CN115970043A - Adhesive for repairing tissue and preparation method and application thereof - Google Patents
Adhesive for repairing tissue and preparation method and application thereof Download PDFInfo
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- CN115970043A CN115970043A CN202211101548.6A CN202211101548A CN115970043A CN 115970043 A CN115970043 A CN 115970043A CN 202211101548 A CN202211101548 A CN 202211101548A CN 115970043 A CN115970043 A CN 115970043A
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- 239000005058 Isophorone diisocyanate Substances 0.000 claims abstract description 41
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Images
Abstract
The invention provides a preparation method of an adhesive for repairing tissues, which comprises the following steps: a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture; b) And mixing the dopamine modified inorganic nanoparticles with the mixture, and reacting to obtain the adhesive. The invention takes diester adhesive prepared by blending sebacic acid glyceride and isophorone diisocyanate as a main body, takes inorganic nano particles modified by dopamine as a filler to prepare the organic-inorganic composite adhesive, and is implanted into biological tissue gaps to promote tissue repair and healing. Compared with the cyanoacrylate adhesive used clinically, the adhesive has the characteristics of low toxicity and suitability for repairing various tissues, thereby solving the problems of cytotoxicity of the adhesive, tissue healing inhibition and the like.
Description
Technical Field
The invention relates to the technical field of materials, in particular to an adhesive for repairing tissues and a preparation method and application thereof.
Background
The tissue adhesives are made of materials that can seal soft tissues such as muscles and skin and prevent the separation of injured tissues by adhesion. Broadly, medical adhesives can be classified into hemostatic agents, sealants, and adhesives. To date, only a few commercially available tissue adhesives with registered trademarks have been approved. One of the most commonly used is fibrin glue (trade name:
etc.). The cyanoacrylate adhesive is evolved from an industrial adhesive and is also widely used as a tissue adhesive with the trade name of->
And &>
However, cyanoacrylates are biologically toxic and can produce formaldehyde upon decomposition. Thus, they are generally limited to external soft tissue wound closure, rather than being applied to adhesive repair of muscle, cartilage and even bone tissue. Polyurethane-based tissue adhesives (trade name TissuGlu), bioGlue protein adhesives (composed of bovine serum albumin and glutaraldehyde), polyethylene glycol (PEG) -based DuraSeal and CoSeal are other representative commercially available tissue adhesives.
When tissue adhesives are used to treat tissue that requires a certain mechanical strength, the adhesive strength requirements of the material are often of concern. However, considering only the strength of the tissue adhesive is not sufficient, the most important properties required for the treatment of cartilage and bone tissue are sufficient adhesive strength to cartilage and bone fragments and the ability to maintain the spatial position of the fragments. In addition, the bone cement should also have tunable biodegradability (to match the growth rate of the new tissue), good biocompatibility, and the ability to promote tissue repair. Furthermore, during application, the tissue adhesive should have the ability to cure rapidly at body temperature to adhere to the sealing tissue.
Mature tissue adhesives have been required for some time in the future not only for orthopedic trauma related procedures, but also for joint, thoracic, oral, neurosurgical and general surgical procedures with considerable application prospects.
Therefore, it is very necessary to develop an adhesive which has low biotoxicity compared with the conventional tissue adhesive, adheres to the tissue and realizes the function of promoting tissue healing on the basis of not adding a biological agent.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide an adhesive for repairing tissue, which has low toxicity and is suitable for repairing various tissues.
The invention provides a preparation method of an adhesive for repairing tissues, which comprises the following steps:
a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture;
b) And mixing the dopamine modified inorganic nano particles with the mixture, and reacting to obtain the adhesive.
Preferably, the dopamine-modified inorganic nanoparticles are inorganic nano-hydroxyapatite or nano-bioglass.
Preferably, the addition amount of the dopamine modified inorganic nanoparticles is 0-10% of the total mass of the mixture.
Preferably, the mass ratio of the sebacic acid glyceride to the isophorone diisocyanate is 0.6; the molecular weight of the polyethylene glycol is 200; the proportion of the polyethylene glycol in the mixture is 0.2-1.0.
