CN115944771A - Bionic hemostatic paste with strong wet adhesion and hemostatic functions and preparation method thereof - Google Patents
Bionic hemostatic paste with strong wet adhesion and hemostatic functions and preparation method thereof Download PDFInfo
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- CN115944771A CN115944771A CN202211683569.3A CN202211683569A CN115944771A CN 115944771 A CN115944771 A CN 115944771A CN 202211683569 A CN202211683569 A CN 202211683569A CN 115944771 A CN115944771 A CN 115944771A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Materials For Medical Uses (AREA)
Abstract
The invention discloses a bionic hemostatic paste with strong wet adhesion and hemostatic functions and a preparation method thereof. The paste has strong wet adhesion effect, can realize rapid hemostasis on penetrating injuries, heavy bleeding and the like through physical adhesion, is convenient to carry, and can realize rapid and strong hemostasis under various conditions.
Description
Technical Field
The invention belongs to the field of nano material preparation and biomedicine, and particularly relates to a bionic hemostatic paste with strong wet adhesion and hemostatic functions and a preparation method thereof.
Background
Uncontrolled bleeding is a major cause of death in many people. As a necessary means for emergency hemostasis, rapid wound closure can effectively reduce blood loss and increase survival chances. Clinically, suturing is a standard procedure for wound closure. However, due to the requirements of pre-operative anesthesia, stringent surgical requirements, and time consuming, such procedures are limited to operating rooms, especially in emergency situations. In addition, the persistence of the operation may cause secondary injury, wound infection, and impaired wound healing, causing pain and inconvenience to the patient. Thus, there is a need for advanced wound closure strategies that are suitable for field operations and that are easy to use in emergency treatment.
Hemostasis can be achieved by different methods, including: (1) physically adhering to tissue or occluding capillary vessels; (2) Chemical (e.g., covalent) interactions and binding to coagulation factors; and (3) absorption of blood cells and plasma. The method of physically adhering tissues or blocking blood vessels is rapid, does not need the time-consuming process of coagulation cascade reaction, and is favorable for rapid hemostasis in battlefields and daily life. However, since the tissue adhesive is injected and filled in the wound filled with a large amount of blood and tissue fluid, a strong wet adhesion is required. Some marine organisms can remain permanently and firmly attached to the marine environment, for example barnacles can grow and multiply on the skin surface of whales, turtles and other different organisms in a high salinity, highly corrosive seawater atmosphere. This benefits from its unique physiological structure and adhesion system. The adhesion system of barnacles is known to consist of two main components: lipid rich matrix and adhesion proteins that cooperate to provide strong adhesion on moist and soiled surfaces. The lipid-rich matrix in the barnacle gum first cleans the underlying matrix by repelling seawater and contaminants on the substrate material, and then the adhesion proteins crosslink with the matrix to form a stable and strong adhesion.
Polyacrylic materials are widely used in various fields of scientific research due to special physicochemical properties, such as common polyacrylic resins, and as pressure-sensitive carbomers common in the medical field. The abundant carboxyl on the polyacrylic acid can not only form abundant hydrogen bonds with tissues, but also modify N-hydroxysuccinimide ester, greatly shorten the time of amide reaction between the polymer and amino on the surfaces of tissues or skins, form covalent bonding, firmly adhere to the surfaces of substrates, and ensure a long-time adhesion effect. The silicone oil phase is responsible for repelling blood, and meanwhile, a better interface bonding environment is created for adhesion; and the silicone oil can protect the combination between the adhesive phase and the substrate from being damaged by liquid scouring within a certain time.
However, for adhesives, an inherent conflict between strength and toughness is always present. On the basis of taking polyacrylic acid derivatives as main adhesion substances, the two-dimensional layered nanosheet hydrotalcite is added, so that deformation energy caused by stress is effectively absorbed, and further expansion of cracks is blocked; meanwhile, the interaction between polymers is increased due to the high specific surface area of the nanosheets, and the energy required for crack generation is increased. The invention starts from the improvement effects of the two aspects, and uses the inorganic filler to avoid using artificial synthetic polymer to obtain the adhesive with good adhesive effect and toughness, thereby improving the inherent conflict of the adhesive.
