An absorbable medical soft tissue adhesive and its preparation method and application

Abstract

The present invention provides an absorbable medical soft tissue adhesive, a preparation method and an application thereof. The raw materials for preparing the adhesive include component A and component B; component A includes cycloalkenone acetal compounds and oxidants; component B includes vinyl monomers, crosslinking agents, substances for promoting tissue and organ healing and reducing agents. The absorbable medical soft tissue adhesive provided by the present invention is formed by in-situ curing through free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in a human body environment. The reaction process is rapid, curing occurs within 20 s to 3 min, the reaction is slightly exothermic and will not burn the human body; after the free radical ring-opening polymerization of the cycloalkenone acetal compounds, the main chain contains an ester bond structure and can be degraded in a physiological environment; the adhesive rapidly obtains high mechanical strength and bonding strength, the bonding strength is >160 KPa within 5 min, is not easily swollen in a physiological environment, and has good physiological stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical adhesives, and particularly relates to an absorbable medical soft tissue adhesive, its preparation method and application. Background Art

[0002] Medical soft tissue adhesives are new medical materials used for bonding biological tissue sites during surgical operations. Soft tissue adhesives can be used for bonding skin, organs, nerves, blood vessels, mucous membranes and other parts, and mostly use medical α-cyanoacrylate adhesives, fibrin biotype adhesives and hydrogel tissue adhesives. Since fibrin biotype adhesives are produced in blood, there is a possibility of cross-infection of infectious diseases such as hepatitis and AIDS during use. Although autologous blood can be used, it is not suitable for emergency treatment because its strength and speed are not ideal. Hydrogel tissue adhesives are polymerized and processed from polymers such as polyethylene glycol, and their degradation will be accelerated under light conditions, seriously affecting their bonding strength. The α-cyanoacrylate-based adhesives avoid the disadvantages of fibrin biotype adhesives and have a fast curing speed and good biocompatibility. Cyanoacrylate was first synthesized by Ardis in the 1940s. Ten years later, an American company first discovered that cyanoacrylate has good bonding properties. Subsequently, Kuff et al. found that this type of adhesive can be used for bonding biological tissues, so it is used as a new type of medical soft tissue adhesive. In the early 1960s, cyanoacrylate adhesives became popular for a while, but during application, their biological toxicity restricted the development of this type of adhesive. After the 1970s, researchers found that modified monomers of cyanoacrylate such as isobutyl cyanoacrylate, n-butyl cyanoacrylate, and n-octyl cyanoacrylate can be used to reduce the biological toxicity of cyanoacrylate adhesives. This discovery promoted the further development of medical soft tissue adhesives.

[0003] Currently, α-cyanoacrylate adhesives have problems such as high hardness, poor toughness, repeated wear will cause tissue damage, and will also cause a series of problems including premature shedding or rupture of the adhesive film, and even reactive inflammatory reactions. Most seriously, due to its non-absorbable property, its clinical application is restricted to a certain extent. Therefore, it is urgent to find a soft tissue adhesive with fast curing and good degradation performance. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide an absorbable medical soft tissue adhesive, its preparation method and application. This adhesive can cure quickly and has a high bonding strength.

[0005] The present invention provides an absorbable medical soft tissue adhesive, and the preparation raw materials include component A and component B:

[0006] Component A includes cycloalkenone acetal compounds and oxidants;

[0007] The component B includes vinyl monomers, crosslinking agents, substances for promoting tissue and organ healing, and reducing agents.

[0008] In the present invention, the molar ratio of the vinyl monomer to the cycloalkenone acetal compound is 0.01 to 100:1; preferably 0.1 to 10:1.

[0009] The molar ratio of the crosslinking agent to the cycloalkenone acetal compound is 0.001 to 0.2:1; preferably 0.005 to 0.05:1.

[0010] The molar ratio of the substance for promoting tissue and organ healing to the cycloalkenone acetal compound is 1×10 -8 to 1×10 -4 :1, preferably 1×10 -7 to 1×10 -6 :1.

