An adaptive bio-based polyurethane porous composite material, its preparation method and application

Abstract

The present invention provides an adaptive bio-based polyurethane porous composite material, its preparation method and application, including: S1: drying the raw materials for synthesizing the polyurethane prepolymer; S2: carrying out a prepolymerization reaction on the dried raw materials to obtain a bio-based polyurethane prepolymer; S3: carrying out a preservation treatment on the bio-based polyurethane prepolymer; S4: mixing the primary hydroxyl group diol with the pre-prepared gelatin solution; S5: carrying out a preservation treatment on the composite foaming agent; S6: carrying out a sterilization treatment on the preserved bio-based polyurethane prepolymer and the composite foaming agent; S7: carrying out a pretreatment and a mixing treatment on the sterilized bio-based polyurethane prepolymer and the composite foaming agent to obtain the adaptive bio-based polyurethane porous composite material. By regulating its components and reaction conditions, the present invention enables it to form faster during the foaming reaction, and the formed material has faster degradability and non-toxic degradation products.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and particularly relates to an adaptive bio-based polyurethane porous composite material, a preparation method thereof, and an application thereof.

Background Art

[0002] Osteoarthropathy is one of the main diseases endangering human health, and cartilage injury has increasingly become the main problem of osteoarthropathy. Articular cartilage is a tissue lacking blood vessels, lymphatic vessels, and nerves. After cartilage is damaged, it can be repaired to a limited extent, but this repair cannot restore the cartilage to its pre-injured state, and its biomechanical properties are too low to withstand excessive loads, resulting in the re-destruction of the newly formed cartilage and making it difficult for the damaged cartilage tissue to be cured through self-repair. Based on these problems, how to achieve cartilage repair and treatment has always been a research hotspot in clinical and materials science. Tissue engineering is an effective method for repairing damaged tissues or organs. However, tissue engineering scaffolds prepared by traditional preparation processes such as electrospinning, 3D printing, freeze-drying, etc. are difficult to precisely conform to the complex shape of the damaged site, which will also cause uneven loading at the defect site after implanting the scaffold, which is not conducive to the growth of newly formed cartilage. Therefore, combining injectable materials with tissue engineering to in-situ generate a tissue engineering scaffold at the cartilage defect provides a new development direction for cartilage repair. Injecting the cartilage repair scaffold directly into the defect site for in-situ molding, and modifying the material to make the physical and chemical properties, biocompatibility, etc. of the repair scaffold more in line with the requirements of cartilage repair, ultimately repairing the damaged cartilage tissue.

[0003] There have been a large number of studies on using foam polyurethane as a tissue engineering scaffold to repair damaged tissues. The formed foam polyurethane material has a spongy porous structure, which is very beneficial to cell migration, adhesion, and tissue growth; at the same time, its mechanical properties such as elasticity are very excellent, and it is very suitable for cartilage repair; in addition, foam polyurethane has the characteristics of in-situ foaming, which is very flexible during use; the good biocompatibility of the formed foam polyurethane has been confirmed by a large number of experiments. These properties make it possible to use foam polyurethane for in-situ foaming and molding at the in-vivo defect site to repair bone / cartilage and other damaged tissues, but there are the following problems: First, the preparation of traditional foam polyurethane materials usually uses catalysts, which brings certain risks to the direct in-situ foaming and molding of foam polyurethane in the body; second, traditional polyurethane materials have the characteristic of low degradation rate, and at the same time, the outermost layer of the foam polyurethane after foaming and molding is closed, and cells cannot enter the large number of pores inside the material for a long time after being implanted into the body; the most important thing is that foam polyurethane usually has a certain toxicity before molding and curing, which has become the biggest obstacle to the use of foam polyurethane for direct in-situ foaming and molding in the body.

[0004] The toxicity of polyurethane foaming directly in the body stems from a large amount of -NCO in the polyurethane prepolymer before material forming. If only pure water is used as the foaming agent, the time for the material to form in the body will be very long, which will cause -NCO to stay in the body for a longer time. More importantly, -NCO will diffuse into the body fluids around the implantation area and contact tissues, bringing a series of serious consequences.

[0005] Therefore, it is necessary to study an adaptive bio-based polyurethane porous composite material, its preparation method and application to address the deficiencies of the existing technology and solve or mitigate one or more of the above problems.

Summary of the Invention

[0006] In view of this, the present invention provides an adaptive bio-based polyurethane porous composite material, its preparation method and application, particularly relates to an injectable in-situ foaming and degradable adaptive bio-based polyurethane porous composite material, its preparation method and application. Without using a catalyst, by regulating its composition and reaction conditions, it can be formed faster during the foaming reaction, and the formed material has faster degradability and non-toxic degradation products.

