An antibacterial bio-based polyurethane dressing and a preparation method thereof

Abstract

The application discloses an antibacterial bio-based cyclic polyurethane dressing, which comprises 140-160 parts of polyether polyol, 25-30 parts of poly-delta-caprolactone polyol, 0.2-0.8 parts of a catalyst, 1.5-2.5 parts of a silicone foam stabilizer, 1-3 parts of deionized water, 6-12 parts of a foaming agent, 1-10 parts of sodium alginate, 1-10 parts of hyaluronic acid, 15-22 parts of diisocyanate, and 30-40 parts of cyclic oligomeric disulfide isocyanate. The antibacterial bio-based cyclic polyurethane dressing has the advantages of broad-spectrum and high-efficiency antibacterial property, rapid hemostasis, repair promotion and excellent water absorption and water retention performance, and is superior to commercially available polyurethane dressings.

Description

[0001] The application belongs to the technical field of biomedical materials, and particularly relates to an antibacterial bio-based polyurethane dressing and a preparation method thereof. BACKGROUND

[0002] Medical wound dressings form a protective barrier by covering skin wounds, which can not only avoid secondary injury of the wound, but also create a favorable microenvironment for tissue repair, and are mainly used for covering sores, wounds and other skin damage, and are an important type of biomedical materials. The research and development of medical wound dressings have been a hot topic in the field.

[0003] Polyurethane materials have excellent biological safety, no teratogenic effect, no allergic reaction, excellent anticoagulation performance, and meet the medical requirements in toxicity tests, and also have good toughness, elasticity and diversified processing performance, and are widely used in the field of wound dressings, common forms of which include films, hydrogels, foams and the like. Since medical dressings have the risk of contacting blood and body fluids, the water absorption rate thereof also needs to meet specific requirements. However, the polyurethane dressings on the market at present mostly use modified polyether, and the application of natural polymer hydrophilic aids is relatively scarce, and there is a certain market gap. In addition, the current bio-based polyurethane dressings also have defects such as single function and component, and are difficult to adapt to wounds with more exudates; meanwhile, the wounds are easily infected with bacteria during the healing process, which seriously hinders the repair process.

[0004] Based on the above status, it has become a key problem to be solved in the field to develop a bio-based antibacterial polyurethane dressing with durable antibacterial effect and adjustable component ratio. SUMMARY

[0005] In order to overcome the deficiencies of the prior art, the application provides an antibacterial bio-based polyurethane dressing, which integrates broad-spectrum high-efficiency antibacterial, rapid hemostasis, repair promotion and excellent water absorption and retention performance, and is superior to the commercially available polyurethane dressings.

[0006] The technical scheme for achieving the object of the application is as follows:

[0007] An antibacterial bio-based polyurethane dressing includes, by weight, 140-160 parts of polyether polyol, 25-30 parts of poly-d-caprolactone polyol, 0.2-0.8 parts of catalyst, 1.5-2.5 parts of silicone foam stabilizer, 1-3 parts of deionized water, 6-12 parts of foaming agent, 1-10 parts of sodium alginate, 1-10 parts of hyaluronic acid, 15-22 parts of diisocyanate, and 30-40 parts of cyclic oligomeric disulfide isocyanate; the general structure of the cyclic oligomeric disulfide isocyanate is shown in formula 1:

[0008] Formula 1 The R is one or more of the following: the ran represents that the cyclic oligomeric disulfide is a random cyclic molecule, wherein x+y is any integer between 3 and 8.

[0009] Specifically, the polyether polyol is one or more of the following: polyethylene glycol, polypropylene glycol, propylene glycol-ethylene glycol copolymer, polytetrahydrofuran diol.

[0010] Specifically, the cyclic oligomeric disulfide isocyanate is obtained by reacting the cyclic oligomeric disulfide with diisocyanate.

[0011] Specifically, the catalyst is an amine catalyst and a zinc catalyst in a molar ratio of 1:(0.1-0.5); the amine catalyst is one or more of the following: triethylenediamine, ethylenediamine, triethylamine, triethanolamine, and hexanediamine; the zinc catalyst is organic zinc ZCAT-H22; the blowing agent is any one of the following: cyclopentane or dichloromethane.

[0012] Preferably, the cyclic oligomeric disulfide isocyanate is prepared by the following preparation method:

[0013] The cyclic oligomeric disulfide is dissolved in anhydrous DMF preheated to 35-45°C and stirred to form a homogeneous solution; under nitrogen protection, 1.05-1.15 eq of diisocyanate relative to the molar amount of the hydroxyl group of the cyclic oligomeric disulfide is added dropwise to the above DMF solution under ice bath at 0-5°C, and the dropwise speed is controlled to be less than 1 mL / min, and the reaction is carried out at 35-40°C for 2-4 h; after the reaction is completed, the solvent is removed under reduced pressure, and the cyclic oligomeric disulfide isocyanate is purified by silica gel column chromatography.