Inspired by the adhesion phase in the barnacle adhesion system and the silicone phase and the inorganic filler in the industrial adhesive, the invention successfully develops the strong-effect adhesive hemostatic paste derived based on the adhesion mechanism of the barnacle of the marine organism, can be used for rapid hemostasis of wounds and acute major hemorrhage, can be effectively adhered to the skin, and shows good hemostasis and wet adhesion performances.
Disclosure of Invention
The invention aims to provide an injectable bionic hemostatic paste with strong adhesion and hemostatic functions, so that the inherent conflict of strength and toughness in an adhesive is solved, and the deep acute major bleeding wound is effectively blocked and emergently treated by smearing and injecting wounds of different types.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention firstly discloses a bionic hemostatic paste with strong wet adhesion and hemostatic functions, which is formed by mixing hydrophobic oil and adhesion;
the adhesive phase is formed by blending polyacrylic acid derivatives and hydrotalcite two-dimensional layered nanosheets;
the polyacrylic acid derivative is polymerized by taking acrylic acid N-hydroxysuccinimide ester and acrylic acid-tert-butyl ester as monomers through reversible addition-fragmentation chain transfer reaction.
Furthermore, in the adhesive phase, the mass ratio of the polyacrylic acid derivative to the hydrotalcite two-dimensional layered nanosheet is 1-9:1. As the mass ratio of the hydrotalcite two-dimensional layered nanosheet in the powder gradually increases, the overall adhesion performance of the material will be worse.
Further, the mass ratio of the adhesive phase to the hydrophobic oil is 1:1-4. With the increase of the content of the hydrophobic oil, the injection performance of the material is enhanced, but the form maintaining capability of the paste after injection is poor, when the mass ratio of the adhesion phase to the hydrophobic oil is 2: the injection performance of the material is the best when 3.
Further, the hydrophobic oil may be silicone oil, vegetable oil, castor oil, or the like, and is most preferably silicone oil.
Further, the hydrotalcite two-dimensional layered nanosheet may be a calcium-aluminum hydrotalcite two-dimensional layered nanosheet, a magnesium-aluminum hydrotalcite two-dimensional layered nanosheet, an iron-aluminum hydrotalcite two-dimensional layered nanosheet, a manganese-aluminum hydrotalcite two-dimensional layered nanosheet, or the like, and is most preferably a calcium-aluminum hydrotalcite two-dimensional layered nanosheet.
The invention also discloses a preparation method of the bionic hemostatic paste, which comprises the following steps:
Dissolving 1.0-4.0 g of tert-butyl acrylate monomer and 0.05-0.34 g of N-hydroxysuccinimide acrylate in 15mL1, 4-dioxane, then adding 28-56 mg of 4-cyano-4- (phenylthiocarbonylthio) valeric acid and 3-6 mg of initiator azobisisobutyronitrile AIBN, and stirring until the solution is uniform and the whole solution is pink transparent liquid; degassing and deoxidizing the reaction system by a freezing thawing pump circulation method, and carrying out oil bath reaction for 12-24 h at 70-90 ℃ in a nitrogen atmosphere;
after the reaction is finished, dropwise adding liquid in the system into excessive n-hexane, and standing for precipitation; washing the precipitate with 3-10 mL of dichloromethane, dripping the precipitate into excessive n-hexane again, standing the precipitate, and removing supernatant to obtain an intermediate polymer; mixing and stirring the intermediate polymer and excessive trifluoroacetic acid for 10-15h, removing unreacted trifluoroacetic acid by using a rotary evaporation instrument, reacting the obtained precipitate with triethylamine for 10-15h, removing the solvent, and drying the obtained precipitate in a vacuum oven at 45 ℃ for 12-24 h to obtain a polyacrylic acid derivative, which is marked as PAA-NHS;
Weighing 0.31-0.93 g CaCl 2 ·2H 2 O and 0.24-0.96 gAlCl 3 ·6H 2 Dissolving O in 5-15 mL of deionized water, adding 20mL of NaOH solution with the concentration of 0.01-0.02 g/mL, and stirring for 10-30 min to obtainMother liquor, then centrifuging and washing the mother liquor (centrifuging for 10-15 min at 9000rpm each time, discarding supernatant to obtain lower-layer precipitate, and repeatedly washing for 3-5 times) to obtain a precipitate Ca-AlLDH precursor; ultrasonically dissolving a Ca-AlLDH precursor into 20-30 mL of deionized water, then placing the mixture into a reaction kettle, and carrying out hydrothermal reaction in an oven at 100 ℃ for 4-8 h; after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtain a calcium-aluminum hydrotalcite two-dimensional layered nanosheet, which is marked as Ca-AlLDH;
Mixing the PAA-NHS obtained in the step (1) and the Ca-AlLDH obtained in the step (2) according to the mass ratio of 1-9:1, grinding, and sieving by a 100-300-mesh sieve to obtain adhesive phase powder;
And (3) mixing the adhesive phase obtained in the step (3) with silicone oil according to the mass ratio of 1:1-4, and uniformly stirring to obtain the bionic hemostatic paste.