[0007] On the one hand, the present invention provides a preparation method of an adaptive bio-based polyurethane porous composite material, and the preparation method includes the following steps:

[0008] S1: After pre-treating the raw materials, carry out a prepolymerization reaction to obtain a bio-based polyurethane prepolymer and store it;

[0009] S2: Prepare a composite foaming agent and store it;

[0010] S3: Sterilize the bio-based polyurethane prepolymer and the composite foaming agent in S1 and S2;

[0011] S4: Carry out pre-treatment and mixing treatment on the sterilized bio-based polyurethane prepolymer and the composite foaming agent to obtain an adaptive bio-based polyurethane porous composite material.

[0012] As described above in the aspect and any possible implementation manner, a further implementation manner is provided, and the S1 specifically includes:

[0013] S11: Dry the raw materials for synthesizing the polyurethane prepolymer;

[0014] S12: Carry out a prepolymerization reaction on the dried raw materials to obtain a bio-based polyurethane prepolymer;

[0015] S13: Carry out storage treatment on the bio-based polyurethane prepolymer;

[0016] For the aspects and any possible implementation manners as described above, a further implementation manner is provided. The raw materials include polyethylene glycol and polyoxyethylene castor oil ether. The specific drying process in S11 is as follows: polyethylene glycol and polyoxyethylene castor oil ether are dried by vacuum distillation.

[0017] For the aspects and any possible implementation manners as described above, a further implementation manner is provided. The specific process of the prepolymerization reaction in S12 is as follows: nitrogen is injected and stirred to raise the temperature. After stabilization, isophorone diisocyanate is injected. At the same time, the ratio of polyethylene glycol and polyoxyethylene castor oil ether is continuously adjusted to carry out the prepolymerization reaction to obtain a bio-based polyurethane prepolymer. The reaction time is 2 to 3 hours.

[0018] For the aspects and any possible implementation manners as described above, a further implementation manner is provided. S2 specifically includes:

[0019] S21: Mix the primary hydroxyl group diol with the pre-prepared gelatin solution to prepare a composite foaming agent;

[0020] S22: Carry out preservation treatment on the composite foaming agent.

[0021] For the aspects and any possible implementation manners as described above, a further implementation manner is provided.

[0022] The specific preparation method of the pre-prepared gelatin solution in S21 is as follows:

[0023] Put the water-soluble biopolymer into deionized water at 36°C - 38°C and stir it electromagnetically for 1 - 2 hours, then let it stand for 1 - 2 hours to obtain the pre-prepared gelatin solution. The concentration of the pre-prepared gelatin solution is 40 - 80 g / L. The water-soluble biopolymer is gelatin, polypeptide, and sodium alginate;

[0024] The specific preparation process in S21 is as follows:

[0025] Dissolve the primary hydroxyl group diol in the pre-prepared gelatin solution, adjust the concentration of the primary hydroxyl group diol to 20 - 40 g / L, stir the prepared solution electromagnetically for 1 hour, and place it in a high-power ultrasonic machine. Ultrasonically treat it at room temperature for 15 - 25 minutes to obtain the composite foaming agent.

[0026] The preservation treatment in S22 is specifically as follows: preserve it at normal temperature by isolating moisture or preserve it at a temperature lower than normal temperature for a long time. The treatment in S5 is to place it in a refrigerator at 3°C - 5°C for refrigeration.

[0027] For the aspects and any possible implementation manners as described above, a further implementation manner is provided. The sterilization treatment in S3 is as follows: use γCo-60 irradiation sterilization in a sealed container. After sterilization, store the bio-based polyurethane prepolymer and the composite foaming agent in a refrigerator at 3°C - 5°C.

[0028] According to the above aspects and any possible implementation, an implementation is further provided, wherein the pretreatment process in S4 is as follows: placing the solid bio-based polyurethane prepolymer and the composite foaming agent into an insulation box, and keeping the temperature at 36°C-38°C for 1 hour to melt them into a liquid with high fluidity;

[0029] The mixing process is as follows: the bio-based polyurethane prepolymer and the composite foaming agent are mixed in a ratio of 2:1 to obtain a mixed material, and the mixed material is immediately stirred at a high speed of 500 to 800 r / min and a stirring time of 1 to 2 minutes. The mixed material changes from a transparent liquid to a milky white liquid state, which is an adaptive bio-based polyurethane porous composite material.

[0030] According to the aspects described above and any possible implementation methods, an adaptive bio-based polyurethane porous composite material is further provided, which is prepared by the preparation method. The adaptive bio-based polyurethane porous composite material can quickly foam to form a porous scaffold with a trabecular bone structure and maintain mechanical properties.

[0031] According to the aspects and any possible implementations described above, an application of an adaptive bio-based polyurethane porous composite material is further provided, and the adaptive bio-based polyurethane porous composite material can be applied to defective tissue repair and non-toxic degradation.

