modified starch complex. S4. Freeze the well-stirred modified starch complex in a refrigerator at -20 °C for 60 h. S5. Lyophilize the frozen modified starch complex in a lyophilizer for 48 h until the modified starch complex is completely dry. S6. Crush the freeze-dried modified starch complex in a pulverizer for 10 min, and repeat the crushing 5 times to obtain the starch-based medical adhesive 3.

[0037] Example 4 This example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified corn starch: The same as in Example 1.

[0038] Phosphate ester-modified corn starch: Add 2 g of NaOH to 80 mL of deionized water, stir to dissolve, then add 20 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 3 g of corn starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of phosphate, and react for 3 h. After the reaction is completed, filter the obtained slurry, and wash the product 5 times with an 85% ethanol solution. Then wash with absolute ethanol, filter, and dry to obtain a phosphate ester-modified corn starch powder sample.

[0039] S1. Weigh 4 g of quaternary ammonium salt-modified corn starch and add it to 100 mL of deionized water. Magnetically stir at 800 rpm in an oil bath at 220 °C for 3 h until the modified starch is completely gelatinized to obtain the modified starch 1 solution; S2. Weigh 8 g of phosphate ester-modified corn starch and add it to 200 mL of deionized water. Magnetically stir at 800 rpm in an oil bath at 220 °C for 3 h until the modified starch is completely gelatinized to obtain the modified starch 2 solution; S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous to obtain the modified starch complex; S4. Place the stirred homogeneous modified starch complex in a refrigerator at -40 °C and freeze it for 12 h; S5. Lyophilize the frozen modified starch complex in a lyophilizer for 48 h until the modified starch complex is completely dry; S6. Crush the freeze-dried modified starch complex in a pulverizer for 10 min, and repeat the crushing 5 times to obtain the starch-based medical adhesive 4.

[0040] Example 5 This example provides a preparation method of a starch-based medical adhesive: Tertiary amino group - modified corn starch: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water, and magnetically stirred until the solution was clear. At the same time, 3 g of 2,3 - epoxypropyl - N,N - dialkylamine was dispersed in 20 mL of deionized water and stirred until completely dissolved. Subsequently, the two solutions were mixed and fully homogenized. Then, 3 g of corn starch was evenly dispersed in 100 mL of deionized water, and the above - mentioned NaOH / DAEPA mixture was added dropwise at a constant speed, and the graft modification was completed by reacting at 40 °C under constant temperature for 24 h. After the reaction, the crude product was dialyzed with deionized water for 3 days (changing water 3 - 4 times a day) to remove unreacted small - molecule impurities. Finally, the tertiary amino group - modified corn starch powder sample was obtained through freeze - drying and pulverizing and sieving.

[0041] Citrate - modified corn starch: 1 g of NaOH was added to 80 mL of deionized water, stirred until dissolved, then 20 mL of isopropanol was added, and the mixture was stirred and heated to 40 °C. Subsequently, 7.5 g of corn starch was added, and nitrogen was introduced. After stirring for 1 h, 4.5 g of citrate was added and the reaction was carried out for 3 h. After the reaction, the obtained slurry was filtered, and the product was washed 5 times with 85% ethanol solution. Subsequently, it was washed with absolute ethanol, filtered, and dried to obtain the citrate - modified corn starch powder sample.

[0042] S1, Weigh 5 g of tertiary amino group - modified corn starch and add it to 100 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 100 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1; S2, Weigh 5 g of citrate - modified corn starch and add it to 100 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 100 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2; S3, Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm, and stir for 20 min until the complex is uniform to obtain the modified starch complex; S4, Place the stirred - uniform modified starch complex in a refrigerator at - 40 °C and freeze it for 24 h; S5, Lyophilize the frozen modified starch complex in a lyophilizer for 48 h until the modified starch complex is completely dry; S6, Pulverize the lyophilized modified starch complex in a pulverizer for 10 min and repeat the pulverization 5 times to obtain the starch - based medical adhesive 5.

[0043] Example 6 This example provides a preparation method of a starch - based medical adhesive: Potato starch modified with tertiary amino groups: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water and stirred magnetically until the solution was clear; at the same time, 3 g of 2,3-epoxypropyl-N,N-dialkylamine was dispersed in 20 mL of deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, 3 g of potato starch was evenly dispersed in 100 mL of deionized water, and the above NaOH / DAEPA mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction was completed, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally the tertiary amino-modified potato starch powder sample was obtained by freeze drying and crushing and sieving.

[0044] Potato starch modified with xanthate: 3 g of NaOH was added to 50 mL of deionized water, and 50 mL of isopropanol was added after stirring to dissolve, and the mixture was stirred and heated to 40 °C. Subsequently, 5 g of potato starch was added, and nitrogen was introduced. After stirring for 1 h, 7.5 g of xanthate was added and reacted for 3 h. After the reaction, the obtained slurry was filtered, and the obtained product was washed with 85% ethanol solution for 5 times. Subsequently, the xanthate-modified potato starch powder sample was obtained by washing with anhydrous ethanol, filtering, and drying.