[0014] Preferably, the preparation method of the cyclic oligomeric disulfide comprises the following steps:

[0015] (1) Synthesis of end-amino-protected cyclic disulfide: lipoic acid and carbonyldiimidazole in a molar ratio of 1:(1.3-1.4) are dissolved in acetonitrile, and stirred at room temperature for 25-35 min; a solution of N-Boc ethylenediamine corresponding to 1.5-2 times the molar amount of lipoic acid is added dropwise, and the reaction temperature is controlled at 0°C, and stirred for 25-35 min, and then the temperature is raised to room temperature and stirred for 4-5 h; acetonitrile is removed under reduced pressure, dichloromethane is added to dilute the reaction solution, and the organic phase is sequentially washed with saturated ammonium chloride aqueous solution and deionized water, and then purified by silica gel column chromatography to obtain end-amino-protected cyclic disulfide, which has the following structure:

[0016]

[0017] (2) Synthesis of ethanolamine-cyclodisulfide: lipoic acid, l-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide were dissolved in anhydrous DMF under nitrogen atmosphere, 0.1-0.2 times of 4-dimethylaminopyridine of the molar amount of lipoic acid was added, and stirred in an ice bath for 25-35 min at 0°C; 1.2-1.3 times of diethanolamine of the molar amount of lipoic acid was dissolved in anhydrous DMF, and added dropwise into the reaction system, and warmed to 35-45°C for 5-6 h; after the reaction was completed, the reaction solution was washed with 5% citric acid aqueous solution, saturated NaHCO3 solution and brine in turn, dried with anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain ethanolamine-cyclodisulfide, the structure of which is shown in the following formula:

[0018]

[0019] (3) Synthesis of cyclic oligomeric disulfide: amino-protected cyclodisulfide and ethanolamine-cyclodisulfide with a molar ratio of 3:2 were added into a thick-walled pressure-resistant bottle, and nitrogen was replaced for three times to ensure anhydrous and anaerobic environment, and then anhydrous tetrahydrofuran was added; phenyl mercaptan and (tert-butylimino) tris (pyrrolidine) phosphine with a molar ratio of 1:1 were dissolved in 80 μL of anhydrous tetrahydrofuran to prepare an initiator solution; the initiator solution was injected into the system, and stirred in an ice bath for 2-3 h at 0°C to start ring-opening polymerization; 0.5 times of trifluoroacetic acid of the molar amount of ethanolamine-cyclodisulfide was added, and the reaction was terminated after stirring at room temperature for 25-30 min; the reaction solution was added dropwise into 40 mL of pre-cooled ether to induce precipitation; the precipitate was dried under high vacuum for 3-4 h to obtain cyclic oligomeric disulfide, the structure of which is shown in the following formula:

[0020]

[0021] The preparation method of the poly-δ-caprolactone polyol comprises the following steps:

[0022] In a glove box, water and oxygen were removed by Schlenk tube flame drying, and base catalyst, 1,3-diphenylurea and benzyl alcohol with a molar ratio of (0.5-2):(1-3):(0.5-2):100 were added, and polymerization was started with δ-caprolactone; after polymerization at room temperature for 1-2 h, acetic acid was added dropwise to quench the reaction; the crude product was dissolved in 0.5 mL of tetrahydrofuran, and a small amount was taken for nuclear magnetic resonance hydrogen spectrum analysis; the above solution was added dropwise into excess pre-cooled methanol to precipitate the polymer, which was washed twice with cold methanol; the precipitate was dried under vacuum at 30°C to obtain poly-δ-caprolactone polyol.

[0023] Preferably, the base catalyst is selected from phosphazene ligand P2-tert-butyl solution.

[0024] Preferably, the molecular weight of the poly-d-caprolactone polyol is 4000-6000 Da.

[0025] Preferably, the diisocyanate includes one or more of diphenylmethane diisocyanate, toluene diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate.

[0026] A preparation method of an antibacterial bio-based polyurethane dressing, comprising the following steps:

[0027] S1. The polyether polyol, poly-d-caprolactone polyol, catalyst, silicone foam stabilizer, deionized water, foaming agent, sodium alginate, hyaluronic acid are added into the premixing and stirring material curing equipment 1 according to the ratio, and after cooling and circulating curing, the materials are fed to the storage cylinder 2 for secondary cooling, constant temperature homogenizing and stirring;

[0028] S2. The diisocyanate and cyclic oligomeric disulfide isocyanate are injected into the homogenizing stirring tank 3 for constant temperature homogenizing and stirring;

[0029] S3. The homogenized materials in the storage cylinder 2 and the homogenizing stirring tank 3 are injected into the static closed mixing mechanism 4 through different speed ratio of screw pumps; after uniform high-speed mixing, the materials are uniformly injected onto the bottom release paper of the coating curing mechanism 5 through a hose, and the product is cured;