[0011] In the present invention, the component B of the absorbable medical soft tissue adhesive preferably further includes an antibacterial agent; the antibacterial agent is selected from one or more of penicillins, cephalosporins, aminoglycosides, macrolides, lincomycins, quinolones, tetracyclines, sulfonamides, silver ions, zinc ions, antibacterial peptides, coumarin compounds, sulfobetaines, polyguanidine polymers, and benzalkonium chloride;

[0012] The molar ratio of the antibacterial agent to the cycloalkenone acetal compound is 1×10 -8 to 1×10 -4 :1, preferably 1×10 -7 to 1×10 -6 :1.

[0013] In the present invention, the cycloalkenone acetal compounds include one or more of 2-methylene-1,3-dioxepane, 2-methylene-4-phenyl-1,3-dioxolane, 5,6-benzo-2-methylene-1,3-dioxepane, and 4,7-dimethyl-2-methylene-1,3-dioxepane.

[0014] The 2-methylene-1,3-dioxepane (MDO) has the structure of formula 101:

[0015]

[0016] The 2-methylene-4-phenyl-1,3-dioxolane (MPDL) has the structure of formula 102:

[0017]

[0018] The 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) has the structure of Formula 103:

[0019]

[0020] The 4,7-dimethyl-2-methylene-1,3-dioxepane (DMMDO) has the structure of Formula 104:

[0021]

[0022] The vinyl monomers include one or more of (meth)acrylic acid, (meth)acrylate, vinyl acetate, maleimide polyethylene glycol carboxylic acid, biotin-PEG-6-maleimide, m-maleimide benzoic acid N-hydroxysuccinimide ester, 6-maleimide hexanoic acid, ethylene glycol vinyl ether, tetraethylene glycol mono vinyl ether, ethylene (2-chloroethyl) ether, (meth)acryloyloxy phosphorylcholine, 10-(2-methacryloyloxy) phosphoric acid monodecyl ester, (meth)acryloylethyl sulfobetaine, 4-methacryloyloxyethyl trimellitic anhydride, methacryloyldopamine, N-acryloyl (trimethylol) aminomethane, (meth)acrylic acid mono polyethylene glycol ester, N,N-dimethylaminoethyl methacrylate, (meth)allylamine, and O-allyl hydroxylamine.

[0023] In the present invention, the crosslinking agent is selected from one or more of methacrylic anhydride, diallyl maleate, bis(2-methacryloyloxyethyl) hydrogen phosphate, tri(ethylene glycol) divinyl ether, diallylamine, triallylamine, N-methyldiallylamine, 1,5-hexadiene, diallyl disulfide, and diallyldimethylsilane;

[0024] The substance for promoting tissue and organ healing is selected from one or more of β-1,3-glucan and its derivatives, hyaluronic acid, and asiaticoside.

[0025] In the present invention, the oxidizing agent includes one or more of benzoyl peroxide, tert-butyl hydroperoxide, ammonium persulfate, and hydrogen peroxide;

[0026] The reducing agent includes one or more of N,N-dimethyl-p-toluidine, sodium metabisulfite, sodium bisulfite, and ferrous sulfate;

[0027] The oxidizing agent in Component A and the reducing agent in Component B serve as an oxidation-reduction free radical polymerization initiator.

[0028] In the present invention, the molar ratio of the oxidizing agent to the cycloalkenone acetal compound is 0.001 - 0.2:1; preferably 0.005 - 0.05:1.

[0029] The molar ratio of the oxidant to the reductant is 0.01 - 10:1, preferably 0.2 - 2:1.

[0030] The present invention provides a preparation method of the absorbable medical soft tissue adhesive described in the above technical solution, comprising the following steps:

[0031] 1) Mix a cycloalkenone acetal compound and an oxidant to obtain component A;

[0032] Mix a vinyl monomer, a crosslinking agent, a substance promoting tissue and organ healing, and a reductant to obtain component B;

[0033] 2) Mix component A and component B evenly, and after a polymerization reaction, obtain the absorbable medical soft tissue adhesive.