The adhesion properties of the resulting hemostatic paste can be adjusted by adjusting the molar ratio of t-butyl acrylate monomer to N-hydroxysuccinimide acrylate when the polyacrylic acid derivative is synthesized. With the increase of the content of the acrylic acid N-hydroxysuccinimide ester monomer, the long-acting adhesion performance of the paste is improved.
The reaction time is 12-24 h when the polyacrylic acid derivative is synthesized. With the increase of time, the conversion rate of the polymerization reaction is increased, and the molecular weight of the synthesized PAA-NHS is increased.
When the calcium-aluminum hydrotalcite two-dimensional layered nanosheet is synthesized, the mass ratio of the calcium salt to the aluminum salt affects the solubility of the nanosheet. As the mass of the aluminum salt increases, the solubility of the nanoplatelets increases and the particle size decreases.
The invention provides a bionic hemostatic paste with strong wet adhesion and hemostatic functions based on the inspiration of a barnacle adhesion system and an inorganic filler toughening mechanism, and the bionic hemostatic paste can be used as a portable hemostatic adhesive and can be used for emergency treatment of deep wounds and emergency times such as acute major hemorrhage. The paste of the invention can also be used after being fully mixed and ground with some commonly used antibiotic drugs, so as to ensure the wound healing after the hemostasis of the wound is finished.
Compared with the prior art, the invention has the beneficial effects that:
1. the hemostatic paste provided by the invention can better give consideration to both strength and toughness.
2. The hemostatic paste has strong underwater adhesion, the tissue adhesion strength can reach 55kPa in a wet state through a tissue adhesive shearing and lapping test, the hemostatic paste can be adhered to irregular operation wounds with a large amount of tissues and blood, and the stable adhesion property can be maintained in various different environments.
3. The hemostatic paste has good biological safety, and after the material is incubated with human umbilical vein endothelial cells, the cells can still keep high survival rate and cannot cause local severe inflammatory reaction.
4. The hemostatic paste of the present invention has better deep hemostatic performance, and the time (about 25 seconds) for achieving effective hemostasis by injection is much shorter than that of speed-treated yarn (about 65 seconds) in a liver perforation (3 mm) model of SD rats.
5. The hemostatic paste of the present invention has a superior deep hemostatic performance, and the time (about 27 seconds) for the hemostatic paste to achieve effective hemostasis by injection is much shorter than that of speed-i-yarn (about 90 seconds) in a liver perforation (3 mm) model of New Zealand rabbits.
6. The hemostatic paste has good injection performance, is convenient to use, can be injected and smeared, is easy to carry, and can be used for various wounds.
7. The hemostatic paste has a large drug-loading platform potential, can be mixed, screened and ground with clinically common antibiotic drugs, and is favorable for expanding application of the paste.
8. The hemostatic paste has simple preparation conditions and extremely convenient storage and transportation.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of PAA-tBu-NHS obtained in example 1.
FIG. 2 is a photograph of the PAA-NHS powder obtained in example 1.
FIG. 3 is a transmission electron micrograph and an elemental distribution chart of Ca-AlLDH obtained in example 1.
FIG. 4 is an atomic force microscope image of Ca-AlLDH obtained in example 1.
FIG. 5 is a photograph of the hemostatic pastes obtained in example 1 with different ratios of adhesive phase to silicone oil, wherein: the graph a shows the change of the form of different component materials from flat to upright, and the graph b shows the comparison of the injection performance of different component materials.
FIG. 6 is a graph of the quantitative data of the shear lap test and the interfacial strength test of the hemostatic paste obtained in example 1 at 4 deg.C, 25 deg.C, 37 deg.C, and 40 deg.C, respectively.