Preferably, the blending in the step A) is carried out under the protection of nitrogen, and the anhydrous and oxygen-free conditions are kept; the blending temperature is 50 ℃, and the blending time is 20min.
Preferably, the preparation method of the sebacic acid glyceride specifically comprises the following steps: carrying out low-pressure polycondensation on sebacic acid and glycerol under the protection of nitrogen; the pressure of the polycondensation is 40mtorr, and the time is 6h; the mass ratio of sebacic acid to glycerol is 1:1.
Preferably, the reaction temperature in step B) is 50 ℃; the time period is 20min.
The invention provides an adhesive for repairing tissues, which is prepared by the preparation method of any one of the technical schemes.
The invention provides application of the adhesive prepared by the preparation method in any one of the technical schemes in preparation of a tissue repair product.
The invention provides a tissue repair product, which comprises the adhesive in the technical scheme.
Compared with the prior art, the invention provides a preparation method of an adhesive for repairing tissues, which comprises the following steps: a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture; b) And mixing the dopamine modified inorganic nano particles with the mixture, and reacting to obtain the adhesive. The invention takes diester adhesive prepared by blending sebacic acid glyceride and isophorone diisocyanate as a main body, takes inorganic nano particles modified by dopamine as a filler to prepare the organic-inorganic composite adhesive, and is implanted into biological tissue gaps to promote tissue repair and healing. Compared with the cyanoacrylate adhesive used clinically, the adhesive has the characteristics of low toxicity and suitability for repairing various tissues (including but not limited to bones), thereby solving the problems of cytotoxicity, tissue healing inhibition and the like of the adhesive.
Drawings
FIG. 1 is a 1H NMR spectrum of glyceryl sebacate (PGS);
FIG. 2 is a FT-IR spectrum of PGS, IPDI, PEG and the three substances after blending;
fig. 3. Bone histopathological appearance at 8 weeks post-surgery time points, percent recovery of tibial length and Micro-CT detection of new bone formation in the fracture region, (n = 3);
fig. 4. Histopathological appearance of bone at 12 weeks post-surgery time points, percent recovery of tibial length and Micro-CT detection of new bone formation in the fracture region, (n = 3);
FIG. 5 modeling and treatment appearance of an animal model; (A) 3D printing a bone cutting guide plate (transverse fracture); (B) designing a 45-degree oblique fracture osteotomy guide plate; (C) fixing the 45-degree bone cutting guide plate on the tibia of the rat for modeling; (D) completing osteotomy and successfully modeling; (E) bone adhesive "liquid scaffold" style of treatment; (F) Maintaining the fracture position, and waiting for the solidification of the 'liquid bracket'; (G) The surfaces of cortex lycii radicis on two sides of the fracture end are pretreated by phosphoric acid etching agent; (H) The PGS + IPDI bone cement fixes the phosphoric acid pre-acid etched cortical bone surface.
Detailed Description
The invention provides an adhesive for repairing tissues and a preparation method and application thereof, and a person skilled in the art can realize the purpose by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention provides a preparation method of an adhesive for repairing tissues, which comprises the following steps:
a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture;
b) And mixing the dopamine modified inorganic nanoparticles with the mixture, and reacting to obtain the adhesive.
The invention provides a preparation method of an adhesive for repairing tissues, which is characterized in that firstly, sebacic glyceride is prepared.
The sebacic acid glyceride is preferably prepared by the following method: carrying out low-pressure polycondensation on sebacic acid and glycerol under the protection of nitrogen; the pressure of the polycondensation is 40mtorr, and the time is 6h; the mass ratio of sebacic acid to glycerol is 1:1.
