CN115944771B - 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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Classifications
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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
Landscapes
- 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 by physical adhesion on penetrating injuries, major bleeding and the like, is convenient to carry, and can realize rapid and powerful hemostasis under various conditions.
Description
Technical Field
The invention belongs to the field of nano material preparation and biological medicine, and in particular relates to bionic hemostatic paste with strong wet adhesion and hemostatic functions and a preparation method thereof.
Background
Uncontrolled bleeding is a leading cause of death in many people. As a necessary means for emergency hemostasis, the rapid wound closure can effectively reduce blood loss and increase survival chances. Clinically, suturing is a standard procedure for wound closure. However, such surgery is limited to the operating room, especially in emergency situations, due to the requirement for pre-operative anesthesia, stringent surgical requirements, and time consuming. In addition, the persistence of the procedure may result in secondary injury, wound infection and wound healing being impeded, causing pain and inconvenience to the patient. Thus, there is a need for advanced wound closure strategies that are suitable for field operation and are easy to use in emergency treatment.
Hemostasis may be achieved by various methods including: (1) physically adhering to tissue or occluding capillaries; (2) Chemical (e.g., covalent) interactions and binding to coagulation factors; (3) absorption of blood cells and plasma. The method of physically adhering tissues or blocking blood vessels is rapid, does not need to undergo a time-consuming process of a coagulation cascade reaction, and is beneficial to rapid hemostasis in battlefield and daily life. But at the same time the tissue adhesive is injected and filled in the wound site filled with a large amount of blood, tissue fluid, so that extremely strong wet adhesion is required. Part of marine organisms can remain permanently and firmly adhered in a marine environment, for example, barnacles can grow and reproduce on the skin surface of different organisms such as whales, turtles and the like in a high-salinity and highly corrosive seawater atmosphere. This benefits its unique physiological structure and adhesion system. The adhesion system of known barnacles consists of two main components: lipid-rich matrix and adhesion proteins that cooperate to provide strong adhesion on wet and contaminated surfaces. The lipid-rich matrix in the barnacle gum cleans the underlying matrix by first repelling seawater and contaminants on the substrate material, and then the adhesion proteins crosslink with the matrix to form a stable and firm adhesion.
Polyacrylic materials are widely used in various fields of scientific research due to their special physicochemical properties, such as common polyacrylic resins, and as pressure-sensitive adhesive carbomers commonly used in the medical field. The rich carboxyl on the polyacrylic acid can not only form rich hydrogen bonds with tissues, but also modify N-hydroxysuccinimide ester, so that the time for the polymer to react with amino groups on the surfaces of the tissues or the skin can be greatly shortened, covalent bonding is formed, the polymer is firmly adhered to the surfaces of the substrates, and the long-time adhesion effect can be ensured. The silicone oil phase is responsible for rejecting blood and simultaneously creates a better interface bonding environment for adhesion; and the silicone oil can protect the bond between the adhesive phase and the substrate from being broken by liquid washout for a certain period of time.
However, for adhesives, an inherent conflict between strength and toughness is always present. According to the invention, based on the polyacrylic acid derivative as the main adhesion substance, the two-dimensional layered nano-sheet hydrotalcite is added, so that deformation energy generated by stress is effectively absorbed, and further expansion of cracks is blocked; meanwhile, because the high specific surface area of the nano-sheet increases the interaction between polymers, the energy required for crack generation is improved. The invention starts from the improvement effects of the two aspects, uses inorganic filler, avoids using artificial synthetic polymer, obtains the adhesive with good adhesive effect and toughness, and improves the inherent conflict of the adhesive.
The invention successfully develops the strong adhesive hemostatic paste based on the marine organism barnacle adhesion mechanism, which can be used for rapid hemostasis of penetration wounds and acute massive hemorrhage, can effectively adhere to skin and shows good hemostasis and wet adhesion performance.
Disclosure of Invention
The invention aims to provide the injectable bionic hemostatic paste with the functions of strong adhesion and hemostasis, so that the internal conflict of strength and toughness in an adhesive is solved, and the effective blocking and emergency treatment of deep acute massive hemorrhage wounds are realized by smearing and injecting different types of wounds.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention discloses a bionic hemostatic paste with strong wet adhesion and hemostatic functions, which is formed by mixing hydrophobic oil and adhesion phase;
the adhesive phase is formed by blending polyacrylic acid derivatives and hydrotalcite two-dimensional lamellar nano-sheets;
the polyacrylic acid derivative is polymerized by taking N-hydroxysuccinimide acrylate and tert-butyl acrylate as monomers through reversible addition-fragmentation chain transfer reaction.
