A photocured bioactive polycitrate-based polyurethane medical adhesive and a method of making the same
The preparation of a photocurable bioactive polycitrate-based polyurethane medical adhesive has solved the problems of rapid and stable adhesion at tissue interfaces and failure in humid environments of existing medical adhesives. It achieves rapid wound closure and good biocompatibility, making it suitable for widespread application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- WUHAN UNIV OF TECH
- Filing Date
- 2023-08-28
- Publication Date
- 2026-07-21
AI Technical Summary
Existing medical adhesives are difficult to form rapid and stable adhesion between tissue interfaces, are prone to failure in humid environments, and lack good bioactivity and biodegradability.
A photocurable bioactive polycitrate-based polyurethane medical adhesive is used. This is achieved by reacting polycitrate diol prepolymer with diisocyanate, hydrophilic chain extender, catalyst, etc., adding small molecule polyol chain extender and vinyl monomer, grafting N-hydroxysuccinimide (NHS) activator, blending hydrophobic polymer, and adding photoinitiator to achieve rapid crosslinking, curing and covalent bonding.
It maintains good adhesion in humid environments, quickly achieves wound closure, is biocompatible and bioactive, is biodegradable, and has a simple preparation process.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a photocurable bioactive polycitrate-based polyurethane medical adhesive and its preparation method. Background Technology
[0002] The common treatment for tissue trauma is surgical sutures. Although sutures can firmly connect damaged tissues, the operation time is long and it is not suitable for traumas requiring emergency care. Furthermore, the secondary tissue damage caused during the operation is not suitable for some fragile organs, nor for organs prone to fluid and gas leakage. Medical adhesives are gradually becoming the most promising alternative to sutures.
[0003] With the increasing clinical demand for medical adhesives, commercial tissue adhesives have been developed. Cyanoacrylate adhesives are the most widely used due to their fast curing speed and high bonding strength, but they suffer from brittleness and difficulty in degradation. Currently, advanced medical adhesives under research mainly use natural polymers such as polysaccharides (alginate, chitosan, hyaluronic acid, etc.) or gelatin as the main chain, and achieve adhesive effects through functionalized side groups. Compared with synthetic materials such as polyurethane and polyester, the functionalization and property control of these substances are more challenging, with adhesion being particularly difficult to improve. Furthermore, existing medical adhesives often use polyphenols, such as catechol, as adhesive groups. These adhesives require the establishment and maintenance of a redox system to achieve long-term adhesion; uncontrolled oxidation may limit their adhesiveness. Therefore, further exploration of medical adhesives that can generate stable adhesion and achieve wet tissue adhesion in a short time has significant research and application implications. Summary of the Invention
[0004] The main objective of this invention is to address the shortcomings of existing medical adhesives, such as difficulty in forming rapid and stable adhesion between tissue interfaces, easy adhesion failure in humid environments, and lack of good bioactivity and biodegradability. This invention provides a photocurable bioactive polycitrate-based polyurethane medical adhesive, focusing on the adhesive matrix and adhesive layer. When injected into the tissue to be bonded, it exhibits rapid and stable adhesion between humid tissues under light irradiation, and possesses good biodegradability, biocompatibility, and bioactivity. Furthermore, the preparation method is relatively simple, easy to operate, and suitable for widespread application.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] A method for preparing a photocurable bioactive polycitrate-based polyurethane medical adhesive includes the following steps:
[0007] 1) The polycitrate diol prepolymer is reacted with diisocyanate, hydrophilic chain extender, catalyst and solvent under a protective atmosphere and heating conditions to obtain an intermediate. Then, a small molecule polyol chain extender is added to carry out a second reaction. After cooling, vinyl monomer is added to carry out a third reaction to obtain double bond-terminated polycitrate-based polyurethane prepolymer. The solvent is then rotary evaporated for later use.
[0008] 2) The double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1) is uniformly dispersed in organic solvent I. An activator and N-hydroxysuccinimide (NHS) are added to the resulting mixed solution. The resulting mixed solution I is subjected to a grafting reaction at room temperature to obtain a double-bond-terminated polycitric acid ester polyurethane prepolymer containing the active ester NHS. The solvent is then rotary evaporated for later use.