[0045] S1, weigh 12 g of potato starch modified with tertiary amino groups and add it to 200 mL of deionized water, stir it in an oil bath at 240 °C with magnetic stirring at 800 rpm for 3 h until the modified starch is completely gelatinized, to obtain modified starch 1 solution; S2, weigh 6 g of xanthate-modified potato starch and add it to 100 mL of deionized water, stir it in an oil bath at 240 °C with magnetic stirring at 800 rpm for 3 h until the modified starch is completely gelatinized, to obtain modified starch 2 solution; S3, mixing the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, stirring for 20 min until the complex is uniform, to obtain a modified starch complex; S4, freezing the uniformly stirred modified starch complex in a -40 ℃ refrigerator for 48 h; S5, freeze-drying the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6, pulverizing the freeze-dried modified starch complex in a pulverizer for 10 min, repeating the pulverization 5 times, and obtaining a starch-based medical adhesive 6.

[0046] Example 7 This embodiment provides a method for preparing a starch-based medical adhesive: Tertiary amino-modified potato starch: same as Example 6.

[0047] Acetate-modified potato starch: Add 0.1 g of NaOH to 90 mL of deionized water, stir to dissolve, then add 10 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 5 g of potato starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of acetic anhydride and react for 3 h. After the reaction, filter the resulting slurry, and wash the obtained product 5 times with 85% ethanol solution. Then wash with anhydrous ethanol, filter and dry to obtain the acetate-modified potato starch powder sample.

[0048] S1, Weigh 21 g of tertiary amino group-modified potato starch and add it to 300 mL of deionized water. Magnetically stir at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1; S2, Weigh 7 g of acetate-modified potato starch and add it to 100 mL of deionized water. Magnetically stir at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2; S3, Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous to obtain the modified starch complex; S4, Place the stirred homogeneous modified starch complex in a refrigerator at -40 °C and freeze it for 60 h; S5, Lyophilize the frozen modified starch complex in a lyophilizer for 72 h until the modified starch complex is completely dry; S6, Grind the lyophilized modified starch complex in a grinder for 10 min, and repeat the grinding 5 times to obtain the starch-based medical adhesive 7.

[0049] Example 8 This example provides a preparation method of a starch-based medical adhesive: Tertiary amino group-modified potato starch: The same as in Example 6.

[0050] Carboxymethylated modified potato starch: Add 3 g of NaOH to 8 mL of deionized water, stir to dissolve, then add 100 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 7.5 g of potato starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of sodium chloroacetate and react for 3 h. After the reaction, filter the resulting slurry, and wash the obtained product 5 times with 85% ethanol solution. Then wash with anhydrous ethanol, filter and dry to obtain the carboxymethylated modified potato starch powder sample.

[0051] S1. Weigh 32 g of tertiary amino group-modified potato starch and add it to 400 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 260 °C for 3 h until the modified starch is completely gelatinized, obtaining modified starch 1 solution. S2. Weigh 8 g of carboxymethylated potato starch and add it to 100 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 260 °C for 3 h until the modified starch is completely gelatinized, obtaining modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous, obtaining a modified starch complex. S4. Place the evenly stirred modified starch complex in a refrigerator at -80 °C for cryogenic freezing for 12 h. S5. Lyophilize the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry. S6. Grind the lyophilized modified starch complex in a grinder for 10 min, and repeat the grinding 5 times to obtain starch-based medical adhesive 8.

[0052] Example 9 This example provides a preparation method of a starch-based medical adhesive: Tertiary amino group-modified potato starch: The same as in Example 6.

[0053] Carboxyethyl-modified potato starch: Add 3 g of NaOH to 20 mL of deionized water, stir to dissolve it, then add 100 mL of isopropanol, stir and heat to 40 °C. Subsequently, add 5 g of potato starch, and introduce nitrogen. After stirring for 1 h, add 7.5 g of ethylene oxide and react for 3 h. After the reaction ends, filter the obtained slurry, and wash the product 5 times with 85% ethanol solution. Then wash it with absolute ethanol, filter and dry to obtain a carboxyethyl-modified potato starch powder sample.

[0054] S1. Weigh 45 g of tertiary amino group-modified potato starch and add it to 500 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 140 °C for 3 h until the modified starch is completely gelatinized, obtaining modified starch 1 solution. S2. Weigh 9 g of carboxyethyl-modified potato starch and add it to 100 mL of deionized water. Magnetically stir it at 800 rpm in an oil bath at 140 °C for 3 h until the modified starch is completely gelatinized, obtaining modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 20 min until the complex is homogeneous, obtaining a modified starch complex. S4, freezing the uniformly stirred modified starch complex in a -80 ℃ refrigerator for 24 h; S5, freeze-drying the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6, grinding the freeze-dried modified starch complex in a grinder for 10 min, repeating the grinding 5 times to obtain a starch-based medical adhesive 9.