[0032] Compared with the prior art, the present invention can achieve the following technical effects:

[0033] (1) The present invention is a new biomedical injectable material. Compared with traditional injectable hydrogels and other materials, the invention is foamed in situ after implantation into the body to form a scaffold with a unique loose porous structure, which is very conducive to the adhesion and migration of various cells. The material can slowly degrade in the body and be excreted through the metabolic system, and can maintain good mechanical properties and porous structure for a long time. Compared with the traditional foam polyurethane using pure water foaming agent, the biomacromolecule composite foaming agent can suppress the toxicity problem in the traditional polyurethane foaming process, and can also solve the structure of the outermost pores closed after the foam polyurethane is molded; the invention has a closed outer layer and an internally connected structure in the initial stage of foaming of the defect in the body, which effectively avoids the contact of a large number of unreacted isocyanate groups with the implanted area, and the closed structure is opened in the later stage, which is conducive to tissue repair;

[0034] (2) The bio-based polyurethane prepolymer of the present invention uses a natural polymer derivative, castor oil polyoxyethylene ether, and a synthetic material, polyethylene glycol, to undergo a prepolymerization reaction with isophorone diisocyanate. Since most natural polymers are degradable, the final foamed polyurethane is also degradable.

[0035] (3) In the present invention, no catalyst is used in the preparation of the material, so there is no potential toxicity during the long-term degradation process. The results of animal experiments and cell tests show that the material has good biocompatibility and has no adverse effects on the experimental subjects after long-term implantation;

[0036] (4) The minimally invasive implantable in-situ forming polyurethane porous composite material prepared in the present invention has mechanical properties close to those of osteochondral tissues, will not cause adverse effects such as osteoporosis and cartilage degenerative lesions, and promotes the repair of cartilage / bone. Since its mechanical properties gradually decline with the slow degradation of the material, the process of mechanical property decline is relatively long, and it has a certain substitution effect on cartilage;

[0037] (5) The minimally invasive implantable in-situ forming polyurethane porous composite material prepared in the present invention can ensure the repeatability of the preparation process and results; the operation process of the preparation steps is simple, several processes are relatively independent, and it is easy to achieve process control; in addition to being used for repairing osteochondral defects, this invention can also be used in various tissue engineering fields, such as dental pulp reconstruction, drug release carriers, immobilized enzyme carriers, bone filling materials, soft tissue filling, anti-adhesion materials, etc.

[0038] Of course, it is not necessary for any product implementing the present invention to achieve all the above-mentioned technical effects simultaneously.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0040] Figure 1 It is the microscopic morphology after the formation of the polyurethane porous composite material in the present invention;

[0041] Figure 2 It is the material formed at the defect tissue without using the present invention and its influence on the surrounding tissues;

[0042] Figure 3 It is the material formed at the defect tissue using the present invention and its influence on the surrounding tissues;

[0043] Figure 4 It is the flowchart of the preparation method of an adaptive bio-based polyurethane porous composite material in the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0044] In order to better understand the technical solutions of the present invention, the following will describe the embodiments of the present invention in detail with reference to the drawings.

[0045] It should be clear that the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the protection scope of the present invention.

[0046] The terms used in the embodiments of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The singular forms of "a", "the" and "said" used in the embodiments of the present invention and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0047] The present invention provides an adaptive bio-based polyurethane porous composite material, its preparation method and application, in particular to an injectable in-situ foaming and degradable adaptive bio-based polyurethane porous composite material, its preparation method and application. Without using a catalyst, by adjusting its components and reaction conditions, it can be molded faster during the foaming reaction, and the molded material has faster degradability and non-toxic degradation products.

[0048] As Figure 4 shown, the present invention provides a preparation method of an adaptive bio-based polyurethane porous composite material, and the preparation method includes the following steps:

[0049] S1: Dry the raw materials for synthesizing the polyurethane prepolymer;

[0050] S2: Carry out a prepolymerization reaction on the dried raw materials to obtain a bio-based polyurethane prepolymer;

[0051] S3: Carry out a preservation treatment on the bio-based polyurethane prepolymer;

[0052] S4: Mix the primary hydroxyl group diol with the pre-prepared gelatin solution to prepare a composite foaming agent;

[0053] S5: Carry out a preservation treatment on the composite foaming agent;

[0054] S6: Sterilize the preserved bio-based polyurethane prepolymer and composite foaming agent;

[0055] S7: Carry out a pretreatment and mixing treatment on the sterilized bio-based polyurethane prepolymer and composite foaming agent to obtain an adaptive bio-based polyurethane porous composite material.

[0056] The raw materials in S1 include polyethylene glycol and castor oil polyoxyethylene ether, and the specific drying treatment process in S1 is: drying polyethylene glycol and castor oil polyoxyethylene ether by vacuum distillation method.

[0057] The prepolymerization reaction process in S2 is specifically as follows: nitrogen is injected and the temperature is raised by stirring, and after stabilization, isophorone diisocyanate is injected, while the ratio of polyethylene glycol and castor oil polyoxyethylene ether is continuously adjusted to perform a prepolymerization reaction to obtain a bio-based polyurethane prepolymer, and the reaction time is 2 to 3 hours.

[0058] The preparation method of the pre-configured gelatin solution in S4 is specifically as follows: placing water-soluble biomacromolecules in 36°C-38°C deionized water and electromagnetically stirring for 1 to 2 hours, and letting it stand for 1 to 2 hours to obtain a pre-configured gelatin solution. The concentration of the pre-configured gelatin solution is 40 to 80 g / L, and the water-soluble biomacromolecules are gelatin, polypeptides and sodium alginate.