[0030] S4. The cured product is transported to the release mechanism 11 of the main equipment for peeling and winding of the upper and lower release papers and transportation of the cured product;

[0031] S5. The product is synchronously pulled into the dehydration process of drying and sterilization through the coating curing mechanism 5 and the microwave sterilization drying equipment 15; after sterilization drying, the product is transported to the wind shower dust removal mechanism 16 for surface dust removal, and then transported to the winding and cutting equipment 17 through the power guide roller of the wind shower dust removal equipment for cutting; the cut product is transported without tension to the winding guide roller for tension-free winding; the wound product is packaged and stored in a light-proof and air-tight manner.

[0032] Preferably, the coating curing mechanism includes an upper release paper feeding mechanism 6, a lower release paper feeding mechanism 7, a comma doctor blade 8, a width adjusting compression roller 9 and a curing oven 10.

[0033] Preferably, the speed ratio is 1:(1.1-1.5); the temperature of the microwave sterilization is ≤60℃, and the DMF solution concentration of the diisocyanate is 20wt%.

[0034] The application of the antibacterial bio-based polyurethane dressing obtained as described above has excellent biocompatibility, self-repairing, wound healing promotion and renewable functions, and can be widely applied to the field of medical materials.

[0035] Advantages

[0036] The application develops an antibacterial bio-based cyclic polyurethane dressing. Through material design and performance optimization, the dressing exhibits significant advantages in multiple dimensions, as follows:

[0037] 1. Synergistic effect of multiple antibacterial mechanisms: relying on the triple mechanism of disrupting microbial cell membrane integrity through disulfide bonds (S-S), causing cell membrane perforation through electrostatic adsorption of quaternary ammonium groups, and enhancing contact efficiency with microbial surface through cyclic oligomeric structure, strong inhibition of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and other pathogenic bacteria is achieved.

[0038] 2. Adjustable and controllable antibacterial performance: by adjusting the amount and type of cyclic oligomeric disulfide isocyanate, such as aromatic diphenylmethane diisocyanate or aliphatic isophorone diisocyanate, the antibacterial efficacy and biocompatibility can be balanced. The aromatic isocyanate enhances bacterial membrane binding through benzene ring hydrophobic interaction, with slightly better antibacterial effect; the aliphatic isocyanate has better biocompatibility, meeting different scene requirements.

[0039] 3. Promoting wound healing: hyaluronic acid activates fibroblast proliferation, and the dynamic exchange characteristics of disulfide bonds adapt to the shrinkage stress of the wound, achieving rapid wound healing.

[0040] 4. Excellent water absorption and retention performance, adapting to various wound needs. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 It is a synthesis route of cyclic oligomeric disulfide polyurethane.

[0042] Figure 2 It is the nuclear magnetic hydrogen spectrum of the amino-protected cyclic disulfide 1.

[0043] Figure 3 It is the nuclear magnetic hydrogen spectrum of the ethanolamine-cyclized cyclic disulfide 1.

[0044] Figure 4 It is the nuclear magnetic hydrogen spectrum of the cyclic oligomeric disulfide 1.

[0045] Figure 5 It is the nuclear magnetic hydrogen spectrum of the cyclic oligomeric disulfide isocyanate 1.

[0046] Figure 6 It is a preparation device of the antibacterial bio-based polyurethane dressing.

[0047] The reference signs include:

[0048] 1 - Premixing and stirring material curing device

[0049] 2 - Storage cylinder

[0050] 3 - Homogenizing stirring tank

[0051] 4 - Static closed mixing mechanism

[0052] 5 - Coating and curing mechanism

[0053] 6 - Upper layer release paper feeding mechanism

[0054] 7 - Lower layer release paper feeding mechanism

[0055] 8 - Comma doctor blade

[0056] 9 - Web width adjusting compression roller

[0057] 10 - Curing oven

[0058] 11 - Release mechanism of main body device

[0059] 12 - Upper layer release paper collecting mechanism

[0060] 13 - Lower layer release paper collecting mechanism

[0061] 14 - Automatic spraying device up and down

[0062] 15 - Microwave sterilization and drying device

[0063] 16 - Air shower dust removal mechanism

[0064] 17 - Winding and slitting device DETAILED DESCRIPTION

[0065] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0066] In the embodiments, the experimental methods used are conventional methods, and the materials, reagents, etc. used are commercially available unless otherwise specified.