[0034] The preparation method of the soft tissue adhesive provided by the present invention is simple, can be prepared and used immediately, is convenient to use during the process, has an ideal operation time window of 1 - 5 minutes, and has strong clinical maneuverability.

[0035] In the present invention, the mixing time in step 2) is 1 - 300 s, preferably 3 - 100 s, more preferably 5 - 20 s.

[0036] In the present invention, after component A and component B are mixed, an in-situ radical ring-opening polymerization reaction occurs in the system. The temperature of the polymerization reaction is 30 - 50 °C, preferably 35 - 38 °C. The polymerization reaction is a ring-opening polymerization reaction with radicals as the active centers. The main chain of the component after radical polymerization contains an ester bond structure.

[0037] The present invention provides an application of the absorbable medical soft tissue adhesive described in the above technical solution or the absorbable medical soft tissue adhesive prepared by the preparation method described in the above technical solution in the preparation of a medical adhesive.

[0038] In the present invention, the parts where the medical adhesive is pasted are wounds or surgical wounds of tissues, organs or skin.

[0039] The medical soft tissue adhesive provided by the present invention comprises component A and component B. When coated on the wounds or surgical incisions of tissues, organs and skin, after mixing component A and component B and quickly coating, an in-situ radical ring-opening polymerization reaction occurs rapidly, realizing the rapid adhesion and closure of the wounds or surgical incisions. The coating and mixing liquid time is 1 - 600 s, preferably 1 - 30 s.

[0040] Compared with the prior art, the absorbable medical soft tissue adhesive provided by the present invention is formed by in-situ curing through free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in the human body environment. The reaction process is rapid, curing occurs within 20 s to 3 min, the reaction is slightly exothermic and will not burn the human body; after the free radical ring-opening polymerization of the cycloalkenone acetal compound, the main chain contains an ester bond structure, which can degrade in the physiological environment (the degradation rate at 8 weeks > 20%), and has good degradation performance; the mild reaction conditions are conducive to the loading of antibacterial agents and substances promoting tissue and organ healing. As the adhesive degrades, these substances are gradually exposed and released, promoting tissue healing and avoiding bacterial infection; the adhesive rapidly obtains high mechanical strength and bonding strength, the bonding strength > 160 KPa within 5 min, and is not easily swollen in the physiological environment, having good physiological stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 It is a schematic diagram of the shear bonding test model for the in-vitro bonding experiment in the present invention;

[0042] Figure 2 It is a test chart of the cytocompatibility of the materials prepared in Examples 1 to 6 of the present invention;

[0043] Figure 3 It is a test chart of the in-vivo degradation of the materials in Comparative Example 1 and Examples 1 to 6 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0044] In order to further illustrate the present invention, the following describes in detail an absorbable medical soft tissue adhesive provided by the present invention, its preparation method and application in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

[0045] Example 1

[0046] Preparation process of the cycloalkenone compound DMMDO:

[0047] Dissolve 2,5 - hexanediol (1.2 g, 10.2 mmol) in a solution of dichloromethane (170 ml) and pyridine (7.5 ml, 91.5 mmol). Replace the air with argon at -20 °C. Subsequently, dropwise add a dichloromethane solution of 90 ml triphosgene (4.55 g, 15.2 mmol) to the above system. React at room temperature for 20 min. Then, extract the product mixture quenched with saturated ammonium chloride (100 ml) with dichloromethane. Wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter, perform vacuum filtration, and distill under reduced pressure. Collect the fraction around 95 °C. Dissolve the product (0.023 g, 0.16 mmol) of the above system in a mixed solvent of tetrahydrofuran / toluene (1:1). Add Petasis reagent (2 ml, 0.5 mmol, a 5 wt% tetrahydrofuran / toluene mixed solution), mix well, replace the air with argon, and react under light protection at 60 - 65 °C for 20 h. Precipitate the product with 10 ml n - hexane, filter, and concentrate to obtain DMMDO.