[0009] 3) The double-bond-terminated polycitrate polyurethane prepolymer containing active ester NHS obtained in step 2) is uniformly dispersed in organic solvent II. A hydrophobic polymer is added to the resulting mixture II and the mixture is blended to obtain a blended solution. The solvent is then removed. Then a photoinitiator is added and the mixture is mixed evenly to obtain the photocurable bioactive polycitrate polyurethane medical adhesive. It is stored at 0-4℃ away from light.
[0010] In the above scheme, the molar ratio of the diisocyanate to the polycitrate prepolymer is 5-6.7:1.
[0011] In the above scheme, the molar ratio of the hydrophilic chain extender to the polycitrate prepolymer is 1.5-2.0:1.
[0012] In the above scheme, the mass ratio of the hydrophilic chain extender in the raw material system obtained from the first reaction is 4.1-6.8 wt%.
[0013] In the above scheme, the amount of catalyst used is 0.1-0.3 wt% of the total mass of raw materials (polycitric acid glycol ester prepolymer, diisocyanate, hydrophilic chain extender, catalyst, and solvent) in one reaction process.
[0014] In the above scheme, the polycitrate prepolymer can be one or more of polyethylene citrate, poly-1,4-butanediol citrate, poly-1,6-hexanediol citrate, poly-1,8-octanediol citrate, and poly-1,10-decanediol citrate; its molecular weight is 500 to 1000.
[0015] Furthermore, the molecular weight of the poly(ethylene glycol) citric acid is 500-800; the molecular weight of the poly(1,4-butanediol) citric acid is 500-800; the molecular weight of the poly(1,6-hexanediol) citric acid is 700-1000; the molecular weight of the poly(1,8-octanediol) citric acid is 700-1000; and the molecular weight of the poly(1,10-decanediol) citric acid is 700-1000.
[0016] In the above scheme, the hydrophilic chain extender mentioned in step 1) can be one or more of the following: dimethylolpropionic acid, dimethylolbutyric acid, sodium 1,2-propanediol-3-sulfonate, sodium 1,4-butanediol-2-sulfonate, N,N-dimethylethanolamine, N-methyldiethanolamine, etc.
[0017] In the above scheme, the diisocyanate may be one or more of hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate, tetramethylphenyl dimethyl diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, etc.
[0018] In the above scheme, the catalyst can be one or more of dibutyltin dilaurate, stannous isooctanoate, zinc isooctanoate, and bismuth isooctanoate.
[0019] In the above scheme, the small molecule polyol chain extender can be one or more of ethylene glycol, propylene glycol, 1,4-butanediol, trimethylolpropane, etc.
[0020] In the above scheme, the solvent can be one or more of N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and toluene.
[0021] In the above scheme, the vinyl monomer can be one or more of hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxyethyl acrylate, etc.
[0022] In the above scheme, the molar ratio of the vinyl monomer to the polycitrate prepolymer is 1.0-1.9:1.
[0023] In the above scheme, the molar ratio of the small molecule polyol chain extender to the polycitrate diol prepolymer is 1.5-2.5:1.
[0024] In the above scheme, the temperature of the first reaction in step 1) is 50-90℃ and the time is 2-3h; the temperature of the second reaction is 50-80℃ and the time is 2-3h; the temperature of the third reaction is 50-80℃ and the time is 2-3h.
[0025] In the above scheme, the organic solvent I can be one or more of dichloromethane, 1,4-dioxane, toluene, etc.
[0026] In the above scheme, in step 2), the content of NHS in mixture I is 3.4-7.0 wt%, the content of double bond-terminated polycitric acid ester-based polyurethane prepolymer in mixture I is 13-28 wt%, and the content of activator in mixture I is 3.5-6.0%.
[0027] In the above scheme, the activator can be selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide EDC, etc.
[0028] In the above scheme, the grafting reaction time is 5-24 hours.
[0029] In the above scheme, the organic solvent II can be one or more of dichloromethane, 1,4-dioxane, toluene, etc.