Further, in the adhesive phase, the mass ratio of the polyacrylic acid derivative to the hydrotalcite two-dimensional lamellar nano-sheet is 1-9:1. As the mass ratio of the hydrotalcite two-dimensional layered nano-sheets in the powder is gradually increased, the adhesion performance of the whole material is poorer.
Further, the mass ratio of the adhesive phase to the hydrophobic oil is 1:1-4. With increasing hydrophobic oil content, the injectability of the material is enhanced, but the paste has poor shape maintenance capability after injection, and when the mass ratio of the adhesive phase to the hydrophobic oil is 2: the injection performance of the material is optimal at 3.
Further, the hydrophobic oil may be silicone oil, vegetable oil or castor oil, etc., most preferably silicone oil.
Further, the hydrotalcite two-dimensional layered nano-sheet can be calcium aluminum hydrotalcite two-dimensional layered nano-sheet, magnesium aluminum hydrotalcite two-dimensional layered nano-sheet, iron aluminum hydrotalcite two-dimensional layered nano-sheet, manganese aluminum hydrotalcite two-dimensional layered nano-sheet and the like, and is most preferably calcium aluminum hydrotalcite two-dimensional layered nano-sheet.
The invention also discloses a preparation method of the bionic hemostatic paste, which comprises the following steps:
step 1, preparing polyacrylic acid derivative
1.0 to 4.0g of tert-butyl acrylate monomer and 0.05 to 0.34g of N-hydroxysuccinimide acrylate are dissolved in 15ml of 1, 4-dioxane, then 28 to 56mg of 4-cyano-4- (phenylthioformyl thio) pentanoic acid and 3 to 6mg of initiator azobisisobutyronitrile AIBN are added, and the mixture is stirred until the solution is uniform, and the whole is pink transparent liquid; degassing and deoxidizing the reaction system by a freeze thawing pump circulation method, and then carrying out oil bath reaction for 12-24 hours 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 the precipitate with 3-10 mL of dichloromethane, then re-dripping the precipitate into excessive n-hexane, standing the precipitate, and discarding the 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 steaming instrument, reacting the obtained precipitate with triethylamine for 10-15h, removing a 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 the calcium-aluminum hydrotalcite two-dimensional layered nano-sheet
Weighing 0.31-0.93 g CaCl 2 ·2H 2 O and 0.24-0.96 g AlCl 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, centrifuging and washing the mother liquor (centrifuging at 9000rpm for 10-15 min 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 Ca-AlLDH precursor in 20-30 mL of deionized water, placing the solution in a reaction kettle, and performing hydrothermal reaction for 4-8 h in a 100 ℃ oven; after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtainThe calcium-aluminum hydrotalcite two-dimensional layered nano-sheet is marked as Ca-AlLDH;
step 3, preparing an adhesive phase
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, and grinding and sieving with a 100-300 mesh sieve to obtain adhesive phase powder;
step 4, preparing 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.
In the synthesis of polyacrylic acid derivatives, the adhesive properties of the resulting hemostatic paste can be adjusted by adjusting the molar ratio of the t-butyl acrylate monomer to the N-hydroxysuccinimide acrylate. With the increase of the monomer content of the N-hydroxysuccinimide acrylate, the long-acting adhesive property of the paste is improved.
In the synthesis of polyacrylic acid derivatives, the reaction time is 12-24 hours. With time, the polymerization conversion increases and the molecular weight of the synthesized PAA-NHS increases.
When synthesizing the two-dimensional layered nano-sheet of calcium-aluminum hydrotalcite, the mass ratio of calcium salt to aluminum salt can influence the solubility of the nano-sheet. As the mass of aluminum salt increases, the solubility of the nanoplatelets increases and the particle size decreases.
The invention provides bionic hemostatic paste with strong wet adhesion and hemostatic functions based on the elicitation of a barnacle adhesion system and an inorganic filler toughening mechanism, and the bionic hemostatic paste can be used as a portable hemostatic adhesive for emergency treatment of deep wounds and emergency moments such as acute massive hemorrhage. The paste of the invention can be fully mixed with some common antibiotics and ground for use, thereby ensuring wound healing after hemostasis is completed.