[0048] Mix the cycloalkenone compound DMMDO (0.1 mol) with benzoyl peroxide (BPO, 2 mol%). Obtain component A. Mix the comonomer methacrylic acid (MA, 2 mol%), 1 mol% bis(2 - methacryloyloxyethyl) hydrogen phosphate cross - linker, 1×10 -6 mol% vancomycin, 2×10 -7 mol% dextran, and N,N’ - dimethyl - p - toluidine (DMPT, 2 mol%) uniformly. Reserve it as component B. Rapidly and uniformly mix component A and component B. Rapidly and uniformly coat the obtained mixture on the defatted pig skin. Cover another piece of pig skin on it and gently press for more than 20 s. Free radical ring - opening polymerization adhesion occurs at room temperature.

[0049] Example 2

[0050] Preparation process of the cycloalkenone compound MDO:

[0051] Add 2 - bromo - 1,1’ - dimethoxyethane (65 g, 0.4 mol), 1,4 - butanediol (36 g, 0.51 mol), and Dowex50 acidic ion - exchange resin (0.5 g) to the reaction flask. React at 115 °C for about 4 h (judge the reaction progress according to the amount of by - product methanol collected). Filter to remove the acidic resin, distill under reduced pressure, and collect the fraction around 95 °C. Dissolve the above product (35 g, 0.18 mol) in 70 ml anhydrous tetrahydrofuran, and add Aliquat 336 (1.67 g, 0.004 mol) to the above reaction flask. When the reaction temperature drops to 0 °C, gradually add t - BuOK (40.41 g, 0.36 mol), maintain the temperature and react for 2 h. Filter to remove the solid, concentrate the organic phase, and distill. The fraction collected at 25 °C is MDO.

[0052] Mix the cycloalkenone compound MDO (0.1 mol) with benzoyl peroxide (BPO, 2 mol%) to obtain Component A; mix the comonomer 10-(2-methacryloyloxy) monodecyl phosphate (MDP, 2 mol%), 2 mol% of bis(methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 2×10 -6 mol% azithromycin, 3×10 -7 mol% hyaluronic acid, and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%). After mixing evenly, reserve it as Component B; quickly and evenly mix Component A and Component B, quickly and evenly coat the obtained mixed solution on the defatted pig skin, cover another piece of pig skin on it, gently press for more than 20 s, and free radical ring-opening polymerization adhesion occurs at room temperature.

[0053] Example 3

[0054] Preparation process of the cycloalkenone compound BMDO:

[0055] Add 2-bromo-1,1'-dimethoxyethane (65 g, 0.4 mol), o-phthalic alcohol (69 g, 0.5 mol), and Dowex 50 acidic ion exchange resin (0.5 g) into the reaction flask, react at 120 °C for ~8 h (judge the reaction progress according to the amount of by-product methanol collected), filter to remove the acidic resin, perform vacuum distillation, and collect the fraction around 160 °C; dissolve the above-obtained product (43.77 g, 0.18 mol) in 70 ml of anhydrous tetrahydrofuran, add Aliquat 336 (1.67 g, 0.004 mol) into the above reaction flask, gradually add t-BuOK (40.41 g, 0.36 mol) when the reaction temperature drops to 0 °C, maintain the temperature and react for 2 h, filter to remove the solid, concentrate the organic phase, and distill. The fraction around 96 - 99 °C collected is BMDO.

[0056] Mix the cycloalkenone compound BMDO (0.1 mol) with benzoyl peroxide (BPO, 2 mol%) to obtain Component A; mix the comonomer methacrylic acid (MA, 2 mol%), 3 mol% of bis(methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 3×10 -6 mol% antimicrobial peptide, 4×10 -7 mol% asiaticoside, and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%). After mixing evenly, reserve it as Component B; quickly and evenly mix Component A and Component B, quickly and evenly coat the obtained mixed solution on the defatted pig skin, cover another piece of pig skin on it, gently press for more than 20 s, and free radical ring-opening polymerization adhesion occurs at room temperature.