[0059] The preparation process in S4 is specifically as follows:

[0060] The primary hydroxyl glycol was dissolved in the pre-prepared gelatin solution to adjust the concentration of the primary hydroxyl glycol to 20-40 g / L. The prepared solution was electromagnetically stirred for 1 hour and placed in a high-power ultrasonic machine for ultrasonic treatment at room temperature for 15-25 minutes to obtain a composite foaming agent.

[0061] The storage process in S3 is specifically: isolating from moisture and storing at room temperature or storing at a temperature lower than room temperature for a long time, and the process in S5 is placing in a refrigerator at 3°C-5°C for refrigeration.

[0062] The sterilization treatment in S6 is as follows: sterilizing by irradiation with γCo-60 in a sealed container, and after sterilization, storing the bio-based polyurethane prepolymer and the composite foaming agent in a refrigerator at 3° C. to 5° C.

[0063] The pretreatment process in S7 is as follows: placing the solid bio-based polyurethane prepolymer and the composite foaming agent into an insulation box, and keeping the temperature at 36°C-38°C for 1 hour to melt them into a liquid with strong fluidity;

[0064] The mixing process is as follows: the bio-based polyurethane prepolymer and the composite foaming agent are mixed in a ratio of 2:1 to obtain a mixed material, and the mixed material is immediately stirred at a high speed of 500 to 800 r / min and a stirring time of 1 to 2 minutes. The mixed material changes from a transparent liquid to a milky white liquid state, which is an adaptive bio-based polyurethane porous composite material.

[0065] The present invention also provides an adaptive bio-based polyurethane porous composite material, which is prepared by the preparation method. The adaptive bio-based polyurethane porous composite material can quickly foam to form a porous scaffold with a structure similar to trabecular bone, maintain mechanical properties, and the micromorphology of the polyurethane porous composite material after molding is as follows: Figure 1 shown.

[0066] The present invention also provides an application of an adaptive bio-based polyurethane porous composite material, which can be applied to defect tissue repair and non-toxic degradation through the adaptive bio-based polyurethane porous composite material.

[0067] The content of the present invention is an injectable in-situ foaming degradable adaptive bio-based polyurethane porous composite material and its preparation method and application. In particular, a bio-based polyurethane prepolymer and a bio-macromolecule composite foaming agent (Bio-Foaming agent) used in conjunction therewith are prepared. The obtained material can be directly foamed in-situ at the bone and cartilage defect sites in the form of injection after high-speed stirring and sufficient mixing. This repair material can also be used for other body tissue filling repairs, in-vivo long-term drug sustained-release stents, etc.

[0068] The bio-based polyurethane prepolymer is prepared by polymerizing artificial synthetic polymer materials and natural bio-based materials. Without using a catalyst, by regulating its composition and reaction conditions, it can be formed faster during the foaming reaction, and the formed material has faster degradability and non-toxic degradation products. Compared with traditional polyurethane foaming agents, the bio-macromolecule composite functional foaming agent (Bio-Foaming agent) in the present invention can not only make polyurethane foam, but also crosslink bio-macromolecules in the polymer during the polyurethane foaming process, solve the problem of small molecule diffusion during the foaming process of traditional foam polyurethane, and at the same time make the porous structure of the material change from internal connection and outer layer closure to complete connection of the inner and outer layers after foaming in the body, effectively solving the toxicity problem of traditional foam polyurethane during in-vivo foaming and molding, and being more conducive to the repair and growth of defect tissues, so that polyurethane can be safely and reliably foamed in-situ in the body to effectively repair defect tissues.

[0069] The technical solution of the present invention is as follows: First, polyethylene glycol and polyoxyethylene castor oil ether for preparing the bio-based polyurethane prepolymer are dried, and a synthesis reaction is carried out under a protective atmosphere to obtain a bio-based polyurethane prepolymer that can be stored for a long time; water-soluble biological macromolecules (such as gelatin) are dissolved in deionized water, and then 1,4-butanediol is added in a certain proportion, fully mixed and ultrasonic-treated, and then left standing to obtain a bio-macromolecule composite foaming agent; the bio-based polyurethane prepolymer and the bio-macromolecule composite foaming agent are fully mixed in a certain proportion and then injected into the tissue defect to be repaired within a specified time.

[0070] The preparation method includes the following steps:

[0071] Step 1: Drying treatment of raw materials for synthesizing polyurethane prepolymer

[0072] The raw materials for synthesizing polyurethane, polyethylene glycol and polyoxyethylene castor oil ether, were dried by vacuum distillation. Weigh 5 - 10 g of polyethylene glycol 1000 and 5 - 10 g of polyoxyethylene castor oil ether respectively and place them in a three-necked flask. Put the above materials into a vacuum drying oven, evacuate to -0.1 Mpa, set the temperature to 105 °C for drying. During drying, the vacuum degree needs to be maintained at -0.1 Mpa, and the vacuum drying lasts for 6 h.