Compared with the prior art, the invention has the beneficial effects that:
1. the hemostatic paste provided by the invention can better compromise the strength and toughness.
2. The hemostatic paste has stronger underwater adhesiveness, can reach the tissue adhesive strength of 55kPa in a wet state through a tissue adhesive shearing lap joint test, can be adhered to an irregular operation wound surface with a large amount of tissues and blood, and can keep stable adhesive property in various different environments.
3. The hemostatic paste has better biological safety, and after the material is incubated with human umbilical vein endothelial cells, the cells can still keep higher survival rate, and local severe inflammatory reaction can not be caused.
4. The hemostatic paste of the invention has better deep hemostatic properties, and the time to achieve effective hemostasis by injection (about 25 seconds) is much shorter than the speed, i.e., yarn (about 65 seconds), in the liver perforation (3 mm) model of SD rats.
5. The hemostatic paste of the invention has better deep hemostatic properties and the time to achieve effective hemostasis by injection (about 27 seconds) is much shorter than the speed, i.e., yarn (about 90 seconds) in a new zealand rabbit liver perforation (3 mm) model.
6. The hemostatic paste has good injectability, 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 great drug carrying platform potential, can be blended with clinically common antibiotic drugs, screened and ground, and is beneficial to the expansion application of the paste.
8. The hemostatic paste has simple preparation conditions and is extremely convenient to store and transport.
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 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 picture of the resulting hemostatic paste at different proportions of the adhesive phase and silicone oil in example 1, wherein: graph a shows the change of the form of the different component materials from flat to upright, and graph b shows the injection performance comparison of the different component materials.
FIG. 6 is a graph of quantitative data of shear lap test and interfacial strength test of the hemostatic paste obtained in example 1 at a temperature of 4℃and 25℃and 37℃and 40℃respectively.
FIG. 7 is a graph of quantitative data of shear lap test and interfacial strength test of the hemostatic paste obtained in example 1 on heart, liver, lung, skin of pigs.
FIG. 8 is the interfacial strength data for the hemostatic pastes obtained with different Ca-AlLDH additions in example 1.
Fig. 9 is a graph showing the hydrodynamic characterization of the self-healing properties of the hemostatic paste obtained in example 1.
Fig. 10 is a graph showing the viability of the hemostatic paste obtained in example 1 incubated with human umbilical vein endothelial cells for 24h and 48h at various concentrations of the leach solution.
Fig. 11 is a graph showing the comparison of hemostasis time (fig. 11 (a)) and blood loss (fig. 11 (b)) of the different hemostatic materials of example 1 applied to SD rat liver scratch hemostasis model.
Fig. 12 is a graph showing the comparison of 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 scratch hemostasis model.
Detailed Description
The following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Example 1
The bionic hemostatic paste was prepared according to the following steps:
step 1, preparing polyacrylic acid derivative
Tert-butyl acrylate (3.16 g,200 mmol) and N-hydroxysuccinimide acrylate (0.34 g,20 mmol) were dissolved in 15ml1, 4-dioxane and stirred until the solution was clear and transparent. 4-cyano-4- (phenylthioformyl thio) pentanoic acid solution (0.028 g,1 mmol) was added dropwise to the above system followed by 300. Mu.L of Azobisisobutyronitrile (AIBN) solution (0.003g, 1 mmol) dropwise. And (3) degassing and deoxidizing the reaction system by a freeze thawing pump circulation method, and carrying out oil bath reaction for 24 hours at 70 ℃ 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 the precipitate with 5mL of dichloromethane, re-dripping the precipitate into excessive n-hexane, standing the precipitate, and discarding the supernatant to obtain an intermediate polymer (designated as PAA-tBu-NHS); the solvent was removed, and a part of the product was dissolved in heavy water, and nuclear magnetic resonance hydrogen spectrum was examined, and the result was shown in FIG. 1, in which the position of the characteristic peak was coincident with the expected polymer structure. The intermediate polymer and excessive trifluoroacetic acid are mixed and stirred for 12 hours, unreacted trifluoroacetic acid is removed by using a rotary evaporator, the obtained precipitate reacts with triethylamine for 12 hours, then the solvent is removed, and the product is placed in a vacuum oven for drying at 45 ℃ for 24 hours, so that the polyacrylic acid derivative PAA-NHS is obtained, and the photo of the polyacrylic acid derivative PAA-NHS is white powder as shown in figure 2.