[0055] Example 10 This embodiment provides a method for preparing a starch-based medical adhesive: Wheat starch modified with tertiary amino groups: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water and stirred magnetically until the solution was clear; at the same time, 3 g of 2,3-epoxypropyl-N,N-dialkylamine was dispersed in 20 mL of deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, 3 g of wheat starch was evenly dispersed in 100 mL of deionized water, and the above NaOH / DAEPA mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction was completed, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally the tertiary amino-modified wheat starch powder sample was obtained by freeze drying and crushing and sieving.

[0056] Carboxypropyl-modified wheat starch: Add 3 g of NaOH to 20 mL of deionized water, stir to dissolve, then add 100 mL of isopropanol, stir and heat to 40 °C. Then, add 5 g of wheat starch, pass nitrogen, stir for 1 h, add 10 g of propylene oxide, and react for 3 h. After the reaction, filter the resulting slurry, and wash the product with 85% ethanol solution 5 times. Then wash with anhydrous ethanol, filter and dry to obtain a carboxypropyl-modified wheat starch powder sample.

[0057] S1, weigh 5 g of wheat starch modified with tertiary amino groups and add it to 100 mL of deionized water, stir it in an oil bath at 280 °C at 800 rpm for 3 h until the modified starch is completely gelatinized, and obtain modified starch 1 solution; S2, weigh 10 g of carboxypropyl-modified wheat starch and add it to 100 mL of deionized water, stir it in an oil bath at 280 °C at 800 rpm for 3 h until the modified starch is completely gelatinized, to obtain modified starch 2 solution; S3, mixing the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, stirring for 15 min until the complex is uniform, to obtain a modified starch complex; S4, freezing the uniformly stirred modified starch complex in a -80 ℃ refrigerator for 48 h; S5, freeze-drying the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6, grinding the freeze-dried modified starch complex in a grinder for 10 min, repeating the grinding 5 times to obtain a starch-based medical adhesive 10.

[0058] Embodiment 11 This embodiment provides a method for preparing a starch-based medical adhesive: Soybean starch modified with quaternary ammonium salt: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water and stirred magnetically until the solution was clear; at the same time, 3 g of 2,3-epoxypropyltrimethylammonium chloride was dispersed in 20 mL of deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, 3 g of soybean starch was evenly dispersed in 100 mL of deionized water, and the above NaOH / EPTAC mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction was completed, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally the soybean starch powder sample modified with quaternary ammonium salt was obtained by freeze drying and crushing and sieving.

[0059] Carboxyethyl modified soybean starch: 3 g NaOH was added to 20 mL deionized water, stirred to dissolve, and then 100 mL isopropanol was added, stirred and heated to 40 °C. Subsequently, 5 g soybean starch was added, and nitrogen was introduced. After stirring for 1 h, 7.5 g ethylene oxide was added and reacted for 3 h. After the reaction was completed, the obtained slurry was filtered, and the obtained product was washed 5 times with 85% ethanol solution. Subsequently, it was washed with anhydrous ethanol, filtered and dried to obtain a carboxyethyl modified soybean starch powder sample.

[0060] S1, weigh 5 g of quaternary ammonium salt-modified soybean starch and add it to 100 mL of deionized water, stir it in an oil bath at 160 °C at 800 rpm for 3 h until the modified starch is completely gelatinized, to obtain modified starch 1 solution; S2, weigh 10 g of carboxyethyl-modified soybean starch and add it to 200 mL of deionized water, stir it in an oil bath at 160 °C at 800 rpm for 3 h until the modified starch is completely gelatinized, and obtain modified starch 2 solution; S3, mixing the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, stirring for 15 min until the complex is uniform, to obtain a modified starch complex; S4, freezing the uniformly stirred modified starch complex in a -80 ℃ refrigerator for 48 h; S5, freeze-drying the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6, grinding the freeze-dried modified starch complex in a grinder for 10 min, repeating the grinding 5 times to obtain a starch-based medical adhesive 11.

[0061] Example 12 This embodiment provides a method for preparing a starch-based medical adhesive: Lotus root starch modified with quaternary ammonium salt: First, 0.9 g of sodium hydroxide was dissolved in 5 mL of deionized water and stirred magnetically until the solution was clear; at the same time, 3 g of 2,3-epoxypropyltrimethylammonium chloride was dispersed in 20 mL of deionized water and stirred until completely dissolved, and then the two solutions were mixed and fully homogenized. Next, 3 g of lotus root starch was evenly dispersed in 100 mL of deionized water, and the above NaOH / EPTAC mixture was added dropwise at a uniform rate, and reacted at a constant temperature of 40 °C for 24 h to complete the grafting modification. After the reaction, the crude product was dialyzed with deionized water for 3 days (changing the water 3-4 times a day) to remove unreacted small molecular impurities, and finally the lotus root starch powder sample modified with quaternary ammonium salt was obtained by freeze drying and crushing and sieving.