[0073] After the drying to remove water is completed, open the vacuum drying oven, immediately seal the three-necked flask containing polyethylene glycol 1000 and polyoxyethylene castor oil ether, and prepare for the prepolymerization reaction.

[0074] Step 2: Polyurethane prepolymerization reaction

[0075] Place the three-necked flask in Step 1 in an oil bath reactor. Connect nitrogen, a stirrer and a rubber stopper to the three necks respectively. After nitrogen flows out stably from the neck, adjust the temperature, heat up to 75 °C and keep it stable for 15 min, then carry out the prepolymerization reaction. Observe the progress of the prepolymerization reaction according to the reaction time and stirring speed. Use a disposable syringe to inject 6 - 10 g of isophorone diisocyanate into the three-necked flask through the rubber stopper in several times, and at the same time continuously adjust the ratio of polyethylene glycol and polyoxyethylene castor oil ether to carry out the prepolymerization reaction. The reaction time is 2 - 3 h. The reaction principle of this step is as follows:

[0076] OCN-R1-NCO + HO-R2-OH → -OCNHR1-NH-COO-R2-O-

[0077] The bio-based polyurethane prepolymer obtained in Step 2 has a relatively high viscosity, so it needs to be quickly poured into a container. The activity of the polyurethane prepolymer is relatively high. It can self-polymerize at high temperature and react with water at room temperature. Therefore, it needs to be stored at room temperature in an environment isolated from moisture, or can be stored at low temperature for a long time.

[0078] Step 3: Preparation of bio-macromolecule composite foaming agent

[0079] Place water-soluble biomacromolecules (including gelatin, peptides, sodium alginate, and one or more other -NH2-rich biomacromolecules) in deionized water at 36°C-38°C and stir them electromagnetically for 1-2 hours to a concentration of 40-80 g / L. Let them sit for 1-2 hours before use. Dissolve a certain amount of primary hydroxyl diol (including 1,4-butanediol, etc.) in the previously prepared gelatin solution, adjusting the concentration of the primary hydroxyl diol to 20-40 g / L. Stir the prepared solution electromagnetically for 1 hour and place it in a high-power ultrasonic machine for approximately 15-25 minutes at room temperature to complete the preparation of the composite foaming agent. After preparation, refrigerate the foaming agent in a refrigerator at 3°C-5°C. Step 3: The preparation of the biomacromolecule composite foaming agent takes a long time. Open-container preparation cannot control the concentration of the biomacromolecules and primary hydroxyl diol. Therefore, this step requires placing all components in a closed container and sealing them after preparation.

[0080] Step 4: Sterilization of polyurethane prepolymer and composite foaming agent

[0081] This material is used for direct foaming in osteochondral defects, so the polyurethane prepolymer and composite foaming agent obtained in steps 2 and 3 must be sterilized. Polyurethane prepolymers undergo self-polymerization at high temperatures, while the macromolecular structure of biomacromolecule composite foaming agents is destroyed at high temperatures. Therefore, high-temperature sterilization is not suitable. Ultraviolet sterilization is not sufficient to kill any bacteria that may be present in the composite foaming agent. Therefore, these two materials need to be placed in a sealed container and sterilized using γCo-60 irradiation. After sterilization, both materials should be stored in a refrigerator at 3°C-5°C.

[0082] Step 5: Preparation of polyurethane porous composite materials

[0083] First, pretreat the polyurethane prepolymer and the composite foaming agent. When stored at 4°C, the polyurethane prepolymer and the composite foaming agent are in solid state. First, put the two into an insulated box and keep them at 36°C-38°C for 1 hour to melt them into a liquid with strong fluidity; take 10-20g of the bio-based polyurethane prepolymer in step 2 and 4-10g of the biomacromolecule composite foaming agent in step 3, mix them, and immediately stir them at high speed, with a stirring speed of 500-800r / min and a stirring time of 1-2min. At this time, the material can be seen to change from a transparent liquid to a milky white liquid state, and the material enters a slow foaming stage for about 3-5 minutes; within 3 minutes, use a disposable syringe to inject the material that has been mixed and turned into a milky white liquid into the defect. After about 10 minutes, the material solidifies and takes shape, and the defect area is filled with the material to form a polyurethane porous composite scaffold with a closed outer layer and connected internally. The closed outer layer of the scaffold will change within 1-2 weeks after implantation in the body and become a fully connected porous scaffold. This step involves 3 reactions:

[0084] Reaction of Polyurethane Prepolymer with Soluble Biomacromolecule (Gelatin)

[0085] R1-NCO + R2-NH2 → R1-NH-CO-NH-R2

[0086] Reaction of Polyurethane Prepolymer with Primary Hydroxyl Diol (1,4-Butanediol)

[0087] OCN-R1-NCO + HO-R2-OH → -OCNHR1-NH-COO-R2-O-

[0088] Reaction of Polyurethane Prepolymer with Water (Foaming Reaction)