FIG. 7 is a graph of the quantitative data of the shear lap test and the interfacial strength test of the hemostatic paste obtained in example 1 on the heart, liver, lung, and skin of a pig.
FIG. 8 is a graph of interfacial strength data for hemostatic pastes obtained with different Ca-AlLDH additions in example 1.
FIG. 9 is a hydrodynamic characterization of the self-healing properties of the hemostatic pastes obtained in example 1.
FIG. 10 is a graph of viability data for 24h and 48h of the hemostatic paste obtained in example 1 incubated with human umbilical vein endothelial cells at different concentrations of leachates.
FIG. 11 is the comparison of the hemostatic time (FIG. 11 (a)) and the blood loss (FIG. 11 (b)) of different hemostatic materials of example 1 applied to the SD rat liver scratch hemostatic model.
Fig. 12 is a comparison of the hemostasis time (fig. 12 (a)) and blood loss (fig. 12 (b)) of the different hemostatic materials of example 1 applied to a new zealand rabbit liver laceration hemostasis model.
Detailed Description
The following examples are given for the detailed implementation and the specific operation procedures, but the scope of the present invention is not limited to the following examples.
Example 1
This example prepares a biomimetic hemostatic paste as follows:
Tert-butyl acrylate (3.16g, 200mmol) and N-hydroxysuccinimide acrylate (0.34g, 20mmol) were dissolved in 15mL1, 4-dioxane, and stirred well until the solution was clear and transparent. A solution of 4-cyano-4- (phenylthiocarbonylthio) pentanoic acid (0.028g, 1mmol) was added dropwise to the above system, followed by further dropwise addition of a solution of 300. Mu.L Azobisisobutyronitrile (AIBN) (0.003g, 1mmol). The reaction system is degassed and deoxidized by a freezing thawing pump circulation method, and then is subjected to oil bath reaction at 70 ℃ for 24 hours under the nitrogen atmosphere.
After the reaction is finished, dropwise adding the liquid in the system into excessive n-hexane, and standing for precipitation; washing the precipitate with 5mL of dichloromethane, dropping the precipitate into excessive n-hexane again, standing the precipitate, and removing the supernatant to obtain an intermediate polymer (marked as PAA-tBu-NHS); removing solvent, taking out part of product, dissolving in heavy water, and performing nuclear magnetic hydrogen spectrum detection, wherein the result is shown in figure 1, and the position of characteristic peak in the figure is identical with the expected polymer structure. Mixing the intermediate polymer with excessive trifluoroacetic acid, stirring for 12h, removing unreacted trifluoroacetic acid by using a rotary evaporator, reacting the obtained precipitate with triethylamine for 12h, removing the solvent, and drying the product in a vacuum oven at 45 ℃ for 24h to obtain the polyacrylic acid derivative PAA-NHS, wherein the photo of the polyacrylic acid derivative PAA-NHS is white powder as shown in figure 2.
Weighing 0.51g of CaCl 2 ·2H 2 O and 0.2414gAlCl 3 ·6H 2 Dissolving O in 5mL of deionized water, adding 20mL of NaOH solution with the concentration of 0.016g/mL, violently stirring for 20min, then centrifugally washing (centrifuging at 9000rpm for 15min each time, discarding the supernatant to obtain a lower-layer precipitate, and repeatedly washing for 3 times) to obtain a Ca-AlLDH precipitate precursor; ultrasonically dissolving a Ca-Al LDH precursor into 30mL of deionized water, placing the mixture into a reaction kettle, and carrying out hydrothermal reaction for 4 hours in an oven at 100 ℃; and after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtain the calcium-aluminum hydrotalcite two-dimensional layered nanosheet Ca-AlLDH. Elemental energy spectrum analysis was performed on the prepared Ca-AlLDH, and as shown in fig. 3, the resulting material had a sheet-like hexagonal structure and the elements were uniformly distributed. As shown in fig. 4, by atomic force microscopyThe thickness range of the two-dimensional layered nanosheet Ca-AlLDH is 6-8 nm, which is in line with the normal range of hydrotalcite materials.
0.16g of PAA-NHS obtained in step 1 and 0.04g of Ca-AlLDH obtained in step 2 were mixed, ground and sieved through a 300-mesh sieve to obtain an adhesive phase.
