CN112979928A - Preparation method of lignin grafted polymer microspheres - Google Patents
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Abstract
The invention provides a preparation method of lignin grafted polymer microspheres. According to the invention, the lignin is modified by adopting alkylation reaction, the solubility of the lignin in an organic solvent is increased, so that the reaction activity is improved, and the polylactic acid and/or polycaprolactone are grafted to prepare the lignin grafted polymer microsphere, so that a means for changing the physical property of PLA is provided, the cost is reduced, and the lignin grafted polymer microsphere also has the advantages of oxidation resistance and the like. The alkylated lignin grafted polymer microsphere can meet the requirements of small particle size, high uniformity, degradability and tissue compatibility of a scaffold material for the microsphere, improves the safety and effectiveness of a porous scaffold, reduces the production cost, has antioxidant activity, is expected to be widely applied to the scaffold material, and has good clinical application prospect.
Description
Technical Field
The invention belongs to the fields of high molecular materials and biomedical engineering, and particularly relates to a preparation method of lignin grafted polymer microspheres.
Background
Tissue engineering is the process of repairing and reconstructing tissue with functional defect to constitute bioactive tissue and organ. The essence is that cell culture technology is utilized to culture cells in vitro or transfer a scaffold tissue structure into a body, and a structure and a tissue organ with corresponding functions are built in the body. The key to the rational utilization of tissue engineering is to find a suitable scaffold material to allow cells to grow and proliferate in the scaffold material well to finally reach a tissue with biological activity, which can exert the repair function (Gaojia. the application of chitosan in the scaffold material of tissue engineering advances [ J ] China cosmetology, 2018(3): 155-.
Tissue engineering porous scaffolds are often required to have a high specific surface area and good inter-pore connectivity, thereby facilitating transport of nutrients and adhesion and growth of cells. Compared with the traditional porous support, the microsphere accumulation type porous support can endow the support with higher specific surface area due to the spherical structure of the accumulation units. Meanwhile, different curvature characteristics of the microsphere surface can generate different influences on behaviors of adhesion, proliferation, migration and the like of cells, and the growth and differentiation of the cells to specific tissues or organs can be induced. The porous structure formed by stacking the microspheres has good connectivity, and is beneficial to the transfer and transportation of nutrient substances (Chinese patent publication CN 102641521A). Microspheres are defined as spherical microparticles, ranging in size from 1 to 1,000 microns, and spheres in size exceeding 1,000 μm are still commonly referred to as microspheres. These microspheres have a wide range of applications, for example in the medical field, in the purification of carrier materials in biochemical science, and as flow indicators.
In recent years, with the rapid development of regenerative medicine and tissue engineering, new tissue engineering scaffolds have become a research hotspot. The tissue engineering material is mainly divided into 3 types (including: Shuhua, Van Yangjiang, Caichia, Liuxia, Dongxiang, Sunpeng.) of natural materials (gelatin, alginate, hyaluronic acid and the like), synthetic materials (polycaprolactone, polylactic acid, polyglycolic acid and the like) and bioactive ceramic materials (hydroxyapatite and the like) (including: Shuhua, Van Changjiang river, Caichuan, Liuxia, Dongxiang, Sunpeng. preparation of covalent cross-linked gelatin microsphere scaffold and osteoblast compatibility research [ J ]. accurate medical journal, 2019,34(3): 268-272.). Polylactic acid (PLA) and Polycaprolactone (PCL) are renewable natural polymers with good biodegradability and biocompatibility, and biomaterials (suture materials or tissue Engineering scaffolds) designed from the natural polymers are widely applied to biomedicine (Kai D, Ren W, Tian L, et al. Engineering poly (lactides) -lignin nanofibers with antibiotic activity for biological application [ J ]. ACS curable Chemistry & Engineering,2016: acussing.6 b 00478.).
The industrial alkaline lignin is a main byproduct of the pulping and papermaking industry and is abundant in reserves. The natural lignin has good antibacterial activity, oxidation resistance and ultraviolet protection performance, and still has wide application prospect when being used as a framework of a drug delivery system. However, the compatibility of the unmodified lignin is poor, and the mechanical property of the composite material is often adversely affected.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a lignin graft polymer, wherein the lignin graft polymer is alkylated lignin graft polylactic acid or alkylated lignin graft polycaprolactone or alkylated lignin graft polylactic acid-caprolactone random copolymer.