[0067] The raw materials and equipment used in the examples and comparative examples are described as follows:

[0068] Cyclic oligomeric disulfide 1: self-made, the preparation method is as follows:

[0069] (1) Synthesis of amino-protected cyclic disulfide: 1.0 eq of lipoic acid and 1.3 times of carbonyldiimidazole relative to the molar amount of lipoic acid were dissolved in anhydrous acetonitrile, and stirred at room temperature for 30 min; a solution of N-Boc ethylenediamine dissolved in anhydrous acetonitrile was added dropwise to the above system, and the reaction temperature was controlled at 0°C for 30 min, and then increased to room temperature for 4.5 h; acetonitrile was removed by vacuum concentration, and the reaction solution was diluted with dichloromethane, and then washed with saturated ammonium chloride aqueous solution and deionized water successively; the organic phase was purified by silica gel column chromatography to obtain an amino-protected cyclic disulfide, the structure of which is shown in the following formula:

[0070]

[0071] (2) Synthesis of ethanolamine-cyclic disulfide: 1 eq of lipoic acid, 1.2 times of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride relative to the molar amount of lipoic acid, and 1.2 times of N-hydroxysuccinimide relative to the molar amount of lipoic acid were dissolved in anhydrous DMF, and 0.1-0.2 times of 4-dimethylaminopyridine relative to the molar amount of lipoic acid was added, and stirred at 0°C for 30 min; 1.2 times of diethanolamine relative to the molar amount of lipoic acid was dissolved in anhydrous DMF, and added dropwise to the reaction system, and the temperature was increased to 40°C for 5 h; after the reaction was completed, the reaction solution was washed with 5% citric acid aqueous solution, saturated NaHCO3 solution and brine successively, and dried with anhydrous sodium sulfate; after purification by silica gel column chromatography, an ethanolamine-cyclic disulfide was obtained, the structure of which is shown in the following formula:

[0072]

[0073] (3) Synthesis of cyclic oligomeric disulfide 1: 30 eq of amino-protected cyclic disulfide and 20 eq of ethanolamine-cyclic disulfide were added to a thick-walled pressure bottle, and nitrogen was replaced three times to ensure anhydrous and anaerobic conditions, and then anhydrous tetrahydrofuran was added; 1 eq of thiophenol and 1 eq of (tert-butylimino) tris (pyrrolidine) phosphine were dissolved in 80 μL of anhydrous tetrahydrofuran to prepare an initiator solution; the initiator solution was injected into the system, and stirring was performed at 0°C for 2 h to start the ring-opening polymerization; 10 eq of trifluoroacetic acid was added, and stirring was performed at room temperature for 30 min to terminate the reaction; the reaction solution was added dropwise into 40 mL of pre-cooled ether to induce precipitation; the precipitate was dried under high vacuum for 4 h to obtain cyclic oligomeric disulfide 1, the structure of which is shown in the following formula:

[0074]

[0075] Cyclic oligomeric disulfide 2: self-made, the difference between the preparation method and that of cyclic oligomeric disulfide 1 is that no N-Boc ethylenediamine solution is added in step (1), and other conditions are unchanged, to obtain cyclic oligomeric disulfide 2;

[0076] Linear disulfide 3: self-made, the preparation method is compared with that of cyclic oligomeric disulfide 1, the difference is that thioctic acid in step (2) is replaced by 3-carboxypropyl disulfide, steps (1) and (3) are not performed, and linear disulfide 3 is obtained;

[0077] Poly-d-caprolactone polyol: self-made, the preparation method is as follows:

[0078] In the glove box, water oxygen is removed by Schlenk tube flame drying, and polymerization is started by adding alkali catalyst, 1,3-diphenylurea and benzyl alcohol and d-caprolactone in a molar ratio of (0.5-2):(1-3):(0.5-2):100, after polymerization at room temperature for 1 h, acetic acid is added dropwise to quench the reaction; the crude product is dissolved in 0.5 mL of tetrahydrofuran; the above solution is added dropwise into excess pre-cooled methanol, and the polymer is precipitated and washed twice with cold methanol; the precipitate is dried under vacuum at 30°C to obtain poly-d-caprolactone polyol with a molecular weight of 5000 Da and a hydroxyl value of 22.4 mgKOH / g.

[0079] Thiophenol: self-made, the preparation method is as follows: 1 eq of sodium thiophenol is suspended in ice water, 30 mL of 10% concentrated hydrochloric acid is slowly added dropwise, the temperature is controlled ≤10°C, after the dropwise addition is completed, stirring is carried out at room temperature for 25-35 min; after the reaction is completed, ether is added for extraction, the organic phases are combined, washed with 5% NaHCO3 solution and deionized water until neutral; the organic phase is dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain thiophenol;

[0080] Diisocyanate: diphenylmethane diisocyanate, purchased from Shanghai Aldrich Biochemical Technology Co., Ltd.;

[0081] Polyether polyol: polyethylene glycol: molecular weight 2000 Da, hydroxyl value 56.1 mgKOH / g, commercially available;

[0082] Foaming agent: cyclopentane, commercially available;