[0062] Carboxymethyl-modified lotus root starch: 3 g NaOH was added to 8 mL deionized water, and 100 mL isopropanol was added after stirring to dissolve, and the mixture was stirred and heated to 40 °C. Subsequently, 7.5 g lotus root starch was added, and nitrogen was introduced. After stirring for 1 h, 7.5 g sodium chloroacetate was added and reacted for 3 h. After the reaction, the obtained slurry was filtered, and the obtained product was washed 5 times with 85% ethanol solution. Subsequently, the product was washed with anhydrous ethanol, filtered, and dried to obtain a carboxymethyl-modified lotus root starch powder sample.

[0063] S1, weigh 2 g of lotus root starch modified with quaternary ammonium salt and add it into 200 mL of deionized water, stir it in an oil bath at 300 °C and 800 rpm for 3 h until the modified starch is completely gelatinized, and obtain modified starch 1 solution; S2, weigh 2 g of carboxymethyl-modified lotus root starch and add it to 200 mL of deionized water, stir it in a 300 °C oil bath at 800 rpm for 3 h until the modified starch is completely gelatinized, and obtain modified starch 2 solution; S3, mixing the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, stirring for 15 min until the complex is uniform, to obtain a modified starch complex; S4, freezing the uniformly stirred modified starch complex in a -80 ℃ refrigerator for 48 h; S5, freeze-drying the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6. Pulverize the freeze-dried modified starch complex in a pulverizer for 10 min and repeat the pulverization 5 times to obtain starch-based medical adhesive 12.

[0064] Example 13 This example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0065] S1. Weigh 0.2 g of quaternary ammonium salt-modified lotus root starch and add it to 200 mL of deionized water. Magnetically stir it in an oil bath at 300 °C at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1. S2. Weigh 1.8 g of carboxymethyl-modified lotus root starch and add it to 200 mL of deionized water. Magnetically stir it in an oil bath at 300 °C at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2. S3. Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm and stir for 15 min until the complex is uniform to obtain a modified starch complex. S4. Quench the stirred modified starch complex in liquid nitrogen for 1 h. S5. Freeze-dry the frozen modified starch complex in a freeze-dryer for 72 h until the modified starch complex is completely dry. S6. Pulverize the freeze-dried modified starch complex in a pulverizer for 10 min and repeat the pulverization 5 times to obtain starch-based medical adhesive 13.

[0066] Example 14 This example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0067] S1. Weigh 1 g of quaternary ammonium salt-modified lotus root starch and add it to 200 mL of deionized water. Magnetically stir it in an oil bath at 300 °C at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1. S2. Weigh 8 g of carboxymethyl-modified lotus root starch and add it to 400 mL of deionized water. Magnetically stir it in an oil bath at 300 °C at 800 rpm for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2. S3. Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm and stir for 15 min until the complex is uniform to obtain a modified starch complex. S4. Quench the uniformly stirred modified starch complex in liquid nitrogen for 2 h; S5. Freeze-dry the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6. Grind the freeze-dried modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain starch-based medical adhesive 14.

[0068] Example 15 This example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0069] S1. Weigh 7 g of quaternary ammonium salt-modified lotus root starch and add it to 350 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 300 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1; S2. Weigh 1 g of carboxymethyl-modified lotus root starch and add it to 200 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 300 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2; S3. Mix the completely gelatinized modified starch solution 1 and modified starch solution 2 under magnetic stirring at 800 rpm and stir for 15 min until the complex is uniform to obtain a modified starch complex; S4. Quench the uniformly stirred modified starch complex in liquid nitrogen for 3 h; S5. Freeze-dry the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6. Grind the freeze-dried modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain starch-based medical adhesive 15.

[0070] Comparative Example 1 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0071] S1. Weigh 0.1 g of quaternary ammonium salt-modified lotus root starch and add it to 200 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 1; S2. Weigh 0.8 g of carboxymethyl-modified lotus root starch and add it to 400 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain modified starch solution 2; S3. Mix the fully gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 15 min until the complex is homogeneous to obtain a modified starch complex; S4. Cryogenically freeze the stirred homogeneous modified starch complex in a -80 °C refrigerator for 48 h; S5. Lyophilize the frozen modified starch complex in a lyophilizer for 72 h until the modified starch complex is completely dry; S6. Grind the lyophilized modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain a low-concentration starch-based medical adhesive 1.