[0057] Example 4

[0058] Preparation process of cycloalkenone compound MPDL:

[0059] Add 2-bromo-1,1'-dimethoxyethane (65 g, 0.4 mol), 1-phenyl-1,2-ethanediol (69 g, 0.5 mol) and Dowex 50 acidic ion exchange resin (0.5 g) into the reaction flask, react at 120 °C for about 4 h (judge the reaction progress according to the amount of by-product methanol collected), filter to remove the acidic resin, and distill under reduced pressure to collect the fraction around 70 °C; dissolve the above product (43.77 g, 0.18 mol) in 70 ml of anhydrous tetrahydrofuran, and add Aliquat 336 (1.67 g, 0.004 mol) into the above reaction flask. When the reaction temperature drops to 0 °C, gradually add t-BuOK (40.41 g, 0.36 mol), maintain the temperature and react for 2 h, filter to remove the solid, concentrate the organic phase, and distill to collect the fraction around 50 °C, which is MPDL.

[0060] Mix cycloalkenone compound MPDL (0.1 mol) with benzoyl peroxide (BPO, 2 mol%) to obtain component A; mix the comonomer 10-(2-methacryloyloxy)phosphoric acid monodecyl ester (MDP, 2 mol%), 3 mol% bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 2×10 -6 mol% benzalkonium chloride, 5×10 -7 mol% hyaluronic acid and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%), mix them evenly and reserve as component B; quickly and evenly mix component A and component B, quickly and evenly coat the obtained mixture on the degreased pigskin, cover another piece of pigskin on it, gently press for more than 20 s, and carry out free radical ring-opening polymerization adhesion at room temperature.

[0061] Example 5

[0062] The preparation process of cycloalkenone compound BMDO is the same as that in Example 3.

[0063] Mix cycloalkenone compound BMDO (0.1 mol) with benzoyl peroxide (BPO, 2 mol%) to obtain component A; mix the comonomer (meth)acryloylethyl sulfobetaine (SBMA, 2 mol%), 3 mol% bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 7×10 -6 mol% coumarin, 4×10 -7Mix 0.1 mol% asiaticoside and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%), and after mixing evenly, reserve it as Component B; quickly and evenly mix Component A and Component B, quickly and evenly coat the obtained mixture on the degreased pigskin, cover another piece of pigskin on it, gently press for more than 20 s, and free radical ring-opening polymerization adhesion occurs at room temperature.

[0064] Example 6

[0065] The preparation process of the cycloalkenone compound MPDL is the same as that in Example 4.

[0066] Mix the cycloalkenone compound MPDL (0.1 mol) with benzoyl peroxide (BPO, 2 mol%) to obtain Component A; mix the comonomer methacryloyldopamine (DMA, 2 mol%), 3 mol% bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinker, 2×10 -6 mol% zinc ions, 5×10 -7 mol% hyaluronic acid and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%), and after mixing evenly, reserve it as Component B; quickly and evenly mix Component A and Component B, quickly and evenly coat the obtained mixture on the degreased pigskin, cover another piece of pigskin on it, gently press for more than 20 s, and free radical ring-opening polymerization adhesion occurs at room temperature.

[0067] Comparative Example 1

[0068] Quickly and evenly coat the mixture of 10 g of 2-octyl cyanoacrylate (OCA) and 5 mg of p-toluenesulfonic acid (PTSA, stabilizer) on the degreased pigskin, cover another piece of pigskin on it, gently press for 20 s, and in-situ polymerization reaction occurs at room temperature to achieve adhesion.

[0069] In vitro adhesion experiment

[0070] According to the GB / T 7124-2008 standard, the in vitro adhesion strength is obtained through shear adhesion testing, and the shear adhesion model is as Figure 1 shown. Before the experiment, select degreased pigskin and cut it into regular plate-shaped splines. The length and width of the splines are 10 cm × 2.5 cm, and the thickness is 0.2 cm. Prepare as described in Examples 1 to 6 and Comparative Example 1, and the bonding area is 2.5 cm × 1.0 cm; place the prepared bonded samples at room temperature for 2 h and then conduct tensile testing. The testing is carried out on a universal testing machine (LLOYD company LD-5 type, the sensor is 2.5 kN), the tensile rate is 5 mm / min, and the shear adhesion strength is calculated by dividing the load force at the fracture of the bonded sample by the bonding area.