[0083] Sodium alginate: purity 99%, purchased from Hubei Xinghengkang Chemical Technology Co., Ltd.;

[0084] Hyaluronic acid: purity 99%, Jinan Luxin Chemical Technology Co., Ltd.;

[0085] Catalyst: triethylenediamine and organic zinc ZCAT-H22 in a molar ratio of 1:0.2, commercially available;

[0086] Silicone foam stabilizer: Synde-217 PU synthetic leather foam stabilizer, purchased from Zhuhai Xianxin New Material Technology Co., Ltd.;

[0087] Alkali catalyst: phosphazene ligand P2-t-butyl solution, phosphazene ligand P2-t-butyl tetrahydrofuran solution with a concentration of 2 mol / L;

[0088] δ-hexalactone: product number D155361, purchased from Shanghai Aladdin Bio-Chem Technology Co., Ltd.;

[0089] 1,3-diphenylurea: product number 1015136, purchased from Shanghai Hauheng Biomedical Technology Co., Ltd.;

[0090] 1,4-butanediol: product number B110391, purchased from Shanghai Aladdin Bio-Chem Technology Co., Ltd.;

[0091] diphenyl phosphate: product number 1044516, purchased from Shanghai Hauheng Biomedical Technology Co., Ltd.;

[0092] 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride: purchased from Shanghai Covalent Chemistry Technology Co., Ltd.;

[0093] N-hydroxysuccinimide: purchased from Shanghai Changming Pharmaceutical Technology Co., Ltd.;

[0094] Preparation Example

[0095] Preparation Example 1

[0096] Cyclic oligomeric disulfide isocyanate 1: self-made, the preparation method is as follows:

[0097] Dissolve 1 eq of cyclic oligomeric disulfide 1 in terms of hydroxyl groups in 40°C preheated anhydrous DMF, and stir to dissolve into a homogeneous phase; under nitrogen protection, 1.1 eq of diphenylmethane diisocyanate is added to the above DMF solution under 0-5°C ice bath, and the dropwise speed is controlled within 1 mL / min, and the reaction is carried out at 40°C for 4 h; after the reaction is completed, the solvent is removed under reduced pressure, and the cyclic oligomeric disulfide isocyanate 1 is purified by silica gel column chromatography.

[0098] Preparation Example 2

[0099] Cyclic oligomeric disulfide isocyanate 2: self-made, the preparation method is compared with that of cyclic oligomeric disulfide isocyanate 1, the difference lies in that cyclic oligomeric disulfide 1 is replaced by cyclic oligomeric disulfide 2, and other conditions are unchanged, to obtain cyclic oligomeric disulfide isocyanate 2.

[0100] Preparation Example 3

[0101] Cyclic oligomeric disulfide isocyanate 3: self-made, the preparation method is compared with that of cyclic oligomeric disulfide isocyanate 1, the difference lies in that diphenylmethane diisocyanate is replaced by isophorone diisocyanate, and other conditions are unchanged, to obtain cyclic oligomeric disulfide isocyanate 3.

[0102] Preparation Example 4

[0103] Linear disulfide isocyanate 4: self-made, the preparation method is the same as that of cyclic oligomeric disulfide isocyanate 1, except that cyclic oligomeric disulfide 1 is replaced by linear disulfide 3, and other conditions are unchanged, to obtain linear disulfide isocyanate 4.

[0104] Example

[0105] Examples 1-5

[0106] Antibacterial bio-based polyurethane dressings 1-5: self-made, the preparation method is as follows:

[0107] S1. The polyether polyol, poly-d-caprolactone polyol, catalyst, silicone foam stabilizer, deionized water, foaming agent, sodium alginate, hyaluronic acid are added into the premixing and stirring material curing equipment 1 according to the ratio, and after cooling and circulating curing, the material is fed to the storage cylinder 2 for secondary cooling at 20-25°C constant temperature and 500-800 rpm homogeneous stirring;

[0108] S2. The diisocyanate and cyclic oligomeric disulfide isocyanate 1-3 are injected into the homogeneous stirring tank 3 for homogeneous stirring at 40°C constant temperature and 300-400 rpm;

[0109] S3. The homogeneously cured raw materials in the storage cylinder 2 and the homogeneous stirring tank 3 are injected into the static closed mixing mechanism 4 through a screw pump at a speed ratio of 1:(1.1-1.5) revolutions, and the temperature is 35-40°C; After uniform high-speed mixing, the product is cured by uniformly injecting it onto the bottom release paper of the coating curing mechanism 5; the hose oscillation frequency is 10-15 times / min; the release paper type is PET release film with a thickness of 100 μm;

[0110] S4. The cured product is transported to the release mechanism 11 of the main equipment for peeling and winding of the upper and lower release papers and transportation of the cured product;

[0111] S5. The product is drawn into the drying and sterilizing dehydration process by the synchronous traction of the coating curing mechanism 5 and the microwave sterilization drying equipment 15; after sterilization and drying, it enters the air shower dust removal mechanism 16 for dust removal on the surface of the product, and then is transported to the winding and cutting equipment 17 through the power guide roller of the air shower dust removal equipment for cutting. The cut product is transported without tension to the winding guide roller for tension-free winding; the wound product is packaged and stored in a light-proof and airtight manner.