[0030] In the above scheme, the hydrophobic polymer mentioned in step 3) can be one or more of PCL1000, PCL2000, PCL5000, PCL12000, PCL15000, PLA1000, PLA2000, PLA5000, PLA8000, etc.
[0031] In the above scheme, the content of the hydrophobic polymer in step 3) in the blend liquid is 1.3-3.3 wt%, and the content of the double-bond-terminated citrate polyurethane prepolymer containing NHS active ester in the blend liquid is 22.2-32.9 wt%.
[0032] In the above scheme, the mixing time for the blending step is 1-4 hours.
[0033] In the above scheme, the photoinitiator can be one or more of TPO, 907, BP, CBP, 369 initiator, I2959, LAP, 754 photoinitiator, 1173, etc., and its content accounts for 0.05-1.5wt% of the total mass of the adhesive.
[0034] In the above scheme, the protective atmosphere can be argon or nitrogen, etc.
[0035] The photocurable bioactive polycitrate-based polyurethane medical adhesive prepared according to the above scheme has good biocompatibility and bioactivity, is injectable, can rapidly crosslink and cure within 30 seconds to achieve non-invasive wound closure, and can maintain good adhesion (up to 40 kPa or more) in humid environments.
[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0037] 1) The main component of the medical adhesive of the present invention is polycitrate-based polyurethane containing NHS active ester. Combined with double bond formation, it can rapidly crosslink and cure under light irradiation within tens of seconds to achieve non-invasive wound closure. The grafted adhesive group NHS active ester can react with primary amines on biological tissues, rapidly forming covalent bonds with tissues without the need for oxidation by other reagents, thus reducing the toxicity of the adhesion process. Polycitrate glycol ester is the soft segment of polyurethane, greatly improving the degradability, biocompatibility, and bioactivity of the polyurethane adhesive. It can also work synergistically with other components and structures to effectively ensure the rapid and high-strength bonding effect of the resulting adhesive. The addition of hydrophobic polymers increases the hydrophobicity of the material, further improving its adhesion in humid environments and reducing the decrease in adhesive strength under humid conditions.
[0038] 2) The photocurable bioactive polycitrate-based polyurethane medical adhesive of the present invention involves a simple preparation process, low raw material prices, and is easy and convenient to use, and can be injected in situ. Attached Figure Description
[0039] Figure 1 The FTIR spectrum of the double-bond-terminated polycitrate polyurethane containing NHS active ester obtained in Example 4 of this invention;
[0040] Figure 2 The 1H-NMR spectrum of the double-bond-terminated polycitric acid ester polyurethane containing NHS active ester obtained in Example 4 of this invention;
[0041] Figure 3 The structural formula of the double-bond-terminated polycitric acid ester polyurethane containing NHS active ester obtained in Example 4 of the present invention is shown below.
[0042] Figure 4 The results of the CCK-8 cytotoxicity test of the photocurable bioactive polycitrate-based polyurethane medical adhesives obtained in Examples 3 and 4 of this invention;
[0043] Figure 5 The adhesion strength of the photocurable bioactive polycitrate-based polyurethane medical adhesives obtained in Example 3, Comparative Example 1, Comparative Example 2 and Comparative Example 3 of the present invention under wet and dry conditions.
[0044] Figure 6 This is a comparison of the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 of the present invention and 3M tissue adhesive treated rat skin wounds for 0 days and 10 days.
[0045] Figure 7 This is a HE staining image of a rat skin wound treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive and 3M tissue glue on day 12. (This is from Example 3 of the present invention.) Detailed Implementation
[0046] This invention is not limited to the embodiments described above. Those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications are also considered within the scope of protection of this invention. Contents not described in detail in this specification are prior art known to those skilled in the art.
[0047] Example 1
[0048] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0049] 1) In a sealed container, add 7.6 g of poly(1,6-hexanediol) citric acid (700 Da), 13.4 ml of isophorone diisocyanate, 2.25 g of dimethylolpropionic acid (DMPA), 49 μl of dibutyltin dilaurate, and 24 ml of N,N-dimethylformamide in sequence. Stir and react for 2.5 h at 80 °C under an Ar atmosphere until the -OH group is completely consumed. Then add 1.8 ml of 1,4-butanediol and react for another 2.5 h until the -OH group is completely consumed. After that, lower the reaction temperature (natural cooling) by 10 °C and add 2 ml of hydroxyethyl methacrylate and react for another 2 h. Remove the solvent by rotary evaporation and set aside.