More preferably specifically: after the magnetic rotor is added into the reactor for drying treatment, sebacic acid and glycerol with the same amount of substances are added into the reactor, and nitrogen is filled after the reactor is vacuumized. The polycondensation reaction was started at 120 ℃ in an oil bath. After reacting for 24 hours under normal pressure, the reaction was again carried out for 24 hours under normal pressure after polycondensation for 6 hours under low pressure (40 mtorr). And (3) finally obtaining the polymer. The chemical reaction formula is as follows:
the key point of the polycondensation reaction experiment is that the amount of sebacic acid and glycerol substances is ensured to be 1:1, the reaction can be ensured to be accurately carried out. The key reaction condition is low-pressure polymerization time in the polycondensation reaction process, and the inventor screens out the optimal low-pressure polycondensation reaction time (6 h) by performing rheological test on the obtained PGS prepolymer product, so that the applicability of the obtained PGS prepolymer is ensured. The average molecular mass of the resulting PGS was 1328 (the polymerization degree of the PGS polymer was 5) as measured by mass spectrometry. Nuclear magnetization of PGS obtained by polycondensation is shown in fig. 1. FIG. 1 shows a 1H NMR spectrum of sebacic acid glyceride (PGS).
And (3) blending the sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture. Then immediately placing the reaction bottle on ice to cool.
According to the invention, the mass ratio of the sebacic acid glyceride to the isophorone diisocyanate is 0.6; the molecular weight of the polyethylene glycol is 200; the proportion of the polyethylene glycol in the mixture is 0.2-1.0.
Specifically, the blending is carried out under the protection of nitrogen, and the anhydrous and anaerobic conditions are kept; the blending temperature is 50 ℃, and the blending time is 20min.
In one embodiment of the present invention, the reaction is specifically:
after a magnetic rotor is added into a reactor for drying treatment, a certain mass of PGS prepolymer is added into a reaction bottle, and then the reaction bottle is filled with the PGS prepolymer, PEG-200 and IPDI substances according to the ratio of the PGS prepolymer to the PEG-200 to the IPDI substances of 0.6:0.4:1.2 calculating the feeding amount of PEG-200 and IPDI, and sequentially feeding and mixing.
The reaction bottle has no water and oxygen in the feeding process. The mixture was mixed at 50 ℃ for 20 minutes under nitrogen atmosphere. Then immediately placing the reaction bottle on ice for cooling, and transferring the reaction bottle to a centrifugal tube which is dried, sterilized and disinfected for storage. The infrared spectra of the raw materials PGS, IPDI, PEG and final mixed product required for physical blending are shown in fig. 2. FIG. 2 is FT-IR spectrum of PGS, IPDI, PEG and the three substances after blending.
Regarding the ratio of the amounts of the PGS prepolymer, PEG-200 and IPDI substance, the ratio of the amounts of the PGS prepolymer and the IPDI substance is ensured to be 0.6:1.2, the proportion of PEG-200 can be adjusted within the range of 0.2 to 1.0, and the fluidity of the obtained mixture is increased with the increase of the proportion of PEG-200.
And mixing the dopamine modified inorganic nano particles with the mixture, and reacting to obtain the adhesive.
The invention firstly prepares the dopamine modified inorganic nano-particles. The dopamine-modified inorganic nano particles are inorganic nano hydroxyapatite or nano bioglass.
In one embodiment of the present invention, a method for preparing dopamine-modified inorganic nanoparticles specifically comprises:
dissolving Tris monomer in deionized water, placing the solution on a magnetic stirrer at room temperature to be completely dissolved, adjusting the pH value to 8.5 by using dilute hydrochloric acid, pouring the prepared solution into a volumetric flask, metering the volume of the deionized water, sealing and storing the volumetric flask in a refrigerator for later use.
Nano hydroxyapatite/nano bioglass was weighed, put into Tris solution, and the nano inorganic particles were dispersed ultrasonically using an ultrasonic cell crusher (500w, 5 min). The dopamine hydrochloride is added into the dispersed suspension and placed on a magnetic stirrer to be stirred for 48 hours at room temperature. And after the reaction is finished, performing centrifugal separation on the product, washing the product for 3 to 4 times by using deionized water, and then performing freeze drying to obtain a brownish black powdery product.