[0112] Comparative example

[0113] Comparative example 1

[0114] Commercially available polyurethane dressing: 3M polyester foam dressing 90613, purchased from Henan Zeguan Medical Instrument Sales Co., Ltd.

[0115] Comparative Example 2

[0116] Antibacterial bio-based polyurethane dressing 6: self-made, the preparation method is compared with the examples, the difference is that the linear disulfide isocyanate 4 is replaced for the cyclic oligomeric disulfide isocyanate 1-3, and other conditions are unchanged, and the antibacterial bio-based polyurethane dressing 6 is obtained.

[0117] Table 1 Formulation of Examples 1-5 and Comparative Examples (by weight)

[0118]

[0119] The following is the test method of the performance parameters involved in the application:

[0120] 1. Bacteriostatic test

[0121] 1.1 Sample preparation: the polyurethane dressing prepared in Examples 1-5 of the application was cut into a circle with a diameter of 5 cm, and was used as the experimental group 1-5; the polyurethane dressing of the comparative example was cut into the same size circle, and was used as the comparative example group; the experimental groups 1-5 and the comparative example group were sequentially loaded into 6 triangular bottles, the bottle opening was sealed, and sterilized at 120℃ for 15 min for standby.

[0122] 1.2 Preparation of bacterial suspension: the preserved bacteria were inoculated on nutrient agar plates by streaking with an inoculation loop, and were cultured in a 37℃ incubator for 24 h; typical colonies on the plates were removed and inoculated into a triangular bottle of broth medium, and were cultured at 37℃ for 24 h; the broth was serially diluted to obtain a bacterial suspension with a content of 1×105 cfu / mL-5×105 cfu / mL.

[0123] 1.3 Test steps: 1 mL of bacterial suspension was inoculated on the dressing in the 6 triangular bottles, and was cultured in a 37℃ incubator with shaking for 48 h; the sample solution before and after shaking was taken, diluted with 9 mL of 0.03 mol / L PBS buffer, and inoculated on agar plates by agar pouring method; colony counting was performed, and then the bacteriostatic rate was calculated, which was the ratio of the difference between the average number of colonies before and after shaking of the test sample to the average number of colonies before shaking, and was calculated as a percentage, as shown in the following formula:

[0124]

[0125] The selected bacteria were Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, and the bacteriostatic test was performed in sequence according to the above method.

[0126] 2. Body surface experiment: 60 rabbits with similar weight and age were randomly divided into 6 groups, 10 rabbits in each group. After the hair on the back of the rabbits was removed with a depilatory agent, the rabbits were anesthetized by intravenous injection of 1% sodium pentobarbital in the auricular vein. Under sterile conditions, a cross-shaped wound was drawn on the surface of the skin in the depilated area of the rabbit, and the polyurethane dressings of Examples 1-5 and Comparative Examples were placed in the wound sites of the rabbits in groups 1-6, respectively. A filter paper strip was used to gently dab and absorb until no blood was exuded, and the bleeding was observed. After 12 h, the polyurethane dressings were removed, the wound conditions were recorded, the polyurethane dressings were replaced daily, and the dressings were used continuously for 3 days. After 3 days, the polyurethane dressings were removed, and the wound conditions were observed.

[0127] 3. Water absorption rate: The medical dressing foam with a size of 50 mm x 50 mm x 50 mm was measured for a mass of m1, then soaked in water and squeezed repeatedly for 30 times, and after 1 h of continued soaking in water, the mass was measured as m2. The water absorption rate was calculated by the following formula:

[0128]

[0129] 4. Water retention rate: The medical dressing foam with a size of 50 mm x 50 mm x 50 mm was measured for a mass of m1, then soaked in water and squeezed repeatedly for 30 times, and after 1 h, the foam was placed on a horizontal plate, and after another 1 h, the mass of the foam was measured as m3. The water absorption rate was calculated by the following formula:

[0130]

[0131] Table 2 Test results of Examples 1-5 and Comparative Examples

[0132]

[0133] As can be seen from Table 2, in terms of antibacterial performance, the antibacterial effect of the antibacterial bio-based polyurethane dressing of the present application is derived from the synergistic effect of multiple mechanisms: the disulfide bond can destroy the integrity of the microbial cell membrane, the quaternary ammonium group causes cell membrane perforation through electrostatic adsorption, and the cyclic oligomeric disulfide structure enhances the contact efficiency with the microbial surface. As can be seen from the different examples, Example 3 performs best, with a bacterial inhibition rate of Staphylococcus aureus as high as 99.3%, presumably due to the higher dosage of cyclic oligomeric disulfide isocyanate 1. In contrast, Example 2 has the lowest dosage of cyclic oligomeric disulfide isocyanate, and the antibacterial performance is relatively weak. In addition, Examples 1 and 4 using diphenylmethane diisocyanate have improved binding efficiency with the bacterial membrane due to the enhanced hydrophobic force of the benzene ring, and the antibacterial effect is better than that of Example 5 using isophorone diisocyanate; however, the aliphatic isocyanate structure of Example 5 gives the material better biocompatibility, with only a slightly lower bacterial inhibition rate.