According to an embodiment of the present invention, the lignin graft polymer comprises a structure as shown in formula (I):
wherein R is1Is selected from C5-15Alkyl, may be C10-12Alkyl, such as dodecyl; r2Selected from polylactic acid chain segment or polycaprolactone or polylactic acid-caprolactone random copolymer.
The invention provides a preparation method of a lignin graft polymer, which comprises the following steps:
(1) alkylation reaction: mixing halogenated alkane, alkali, an organic solvent and lignin, stirring, refluxing, reacting, centrifuging, removing supernatant to obtain a solid, washing with a polar solvent, and drying to obtain alkylated lignin;
(2) polymerization reaction: and (2) removing water from the alkylated lignin obtained in the step (1) by using anhydrous toluene, adding a catalyst and a grafting monomer under the protection of inert gas, and initiating monomer polymerization to obtain a lignin graft polymer.
According to an embodiment of the invention, in step (1) the haloalkane is selected from halo C5-15Alkane, which may be halogenated C10-12Alkanes, preferably bromo-C10-12An alkane, for example, is monobromododecane.
According to an embodiment of the present invention, the lignin of step (1) is prepared from alkali lignin, which comprises dissolving alkali lignin in water, adjusting the pH to a strong alkalinity, and removing insoluble impurities; adjusting the pH value to be strong acid, and centrifuging to obtain purified lignin;
according to an embodiment of the present invention, the reaction solvent in step (1) is a mixed solution of water and an organic solvent; the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, pentanol and hexanol, and is preferably isopropanol; the water is preferably ultrapure water; the volume ratio of water to organic solvent is 1:1 to 5:1, preferably 4: 1.
According to an embodiment of the present invention, the alkylation reaction in step (1) is stirred under reflux for more than 20 hours, preferably more than 60 hours. When the reaction time reaches 60 hours, the alkylated lignin generated in the reaction process is separated out, the viscosity of the reaction system is increased, even solid-liquid separation is carried out, and the reaction end point is reached.
According to an embodiment of the present invention, the polar solvent of step (1) is one or more of n-pentane, n-hexane, n-heptane, cyclohexane or petroleum ether, preferably n-hexane.
According to an embodiment of the invention, in step (1), the mass ratio of haloalkane to lignin is (0.8-14):1, preferably (1-5):1, e.g. 1:1, 2:1, 3: 1; in the step (1), the molar ratio of the halogenated alkane to the active phenolic hydroxyl groups in the lignin is (1.2-10):1, preferably (1.5-6):1, such as 1.5:1, 2:1, 3:1, 4:1, 5:1, and the molar amount of the halogenated alkane is excessive relative to the active phenolic hydroxyl groups in the lignin.
According to an embodiment of the invention, in the step (2), the mass ratio of the alkylated lignin to the grafting monomer is 1 (10-200), such as 1:13.7, 1:62.5, 1: 139.7.
According to an embodiment of the present invention, the monomer in the step (2) is selected from at least one of levolactide (L-LA), dextrolactide monomer (D-LA) or caprolactone monomer.
According to the embodiment of the invention, the water removal of the anhydrous toluene in the step (2) is carried out for three times or more at 135 ℃ by azeotropy, so that the water content is less than or equal to 0.4 ppm.
According to an embodiment of the present invention, the catalyst in the step (2) is stannous octoate.
The invention provides a lignin grafted polymer copolymer microsphere, which comprises the lignin grafted polymer.
The invention also provides a preparation method of the lignin graft polymer copolymer microsphere, which comprises the steps of dissolving the lignin graft polymer in a solvent to prepare an oil phase (O phase), and mixing the oil phase (O phase) with a pore-forming agent solution (W phase) to obtain a primary emulsion; and adding the primary emulsion into an emulsifier solution, stirring to obtain a secondary emulsion, washing with distilled water, and freeze-drying to obtain the lignin graft polymer copolymer microspheres.