Step 2, preparing the calcium-aluminum hydrotalcite two-dimensional layered nano-sheet
Weigh 0.51g CaCl 2 ·2H 2 O and 0.2414g AlCl 3 ·6H 2 O is dissolved in 5mL of deionized water, 20mL of NaOH solution with the concentration of 0.016g/mL is added, the stirring is vigorously carried out for 20min, then centrifugal washing is carried out (centrifugal washing is carried out for 15min at the rotating speed of 9000rpm each time, supernatant fluid is discarded, lower-layer sediment is obtained, and washing is repeated for 3 times) so as to obtain sediment Ca-AlLDH precursor; ultrasonically dissolving a Ca-Al LDH precursor in 30mL of deionized water, placing the solution in a reaction kettle, and performing hydrothermal reaction for 4 hours in a 100 ℃ oven; after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtain the calcium aluminum hydrotalcite two-dimensional lamellar nano-sheet Ca-AlLDH. Analysis of elemental energy spectra was performed on the prepared Ca-AlLDH, as shown in fig. 3, and the obtained material had a plate-like hexagonal structure and the elemental distribution was uniform. As shown in FIG. 4, the thickness range of the two-dimensional layered nano-sheet Ca-AlLDH is 6-8 nm according to the normal range of hydrotalcite materials through the test of an atomic force microscope.
Step 3, preparing an adhesive phase
After 0.16g of PAA-NHS obtained in step 1 and 0.04g of Ca-AlLDH obtained in step 2 were mixed, they were ground and sieved through a 300-mesh sieve to obtain an adhesive phase.
Step 4, preparing bionic hemostatic paste
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 stirring uniformly to obtain the bionic hemostatic paste. As shown in fig. 5, a graph a shows the change of the form of the different component materials from the flat state to the upright state, and thus the molding property of the materials is judged. As shown in fig. 5a, the properties of the paste material gradually improved with the increase in the mass of the silicone oil, but the paste material was more fluid when the mass of the silicone oil increased to 0.4 g. When the mass of the silicone oil is 0.3g, namely the mass ratio of the adhesive phase to the silicone oil is 2:3, the molding property of the prepared material is optimal. In fig. 5b, taking into account the injectability of the different component materials, it can also be derived when the mass ratio of the adhesive phase to the silicone oil phase is 2:3, the paste passed through the 1mL syringe most smoothly, and the material morphology after injection remained intact. The mass ratio of the adhesion phase to the silicone oil corresponding to the follow-up experimental data is 2: 3.
The tensile load of the hemostatic paste in the lap shear state was determined using standard test method for tissue adhesive strength characteristics astm f2255-2005 (2015). The preparation procedure of the fresh pig skin graft prescribed by the pharmaceutical industry standard YY/T0729.1-2009 is adopted, and the pig skin has the length of 20mm, the width of 10mm and the thickness of 2mm. Testing with Instron model5943 model universal tester at 25deg.C with shear stretching speed of 5mm/min, repeating measurement at least three times for each group of samples, and recording corresponding F Tensile load . And the data result statistical analysis of the shear strength and the interface toughness is carried out, as shown in figure 6, the adhesion test is carried out at the temperature of 4 ℃, 25 ℃, 37 ℃ and 45 ℃ and the results have no large variation in the shear strength and the interface toughness, so that the material can show good adhesion performance at different temperatures. As shown in figure 7, the test of shear strength and interfacial toughness of the heart, liver, lung and skin of pigs shows that the paste material can keep good adhesion effect on different organs, and the paste material can be applied to hemostasis adhesion of different organs. As shown in FIG. 8, to confirm the increase in interfacial strength of the paste material with hydrotalcite additionStrong, with increasing Ca-AlLDH addition, the test result of interface strength shows a tendency of rising and then falling, and when the addition amount is 40mg, the interface strength is maximum and is about 200 J.m -2 Compared with paste without hydrotalcite addition, the paste has larger improvement. The addition of Ca-AlLDH makes the paste compatible with higher strength and interface toughness.