In one embodiment of the present invention, a method for preparing dopamine-modified inorganic nanoparticles specifically comprises:
0.6057g Tris monomer is dissolved in a beaker containing 450mL deionized water, the beaker is placed on a magnetic stirrer at room temperature to be completely dissolved, the pH value is adjusted to 8.5 by using 1mol/L diluted hydrochloric acid, the prepared solution is poured into a 500mL volumetric flask, the deionized water is used for constant volume, and the flask is sealed and stored in a refrigerator for standby. 0.2g of nano-hydroxyapatite/nano-bioglass was weighed into a flask containing 100mL of Tris solution, and the nano-inorganic particles were dispersed by ultrasonic dispersion using an ultrasonic cell disruptor (500W, 5 min). 0.2478g dopamine hydrochloride was added to the dispersed suspension and stirred on a magnetic stirrer at room temperature for 48h. And after the reaction is finished, performing centrifugal separation on the product, washing the product for 3 to 4 times by using deionized water, and then performing freeze drying to obtain a brownish black powdery product.
The dopamine modified inorganic nano particles are put into a reaction bottle according to the proportion of 0 to 10 percent of the total mass of the PGS + IPDI mixture, and are uniformly mixed under magnetic stirring to prepare the organic-inorganic composite adhesive with two formulas of PGS + IPDI + nHA and PGS + IPDI + nBG.
According to the invention, the reaction is carried out under the protection of nitrogen atmosphere and the anhydrous and oxygen-free conditions in a reaction bottle, and the mixture is mixed for 20 minutes at 50 ℃.
The organic-inorganic composite adhesive provided by the invention can promote tissue healing on the premise of not reducing the adhesive strength.
The invention provides an adhesive for repairing tissues, which is prepared by the preparation method of any one of the technical schemes.
The preparation method of the invention has already been clearly described, and is not repeated herein.
The invention provides application of the adhesive prepared by the preparation method in any one of the technical schemes in preparation of a tissue repair product.
The repaired tissue of the present invention may include bone tissue and may also include soft tissue.
The invention provides a tissue repair product, which comprises the adhesive in the technical scheme.
The invention provides a preparation method of an adhesive for repairing tissues, which comprises the following steps: a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture; b) And mixing the dopamine modified inorganic nano particles with the mixture, and reacting to obtain the adhesive. The invention takes diester adhesive prepared by blending sebacic acid glyceride and isophorone diisocyanate as a main body, takes inorganic nano particles modified by dopamine as filler to prepare organic-inorganic composite adhesive, and the organic-inorganic composite adhesive is implanted into biological tissue gaps to promote tissue repair and healing. Compared with the cyanoacrylate adhesive used clinically, the adhesive has the characteristics of low toxicity and suitability for repairing various tissues (including but not limited to bones), thereby solving the problems of cytotoxicity, tissue healing inhibition and the like of the adhesive.
In order to further illustrate the present invention, the following will describe in detail an adhesive for repairing tissue, its preparation method and application.
Example 1 screening and preparation of reaction conditions for Polymalvidin
After the magnetic rotor is added into the reactor for drying treatment, sebacic acid and glycerol with the same amount of substances are added into the reactor, and nitrogen is filled after the reactor is vacuumized. The polycondensation reaction was started at 120 ℃ in an oil bath. After reacting for 24 hours under normal pressure, performing polycondensation reaction for a period of time (3 h/4h/5h/6h/7 h) under low pressure (40 mtorr), and then reacting for 24 hours under normal pressure again [126] . The final polymer was used for detection and downstream experiments. The chemical reaction formula is as follows:
the key point of the polycondensation reaction experiment is that the amount of sebacic acid and glycerol substances is ensured to be 1:1, the reaction can be ensured to be accurately carried out. The key reaction condition is low-pressure polymerization time in the polycondensation reaction process, and the optimal low-pressure polycondensation reaction time is screened out by performing rheological test on the obtained PGS prepolymer product, so that the applicability of the obtained PGS prepolymer is ensured.
After screening for optimal low pressure reaction conditions, we tested the resulting final product for nuclear magnetization to demonstrate the accuracy of the reaction. FIG. 1 is a 1H NMR spectrum of glyceryl sebacate (PGS); it can be seen from the figure that the resonances at both 1.25ppm and 1.71ppm are attributed to the methylene protons (d) and (e) in the PGS backbone; the resonance signal at 2.25ppm was attributed to the methylene proton (c) attached to the ester bond carbonyl on the PGS backbone; the resonance peak at 5.0ppm corresponds to the methine proton (b) attached to the hydroxyl group on the PGS backbone; the resonance signal at 4.25ppm was assigned to the main chain methylene proton (a). The hydrogen spectrum nuclear magnetic test result verifies the correct synthesis of the PGS prepolymer in the material preparation process.