According to an embodiment of the invention, the solvent is dichloromethane or chloroform.
According to an embodiment of the present invention, the mass-to-volume ratio (g/mL) of the lignin graft polymer to the solvent in the oil phase is 1 (5-40), preferably 1 (10-35), such as 1:16, 1: 32.
According to an embodiment of the invention, the mass ratio of the lignin graft polymer to the pore former is 1 (0-0.5), such as 1: 0.25.
According to an embodiment of the invention, the pore former is ammonium bicarbonate and the pore former solution has a mass volume concentration of 0-0.1g/mL, for example: 0g/mL, 0.05g/mL, 0.1 g/mL; the solvent used by the pore-forming agent solution is deionized water. When the mass volume concentration of the pore-forming agent solution is 0g/mL, the size of the lignin graft polymer copolymer microsphere is 180-220 microns and is 0.05g/mL, the size of the lignin graft polymer copolymer microsphere is 230-270 microns and is 0.1g/mL, the size of the lignin graft polymer copolymer microsphere is 260-300 microns; the addition of the pore-forming agent enables the microspheres to have a porous structure, and the content of pores is along with NH4HCO3The content increases.
According to an embodiment of the invention, the volume ratio of the oil phase to the pore former solution is (2-5) to 1, e.g., 3.2: 1; the volume ratio of the oil phase to the emulsifier is 1 (20-50), preferably 1 (30-40), such as 1:37.5
According to an embodiment of the present invention, the emulsifier is polyvinyl alcohol (PVA), and the solvent used for the emulsifier solution is deionized water;
the mass volume concentration of the emulsifier solution is 0-0.01g/mL, such as 0.001g/mL, 0.002 g/mL, 0.005 g/mL;
according to the invention, the mass volume concentration of the lignin graft polymer and the solvent is 0.05-0.1g/mL, preferably 0.0625 g/mL.
In the invention, the lignin graft polymer graft chain segment R2The number average molecular weight of (A) is in the range of 1000 to 3000.
The invention also provides a microsphere porous scaffold material which comprises the lignin grafted polymer copolymer microsphere.
The invention also provides the use of lignin-grafted polymers or polymeric microspheres, which may be used in tissue engineering, which may or may not contain a drug for use in therapy.
Advantageous effects
Compared with the traditional preparation method, the alkylation method can completely react without using a phase transfer agent, and avoids the influence on the optical activity of the polymer, the crystallization and the crystal morphology of the polymer and the performance of the material caused by the introduction of a catalyst in the synthesis process of the polyesters such as LA, CL and the like. The lignin grafted random copolymer obtained by combining polylactic acid and caprolactone improves the flexibility of the lignin-based polyester.
The porous microsphere scaffold prepared by the method can realize the synchronous formation of microspheres and a porous structure, the preparation method is simple and feasible, the raw materials are easy to obtain, the cost is low, the size and the pore diameter of the microspheres can be conveniently controlled by adjusting the freezing time, the freezing temperature, the concentration of a solution and the constant temperature, the porosity is high, the connectivity of pores is good, the pore diameter of surface pores is more uniform, the mechanical strength is excellent, the biocompatibility is good, the scaffold is degradable, has antioxidant activity, is expected to be widely applied to tissue scaffold materials, and has good clinical application prospect.
Drawings
FIG. 1 is a synthetic scheme of alkylated lignin graft polymers prepared in examples 1, 2.
FIG. 2 nuclear magnetism of alkylated lignin prepared in example 1a1H NMR spectrum.
FIG. 3 shows nuclear magnetism of alkylated lignin grafted polylactic acid prepared in a of example 11H NMR spectrum.
FIG. 4 is a GPC chart of alkylated lignin grafted polylactic acid prepared according to the method of example 1 under different charge ratios of alkylated lignin and D-LA.
FIG. 5 is a scanning electron microscope image of the alkylated lignin grafted polylactic acid copolymer microspheres prepared in example 4.