[0134] The in vivo experiment results show that the hemostatic performance of the dressing mainly depends on the ionic cross-linking effect of sodium alginate, and the hemostatic speed is ranked as: Example 3 > Example 1 > Example 5 > Example 4 > Example 2. Among them, Example 3 can accelerate the aggregation of blood cells due to containing more negative charge sites, while the comparative example lacking functional disulfide bond only relies on physical compression, and the hemostatic time is as long as 45 seconds, which is significantly behind.

[0135] The comparison of water absorption and retention performance reflects the correlation between material structure and performance. The water absorption rate is ranked as: Example 2 > Example 4 > Example 1 > Example 5 > Example 3. The high water absorption rate of Example 2 is due to low cross-linking density, and hyaluronic acid and sodium alginate further improve the water absorption capacity; while Example 3 increases the cross-linking points due to high dose of cyclic oligomeric disulfide isocyanate, which limits the swelling space, and the water absorption rate is the lowest. The water retention rate is ranked as: Example 3 > Example 5 > Example 1 > Example 4 > Example 2; at the same time, the structure of isophorone diisocyanate in Example 5 improves the flexibility of the chain segment and enhances the water molecule wrapping capacity, while the water retention rate of the commercial polyurethane dressing is 81.2%, which is significantly lower than that of the dressing of the application.

[0136] The preferred embodiments of the application disclosed above are only used to help explain the application. The preferred embodiments do not describe all the details and do not limit the application to the specific embodiments described. Obviously, many modifications and changes can be made according to the content of the specification. The specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the application, so that those skilled in the art can well understand and utilize the application. The application is limited only by the claims and their full scope and equivalents.

Claims

1. An antimicrobial bio-based polyurethane dressing, characterized by, The poly-d-caprolactone polyol is prepared by the following steps: under anhydrous and anaerobic conditions, alkali catalyst, 1,3-diphenylurea, benzyl alcohol and δ-caprolactone in a molar ratio of (0.5-2):(1-3):(0.5-2):100 are polymerized at room temperature for 1-3 hours, and the reaction is quenched by dropwise adding acetic acid, and the poly-d-caprolactone polyol is obtained after purification. The R is one or several of the following: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R 2. The antibacterial bio-based polyurethane dressing of claim 1, wherein, The poly-d-caprolactone polyol is prepared by the following steps: under anhydrous and anaerobic conditions, alkali catalyst, 1,3-diphenylurea, benzyl alcohol and δ-caprolactone in a molar ratio of (0.5-2):(1-3):(0.5-2):100 are polymerized at room temperature for 1-3 hours, and the reaction is quenched by dropwise adding acetic acid, and the poly-d-caprolactone polyol is obtained after purification. The poly-d-caprolactone polyol is prepared by the following steps: under anhydrous and anaerobic conditions, alkali catalyst, 1,3-diphenylurea, benzyl alcohol and δ-caprolactone in a molar ratio of (0.5-2):(1-3):(0.5-2):100 are polymerized at room temperature for 1-3 hours, and the reaction is quenched by dropwise adding acetic acid, and the poly-d-caprolactone polyol is obtained after purification.

3. The antibacterial bio-based polyurethane dressing as claimed in claim 1, wherein, The poly-d-caprolactone polyol is prepared by the following steps: under anhydrous and anaerobic conditions, alkali catalyst, 1,3-diphenylurea, benzyl alcohol and δ-caprolactone in a molar ratio of (0.5-2):(1-3):(0.5-2):100 are polymerized at room temperature for 1-3 hours, and the reaction is quenched by dropwise adding acetic acid, and the poly-d-caprolactone polyol is obtained after purification.

4. The antibacterial bio-based polyurethane dressing of claim 1, wherein, The catalyst is an amine catalyst and a zinc catalyst in a molar ratio of 1:(0.1-0.5); the amine catalyst is one or more of triethylenediamine, ethylenediamine, triethylamine, triethanolamine and hexanediamine; the zinc catalyst is organic zinc ZCAT-H22; and the foaming agent is any one of cyclopentane or dichloromethane.