Example 2 preparation of a mixture of polyglycerol sebacic acid ester and isophorone diisocyanate
After a magnetic rotor is added into a reactor for drying treatment, a certain mass of PGS prepolymer is added into a reaction bottle, and then the reaction bottle is filled with the PGS prepolymer, PEG-200 and IPDI substances according to the ratio of the PGS prepolymer to the PEG-200 to the IPDI substances of 0.6:0.4:1.2 calculating the feeding amount of PEG-200 and IPDI, and sequentially feeding and mixing. During the feeding process, the anhydrous and anaerobic conditions in the reaction bottle are kept. The mixture was mixed at 50 ℃ for 20 minutes under nitrogen atmosphere. And immediately placing the reaction bottle on ice for cooling, transferring the reaction bottle into a centrifugal tube which is dried, sterilized and disinfected, and storing the reaction bottle for testing and downstream experiments.
To clarify the presence of both hydroxyl and isocyanate groups in the resulting mixture, we made infrared measurements of a sample of the mixture. And detecting a Fourier transform infrared spectrum (FT-IR) by a Bio-Rad Win-IR infrared spectrometer, and performing sample test by using a potassium bromide tabletting method. The infrared spectrogram proves that the PGS + IPDI diester mixture prepared by the inventor can react with amino groups on broken ends of bone tissues or the surface of cortical bone, and has adhesiveness. FIG. 2 is FT-IR spectrum of PGS, IPDI, PEG and the three substances after blending. As can be seen from the figure, PGS, PEG appears strong and wide characteristic peak of-OH at 3448cm-1, asymmetric stretching vibration absorption peak of-N = C = O at 2275cm-1 in IPDI, crosslinked product is obtained by physical blending, infrared analysis of the crosslinked product appears narrow characteristic peak of-NH-COO-at 3400cm-1, strong and wide characteristic peak of-OH still exists at 3448cm-1, characteristic peak of-C = O of PGS still remains at 1775cm-1, which proves that the raw materials used in the experiment still exist and crosslinked product is generated.
This infrared characterization test demonstrates that both-N = C = O and-OH are present in the mixture system, which may provide a theoretical basis for the bone cement to react with reactive amino groups present at the fracture ends and cortical bone surface, resulting in cross-linking adhesion. PEG introduced into the system can not only dilute-OH groups of PGS prepolymer, but also improve the fluidity of the mixture, and provides feasible guarantee for the injectability and quantitative application of bone adhesive.
Example 3 preparation of inorganic nanoparticles (nHA and nBG)
0.6057g Tris monomer is dissolved in a beaker containing 450mL deionized water, the beaker is placed on a magnetic stirrer at room temperature to be completely dissolved, the pH value is adjusted to 8.5 by using 1mol/L diluted hydrochloric acid, the prepared solution is poured into a 500mL volumetric flask, the deionized water is used for constant volume, and the flask is sealed and stored in a refrigerator for standby. 0.2g of nano-hydroxyapatite/nano-bioglass was weighed and placed in a flask containing 100mL of Tris solution, and the nano-inorganic particles were ultrasonically dispersed using an ultrasonic cell disruptor (500W, 5min). 0.2478g dopamine hydrochloride was added to the dispersed suspension and stirred on a magnetic stirrer at room temperature for 48h. And after the reaction is finished, performing centrifugal separation on the product, washing the product for 3-4 times by using deionized water, and then performing freeze drying to obtain a brownish black powdery product for testing and downstream experiments.
After the inorganic nanoparticles are prepared, the inorganic nanoparticles in two states before and after being modified by dopamine are characterized by particle size, potential, transmission electron microscope and the like so as to determine the characteristics of the inorganic nanoparticles. The particle size and the Potential of the inorganic nanoparticles are detected by Zeta Potential/BI-90Plus, and the sample concentration is 0.1mg/mL.