[0050] 2) Take 25g of the double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1), add 90ml of 1,4-dioxane and mix well. Add 5.17g of EDC and 6.2g of NHS to the resulting mixed solution for grafting reaction (at room temperature) for 18h to obtain double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester. Purify and retain for later use.
[0051] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester obtained in step 2), add 20ml of dichloromethane and mix well, add 0.5g of PLA5000 to the resulting mixture and mix, then remove the solvent by rotary evaporation.
[0052] 4) Add photoinitiator I2959 (0.15wt% of the total mass of the adhesive, the same below) to the product obtained in step 3) and put it into a 2ml syringe. Inject it into the part to be bonded. Under 365nm ultraviolet light irradiation, the overlap shear strength can reach 84.1kPa within 30s.
[0053] Example 2
[0054] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0055] 1) In a sealed container, add 8g of 1,8-octanediol citric acid prepolymer with a molecular weight of 800 Da, 9.1ml of HDI (hexamethylene diisocyanate), 2.25g of DMPA, 31μl of stannous isooctanoate, and 20ml of N,N-dimethylacetamide in sequence. Stir and react for 3h at 80℃ under Ar atmosphere protection until the -OH group is completely consumed. Add 1.15ml of propylene glycol and react for 2h until the -OH group is completely consumed. Then, lower the reaction temperature by 10℃ and add 1.2ml of hydroxyethyl acrylate and react for 2h. Remove the solvent by rotary evaporation and set aside.
[0056] 2) Take 20g of the double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1), add 108ml of 1,4-dioxane to it and mix well. Add 5g of EDC and 6g of NHS to the resulting mixed solution for grafting reaction. The reaction time is 18h to obtain the double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester. Rotary evaporate the solvent for later use.
[0057] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester obtained in step 2), add 20ml of dichloromethane and mix evenly, add 1g of PCL1000 to the resulting mixture and mix, and then rotary evaporate the solvent.
[0058] 4) Add photoinitiator 369 (0.5wt%) to the product obtained in step 3), put it into a 2ml syringe, and inject it into the area to be bonded. Under 323nm ultraviolet light irradiation, the overlap shear strength can reach 78.8kPa within 30s.
[0059] Example 3
[0060] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0061] 1) In a sealed container, add 8g of 1,10-decanediol prepolymer with a molecular weight of 800 Da, 11.8ml of IPDI (isophorone diisocyanate), 2.25g of DMPA, 54μl of dibutyltin dilaurate, and 23ml of N,N-dimethylacetamide in sequence. Stir and react for 2.5h at 80℃ under Ar atmosphere protection until the -OH group is completely consumed. Add 1.15ml of propylene glycol and react for 2.5h until the -OH group is completely consumed. Then, lower the reaction temperature by 10℃ and add 1.5ml of hydroxyethyl methacrylate. After reacting for 2h, remove the solvent by rotary evaporation and set aside.
[0062] 2) Take 20g of the double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1), add 75ml of 1,4-dioxane and mix well. Add 5g of EDC and 6g of NHS to the resulting mixed solution for grafting reaction. The reaction time is 18h to obtain double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester. Remove the solvent by rotary evaporation and set aside for later use.
[0063] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing active ester NHS obtained in step 2), add 20ml of dichloromethane and mix well, add 0.8g of PCL2000 to the resulting mixture and blend, then rotary evaporate the solvent.
[0064] 4) Add photoinitiator LAP (0.1wt%) to the product obtained in step 3, put it into a 2ml syringe, and inject it into the area to be bonded. Under 405nm ultraviolet light irradiation, the overlap shear strength can reach 81.4kPa within 30s.