[0089] 2R-NCO + H2O → R-NH-CO-NH-R + CO2

[0090] The material of the present invention can quickly foam at the defect tissue site to form a porous scaffold with a trabecular bone-like structure, maintain good mechanical properties for a long time, support the defect site while repairing the defect tissue; the material is non-toxic during the in vivo foaming and degradation processes, and can repair the defect tissue safely and effectively through minimally invasive surgery and other methods; the -NH2, -OH, water and -NCO contained in the biopolymer composite foaming agent have different reaction rates, and based on this, while keeping the material injectable, the -NCO in the prepolymer and the biopolymer composite foaming agent undergo a cross-linking reaction during the foaming reaction. The natural macromolecular material in the composite foaming agent reacts rapidly with the -NCO-containing substance to polymerize, and the primary hydroxyl group diol also polymerizes with the -NCO-containing substance, making each component polymerize into a macromolecule, thereby inhibiting the diffusion of -NCO in the implantation area, reacting with water to generate a large amount of CO2 bubbles to form a porous morphology with a closed outer layer and interconnected interior. After about one week, the pores in the outer layer reopen. Therefore, after the composite foaming agent and the polyurethane prepolymer are fully mixed, they can quickly foam and form in situ in the implantation area, and their toxicity can be effectively controlled; a biopolymer composite foaming agent is prepared using water-soluble biopolymers, primary hydroxyl group diols, and water. The water-soluble biopolymer used is gelatin, and this biopolymer is not limited to gelatin, but also includes biological macromolecular materials such as amino acids, polypeptides, structural proteins, natural fibers, chitin, and sodium alginate; the primary hydroxyl group diol is not limited to 1,4-butanediol but also includes other diols; in addition to water, the foaming agent also includes materials containing water or capable of quickly gasifying to form pores, such as PBS buffer, physiological saline, and dry ice; the polyether polyol, polyester polyol, and isocyanate used to synthesize the polyurethane prepolymer can make the material form a polyurethane porous composite material with uniform pores, appropriate pore size, and certain mechanical properties, including polyethylene glycol, polyoxyethylene castor oil ether, and isophorone diisocyanate. The synthesized bio-based polyurethane prepolymer is stored in a dry environment with a temperature less than 45°C. This polyether polyol is not limited to polyethylene glycol, but also includes polytetrahydrofuran diol, propylene oxide polyether polyol, and tetrahydrofuran polyether polyol; this isocyanate is not limited to isophorone diisocyanate, but also includes hexamethylene diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, lysine diisocyanate, triisocyanate, aliphatic isocyanate, cycloaliphatic isocyanate, and aromatic isocyanate; a biopolymer composite foaming agent is prepared using water-soluble biopolymers, primary hydroxyl group diols, and water, a bio-based polyurethane prepolymer is prepared using polyether polyol, polyester polyol, and polyisocyanate as raw materials, and a two-step method is used to prepare porous polyurethane. All raw materials in the present invention need to be dried. Among them, polyethylene glycol and polyoxyethylene castor oil ether need to be vacuum dried at 105°C for 6 hours, and isophorone diisocyanate needs to be of analytical pure or higher purity level.

[0091] Example 1:

[0092] Step 1: Polyurethane prepolymerization reaction

[0093] Weigh 5 - 10 g of dehydrated polyethylene glycol 1000 and 5 - 10 g of castor oil polyoxyethylene ether and place them in a three-necked flask. The three-necked flask is placed in an oil bath reactor. Nitrogen, a stirrer, and a rubber stopper are connected to the three openings respectively. After nitrogen flows out stably from the opening, adjust the temperature. Heat up to 65 °C and keep it stable for 15 min. Then use a disposable syringe to inject 6 - 10 g of isophorone diisocyanate into the three-necked flask through the rubber stopper to carry out the prepolymerization reaction. The reaction time is 2 h.

[0094] Step 2: Preparation of composite blowing agent

[0095] Put gelatin into deionized water at 37 °C and stir magnetically for 1 - 2 h with a concentration of 40 - 80 g / L. Let it stand for 1 - 2 h for later use. Dissolve a certain amount of 1,4-butanediol into the previously prepared gelatin solution and adjust the concentration of primary hydroxyl group diol to 20 - 40 g / L. After ultrasonic treatment, the composite blowing agent is made. After the composite blowing agent is made, place it in a refrigerator at 4 °C for refrigeration.

[0096] Step 3: Sterilization of polyurethane prepolymer and composite blowing agent

[0097] This material is used for direct foaming and molding at the osteochondral defect site. Therefore, the polyurethane prepolymer and blowing agent obtained in Step 1 and Step 2 must be sterilized. Put the above two materials into a sealed container and sterilize them by γCo-60 irradiation. After sterilization, place the above two materials in a refrigerator at 4 °C for refrigerated storage.

[0098] Step 4: Preparation of polyurethane porous composite

[0099] Keep the two materials obtained in Example 1 at 37 °C for 1 h respectively, mix the two materials and stir at high speed for 1 - 2 min. At this time, the mixed material is milky white. Use disposable syringes and other equipment to inject the mixed material into the cartilage defect site. After about 8 min, the material expands and solidifies to form a mold, filling the defective part, and then suture the wound.