[0072] Comparative Example 2 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0073] S1. Weigh 50 g of quaternary ammonium salt-modified lotus root starch and add it to 100 mL of deionized water. Under magnetic stirring at 800 rpm in an oil bath at 120 °C, stir for 3 h until the modified starch is completely gelatinized to obtain a modified starch 1 solution; S2. Weigh 100 g of carboxymethyl-modified lotus root starch and add it to 200 mL of deionized water. Under magnetic stirring at 800 rpm in an oil bath at 120 °C, stir for 3 h until the modified starch is completely gelatinized to obtain a modified starch 2 solution; S3. Mix the fully gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 15 min until the complex is homogeneous to obtain a modified starch complex; S4. Cryogenically freeze the stirred homogeneous modified starch complex in a -80 °C refrigerator for 48 h; S5. Lyophilize the frozen modified starch complex in a lyophilizer for 72 h until the modified starch complex is completely dry; S6. Grind the lyophilized modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain a high-concentration starch-based medical adhesive 1.

[0074] Comparative Example 3 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0075] S1. Weigh 0.05 g of quaternary ammonium salt-modified lotus root starch and add it to 1 mL of deionized water. Under magnetic stirring at 800 rpm in an oil bath at 120 °C, stir for 3 h until the modified starch is completely gelatinized to obtain a modified starch 1 solution; S2. Weigh 10 g of carboxymethyl-modified lotus root starch and add it to 200 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized, obtaining a modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 15 min until the complex is homogeneous, obtaining a modified starch complex. S4. Place the well-stirred modified starch complex in a refrigerator at -80 °C for cryogenic freezing for 48 h. S5. Lyophilize the frozen modified starch complex in a lyophilizer for 72 h until the modified starch complex is completely dry. S6. Grind the lyophilized modified starch complex in a grinder for 10 min, and repeat the grinding 5 times to obtain a low-proportion starch-based medical adhesive 1.

[0076] Comparative Example 4 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified lotus root starch: the same as in Example 12. Carboxymethyl-modified lotus root starch: the same as in Example 12.

[0077] S1. Weigh 15 g of quaternary ammonium salt-modified lotus root starch and add it to 300 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized, obtaining a modified starch 1 solution. S2. Weigh 0.1 g of carboxymethyl-modified lotus root starch and add it to 2 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized, obtaining a modified starch 2 solution. S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm, and stir for 15 min until the complex is homogeneous, obtaining a modified starch complex. S4. Place the well-stirred modified starch complex in a refrigerator at -80 °C for cryogenic freezing for 48 h. S5. Lyophilize the frozen modified starch complex in a lyophilizer for 72 h until the modified starch complex is completely dry. S6. Grind the lyophilized modified starch complex in a grinder for 10 min, and repeat the grinding 5 times to obtain a low-proportion starch-based medical adhesive 2.

[0078] Comparative Example 5 This comparative example provides a preparation method of a starch-based medical adhesive: Tertiary amino group-modified potato starch and acetate-modified potato starch are the same as in Example 7.

[0079] S1. Weigh 2 g of tertiary amino group-modified potato starch and 2 g of acetate-modified potato starch; S2. Grind the two kinds of modified starches in a grinder for 10 min respectively; S3. Mix the ground two kinds of modified starches to obtain non-gelatinized starch-based medical adhesive 1.

[0080] Comparative Example 6 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified corn starch and carboxymethylated corn starch are the same as those in Example 1.

[0081] S1. Weigh 2 g of quaternary ammonium salt-modified corn starch and 4 g of carboxymethylated corn starch; S2. Grind the two kinds of modified starches in a grinder for 10 min respectively; S3. Mix the ground two kinds of modified starches to obtain non-gelatinized starch-based medical adhesive 2.

[0082] Comparative Example 7 This comparative example provides a preparation method of a starch-based medical adhesive: Quaternary ammonium salt-modified corn starch is the same as that in Example 1.

[0083] S1. Weigh 10 g of quaternary ammonium salt-modified corn starch; S2. Add the modified starch into 500 mL of deionized water, and magnetically stir it in an oil bath at 300 °C with a speed of 800 rpm for 3 h until the modified starch is completely gelatinized; S3. Freeze the gelatinized modified starch in a refrigerator at -80 °C for 48 h; S4. Lyophilize the frozen modified starch in a lyophilizer for 72 h until the modified starch complex is completely dry; S5. Grind the lyophilized modified starch in a grinder for 10 min, and repeat the grinding 5 times to obtain single-component starch-based medical adhesive 1.

[0084] Comparative Example 8 This comparative example provides a preparation method of a starch-based medical adhesive: Carboxymethylated corn starch is the same as that in Example 1.

[0085] S1. Weigh 10 g of carboxymethyl-modified corn starch; S2. Add the modified starch into 500 mL of deionized water, and magnetically stir it in an oil bath at 300 °C with a speed of 800 rpm for 3 h until the modified starch is completely gelatinized; S3. Freeze the gelatinized modified starch in a refrigerator at -80 °C for 48 h; S4. Freeze-dry the frozen modified starch in a freeze dryer for 72 h until the modified starch complex is completely dry; S5. Grind the freeze-dried modified starch in a grinder for 10 min and repeat the grinding 5 times to obtain the single-component starch-based medical adhesive 2.