[0065] Example 4
[0066] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0067] 1) In a sealed container, add 7.8g of polycitric acid-1,10-decanediol prepolymer with a molecular weight of 780 Da, 13.8ml of IPDI, 2.25g of DMPA, 41μl of dibutyltin dilaurate, and 25ml of N,N-dimethylacetamide in sequence. Stir and react for 2.5h at 80℃ under Ar atmosphere protection until the -OH group is completely consumed. Add 1.8ml of 1,4-butanediol and react for 2.5h until the -OH group is completely consumed. Then, lower the reaction temperature by 10℃ and add 1.6ml of hydroxyethyl acrylate. After reacting for 2h, remove the solvent by rotary evaporation and set aside.
[0068] 2) Take 25g of the double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1), add 77ml of 1,4-dioxane and mix well. Add 5.17g of EDC and 6.2g of NHS to the resulting mixed solution for grafting reaction. The reaction time is 18h to obtain the double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester. Remove the solvent by rotary evaporation and set aside for later use.
[0069] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester obtained in step 2), add 20ml of dichloromethane and mix evenly, add 0.6g of PCL2000 to the resulting mixture and blend, then rotary evaporate the solvent.
[0070] 4) Add initiator LAP (0.1wt%) to the product obtained in step 3), put it into a 2ml syringe, and inject it into the area to be bonded. Under 405nm ultraviolet light irradiation, the overlap shear strength can reach 82.4kPa within 30s.
[0071] Example 5
[0072] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0073] 1) In a sealed container, add 7.6g of 1,4-butanediol citric acid (700 Da), 13.4ml of IPDI, 2.25g of DMPA, 40μl of bismuth isooctanoate, and 24ml of N,N-dimethylacetamide in sequence. Stir and react for 2h at 70℃ under Ar atmosphere protection until the -OH group is completely consumed. Add 1.8ml of 1,4-butanediol and react for 3h until the -OH group is completely consumed. Then, lower the reaction temperature by 10℃ and add 1.5ml of hydroxyethyl acrylate. React for 2h and remove the solvent by rotary evaporation. Set aside for later use.
[0074] 2) Take 25g of the double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1), add 90ml of 1,4-dioxane and mix well. Add 5.17g of EDC and 6.2g of NHS to the resulting mixed solution for grafting reaction. The reaction time is 18h to obtain the double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester. Remove the solvent by rotary evaporation and set aside for later use.
[0075] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester obtained in step 2), add 20ml of dichloromethane and mix well, add 0.9g of PCL2000 to the resulting mixture and blend, then rotary evaporate the solvent.
[0076] 4) Add photoinitiator I2959 (0.15wt%) to the product obtained in step 3) into a 2ml syringe and inject it into the area to be bonded. Under 365nm ultraviolet light irradiation, the overlap shear strength can reach 78.4kPa within 30s.
[0077] Example 6
[0078] A photocurable bioactive polycitrate-based polyurethane medical adhesive, the preparation method of which includes the following steps:
[0079] 1) In a sealed container, add 7.8g of polycitric acid-1,10-decanediol prepolymer with a molecular weight of 800 Da, 12.8ml of MDI (diphenylmethane-4,4'-diisocyanate), 2.5g of DMBA (dimethylolbutyric acid), 44μl of stannous isooctanoate, and 26ml of N,N-dimethylformamide in sequence. Stir and react for 2h at 80℃ under Ar atmosphere protection until -OH is completely consumed. Add 1.5ml of 1,4-butanediol and react for 3h until -OH is completely consumed. Then, lower the reaction temperature by 10℃ and add 1.5ml of hydroxyethyl acrylate and react for 2h. Remove the solvent by rotary evaporation and set aside.
[0080] 2) Take 25g of the double-bond-terminated polycitric acid ester-based polyurethane prepolymer obtained in step 1), add 90ml of 1,4-dioxane and mix well. Add 5.17g of EDC and 6.2g of NHS to the resulting mixed solution for grafting reaction. The reaction time is 18h. The solvent of the double-bond-terminated polycitric acid ester-based polyurethane prepolymer containing NHS active ester is removed by rotary evaporation and set aside for later use.
[0081] 3) Take 10g of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester obtained in step 2), add 20ml of dichloromethane and mix evenly, add 0.6g of PCL2000 to the resulting mixture and blend, then rotary evaporate the solvent.