[0071] Table 1 In vitro adhesion strength (KPa)

[0072]

[0073] The bonding test results are shown in Table 1.

[0074] As shown in Table 1: The bonding strengths of the materials in Examples 1 to 6 are all above 160 KPa, and the maximum bonding strength is higher than that of Comparative Example 1, showing good bonding performance. It can be seen that as the proportion of the comonomer increases, the bonding strength of the material gradually increases. This is because the preferred 10-(2-methacryloyloxy) monodecyl phosphate comonomer and methacryloyldopamine can improve the polarity and hydrophilicity of the material, increase the contact and infiltration with tissues, and the phosphate groups and dopamine groups in the structure can achieve covalent bonding with tissues, so it has high bonding strength. In addition, the preferred dextran, hyaluronic acid and asiaticoside active ingredients in the copolymer can play a role in reinforcing the molecular chain, improve the mechanical strength of the material, and the hydroxyl groups on the molecular chain can form hydrogen bond interactions with the amino groups on the tissue, thereby further improving the bonding strength.

[0075] In vitro cell compatibility experiment

[0076] According to the requirements for cytotoxicity experiments in GB / T 16886 "Biological Evaluation of Medical Devices", MC3T3 was selected as the test cell line. The cured samples in Examples 1 to 6 were prepared into shapes with a sample size of 0.5 cm × 0.5 cm. After sterilizing the samples, they were placed in a culture medium to prepare sample extracts. 5 extract samples were prepared for each group. The sample culture medium extracts were used for L929 cell culture and cultured at 37°C and 5% CO2 for 24 h. Then, the cell viability was detected by the CCK8 method, and the average value of each group of results was taken.

[0077] The cell compatibility tests of the materials in Examples 1 to 6 are as Figure 2 shown.

[0078] As Figure 2 shown: The materials in Examples 1 to 6 all showed good cell compatibility, could significantly promote cell growth, and the cell viabilities were all above 100%.

[0079] In vivo degradation experiment

[0080] Balb / c mice (20 g, female) had their back hair removed in a sterile environment, and their skin was cleaned. Subsequently, they were placed in a chamber of an isoflurane anesthesia machine for anesthesia and fixed on the operating table, with an anesthesia mask maintaining the anesthesia. The skin around the back was disinfected with iodophor, and an incision (~1 cm) was made on its back with a scalpel. The fascia between the skin and muscle was separated with scissors and forceps to form a small pocket. The solidified samples in Comparative Example 1 and Examples 1 - 6 were made into a size of 0.5 cm × 0.5 cm and implanted subcutaneously in the back. The tissue was sutured and disinfected again with iodophor. Six mice were randomly implanted for each case. After 8 weeks of breeding, the mice were euthanized, and the samples in Comparative Example 1 and Examples 1 - 6 were taken out. The morphology of the samples was observed, the weight of the samples was measured, and the degradation rate was calculated by comparing with the samples before implantation.

[0081] The in vivo degradation tests of the materials in Comparative Example 1 and Examples 1 - 6 were as Figure 3 shown.

[0082] As Figure 3 shown: The materials in Examples 1 - 6 all showed good degradation rates after maintaining for 8 weeks in the physiological environment. The degradation of the materials in Examples 1, 2, 3, and 5 was the most obvious, and the maximum degradation rate reached 38.5%. And with the increase in the proportion of DMMDO / BMDO, the degradation degree of the materials became more obvious, indicating that the introduction of the MDO ring - opening polymer and its side - chain ester bonds provided better degradation performance for the materials. In addition, the degradation rate of the material in Comparative Example 1 after 8 weeks was 1.1%, and the degradability of the material was poor, far lower than that of Examples 1 - 6, indicating the superior in vivo degradation performance of the tissue - adhesive material constructed by the present invention.