[0100] Example 2:

[0101] Step 1: Preparation of polyurethane prepolymer

[0102] Weigh 5 - 10 g of dehydrated polyethylene glycol 1000 and place it in a round-bottom flask. The flask is placed in an oil bath reactor. Heat up to 120 °C and stir for 2 h, then seal the bottle mouth. After cooling down to 75 °C, add 6 - 10 g of isophorone diisocyanate to the round-bottom flask to carry out the prepolymerization reaction. The reaction time is 2 h. After the reaction is over, pour it out for later use.

[0103] Step 2: Preparation of composite blowing agent

[0104] Put the water-soluble polypeptide into deionized water at 50 °C and stir it magnetically for 1-2 h, with a concentration of 30-700 g / L. Then directly dissolve a certain amount of ethylene glycol into the previously prepared polypeptide solution, and adjust the ethylene glycol concentration to 20-40 g / L. After ultrasonic treatment, the composite foaming agent is completed. After the composite foaming agent is completed, it is stored in a refrigerator at 4 °C.

[0105] Step 3: Preparation of polyurethane porous composite

[0106] Directly mix the two materials obtained in Example 2 and stir them at high speed for 1-2 min. Inject the milky white material after mixing into the cartilage defect. After the material solidifies and forms, fill the defective part and suture the wound.

[0107] The influence of the repair material described in the present invention on the surrounding tissues after injection at the defect site is as Figure 3 shown. The influence of not using the repair material described in the present invention on the surrounding tissues after injection at the defect site is as Figure 2 shown. By Figure 2 and Figure 3 comparison, it can be found that the bio-macromolecule composite foaming agent (Bio-Foaming agent) used in the present invention is composed of water-soluble bio-macromolecules, primary hydroxyl group diol and water. This enables the -NCO contained in the material in the early stage to be quickly reacted with -NH2 in the water-soluble macromolecules and -OH in the primary hydroxyl group diol after the material is injected and implanted at the defect in the body. The reaction product gelation inhibits the diffusion of residual -NCO; in the initial stage of material foaming and forming, a structure with a closed outer layer and interconnected interior is formed, greatly reducing the contact area between body fluid and the material; about 1 week later, the pores in the outermost layer of the scaffold are reopened, and cells migrate into the interior of the scaffold along the opened pores. At this time, the -NCO in the material has been completely reacted, so there are no adverse reactions, which effectively solves the toxicity problem in the in-situ foaming and forming process; optimize the component ratio of the polyurethane prepolymer, prepare the polyurethane prepolymer without using a catalyst, and its forming and curing time is shorter during the foaming reaction, and there is no toxicity during the later degradation process of the material.

[0108] The present invention relates to a method for preparing a material that can be used for bone and cartilage repair, can be minimally invasively implanted, and can form a porous scaffold in situ by foaming at any shape defect. This material has degradability and self - adaptability. It fills and solidifies at the tissue defect site and integrates with the defect tissue. After tissue repair, it slowly degrades and is excreted from the body through the body's metabolic system. Its main characteristics are as follows: The material prepared by this invention can be formed in situ at the bone and cartilage parts with any defect shape, can be mass - produced, and can ensure the repeatability of the preparation process and results. Using this material, it can quickly fill the defect and form a porous structure similar to the bone structure, with good biocompatibility. After filling and forming at the defect site, the material has good mechanical properties and degradation properties, which can promote bone and cartilage repair, and at the same time can effectively avoid problems such as possible cartilage degenerative lesions during the bone and cartilage defect repair process. This method mainly includes the following steps: pretreatment of polyurethane prepolymer materials; synthesis of polyurethane prepolymers; preparation of biopolymer composite blowing agents; preparation of injectable bio - based polyurethane materials. This repair material is not only applicable to bone and cartilage repair, but can also be applied to tissue engineering, as a filling repair material for the repair of defects in other body tissues; this material has a high porosity, a certain pore size, a good degradation rate, and non - toxic degradation products that can be excreted from the body through the body's metabolic system, so it can also be used as a long - term drug - releasing material. Drugs are loaded into the material, and the drugs are stably released to the material implantation site as the material degrades. A series of materials prepared by the present invention are convenient for mass production, are easy to store under specified conditions, and have broad application prospects.

[0109] The above has introduced in detail an adaptive bio - based polyurethane porous composite material and its preparation method and application provided by the embodiments of the present application. The description of the above embodiments is only used to help understand the method and its core idea of the present application; at the same time, for those of ordinary skill in the art, according to the idea of the present application, there will be changes in the specific implementation manner and application scope. In summary, the content of this specification should not be construed as a limitation of the present application.