Self-healing performance evaluation was performed on a gel formed by fully soaking a hemostatic paste (1 mL) in water and a gel formed by a paste material without Ca-AlLDH addition using a TADiscoveryDHR-3 type rotarheometer: the test temperature was 25℃and the test gap was 1000. Mu.m. And (3) testing 1mL of the sample under the pressure of 1% (part I in the figure) for 2 minutes in a time scanning mode, testing under the pressure of 100% (part II in the figure), and testing under the pressure of 1% for 2 minutes (part III in the figure) to obtain a change graph of the storage modulus and the loss modulus of the implant. As can be seen from fig. 9, the implant is inverted in storage modulus and loss modulus at higher pressure, the implant is changed from colloid to liquid, and is changed into colloid after recovering 1% of pressure, the recovered storage modulus is as high as 90%, the paste is proved to have 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 5 experimental groups of four bionic hemostatic paste leachates with different volume concentrations of 0.5%, 1%, 5% and 10% (the leachates are prepared by adding hemostatic paste into excessive ionized water) were designed, and 4 parallel experiments in each group are used as controls. HUVECs cells were cultured using 96-well plates, the cell density per well was controlled to 4000-5000 cells per well volume of 100. Mu.L, and the 96-well plates were placed in CO 2 Culturing in incubator for 5 hr, adding 100 μl of corresponding component medicine into each well after HUVECs cells are adhered normally, and placing into CO 2 Culturing in an incubator for 24 hours and 48 hours. At the end of the incubation time, 20. Mu. LMTT solution (5 mg/mL, i.e., 0.5% MTT) was added to each well and incubation was continued for 4h. The culture was then terminated and the liquid in the wells was discarded. 150 μl of dimethyl sulfoxide was added to each well, and the mixture was shaken on a shaker at low speed for 10min to dissolve the crystals sufficiently. Absorbance was measured for each well at OD490nm in an enzyme-linked immunosorbent assay. As shown in fig. 10, compared with the paste withoutThe co-incubated blank group can still keep better cell activity by using the leaching solution with the concentration of 5%, which indicates that the material can keep better cell safety despite the fact that the material contains the artificially synthesized high molecular polymer. When the concentration of the paste leaching solution is 10%, the cell survival rate is lower, but the concentration of the paste leaching solution at the same level is difficult to reach in the using process, so that the judgment of the biological safety of the material is not affected.
Blank, PAA-NHS, silicone oil, ca-AlLDH, PAA (i.e., polyacrylic acid, the preparation method of which was the same as PAA-NHS, except that no N-hydroxysuccinimide acrylate was present in the synthesized monomer), silicone oil + Ca-AlLDH, PAA-NHS + silicone oil, PAA-NHS + Ca-AlLDH, gauze, gelatin sponge, instant yarn, and bionic hemostatic paste were designed for a total of 12 experimental groups, all of which maintained the same amount of hemostatic material, with 3 rats per group as parallel controls. After the rats were anesthetized and fixed, the abdominal cavity was opened layer by layer to expose the liver, and the tissue fluid and blood on the liver surface were blotted with a sterile cotton swab. Then, the liver is perforated by a biopsy punch (3 mm), after free bleeding for 3s, hemostatic materials of corresponding components are immediately injected or smeared on the surface of a rat liver wound, and sterile filter paper is paved below the hemostatic materials. After starting timing, confirming whether the wound is coagulated or not every 5s, photographing and video recording the wound, and recording the coagulation time. After the experiment is finished, sterile filter papers are respectively weighed for poor quality before and after hemostasis, and the liver hemorrhage amount of the rat is calculated. The experimental procedure should be repeated more than three times. As shown in FIG. 11, compared with gauze, gelatin sponge and instant gauze, which are widely used daily or clinically, the prepared hemostatic paste has the shortest hemostatic time (about 25 s) and blood loss (40.8+/-5.4 mg) and has good wet adhesion property; meanwhile, compared with the PAA-NHS group, the silicone oil group, the Ca-AlLDH group, the silicone oil+Ca-AlLDH group, the PAA-NHS+silicone oil group and the PAA-NHS+Ca-AlLDH group, the better hemostatic data of the paste group prove that the combination of the PAA-NHS group, the silicone oil+Ca-AlLDH group, the PAA-NHS group and the PAA-NHS+Ca-AlLDH group can exert the respective functions to the greatest extent, so that the adhesive performance is improved, and the hemostatic time is shortened. Compared with polyacrylic acid groups, the hemostatic time and the blood loss of the polyacrylic acid derivative groups are reduced to a certain extent, the hemostatic time is about 5 seconds faster than that of the polyacrylic acid groups, the hemostatic amount is 25mg less, and the polyacrylic acid derivatives are selected from the paste rather than polyacrylic acid.