And (3) mixing the adhesive phase obtained in the step (3) with silicone oil according to different mass ratios (respectively 0.2/0, 0.2/0.1, 0.2/0.2, 0.2/0.3 and 0.2/0.4) and uniformly stirring to obtain the bionic hemostatic paste. As shown in fig. 5, a is a graph showing the change of the shape of the materials with different components from flat to upright, thereby judging the formability of the materials. As shown in fig. 5a, the properties of the paste material gradually worked well with increasing mass of the silicone oil, but the paste material flowability was stronger when the mass of the silicone oil was increased to 0.4 g. When the mass of the silicone oil is 0.3g, the mass ratio of the adhesive phase to the silicone oil is 2: and 3, the prepared material has the best molding performance. In fig. 5b, the injection performance of the materials with different components is considered, and by injecting the pastes with different components, it can also be obtained that when the mass ratio of the adhesive phase to the silicone oil is 2: at 3, the paste passed most smoothly through a 1mL syringe, and the morphology of the material after injection remained intact. The subsequent experimental data correspond to the mass ratio of the adhesive phase to the silicone oil being 2: 3.
The tensile load of the hemostatic paste in lap shear was determined using standard test method for tissue adhesive strength properties, astm f2255-2005 (2015). The preparation method adopts a preparation procedure of a fresh pigskin graft specified by a pharmaceutical industry standard YY/T0729.1-2009, and the pigskin has the length of 20mm, the width of 10mm and the thickness of 2mm. Testing by an Instron model5943 type universal tester at 25 ℃ and at a shear tensile speed of 5mm/min, repeatedly measuring each group of samples for at least three times, and recording the corresponding F Tensile load . And statistical analysis of the data results of shear strength and interfacial toughness was performed, as shown in FIG. 6, the adhesion test was performed at 4 deg.C, 25 deg.C, 37 deg.C, and 45 deg.C, and the results did not change greatly regardless of shear strength and interfacial toughness, thus indicating that the material is differentExhibit good adhesion properties at all temperatures. As shown in figure 7, the shear strength and interface toughness of the heart, liver, lung and skin of the pig are tested, so that the paste material can maintain a good adhesion effect on different organs, and the application of the material in hemostasis adhesion of different organs is shown. As shown in FIG. 8, in order to confirm the enhancement of the interface strength of the paste material by the hydrotalcite addition, the test results of the interface strength exhibited a tendency of rising first and then falling as the addition amount of Ca-AlLDH was increased, and the interface strength was the largest at about 200 J.m. -2 Compared with the paste without hydrotalcite, the paste has a great improvement. The addition of Ca-AlLDH allows the paste to have both higher strength and interfacial toughness.
The self-healing performance of the gel formed after the hemostatic paste (1 mL) was fully soaked in water and the gel formed by the paste material without Ca-AlLDH addition were evaluated using a tadiscoveryldhr-3 type rotary rheometer: the test temperature was 25 ℃ and the test gap was 1000. Mu.m. The change of storage modulus and loss modulus of the implant is obtained by testing 1mL of sample under 1% pressure for 2 minutes in time scanning mode (part I in the figure), then under 100% pressure for 1 minute (part II in the figure), and finally under 1% pressure for 2 minutes again (part III in the figure). As can be seen from figure 9, the storage modulus and the loss modulus of the implant are reversed under higher pressure, the implant is changed from colloid to liquid and is changed into colloid after 1% of pressure is recovered, the recovered storage modulus is up to 90%, the paste has better self-healing capability, and the addition of Ca-Al LDH is proved to enhance the structural rigidity of the material.
A blank group and four groups of 0.5%, 1%, 5% and 10% bionic hemostatic paste leachate (the leachate is prepared by adding hemostatic paste into excessive ionized water) with different volume concentrations are designed to form 5 experimental groups, and each group of 4 parallel experiments are used as controls. Culturing HUVECs cells in 96-well plate, controlling cell density at 4000-5000 per well and 100 μ L per well, placing 96-well plate in CO 2 Culturing in incubator for 5h, adding 100 μ L of corresponding component medicine into each well after HUVECs adhere normally, and placing in CO 2 Culturing in an incubator for 24h and 48h. After the incubation time was complete, 20 μ L MTT solution (5 mg/mL, i.e., 0.5% MTT) was added per well and incubation was continued for 4h. The culture was then terminated and the wells were discarded. Adding 150 μ L dimethyl sulfoxide into each well, and shaking on a shaking table at low speed for 10min to dissolve the crystals completely. The absorbance of each well was measured at OD490nm in an ELISA detector. As shown in fig. 10, the experimental group using the leachate at a concentration of 5% can still maintain better cell activity than the blank group without co-incubation with the paste, indicating that the material can maintain better cell safety despite the inclusion of the artificially synthesized high molecular polymer in the material. When the concentration of the paste leaching solution is 10%, the cell survival rate is low, but the concentration of the paste leaching solution is difficult to reach the same level in the use process, so the judgment on the biological safety of the material is not influenced.