[0082] 4) Add photoinitiator I2959 (0.5wt%) to the product obtained in step 3) into a 2ml syringe and inject it into the area to be bonded. Under 365nm ultraviolet light irradiation, the overlap shear strength can reach 75kPa within 30s.
[0083] Comparative Example 1
[0084] A photocurable bioactive polycitrate-based polyurethane medical adhesive is prepared in a manner similar to that of Example 2, except that the amount of EDC used in step 2) is 12g; the resulting medical adhesive is loaded into a 2ml syringe and injected into the area to be bonded, and the overlap shear strength is only 28kPa within 60s under 323nm ultraviolet light irradiation.
[0085] Comparative Example 2
[0086] A photocurable bioactive polycitrate-based polyurethane medical adhesive is prepared in a manner similar to that of Example 4, except that in step 1), the polycitrate-1,10-decanediol prepolymer is replaced with poly(1,4-butanediol adipate). The resulting medical adhesive is loaded into a 2ml syringe and injected into the area to be bonded. Under 405nm ultraviolet light irradiation, the overlap shear strength is only 33kPa within 120s.
[0087] Comparative Example 3
[0088] A photocurable bioactive polycitrate-based polyurethane medical adhesive is prepared in a manner similar to that of Example 3, except that N-hydroxysuccinimide (NHS) is not introduced in step 2). The resulting medical adhesive is loaded into a 2ml syringe and injected into the area to be bonded. Under 405nm ultraviolet light irradiation, the overlap shear strength is only 20kPa within 30s.
[0089] Figure 1 The FTIR spectrum of the double-bond-terminated polycitric acid ester polyurethane prepolymer containing NHS active ester prepared in Example 4 shows that at 1810 cm⁻¹... -1 1780cm -1 and 1740cm -1 The characteristic peaks indicate that NHS ester groups can be successfully introduced into the obtained adhesive. Figure 2 The image shows the 1-NMR spectrum of the double-bond-terminated polycitrate polyurethane prepolymer containing NHS active ester prepared in Example 4. Multiple peaks near 1.53 ppm and 2.79 ppm indicate the successful introduction of polycitrate-diol ester; in addition, the proton peak at 2.75 ppm indicates the successful introduction of NHS ester.
[0090] Figure 4 The results of the CCK-8 cytotoxicity test of the photocurable bioactive polycitrate-based polyurethane medical adhesives obtained in Examples 3 and 4 of this invention show that the obtained photocurable bioactive polycitrate-based polyurethane medical adhesives have no significant cytotoxicity.
[0091] Figure 5 The results of the adhesion strength tests of the photocurable bioactive polycitric acid ester-based polyurethane medical adhesives obtained in Example 3 and Comparative Examples 1, 2 and 3 of this invention under wet and dry conditions show that the prepared medical adhesives have higher adhesion strength to pigskin tissue under both wet and dry conditions.
[0092] Figure 6 The image shows a comparison of rat skin wounds treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 of this invention and 3M tissue adhesive (commercially available) for 0 days and 10 days. It can be seen that the wounds treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 of this invention have a better healing effect.
[0093] Figure 7The images show HE staining of rat skin wounds treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 of this invention and 3M tissue adhesive (commercially available) on day 12. It can be seen that the wound treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 has completely healed, while the rat skin wound treated with 3M tissue adhesive (commercially available) has not completely healed and is in a scab state. The tissue reconstruction effect indicates that the wound treated with the photocurable bioactive polycitrate-based polyurethane medical adhesive obtained in Example 3 has a greater amount of collagen deposition.
[0094] This invention is not limited to the embodiments described above. Those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications are also considered within the scope of protection of this invention. Contents not described in detail in this specification are prior art known to those skilled in the art.