FIG. 6 is an SEM image of the morphology of alkylated lignin-grafted polylactic acid copolymer microspheres according to the method of example 4 at different pore former mass-volume concentrations in the first emulsifier. a is1,b1,c1The shape of the microsphere is larger under a larger visual field; a is2,b2,c2The morphology of a single microsphere; a is3,b3,c3Is an enlarged microsphere surface morphology, wherein a1,a2,a3NH of (2)4HCO3The mass volume concentration is 0 g/mL; b1,b2,b3NH of (2)4HCO3The mass volume concentration is 0.05 g/mL; c. C1,c2,c3NH of (2)4HCO3The mass volume concentration is 0.1 g/mL.
FIG. 7 is an SEM image of the morphology of alkylated lignin grafted polylactic acid copolymer microspheres prepared according to the method of example 4 under the condition of different mass-to-volume ratios of the alkylated lignin grafted polymer to the solvent. a is1,b1The shape of the microsphere is larger under a larger visual field; a is2,b2The morphology of a single microsphere; a is3,b3The surface appearance of the microsphere is enlarged. Wherein a is1,a2,a3The mass volume ratio of the alkylated lignin graft polymer to the solvent is 0.0625 g/mL; b1,b2,b3The mass-volume ratio of the alkylated lignin graft polymer to the solvent is 0.0313 g/mL.
FIG. 8 is a scanning electron microscope image of the alkylated lignin-grafted polylactic acid-polycaprolactone random copolymer microspheres prepared in example 6.
Definition and description of terms
Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
"alkane" used herein alone or as suffix or prefix, is intended to preferably denote a straight or branched chain saturated aliphatic alkane having the indicated number of carbon atoms. Examples of alkanes include, but are not limited to, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tridecane, n-tetradecane, n-pentadecane.
The term "haloalkane" denotes an alkane in which one, two or more hydrogens are replaced by fluorine, chlorine, bromine or iodine, and examples of haloalkanes include, but are not limited to, fluoro-n-pentane, bromo-n-pentane, chloro-n-pentane, iodo-n-pentane, bromo-n-hexane, bromo-n-heptane, bromo-n-octane, bromo-n-nonane, bromo-n-decane, bromo-undecane, bromo-dodecane, iodo-dodecane, bromo-tridecane, bromo-tetradecane, bromo-pentadecane.
The term "inert gas" as used herein, unless otherwise specified, includes gases inert to the reaction, such as nitrogen and noble gases, such as argon.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The units of mass-volume concentrations in the following examples are all g/mL.
Example 1: preparation of alkylated lignin grafted polylactic acid
a, (1) lignin purification: preparing 150mL of 50% alkali lignin solution by using deionized water, preparing 1mol/L NaOH solution to adjust the pH value of the solution to 12, and centrifuging for 15min at 8000r/min by using a centrifuge; carrying out suction filtration on the supernatant to remove insoluble impurities such as suspended cellulose, hemicellulose and the like to obtain a reddish brown transparent solution; slowly dropwise adding 1mol/L hydrochloric acid into the obtained reddish brown transparent solution, adjusting the pH value to 2 to precipitate lignin, and centrifuging for 15min at 8000r/min by using a centrifuge; removing supernatant, washing precipitate with hydrochloric acid solution with pH of 2, freezing with liquid nitrogen for 5min, drying in freeze dryer until no water is apparent, and drying in vacuum oven at 40 deg.C for two days to obtain purified lignin.
(2) Alkylation reaction: and (3) placing the purified lignin in a vacuum oven, drying at 105 ℃ for more than 24 hours, and measuring the total hydroxyl content of 7.298mmol/g and the active phenolic hydroxyl content of 2.673mmol/g in the lignin. The mixture was added to a 250mL beaker using ultrapure water and isopropanol at a volume ratio of 4:1 to prepare an isopropanol solution150mL of solution, 15g of monobromododecane was dissolved in 60mL of isopropanol solution, the mass ratio of monobromododecane to lignin was 1:1, and the molar ratio of monobromododecane to the active phenolic hydroxyl group content of lignin was about 1.5:1, into a 250mL round bottom flask, followed by 15g lignin and 9g K2CO3Stirring and refluxing for 60h at 130 ℃ in an oil bath. After the reaction is finished, cooling to room temperature, centrifuging the product at 8000r/min for 15min, taking out the precipitate, freezing the precipitate for 5min by using liquid nitrogen, putting the precipitate into a freeze dryer, and drying until no obvious water exists; after complete drying, the product is washed with n-hexane for a plurality of times and centrifuged to remove unreacted monobromododecane; finally, the obtained product is placed in a vacuum drying oven at 50 ℃ overnight to obtain the alkylated lignin.