A blank group, PAA-NHS group, silicone oil group, ca-AlLDH group, PAA group (i.e., polyacrylic acid group, which was prepared in the same manner as PAA-NHS except that N-hydroxysuccinimide acrylate was not present in the monomers synthesized), silicone oil + Ca-AlLDH group, PAA-NHS + silicone oil group, PAA-NHS + Ca-AlLDH group, gauze group, gelatin sponge group, instant gauze group, and biomimetic hemostatic paste group were designed for 12 experimental groups, all of which maintained the same amount of hemostatic material, and 3 rats per group served as a parallel control. After anesthetizing and immobilizing the rats, the abdominal cavity was opened layer by layer to expose the liver, and interstitial fluid and blood on the surface of the liver were blotted with a sterile cotton swab. The liver was then perforated with a biopsy punch (3 mm) and immediately after 3s of free bleeding, a haemostatic material of the corresponding composition was injected or smeared onto the surface of the rat liver wound, under which sterile filter paper was laid. After the timing is started, whether the wound is coagulated blood or not needs to be confirmed every 5s, the wound is photographed and recorded, and the coagulation time is recorded. After the experiment is finished, the sterile filter paper is respectively weighed for the mass difference before and after hemostasis, and the liver hemorrhage amount of the rat is calculated. The experimental procedure should be repeated three more times. As shown in fig. 11, compared to the widely used hemostatic materials in daily or clinical use, such as gauze group, gelatin sponge group, and instant yarn group, the prepared hemostatic paste has the shortest hemostatic time (about 25 s) and blood loss (40.8 ± 5.4 mg), and is beneficial to good wet adhesion performance; meanwhile, compared with the PAA-NHS group, the silicon oil group, the Ca-AlLDH group, the silicon oil + Ca-AlLDH group, the PAA-NHS + silicon oil group and the PAA-NHS + Ca-AlLDH group, better hemostasis data of the paste group prove that the combination of the three groups can exert respective functions to the maximum extent, so that the adhesion performance is increased, and the hemostasis time is shortened. Compared with the polyacrylic acid group, the polyacrylic acid derivative group has a certain reduction in hemostasis time and blood loss, the polyacrylic acid derivative group has a faster hemostasis time of about 5 seconds than the polyacrylic acid group, and the hemostasis amount is 25mg less, and the fact that the polyacrylic acid derivative rather than the polyacrylic acid is selected as a better choice in the paste is confirmed.
Blank groups, gauze groups, gelatin sponge groups, instant yarn groups and biomimetic hemostatic paste 5 experimental groups were designed, all experimental groups kept the same amount of hemostatic material, and 3 new zealand female rabbits per group served as parallel controls. After the rabbits were anesthetized and fixed, the abdominal cavity was opened layer by layer to expose the liver, and interstitial fluid and blood on the surface of the liver were blotted with a sterile cotton swab. Then, the liver was perforated by a biopsy punch (3 mm), and after bleeding freely for 3s, a hemostatic material of the corresponding composition was immediately applied to the surface of the rabbit liver wound by injection or spreading, and a sterile filter paper was laid under the hemostatic material. After the timing is started, whether the wound is coagulated blood or not needs to be confirmed every 5s, the wound is photographed and recorded, and the coagulation time is recorded. And after the experiment is finished, respectively weighing sterile filter paper for mass difference before and after hemostasis, and calculating the liver bleeding amount of the rabbit. The experimental procedure should be repeated three more times. As shown in fig. 12, compared to the gauze group, the gelatin sponge group, and the instant yarn group, the prepared hemostatic paste has the shortest hemostatic time (about 27 s) and blood loss (0.18 ± 0.05 g), which is significantly improved compared to the control experimental group (about 410 s) and blood loss (6.43 ± 0.13 g), and is also better than the clinical commonly used instant yarn (about 90 s) and blood loss (1.44 ± 0.21 g). The hemostatic paste of this example exhibited strong hemostatic properties.