Claims
1. A method for preparing a photocurable bioactive polycitrate-based polyurethane medical adhesive, characterized in that, Includes the following steps: 1) The polycitrate diol prepolymer is reacted with diisocyanate, hydrophilic chain extender, catalyst and solvent under a protective atmosphere and heating conditions to obtain an intermediate; then a small molecule polyol chain extender is added to carry out a second reaction and the temperature is lowered; then vinyl monomer is added to carry out a third reaction to obtain double bond-terminated polycitrate-based polyurethane prepolymer, and the solvent is rotary evaporated for later use. 2) The double-bond-terminated polycitric acid ester polyurethane prepolymer obtained in step 1) is uniformly dispersed in organic solvent I. An activator and N-hydroxysuccinimide are added to the resulting mixed solution. The resulting mixed solution I is subjected to a grafting reaction at room temperature to obtain a double-bond-terminated polycitric acid ester polyurethane prepolymer containing the active ester NHS. The solvent is then rotary evaporated for later use. 3) The double-bond-terminated polycitrate polyurethane prepolymer containing active ester NHS obtained in step 2) is uniformly dispersed in organic solvent II. A hydrophobic polymer is added to the resulting mixture II and the mixture is blended to obtain a blend solution. The solvent is then removed. Then a photoinitiator is added and the mixture is mixed evenly to obtain the photocurable bioactive polycitrate polyurethane medical adhesive.
2. The preparation method according to claim 1, characterized in that, The molar ratio of diisocyanate to polycitrate prepolymer is 5-6.7:1; the molar ratio of hydrophilic chain extender to polycitrate prepolymer is 1.5-2.0:1; the amount of catalyst is 0.1-0.3 wt% of the total mass of raw materials in one reaction; and the mass ratio of hydrophilic chain extender in the raw material system obtained in one reaction is 4.1-6.8 wt%.
3. The preparation method according to claim 1, characterized in that, The polycitrate prepolymer is one or more of poly(ethylene citrate), poly(1,4-butanediol citrate), poly(1,6-hexanediol citrate), poly(1,8-octanediol citrate), and poly(1,10-decanediol citrate), with a molecular weight of 500-1000; the diisocyanate is one or more of hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate, tetramethylphenyl diisocyanate, diphenylmethane diisocyanate, and dicyclohexylmethane diisocyanate.
4. The preparation method according to claim 1, characterized in that, The hydrophilic chain extender mentioned in step 1) is one or more of dimethylolpropionic acid, dimethylolbutyric acid, sodium 1,2-propanediol-3-sulfonate, sodium 1,4-butanediol-2-sulfonate, N,N-dimethylethanolamine, and N-methyldiethanolamine; the catalyst is one or more of dibutyltin dilaurate, stannous isooctanoate, zinc isooctanoate, and bismuth isooctanoate; the small molecule polyol chain extender is one or more of ethylene glycol, propylene glycol, 1,4-butanediol, and trimethylolpropane; and the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and toluene.
5. The preparation method according to claim 1, characterized in that, The vinyl monomer is one or more of hydroxyethyl methacrylate, hydroxypropyl methacrylate, and hydroxyethyl acrylate.
6. The preparation method according to claim 1, characterized in that, The molar ratio of the vinyl monomer to the polycitrate prepolymer is 1.0-1.9:1; the molar ratio of the small molecule polyol chain extender to the polycitrate prepolymer is 1.5-2.5:
1.
7. The preparation method according to claim 1, characterized in that, In step 1), the temperature of the first reaction is 50-90℃ and the time is 2-3h; the temperature of the second reaction is 50-80℃ and the time is 2-3h; and the temperature of the third reaction is 50-80℃ and the time is 2-3h.
8. The preparation method according to claim 1, characterized in that, In step 2), the content of N-hydroxysuccinimide in mixture I is 3.4-7.0 wt%, the content of double bond-terminated polycitric acid ester-based polyurethane prepolymer in mixture I is 13-28 wt%, and the content of activator in mixture I is 3.5-6.0 wt%.
9. The preparation method according to claim 1, characterized in that, The hydrophobic polymer is one or more of PCL1000, PCL2000, PCL5000, PCL12000, PCL15000, PLA1000, PLA2000, PLA5000, and PLA8000; the content of the hydrophobic polymer in the blend is 1.3-3.3 wt%.
10. The photocurable bioactive polycitrate-based polyurethane medical adhesive prepared by the preparation method according to any one of claims 1 to 9.