In the pre-mixing operation of 1.2, the prepared dopamine modified inorganic nanoparticles are put into a reaction bottle according to the proportion of 1 percent (0 percent to 10 percent) of the total mass of the PGS + IPDI mixture, and are uniformly mixed under magnetic stirring to prepare the functional composite bone adhesive with two formulas of PGS + IPDI + nHA (hereinafter, simply referred to as + nHA) and PGS + IPDI + nBG (hereinafter, simply referred to as + nBG) for testing and downstream experiments.
Example 4 surgical grouping and fixation of groups of fractures
72 SD rats, randomly grouped by preoperative row, were divided into 6 groups of 12 rats each. Grouping is as follows: PGS + IPDI group, + nHA group, + nBG group, phosphate pretreatment group, kang Pate group, blank control group.
After 72 SD rats were anesthetized by small inhalation of isoflurane, 2% sodium pentobarbital was injected intraperitoneally at 2.0mL/kg body weight. After anesthesia was effective, the left lower limb of the rat was shaved and skin-prepared at the anterior medial tibial incision site, partially sterilized and covered with a sterile drape. The skin was incised longitudinally along the longitudinal axis of the medial tibia, approximately 2cm long, and the subcutaneous tissue and fascia were separated to expose the medial-anterior cortical bone of the tibia. The 45-degree oblique bone cutting guide plate is fixed on the front inner side of the tibia through the hemostatic forceps, and a standard 45-degree oblique fracture model is obtained by cutting bones on the front inner side of the tibia according to the direction of the bone cutting guide plate by using an electric saw. The operation process is careful and gentle as possible, and fibula fracture and soft tissue injury are avoided.
After the fracture model is built, different bone adhesives are respectively implanted according to preoperative grouping for repair treatment. Grouping is as follows: the PGS + IPDI group is that 100 muL of PGS + IPDI bone adhesive is injected at the fracture gap, the + nHA group is that 100 muL of PGS + IPDI + nHA bone adhesive is injected at the fracture gap, the + nBG group is that 100 muL of PGS + IPDI + nBG bone adhesive is injected at the fracture gap, the phosphate pretreatment group is that 100 muL of phosphate acid etching agent is firstly coated on the cortex of both ends of the fracture, gauze wiping is carried out after 30 seconds of acid etching, 100 muL of PGS + IPDI bone adhesive is coated on both ends of the fracture after physiological saline is washed clean and wiped dry, the Kang Pate group is that 100 muL of Kang Pa tissue adhesive is injected at the fracture gap, and the blank control group is that only molding is carried out without any fixing treatment (as shown in figure 5). After the fixed fracture is firm (after blank control group modeling), the incision is flushed by normal saline, and 3-0 and 2-0 mousse suture lines are selected to sew the incision layer by layer. Each rat was injected intramuscularly with 8 million units of penicillin 2 hours before surgery and 3 days after surgery (1 time/day) to prevent infection. These experimental rats were housed in individual cages to avoid mutual biting into the lower limb surgical incision until the wound healed. The results are shown in fig. 5, fig. 5. Model creation of animal model and treatment appearance; and (A) 3D printing a bone cutting guide plate (transverse fracture). And (B) designing a 45-degree oblique fracture osteotomy guide plate. And (C) fixing the 45-degree bone cutting guide plate on the tibia of the rat for modeling. And (D) completing osteotomy and successfully modeling. (E) bone cement "fluid scaffold" mode of treatment. (F) Maintain the fracture position and wait for the 'liquid scaffold' to solidify. (G) The surface of cortical bone on both sides of the fracture end is pretreated by phosphoric acid corrosion agent. (H) PGS + IPDI bone cement fixes the phosphate pre-acid etched cortical bone surface.