[0110] As used in the specification and claims, certain terms are used to refer to specific components. Those skilled in the art should understand that hardware manufacturers may use different terms to refer to the same component. The specification and claims do not distinguish components by the difference in names, but by the difference in functions of the components. As used throughout the specification and claims, the terms "comprising" and "including" are open-ended terms and should be interpreted as "comprising / including but not limited to". "Substantially" means within an acceptable error range. Those skilled in the art can solve the technical problem within a certain error range and basically achieve the technical effect. The following description in the specification is the preferred embodiment for implementing the present application, but the description is for the purpose of explaining the general principles of the present application and is not intended to limit the scope of the present application. The protection scope of the present application shall be subject to what is defined by the appended claims.

[0111] It should also be noted that the term "including", "comprising" or any other variant thereof is intended to cover non-exclusive inclusion, so that a commodity or system including a series of elements not only includes those elements, but also includes other elements not expressly listed, or elements inherent to such commodity or system. Without further limitation, an element defined by the statement "including one..." does not exclude the existence of another identical element in the commodity or system including the said element.

[0112] It should be understood that the term "and / or" used herein is only an associative relationship describing associated objects, indicating that three relationships may exist. For example, A and / or B may represent: A exists alone, A and B exist simultaneously, and B exists alone. In addition, the character " / " herein generally represents an "or" relationship between the associated objects before and after.

[0113] The above description shows and describes several preferred embodiments of the present application. However, as mentioned above, it should be understood that the present application is not limited to the form disclosed herein, should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be changed within the scope of the application concept described herein through the above teachings or the technology or knowledge in the relevant field. And any changes and modifications made by those skilled in the art without departing from the spirit and scope of the present application shall fall within the protection scope of the appended claims of the present application.

Claims

1. A preparation method of an adaptive bio-based polyurethane porous composite material, characterized in that, The preparation method comprises the following steps: S1: Pre-polymerization reaction is performed after pre-treating the raw materials to obtain and store bio-based polyurethane prepolymer; S2: preparing and preserving a composite foaming agent; S3: sterilizing the bio-based polyurethane prepolymer and composite foaming agent in S1 and S2; S4: pretreating and mixing the sterilized bio-based polyurethane prepolymer and the composite foaming agent to obtain an adaptive bio-based polyurethane porous composite material; Said S1 specifically includes: S11: Drying the raw materials for synthesizing polyurethane prepolymer; S12: performing a prepolymerization reaction on the dried raw materials to obtain a bio-based polyurethane prepolymer; S13: preserving the bio-based polyurethane prepolymer; The raw materials include polyethylene glycol and castor oil polyoxyethylene ether, and the drying process in S11 is specifically as follows: drying the polyethylene glycol and castor oil polyoxyethylene ether by vacuum distillation; The prepolymerization reaction process in S12 is specifically as follows: nitrogen is injected and stirred to increase the temperature, and after stabilization, isophorone diisocyanate is injected, while the ratio of polyethylene glycol and castor oil polyoxyethylene ether is continuously adjusted to perform a prepolymerization reaction to obtain a bio-based polyurethane prepolymer, and the reaction time is 2 to 3 hours; The S2 specifically includes: S21: mixing a primary hydroxyl glycol with a pre-formulated gelatin solution to prepare a composite foaming agent; S22: Preserving the composite foaming agent; The method for preparing the pre-configured gelatin solution in S21 is specifically as follows: The water-soluble biomacromolecules are placed in deionized water at 36°C-38°C and electromagnetically stirred for 1-2 hours, and allowed to stand for 1-2 hours to obtain a pre-configured gelatin solution having a concentration of 40-80 g / L, wherein the water-soluble biomacromolecules are gelatin, polypeptides and sodium alginate; The preparation process in S21 is specifically as follows: Dissolving a primary hydroxyl glycol in a pre-prepared gelatin solution to adjust the concentration of the primary hydroxyl glycol to 20-40 g / L, electromagnetically stirring the prepared solution for 1 hour, and placing the solution in a high-power ultrasonic machine for ultrasonic treatment at room temperature for 15-25 minutes to obtain a composite foaming agent; The storage process in S22 specifically includes: isolating the water and storing at room temperature or storing at a temperature lower than room temperature for a long time; The sterilization treatment in S3 is as follows: sterilizing by irradiation with γCo-60 in a sealed container, and after sterilization, storing the bio-based polyurethane prepolymer and the composite foaming agent in a refrigerator at 3°C-5°C; The pretreatment process in S4 is as follows: placing the solid bio-based polyurethane prepolymer and the composite foaming agent into an insulation box, and keeping the temperature at 36°C-38°C for 1 hour to melt them into a liquid with strong fluidity; The mixing process is as follows: the bio-based polyurethane prepolymer and the composite foaming agent are mixed in a ratio of 2:1 to obtain a mixed material, and the mixed material is immediately stirred at a high speed of 500 to 800 r / min and a stirring time of 1 to 2 minutes. The mixed material changes from a transparent liquid to a milky white liquid state, which is an adaptive bio-based polyurethane porous composite material.

2. An adaptive bio-based polyurethane porous composite material, characterized in that, Prepared by the preparation method described in claim 1 above, the self-adaptive bio-based polyurethane porous composite material can quickly foam to form a porous scaffold with a trabecular bone-like structure and maintain mechanical properties.

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