(3) Polymerization reaction: placing the alkylated lignin in a vacuum drying oven for drying at 80 ℃ overnight; placing a Schlenk reaction tube filled with magnetons, a dehydrator, a 250mL round-bottom flask and a needle head glass needle tube in a 120 ℃ oven for 2 hours, and drying for later use; and (4) building a dewatering device, opening a heating sleeve switch, and steaming the methylbenzene to dewater for more than 2 hours until the methylbenzene is discolored.
Taking out the alkylated lignin from the vacuum drying oven, adding 0.365g of the alkylated lignin into a dried 250mL round-bottom flask, putting up a dehydrator, connecting a condenser pipe and a drying ball, and putting the 250mL round-bottom flask in the device into an oil bath; opening the double-row pipe, connecting the baked needle tube with a needle, performing hot pumping three times by using the double-row pipe, performing last pumping to leave part of argon, sucking 60mL of anhydrous toluene from a toluene dewatering device, removing bubbles, adding the anhydrous toluene into a 250mL round-bottom flask containing alkylated lignin, and performing azeotropic dewatering of toluene in 135 ℃ oil bath; after evaporating half of toluene, pumping out the needle tube again, taking anhydrous toluene, adding the anhydrous toluene into the round-bottom flask, and repeating the operation for 3 times; and finally carrying out azeotropic dehydration, and evaporating anhydrous toluene to obtain the residual 20-25 mL.
Pumping and discharging the dried Schlenk reaction tube for three times while the tube is hot, weighing 5g D-LA monomer under the protection of argon, and adding the monomer into the reaction tube, wherein the mass ratio of the alkylated lignin to the D-LA is 1: 13.7; next, 100. mu.L of Sn (Oct) was added under an argon atmosphere2Toluene solution (0.245 g/mL); finally, the needle cylinder is drained for three times, and the alkylated wood after azeotropy in the round-bottom flask is takenPlacing the toluene solution in a reaction tube under the protection of argon; finally, the reaction tube is sealed and reacted for more than 48 hours in an oil bath at 110 ℃.
After the reaction is finished, cooling the reaction tube at room temperature, adding 25mL of chloroform, dissolving the product, centrifuging for 15min at 8000r/min by using a centrifuge, and removing unreacted alkylated lignin; then, precipitating and separating out the product by using 200mL of methanol, putting the product into a centrifuge 8000r/min for centrifugation for 15min, repeatedly washing the product for three times, and removing unreacted monomers; finally, the product was collected and dried in a vacuum oven at 40 ℃ (66% yield) to obtain alkylated lignin grafted polylactic acid with weight average molecular weight Mw＝8.8kg·mol-1，MnIs the number average molecular weight M of the polymern＝5.6kg·mol-1Polymer dispersity index PDI of 1.57(PDI of M)w/Mn) The number average molecular weight of the grafted polylactic acid segment is 1.33 kg/mol-1。
b. Basically, the method a in the embodiment 1 is different in that: the amount of the alkylated lignin in the step (3) was 0.08g, and the obtained alkylated lignin-grafted polylactic acid (yield 91%) had a weight-average molecular weight Mw＝17.5 kg·mol-1，MnIs the number average molecular weight M of the polymerw＝15.0kg·mol-1Polymer dispersity index PDI of 1.17(PDI of M)w/Mn) The number average molecular weight of the grafted polylactic acid segment is 2.00kg & mol-1
c. Basically, the method a in the embodiment 1 is different in that: the amount of the alkylated lignin in the step (3) was 0.036g, and the obtained alkylated lignin-grafted polylactic acid (yield 98%) had a weight-average molecular weight Mw＝24.7 kg·mol-1，MnIs the number average molecular weight M of the polymerw＝18.5kg·mol-1Polymer dispersity index PDI ═ 1.33(PDI ═ M)w/Mn) The number average molecular weight of the grafted polylactic acid segment is 2.27 kg/mol-1。
Example 2: preparation of alkylated lignin grafted polycaprolactone
(1) And (3) lignin purification: preparing 150mL of 50% alkali lignin solution by using deionized water, preparing 1mol/L NaOH solution to adjust the pH value of the solution to 12, and centrifuging for 15min at 8000r/min by using a centrifuge; carrying out suction filtration on the supernatant to remove insoluble impurities such as suspended cellulose, hemicellulose and the like to obtain a reddish brown transparent solution; slowly dropwise adding 1mol/L hydrochloric acid into the obtained reddish brown transparent solution, adjusting the pH value to 2 to precipitate lignin, and centrifuging for 15min at 8000r/min by using a centrifuge; removing supernatant, washing precipitate with hydrochloric acid solution with pH of 2, freezing with liquid nitrogen for 5min, drying in freeze dryer until no water is apparent, and drying in vacuum oven at 40 deg.C for two days to obtain purified lignin.