[0086] Comparative Example 9 This comparative example provides a preparation method of a starch-based medical adhesive: Decylamine-modified corn starch: Disperse 4 g of corn starch evenly in 200 mL of deionized water, add 1 mL of epichlorohydrin and 3 mL of N,N-dimethyldecylamine, and react at a constant temperature of 40 °C for 24 h to complete the graft modification. After the reaction, the crude product is dialyzed with deionized water for 3 days (changing water 3-4 times a day) to remove unreacted small molecule impurities, and finally a powder sample of decylamine-modified corn starch is obtained through freeze-drying and sieving.

[0087] Carboxymethyl-modified corn starch is the same as in Example 1.

[0088] S1. Weigh 1 g of decylamine-modified corn starch and add it to 200 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain the modified starch 3 solution; S2. Weigh 2 g of carboxymethyl-modified corn starch and add it to 200 mL of deionized water. Stir magnetically at 800 rpm in an oil bath at 120 °C for 3 h until the modified starch is completely gelatinized to obtain the modified starch 2 solution; S3. Mix the completely gelatinized modified starch 1 solution and the modified starch 2 solution under magnetic stirring at 800 rpm and stir for 15 min until the complex is uniform to obtain the modified starch complex; S4. Freeze the well-stirred modified starch complex in a refrigerator at -80 °C for 48 h; S5. Freeze-dry the frozen modified starch complex in a freeze dryer for 72 h until the modified starch complex is completely dry; S6. Grind the freeze-dried modified starch complex in a grinder for 10 min and repeat the grinding 5 times to obtain the starch-based medical adhesive.

[0089] Experimental Example 1 Respectively use the medical adhesives prepared in Examples 1-15 and Comparative Examples 1-9 as test objects, and test their tissue peeling strength and adhesion time. The test method is: Apply the test sample between two pieces of fresh pig skin, and the contact area is 1×2.5 cm 2, pick up the bonded pigskin every 2 seconds and hang a 50g weight at one end. Record the tissue adhesion time when the two pieces of pigskin are completely bonded without sliding and can bear the weight of the 50g weight. After 5 minutes of adhesion, record the tissue peel strength in the tensile tester to obtain the data in Table 1.

[0090] Table 1 Adhesion time and adhesion strength of medical adhesives on pigskin tissue

[0091] Adhesion strength and adhesion time are the core properties of a medical adhesive, determining whether the medical adhesive can provide timely and stable adhesion during use.

[0092] It can be seen from the data comparison in Table 1 that in Comparative Examples 1 and 2, the concentration of the modified starch solution is too low or too high, which easily leads to difficult full cross-linking when the two modified starch solutions are mixed, resulting in too weak strength of the adhesive body and difficult to form effective adhesion on the tissue; in Comparative Examples 3 and 4, the mass ratio of the two modified starches is too high or too low, resulting in a serious excess of a certain group and insufficient cross-linking density, and the strength of the adhesive body is too weak to form effective adhesion on the tissue; in Comparative Examples 5 and 6, it is a simple mixture of two ungelatinized modified starches. Due to the limitation of the crystal structure, after contacting the interfacial water on the tissue, the modified starch granules can only swell to a certain extent, the molecular chain diffusion is restricted, and the adhesion groups cannot be exposed, and only the groups on the particle surface participate in adhesion, resulting in insufficient adhesion strength; in Comparative Examples 7 and 8, they are single-component modified starches. Although there are sufficient adhesion groups in their molecular structures, the intermolecular forces are weak and it is difficult to form effective cross-links, and the strength of the adhesive body is too weak to form effective adhesion on the tissue; in Comparative Example 9, the starch modified with decylamine has a relatively long alkane chain in the decylamine group, with strong hydrophobicity, which affects the solubility of the material and the combination with the tissue interface, resulting in insufficient adhesion strength; Examples 1-15 are all composites obtained by freeze-drying two modified starches carrying positive and negative charge groups after high-temperature gelatinization. A large number of adhesion groups carried on the molecular chains of the modified starches can form hydrogen bonds and electrostatic interactions between positive and negative ions with the tissue interface. The enhancement of molecular chain diffusion during the gelatinization process enables the molecular chains to quickly diffuse into the tissue gaps, and a mechanical interlocking effect is formed after curing. The multi-level adhesion network greatly improves its adhesion strength compared with Comparative Examples 1-9.

[0093] Experimental Example 2 The medical adhesives prepared in Examples 1-15 and Comparative Examples 1-9 were used as test objects, and their gel strength after gelation was tested. The test method was as follows: The test samples were formulated into gels with a solid content of 10% using PBS solution. A stress-controlled rotational rheometer (model: HR-1, manufacturer: TA Instrument) was used to measure the rheological properties of the hydrogels. The test plate was 20 mm. The storage modulus and loss modulus were measured at a strain of 1%. Whether it was an elastic solid was determined based on whether the storage modulus was greater than the loss modulus. The maximum deformation was measured at a frequency of 1 Hz.