[0083] As can be seen from the above examples, compared with the prior art, the absorbable medical soft - tissue adhesive provided by the present invention is formed by in - situ curing through free - radical ring - opening polymerization under the initiation of an oxidation - reduction free - radical polymerization initiator in the human body environment. The reaction process is rapid, curing occurs within 20 s - 3 min, the reaction is slightly exothermic and will not burn the human body. After the free - radical ring - opening polymerization of the cycloalkenone acetal - type compound, the main chain contains an ester - bond structure, which can degrade in the physiological environment (the degradation rate > 20% after 8 weeks), and has good degradation performance. The mild reaction conditions are conducive to the loading of antibacterial agents and substances promoting tissue and organ healing. As the adhesive degrades, these substances are gradually exposed and released, promoting tissue healing and avoiding bacterial infection. The adhesive rapidly obtains high mechanical strength and bonding strength, and the bonding strength > 160 KPa within 5 min, and is not easily swollen in the physiological environment, having good physiological stability.

[0084] The above - mentioned are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. An absorbable medical soft tissue adhesive, the preparation raw materials of which include component A and component B: Component A includes cycloalkenone acetal compounds and oxidants; the cycloalkenone acetal compounds include one or more of 2-methylene-1,3-dioxepane, 2-methylene-4-phenyl-1,3-dioxolane, 5,6-benzo-2-methylene-1,3-dioxepane, and 4,7-dimethyl-2-methylene-1,3-dioxepane; the oxidant is benzoyl peroxide; Component B includes vinyl monomers, crosslinking agents, substances promoting tissue and organ healing, and reducing agents; The vinyl monomers include 10-(2-methacryloyloxy) monodecyl phosphate, methacryloyldopamine, methacrylic acid, or (meth)acryloyloxy sulfobetaine; The crosslinking agent is bis(2-methacryloyloxyethyl) hydrogen phosphate; The substances promoting tissue and organ healing are selected from one or more of β-1,3-glucan and its derivatives, hyaluronic acid, and asiaticoside; The reducing agent is N,N-dimethyl-p-toluidine; The molar ratio of the oxidant to the cycloalkenone acetal compounds is 0.005~0.05:1; The molar ratio of the oxidant to the reducing agent is 0.2~2:1; The molar ratio of the vinyl monomers to the cycloalkenone acetal compounds is 0.1~10:1; The molar ratio of the crosslinking agent to the cycloalkenone acetal compounds is 0.005~0.05:1; The molar ratio of the tissue and organ healing promoting substance to the cycloalkenone acetal compound is 1×10 -7 ~1×10 -6 :

1.

2. The absorbable medical soft tissue adhesive according to claim 1, wherein, Component B further includes an antibacterial agent; The antibacterial agent is selected from one or more of penicillins, cephalosporins, aminoglycosides, macrolides, lincosamides, quinolones, tetracyclines, sulfonamides, silver ions, zinc ions, antimicrobial peptides, coumarin compounds, polyguanidine polymers, and benzalkonium chloride; The molar ratio of the antibacterial agent to the cycloalkenone acetal compound is 1×10 -8 ~1×10 -4 :

1.

3. A preparation method of the absorbable medical soft tissue adhesive according to any one of claims 1~2, comprising the following steps: 1) Mix the cycloalkenone acetal compounds and the oxidant to obtain component A; Mix the vinyl monomers, crosslinking agents, substances promoting tissue and organ healing, and reducing agents to obtain component B; 2) Mix component A and component B evenly, and after polymerization reaction, obtain the absorbable medical soft tissue adhesive.

4. The preparation method according to claim 3, characterized in that, The time for mixing evenly in step 2) is 1~300 s.

5. Use of the absorbable medical soft tissue adhesive according to any one of claims 1~2 or the absorbable medical soft tissue adhesive prepared by the preparation method according to any one of claims 3~4 in the preparation of medical adhesives.

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