(2) Alkylation reaction: and (3) placing the purified lignin in a vacuum oven, drying at 105 ℃ for more than 24 hours, and measuring the total hydroxyl content of 7.298mmol/g and the active phenolic hydroxyl content of 2.673mmol/g in the lignin. Adding ultrapure water and isopropanol into a 250mL beaker in a ratio of 4:1 to prepare 150mL of isopropanol solution, dissolving 15g of monobromododecane in 60mL of isopropanol solution, wherein the mass ratio of the monobromododecane to the lignin is 1:1, and the molar ratio of the monobromododecane to the active phenolic hydroxyl content in the lignin is about 1.5:1, into a 250mL round bottom flask, followed by 15g lignin and 9g K2CO3Stirring and refluxing for 60h at 130 ℃ in an oil bath. After the reaction is finished, cooling to room temperature, centrifuging the product at 8000r/min for 15min, taking out the precipitate, freezing the precipitate for 5min by using liquid nitrogen, putting the precipitate into a freeze dryer, and drying until no obvious water exists; after complete drying, the product is washed with n-hexane for a plurality of times and centrifuged to remove unreacted monobromododecane; finally, the obtained product is placed in a vacuum drying oven at 50 ℃ overnight to obtain the alkylated lignin.
(3) Polymerization reaction: placing the alkylated lignin in a vacuum drying oven for drying at 80 ℃ overnight; placing a Schlenk reaction tube filled with magnetons, a dehydrator, a 250mL round-bottom flask and a needle head glass needle tube in a 120 ℃ oven for 2 hours, and drying for later use; and (4) building a dewatering device, opening a heating sleeve switch, and steaming the methylbenzene to dewater for more than 2 hours until the methylbenzene is discolored.
Taking out the alkylated lignin from the vacuum drying oven, adding 0.365g of the alkylated lignin into a dried 250mL round-bottom flask, putting up a dehydrator, connecting a condenser pipe and a drying ball, and putting the 250mL round-bottom flask in the device into an oil bath; opening the double-row pipe, connecting the baked needle tube with a needle, performing hot pumping three times by using the double-row pipe, performing last pumping to leave part of argon, sucking 60mL of anhydrous toluene from a toluene dewatering device, removing bubbles, adding the anhydrous toluene into a 250mL round-bottom flask containing alkylated lignin, and performing azeotropic dewatering of toluene in 135 ℃ oil bath; after evaporating half of toluene, pumping out the needle tube again, taking anhydrous toluene, adding the anhydrous toluene into the round-bottom flask, and repeating the operation for 3 times; and finally carrying out azeotropic dehydration, and evaporating anhydrous toluene to obtain the residual 20-25 mL.
The dried Schlenk reaction tube is pumped and discharged for three times while being hot, and 5g of caprolactone monomers are weighed and added into the reaction tube under the protection of argon; next, 100. mu.L of Sn (Oct) was added under an argon atmosphere2Toluene solution (0.245 g/mL); finally, the needle cylinder is drained for three times, the alkylated lignin toluene solution after azeotropy in the round-bottom flask is taken and placed in a reaction tube under the protection of argon; finally, the reaction tube is sealed and reacted for more than 48 hours in an oil bath at 110 ℃.