[0094] Table 2 Rheological tests of medical adhesives

[0095] Powdery medical adhesives should be able to absorb tissue interface water and cure to form a gel with a certain mechanical strength, providing an effective physical barrier for wound tissues.

[0096] It can be seen from Table 2 that in Comparative Examples 1 and 2, the concentration of the modified starch solution was too low or too high, which easily led to insufficient cross-linking when the two modified starch solutions were mixed, resulting in too weak strength of the adhesive body. It was very likely to break under the action of tissue deformation and could not form an effective physical barrier. In Comparative Examples 3 and 4, the mass ratio of the two modified starches was too high or too low, resulting in a serious excess of a certain group and insufficient cross-linking density. The strength of the adhesive body was too weak and was very likely to break under the action of tissue deformation and could not form an effective physical barrier. Comparative Examples 5 and 6 were simple mixtures of two ungelatinized modified starches. Due to the limitation of the crystalline structure, after contacting the interfacial water on the tissue, the modified starch particles could only swell to a certain extent, the molecular chain diffusion was restricted, and a large number of active groups could not be exposed. Only the groups on the particle surface participated in the cross-linking reaction, resulting in insufficient cross-linking strength. Although a gel structure could be formed, the gel strength was relatively low and was very likely to break under the action of tissue deformation and could not form an effective physical barrier. In Comparative Examples 7 and 8, since the medical adhesives were prepared from single-component modified starches, the intermolecular cross-linking was insufficient, and a gel structure could not be formed after absorbing the interfacial water, so a physical barrier could not be formed. In Comparative Example 9, the starch modified with decylamine had a relatively long alkane chain in the decylamine group and strong hydrophobicity, which was prone to aggregation in water, resulting in insufficient cross-linking density. Examples 1-15 were all composites obtained by freeze-drying two modified starches carrying positive and negative charge groups after high-temperature gelatinization. A large number of active groups carried on the modified starch molecular chains could form hydrogen bonds and electrostatic interactions between positive and negative ions between the molecular chains, with a relatively high cross-linking degree. The gel strength formed was much higher than that of Comparative Examples 1-8, and an effective physical barrier could be formed even under the action of tissue deformation.

[0097] Experimental Example 3 The medical adhesives prepared in Examples 1-15 and Comparative Examples 1-9 were used as test objects to test their liquid absorption capacity. The test method was as follows: Weigh 50 mg of the test sample, immerse it in PBS solution, take out the test sample every 1 minute, absorb the excess water on the surface of the sample with filter paper, weigh its mass, the maximum absorption time was 20 minutes, and calculate the liquid absorption rate of the sample and the liquid absorption multiple at the 20-minute time point.

[0098] Table 3 Test of Liquid Absorption Rate and Liquid Absorption Multiple of Medical Adhesives

[0099] Interface water is one of the main factors affecting the adhesion of medical adhesives to tissues. Powdered medical adhesives can absorb tissue interface water, weaken or eliminate the influence of interface water on the adhesion performance of materials. Therefore, good liquid absorption capacity is the core performance of powdered medical adhesives.

[0100] It can be seen from Table 3 that in Comparative Examples 1 and 2, the concentration of the modified starch solution was too low or too high, which easily led to insufficient cross-linking when the two modified starch solutions were mixed, resulting in too weak strength of the adhesive body. When absorbing liquid, the colloid was easily dissolved and the liquid absorption capacity was limited; in Comparative Examples 3 and 4, the mass ratio of the two modified starches was too high or too low, resulting in a serious excess of a certain group and insufficient cross-linking density, and the strength of the adhesive body was too weak. When absorbing liquid, the colloid was easily dissolved and the liquid absorption capacity was limited; in Comparative Examples 5 and 6, it was a simple mixture of two ungelatinized modified starches. Due to the limitation of the crystal structure, the modified starch particles could only swell to a certain extent after contacting the interface water on the tissue, and the liquid absorption capacity was limited; in Comparative Examples 7 and 8, since the medical adhesives were prepared from single-component modified starches, the intermolecular cross-linking was insufficient, and the gelatinization process destroyed the limitation of the crystal structure on the diffusion of molecular chains, making the sample dissolve in PBS solution and unable to achieve the function of absorbing tissue interface water; In Comparative Example 9, the starch modified with decylamine had a relatively long alkane chain in the decylamine group and strong hydrophobicity. When the material contacted the tissue, it would repel water molecules, resulting in a greatly reduced liquid absorption capacity; Examples 1-15 were all composites obtained by freeze-drying the two modified starches after high-temperature gelatinization. The gelatinization process exposed a large number of hydrophilic groups on the molecular chains of the modified starches, and absorbed water through hydration, and its liquid absorption capacity was greatly improved compared with Comparative Examples 1-9.