Example 5 Micro-CT analysis of nascent bone formation (8W and 12W time nodes)
Two time points of 8 weeks and 12 weeks post-surgery 3 SD rats per group were sacrificed randomly (over-inhaled isoflurane). The two lower limbs of each rat are completely taken, and the tibiofibula part is cleaned of soft tissues on the surface and the anklebone skin and other soft tissues are reserved by using an orthopedic surgical instrument such as a scalpel, a stripper and the like. All specimens were photographed and the tibia length was measured. Micro-CT scanning is carried out on the left tibiofibula specimen, and then the left tibiofibula specimen is fixed by paraformaldehyde with the concentration of 4% (w/v) for subsequent pathological histological analysis. The level of regeneration of new bone tissue near the fracture line was assessed by Micro-CT radiographic analysis. The sample was scanned at 9 μm camera pixel size, 27.22 μm pixel size, 80kV and 100 μ A. The data sets were acquired in 0.6 steps over a 180 ° angular range with 666 row numbers and 1000 column numbers. After scanning, data are reconstructed by NRecon software and a reconstruction angle range of 192.60 degrees, and a sample is subjected to three-dimensional reconstruction analysis by CT-VOX. Bone morphological parameters of newly formed bone in the ROI region were calculated using CT-Analyser software. The ROI was set as a rectangular region near the fracture line (8W specimen ROI rectangle size 1mm × 4 mm. Measurement of bone volume within ROI (BV, mm) 3 ) And percent bone volume to tissue volume (BV/TV,%). The results are shown in FIGS. 3 and 4, FIG. 3. Histopathological appearance of bone at 8 weeks post-surgery, percent recovery of tibial length and Micro-CT detection of new bone formation in the fractured region,(n = 3); fig. 4. Bone histopathological appearance at 12 weeks post-operative time points, percent recovery of tibial length and Micro-CT detection of new bone formation in the fracture region, (n = 3); the figure shows that the multi-formula bone adhesive added with the inorganic nanoparticles has extremely high fracture repair potential, and compared with the simple diester bone adhesive, the inorganic nanoparticles in the formula provide a bridge function for bone tissue regeneration at fracture ends, and the continuity between new bone trabeculae is enhanced. In addition, the surface of the cortex of the bone is corroded by phosphoric acid, and then the two sides of the cortex surface of the fractured end of the fracture are bonded and fixed by PGS + IPDI (poly-p-phenylene diamine tetraacetic acid) diester bone adhesive, so that the fixing mode like a 'liquid steel plate' also shows certain stability.
Claims (10)
1. A method of preparing an adhesive for repairing tissue, comprising the steps of:
a) Blending sebacic acid glyceride and isophorone diisocyanate in the presence of polyethylene glycol to obtain a mixture;
b) And mixing the dopamine modified inorganic nanoparticles with the mixture, and reacting to obtain the adhesive.
2. The preparation method according to claim 1, wherein the dopamine-modified inorganic nanoparticles are inorganic nano-hydroxyapatite or nano-bioglass.
3. The preparation method according to claim 1, wherein the dopamine-modified inorganic nanoparticles are added in an amount of 0 to 10% by mass based on the total mass of the mixture.
4. The preparation method according to claim 1, characterized in that the mass ratio of the sebacic acid glyceride to the isophorone diisocyanate is 0.6; the molecular weight of the polyethylene glycol is 200; the proportion of the polyethylene glycol in the mixture is 0.2-1.0.
5. The preparation method according to claim 1, wherein the blending of step A) is carried out under the protection of nitrogen and the anhydrous and oxygen-free conditions are maintained; the blending temperature is 50 ℃, and the blending time is 20min.
6. The preparation method according to claim 1, wherein the preparation method of the sebacic acid glyceride specifically comprises the following steps: carrying out low-pressure polycondensation on sebacic acid and glycerol under the protection of nitrogen; the pressure of the polycondensation is 40mtorr, and the time is 6h; the mass ratio of sebacic acid to glycerol is 1:1.
7. The method of claim 1, wherein the reaction temperature of step B) is 50 ℃; the time is 20min.
8. An adhesive for repairing tissue, which is produced by the production method according to any one of claims 1 to 7.
9. Use of the adhesive prepared by the method of any one of claims 1 to 7 in the preparation of a product for repairing tissue.
10. A repaired tissue product comprising the adhesive of claim 8.
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