After the reaction is finished, cooling the reaction tube at room temperature, adding 25mL of chloroform, dissolving the product, centrifuging for 15min at 8000r/min by using a centrifuge, and removing unreacted alkylated lignin; then, precipitating and separating out the product by using 200mL of methanol, putting the product into a centrifuge 8000r/min for centrifugation for 15min, repeatedly washing the product for three times, and removing unreacted monomers; finally, the product was collected and dried in a vacuum oven at 40 deg.C (68% yield) to yield the alkylated lignin-grafted polycaprolactone.
Example 3: preparation of alkylated lignin grafted polylactic acid-caprolactone random copolymer
(1) And (3) lignin purification: preparing 150mL of 50% alkali lignin solution by using deionized water, preparing 1mol/L NaOH solution to adjust the pH value of the solution to 12, and centrifuging for 15min at 8000r/min by using a centrifuge; carrying out suction filtration on the supernatant to remove insoluble impurities such as suspended cellulose, hemicellulose and the like to obtain a reddish brown transparent solution; slowly dropwise adding 1mol/L hydrochloric acid into the obtained reddish brown transparent solution, adjusting the pH value to 2 to precipitate lignin, and centrifuging for 15min at 8000r/min by using a centrifuge; removing supernatant, washing precipitate with hydrochloric acid solution with pH of 2, freezing with liquid nitrogen for 5min, drying in freeze dryer until no water is apparent, and drying in vacuum oven at 40 deg.C for two days to obtain purified lignin.
(2) Alkylation reaction: and (3) placing the purified lignin in a vacuum oven, drying at 105 ℃ for more than 24 hours, and measuring the total hydroxyl content of 7.298mmol/g and the active phenolic hydroxyl content of 2.673mmol/g in the lignin. Adding ultrapure water and isopropanol into a 250mL beaker in a ratio of 4:1 to prepare 150mL of isopropanol solution, dissolving 15g of monobromododecane in 60mL of isopropanol solution, wherein the mass ratio of the monobromododecane to the lignin is 1:1, and the molar ratio of the monobromododecane to the active phenolic hydroxyl content in the lignin is about 1.5:1, into a 250mL round bottom flask, followed by 15g lignin and 9g K2CO3Stirring and refluxing for 60h at 130 ℃ in an oil bath. After the reaction is finished, cooling to room temperature, centrifuging the product at 8000r/min for 15min, taking out the precipitate, freezing the precipitate for 5min by using liquid nitrogen, putting the precipitate into a freeze dryer, and drying until no obvious water exists; after complete drying, the product is washed with n-hexane for a plurality of times and centrifuged to remove unreacted monobromododecane; finally, the obtained product is placed in a vacuum drying oven at 50 ℃ overnight to obtain the alkylated lignin.
(3) Polymerization reaction: placing the alkylated lignin in a vacuum drying oven for drying at 80 ℃ overnight; placing a Schlenk reaction tube filled with magnetons, a dehydrator, a 250mL round-bottom flask and a needle head glass needle tube in a 120 ℃ oven for 2 hours, and drying for later use; and (4) building a dewatering device, opening a heating sleeve switch, and steaming the methylbenzene to dewater for more than 2 hours until the methylbenzene is discolored.
Taking out the alkylated lignin from the vacuum drying oven, adding 0.365g of the alkylated lignin into a dried 250mL round-bottom flask, putting up a dehydrator, connecting a condenser pipe and a drying ball, and putting the 250mL round-bottom flask in the device into an oil bath; opening the double-row pipe, connecting the baked needle tube with a needle, performing hot pumping three times by using the double-row pipe, performing last pumping to leave part of argon, sucking 60mL of anhydrous toluene from a toluene dewatering device, removing bubbles, adding the anhydrous toluene into a 250mL round-bottom flask containing alkylated lignin, and performing azeotropic dewatering of toluene in 135 ℃ oil bath; after evaporating half of toluene, pumping out the needle tube again, taking anhydrous toluene, adding the anhydrous toluene into the round-bottom flask, and repeating the operation for 3 times; and finally carrying out azeotropic dehydration, and evaporating anhydrous toluene to obtain the residual 20-25 mL.