The present invention is not intended to be limited to the exemplary embodiments but rather to cover all modifications, equivalents, and improvements falling within the spirit and scope of the present invention.
Claims (6)
1. A bionic hemostatic paste with strong wet adhesion and hemostatic functions is characterized in that: the bionic hemostatic paste is formed by mixing hydrophobic oil and an adhesive phase;
the adhesive phase is formed by blending polyacrylic acid derivatives and hydrotalcite two-dimensional layered nanosheets;
the polyacrylic acid derivative is polymerized by taking acrylic acid N-hydroxysuccinimide ester and acrylic acid-tert-butyl ester as monomers through reversible addition-fragmentation chain transfer reaction.
2. The biomimetic hemostatic paste of claim 1, wherein: the mass ratio of the adhesive phase to the hydrophobic oil is 1:1-4.
3. The biomimetic hemostatic paste of claim 1, wherein: in the adhesive phase, the mass ratio of the polyacrylic acid derivative to the hydrotalcite two-dimensional layered nanosheet is 1-9:1.
4. The biomimetic hemostatic paste of claim 1, wherein: the hydrophobic oil is silicone oil.
5. The biomimetic hemostatic paste of claim 1, wherein: the hydrotalcite two-dimensional layered nanosheet is a calcium-aluminum hydrotalcite two-dimensional layered nanosheet.
6. A method for preparing a biomimetic hemostatic paste according to any one of claims 1-5, comprising the steps of:
step 1, preparation of polyacrylic acid derivatives
Dissolving 1.0-4.0 g of tert-butyl acrylate monomer and 0.05-0.34 g of N-hydroxysuccinimide acrylate in 15mL1, 4-dioxane, then adding 28-56mg of 4-cyano-4- (phenylthiocarbonylthio) valeric acid and 3-6 mg of initiator azobisisobutyronitrile, and stirring until the solution is uniform; degassing and deoxidizing the reaction system by a freezing thawing pump circulation method, and carrying out oil bath reaction for 12-24 h at 70-90 ℃ in a nitrogen atmosphere;
after the reaction is finished, dropwise adding the liquid in the system into excessive n-hexane, and standing for precipitation; washing with 3-10 mL of dichloromethane, dripping into excessive n-hexane again, standing for precipitation, and removing supernatant to obtain an intermediate polymer; mixing and stirring the intermediate polymer and excessive trifluoroacetic acid for 10-15h, removing unreacted trifluoroacetic acid by using a rotary evaporator, reacting the obtained precipitate with triethylamine for 10-15h, removing the solvent, and drying the obtained precipitate in a vacuum oven at 45 ℃ for 12-24 h to obtain a polyacrylic acid derivative, which is marked as PAA-NHS;
step 2, preparing calcium-aluminum hydrotalcite two-dimensional layered nanosheets
Weighing 0.31-0.93 g of CaCl 2 ·2H 2 O and 0.24-0.96 gAlCl 3 ·6H 2 Dissolving O in 5-15 mL of deionized water, adding 20mL of NaOH solution with the concentration of 0.01-0.02 g/mL, stirring for 10-30 min to obtain mother liquor, and then centrifugally washing the mother liquor for 3-5 times to obtain a Ca-Al LDH precursor precipitate; ultrasonically dissolving a Ca-Al LDH precursor into 20-30 mL of deionized water, placing the solution into a reaction kettle, and carrying out hydrothermal reaction for 4-8 h in a drying oven at 100 ℃; after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtain a calcium-aluminum hydrotalcite two-dimensional layered nanosheet, which is marked as Ca-Al LDH;
step 3, preparation of an adhesive phase
Mixing the PAA-NHS obtained in the step (1) and the Ca-Al LDH obtained in the step (2) according to the mass ratio of 1-9:1, grinding, and sieving by a sieve of 100-300 meshes to obtain an adhesive phase;
step 4, preparing the bionic hemostatic paste
And (3) mixing the adhesive phase obtained in the step (3) with silicone oil according to the mass ratio of 1:1-4, and uniformly stirring to obtain the bionic hemostatic paste.
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