A blank group, a gauze group, a gelatin sponge group, a quick-acting yarn group and 5 experimental groups of bionic hemostatic paste were designed, all of which maintained the same amount of hemostatic material, with 3 new zealand female rabbits per group as parallel controls. After the rabbit was anesthetized and fixed, the abdominal cavity was opened layer by layer to expose the liver, and the tissue fluid and blood on the liver surface were blotted with a sterile cotton swab. Then, the liver is perforated by a biopsy punch (3 mm), after free bleeding for 3s, the hemostatic material of the corresponding component is immediately injected or smeared on the surface of the liver wound of the rabbit, and sterile filter paper is paved below the hemostatic material. After starting timing, confirming whether the wound is coagulated or not every 5s, photographing and video recording the wound, and recording the coagulation time. And after the experiment is finished, the sterile filter paper is respectively weighed to obtain poor quality before and after hemostasis, and the liver hemorrhage amount of the rabbit is calculated. The experimental procedure should be repeated more than three times. As shown in FIG. 12, the prepared hemostatic paste has the shortest hemostatic time (about 27 s) and blood loss (0.18.+ -. 0.05 g) compared with the gauze group, the gelatin sponge group and the instant yarn group, and has the obvious improvement compared with the hemostatic time (about 410 s) and blood loss (6.43.+ -. 0.13 g) of the control experiment group and is better than the hemostatic time (about 90 s) and blood loss (1.44.+ -. 0.21 g) of the instant yarn which is clinically used. The hemostatic paste of this example exhibited a strong hemostatic performance.
The foregoing is illustrative of the present invention and is not to be construed as limiting thereof, but rather as merely providing for the purpose of describing various modifications, equivalent arrangements and improvements within the spirit and principles of the invention.
Claims (5)
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, wherein the mass ratio of the adhesive phase to the hydrophobic oil is 1:1-4;
the adhesive phase is formed by blending polyacrylic acid derivatives and hydrotalcite two-dimensional lamellar nano-sheets;
the polyacrylic acid derivative is polymerized by taking N-hydroxysuccinimide acrylate and tert-butyl acrylate as monomers through reversible addition-fragmentation chain transfer reaction.
2. The biomimetic hemostatic paste according to claim 1, wherein: in the adhesive phase, the mass ratio of the polyacrylic acid derivative to the hydrotalcite two-dimensional lamellar nano-sheet is 1-9:1.
3. The biomimetic hemostatic paste according to claim 1, wherein: the hydrophobic oil is silicone oil.
4. The biomimetic hemostatic paste according to claim 1, wherein: the hydrotalcite two-dimensional layered nano-sheet is a calcium aluminum hydrotalcite two-dimensional layered nano-sheet.
5. A method for preparing the bionic hemostatic paste according to any one of claims 1-4, comprising the steps of:
step 1, preparing polyacrylic acid derivative
1.0 to 4.0g of tert-butyl acrylate monomer and 0.05 to 0.34g of N-hydroxysuccinimide acrylate are dissolved in 15ml of 1, 4-dioxane, then 28 to 56mg of 4-cyano-4- (phenylthioformyl thio) pentanoic acid and 3 to 6mg of initiator azodiisobutyronitrile are added, and the mixture is stirred until the solution is uniform; degassing and deoxidizing the reaction system by a freeze thawing pump circulation method, and then carrying out oil bath reaction for 12-24 hours 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, re-dripping into excessive n-hexane, standing for precipitation, and discarding 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 steaming instrument, reacting the obtained precipitate with triethylamine for 10-15h, removing a 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 the calcium-aluminum hydrotalcite two-dimensional layered nano-sheet
Weighing 0.31-0.93 g CaCl 2 ·2H 2 O and 0.24-0.96 g AlCl 3 ·6H 2 O is dissolved in 5-15 mL of deionized water, 20mL of NaOH solution with the concentration of 0.01-0.02 g/mL is added and stirred for 10-30 min to obtain mother liquor, and then the mother liquor is centrifugally washed for 3-5 times to obtain a precipitated Ca-Al LDH precursor; ultrasonically dissolving Ca-Al LDH precursor in 20-30 mL of deionized water, placing the solution in a reaction kettle, and performing hydrothermal reaction for 4-8 h in a 100 ℃ oven; after the reaction is finished, centrifuging, and freeze-drying the obtained precipitate to obtain a calcium-aluminum hydrotalcite two-dimensional layered nano-sheet, which is marked as Ca-Al LDH;
step 3, preparing 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 with a 100-300 mesh sieve to obtain an adhesive phase;
step 4, preparing 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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