5. The antimicrobial bio-based polyurethane dressing of claim 1, wherein, The cyclic oligomeric disulfide is reacted with diisocyanate to obtain the cyclic oligomeric disulfide isocyanate; the molecular weight of the cyclic oligomeric disulfide ranges from 1000 to 4000 Da; and the molecular weight of the cyclic oligomeric disulfide isocyanate ranges from 1200 to 4200 Da, and the average molecular weight ranges from 2800 to 3200 Da.

6. The antimicrobial bio-based polyurethane dressing of claim 1, wherein, The diisocyanate includes one or more of diphenylmethane diisocyanate, toluene diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate and dicyclohexylmethane diisocyanate.

7. The antimicrobial bio-based polyurethane dressing of claim 1, wherein, The cyclic oligomeric disulfide isocyanate is prepared by the following method: The cyclic oligomeric disulfide is dissolved in 35-45°C preheated anhydrous DMF and stirred to form a homogeneous solution; under nitrogen protection and 0-5°C ice bath, diisocyanate in a molar amount of 1.05-1.15 eq relative to the hydroxyl group of the cyclic oligomeric disulfide is added dropwise to the above DMF solution, and the reaction is carried out at 35-40°C for 2-4 hours; after the reaction is completed, the solvent is removed under reduced pressure, and the cyclic oligomeric disulfide isocyanate is purified by silica gel column chromatography.

8. The antibacterial bio-based polyurethane dressing as claimed in claim 1, wherein, The cyclic oligomeric disulfide is prepared by the following method: (1) Synthesis of amino-protected cyclic disulfide: lipoic acid and carbonyldiimidazole in a molar ratio of 1:(1.3-1.4) are dissolved in acetonitrile, and an N-Boc ethylenediamine solution equivalent to 1.5-2 times the molar amount of lipoic acid is added dropwise, stirred at 0-5°C for 25-35 min, and then stirred at room temperature for 4-5 h to obtain amino-protected cyclic disulfide; (2) Synthesis of ethanolamine-cyclodisulfide: under nitrogen atmosphere, lipoic acid, l-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxy succinimide were dissolved in DMF under ice bath conditions, 0.1-0.2 times of 4-dimethylaminopyridine corresponding to the molar amount of lipoic acid was added, and stirring was performed; 1.2-1.3 times of diethanolamine corresponding to the molar amount of lipoic acid was added, and reaction was performed at 35-45°C for 5-6h to prepare ethanolamine-cyclodisulfide; (3) Synthesis of cyclic oligomeric disulfide: under anhydrous and anaerobic conditions, amino-protected cyclic disulfide and ethanolamine-cyclodisulfide in a molar ratio of 3:2 were added to a thick-walled pressure bottle, tetrahydrofuran and an initiator were added, and stirring was performed under ice bath at 0°C for 2-3h to start ring-opening polymerization; then, trifluoroacetic acid was added to terminate the reaction, and pre-cooled ether was added drop by drop to induce precipitation; the precipitate was dried under high vacuum to prepare cyclic oligomeric disulfide, the structure of which is shown in the following formula:

9. The method of preparing an antimicrobial bio-based polyurethane dressing according to any one of claims 1 to 8, wherein, The method comprises the following steps: S1. The polyether polyol, poly-d-caprolactone polyol, catalyst, silicone foam stabilizer, deionized water, foaming agent, sodium alginate, and hyaluronic acid are mixed and stirred in a premixing and aging device according to the proportions, and after cooling and circulating aging, the mixture is fed to a storage cylinder for secondary cooling, constant temperature homogenizing and stirring; S2. The diisocyanate and cyclic oligomeric disulfide isocyanate are injected into the homogenizing and stirring tank for constant temperature homogenizing and stirring; S3. The homogenized raw materials in the storage cylinder and the homogenizing and stirring tank are injected into a static closed mixing mechanism through a screw pump at different speed ratios, uniformly and rapidly mixed, and then uniformly injected through a hose onto the bottom layer of release paper in a coating and aging mechanism for aging of the product; S4. The aged product is transported to a release mechanism of a main device for peeling and winding of the upper and lower release papers and transportation of the aged product; S5. The product is synchronously drawn into a microwave sterilization and drying device through the coating and aging mechanism, subjected to a dehydration process for drying and sterilization, subjected to dust removal on the surface in a wind shower dust removal mechanism, and then transported to a winding and cutting device through a power guide roller of the wind shower dust removal device for cutting, and the cut product is transported without tension to a winding guide roller for tension-free winding; and the wound product is packaged and stored in a light-proof and air-tight manner.

10. The method of preparing an antimicrobial bio-based polyurethane dressing as claimed in claim 9, wherein, The coating and aging mechanism comprises an upper release paper feeding mechanism, a lower release paper feeding mechanism, a comma doctor blade, a width adjusting compression roller, and an aging oven.

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