[0101] Experimental Example 4 In this experimental example, the performance of the starch-based medical adhesives prepared in different examples was tested: The tensile strength of the starch-based medical adhesive 1 obtained in Example 1 after bonding was tested, and the results were as Figure 1 shown. From Figure 1It can be seen that the starch-based medical adhesive can withstand a tensile force of 1 kg, is applicable to stretched wounds, and can achieve effective closure.

[0102] The tissue compliance of the starch-based medical adhesive 2 obtained in Example 2 after adhesion was tested, and the results are as Figure 2 shown. It can be seen from Figure 2 that the starch-based medical adhesive can adhere to porcine skin tissue and withstand twisting without falling off, and can be used for the closure of wounds in dynamic parts.

[0103] The scanning electron micrograph of the cross-linked structure of the starch-based medical adhesive 5 obtained in Example 5 is as Figure 3 shown. It can be seen from Figure 3 that the starch-based medical adhesive connects linear molecules together to form a network structure, thereby improving the strength and elasticity of the adhesive.

[0104] The adhesion experiment of the starch-based medical adhesive 3 obtained in Example 3 on the back of rats was carried out, and the results are as Figure 4 shown. It can be seen from Figure 4 that the starch-based medical adhesive can be widely used for the closure of biological tissue wounds.

[0105] Experimental method for the adhesion experiment on the back of rats: Select SPF-grade rats weighing 250 g, remove the hair on the back, create a surgical wound with a length of 2 cm and a depth of 5 mm. After hemostasis, spray the starch-based medical adhesive 3 for the adhesion experiment. It can be adhered in 1 minute, and the rats after adhesion are not affected in their activities, and no wound cracking is seen after activity.

[0106] The cytotoxicity experiment of the starch-based medical adhesive 4 obtained in Example 4 is as Figure 5 shown. It can be seen from Figure 5 that the starch-based medical adhesive has high biosafety.

[0107] The bursting pressure test of the starch-based medical adhesive 5 obtained in Experimental Example 5 and the non-gelatinized starch-based medical adhesive 1 obtained in Comparative Example 1 was carried out, and the results are as Figure 6 shown. It can be seen from Figure 6 that the bursting pressure of the starch-based medical adhesive is much higher than that of the non-gelatinized starch-based medical adhesive.

[0108] It can be seen from this that the starch-based medical adhesive of the present invention has low cytotoxicity, high adhesion strength, and does not affect the subsequent movement of rats after adhesion.

[0109] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it on the basis of the present invention, which will be obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of the present invention claimed.

Claims

1. A preparation method of a starch-based medical adhesive, characterized in that, The method includes the following steps: Step 1: Pretreatment of modified starch Add modified starch 1 into water, heat and stir for gelatinization in an oil bath to obtain a modified starch 1 solution; add modified starch 2 into water, heat and stir for gelatinization in an oil bath to obtain a modified starch 2 solution. Step 2: Mixing Mix the modified starch 1 solution and the modified starch 2 solution, and stir evenly to obtain a modified starch complex. Step 3: Freezing, drying and pulverizing First, subject the modified starch complex to cryogenic freezing treatment, then perform freeze-drying treatment, and pulverize the freeze-dried modified starch complex to obtain a starch-based medical adhesive.

2. The preparation method of a starch-based medical adhesive according to claim 1, characterized in that, The modified starch 1 is one or more of carboxymethyl-modified starch, carboxyethyl-modified starch, carboxypropyl-modified starch, phosphate ester-modified starch, xanthate ester-modified starch, citrate ester-modified starch, acetate ester-modified starch, and acetylated diphosphate ester-modified starch.

3. The preparation method of a starch-based medical adhesive according to claim 1, wherein, The modified starch 2 is quaternary ammonium salt-modified starch and / or tertiary aminoalkyl-modified starch.

4. The preparation method of a starch-based medical adhesive according to claim 2 or 3, characterized in that, The starch is one or more of legume starch, tuber starch, sweet potato starch, potato starch, cereal starch, wheat starch, water chestnut starch, lotus root starch, and corn starch.

5. The preparation method of a starch-based medical adhesive according to claim 1, characterized in that, In Step 1, the heating temperature is 40 - 300 °C.

6. The preparation method of a starch-based medical adhesive according to claim 1, wherein, In Step 1, the concentrations of both the modified starch 1 solution and the modified starch 2 solution are 0.1% - 10%.

7. The preparation method of a starch-based medical adhesive according to claim 1, characterized in that, In Step 2, the mass ratio of the modified starch 1 solution to the modified starch 2 solution is 0.1 - 0.9:0.9 - 0.

1.

8. The preparation method of a starch-based medical adhesive according to claim 1, characterized in that, In Step 3, the temperature of cryogenic freezing is -10— -270 °C.

9. A starch-based medical adhesive, characterized in that, The starch-based medical adhesive is prepared by the preparation method of the starch-based medical adhesive according to any one of claims 1 - 8.

10. Use of a starch-based medical adhesive in the preparation of materials related to wound closure.

Images