Pumping and discharging the dried Schlenk reaction tube for three times while the tube is hot, and weighing 5g of CL monomer and 5g D-LA under the protection of argon gas and adding the CL monomer and the 5g D-LA into the reaction tube; then, under the protection of argon, 100. mu.L of Sn (Oct)2 toluene solution (0.245g/mL) was added; finally, the needle cylinder is drained for three times, the alkylated lignin toluene solution after azeotropy in the round-bottom flask is taken and placed in a reaction tube under the protection of argon; finally, the reaction tube is sealed and reacted for more than 48 hours in an oil bath at 110 ℃.
After the reaction is finished, cooling the reaction tube at room temperature, adding 25mL of chloroform, dissolving the product, centrifuging for 15min at 8000r/min by using a centrifuge, and removing unreacted alkylated lignin; then, precipitating and separating out the product by using 200mL of methanol, putting the product into a centrifuge 8000r/min for centrifugation for 15min, repeatedly washing the product for three times, and removing unreacted monomers; finally, the product was collected and dried in a vacuum oven at 40 ℃ (55% yield) to obtain an alkylated lignin grafted polylactic acid-caprolactone random copolymer with a weight average molecular weight Mw of 13.4kg · mol-1Number average molecular weight Mn of 10.9 kg/mol-1Polymer dispersibility index PDI ═ 1.23(PDI ═ Mw/Mn), the number average molecular weight of the grafted polylactic acid segment: 0.76 kg. mol-1Number average molecular weight of the grafted polycaprolactone segment: 0.91 kg mol-1。
Example 4: preparation of alkylated lignin grafted polylactic acid copolymer microspheres
0.25g of the alkylated lignin-grafted polylactic acid polymer prepared in example 1 was weighed into a clean glass vial, 4mL of chloroform was added as a solvent, and dissolved by magnetic stirring to obtain an oil phase. And taking a clean bottle, and preparing 1.25mL of ammonium bicarbonate aqueous solution with the mass volume concentration of 0.05g/mL, wherein the solvent of the ammonium bicarbonate aqueous solution is deionized water, and the ammonium bicarbonate solution is used as an internal water phase. Mixing the internal water phase and the oil phase together under the condition of ice bath, homogenizing for three minutes at the maximum rotation speed of a homogenizer to obtain a primary emulsion, pouring the homogenized primary emulsion into 150mL of PVA deionized water solution with the mass volume concentration of 0.001g/mL, and stirring for four hours to obtain a secondary emulsion. And in the process of secondary emulsification, obtaining porous microspheres, repeatedly washing the obtained microspheres with distilled water, and freeze-drying to obtain the alkylated lignin grafted polylactic acid copolymer microspheres.
Example 5: preparation of alkylated lignin grafted polycaprolactone copolymer microspheres
0.25g of the alkylated lignin-grafted polycaprolactone polymer prepared in example 2 was weighed into a clean glass vial, 4mL of chloroform was added as solvent and dissolved by magnetic stirring to give an oil phase. And taking a clean bottle, and preparing 1.25mL of ammonium bicarbonate solution with the mass volume concentration of 0.05g/mL, wherein the solvent is deionized water, and the ammonium bicarbonate solution is used as an internal water phase. Mixing the internal water phase and the oil phase together under the condition of ice bath, homogenizing for three minutes at the maximum rotation speed of a homogenizer to obtain a primary emulsion, pouring the homogenized primary emulsion into 150mL of PVA deionized water solution with the mass volume concentration of 0.001g/mL, and stirring for four hours to obtain a secondary emulsion. And in the process of secondary emulsification, obtaining porous microspheres, repeatedly washing the obtained microspheres with distilled water, and freeze-drying to obtain the alkylated lignin grafted polycaprolactone copolymer microspheres.
Example 6: preparation of alkylated lignin grafted polylactic acid-caprolactone random copolymer microspheres
0.25g of the alkylated lignin graft polylactic acid-caprolactone random copolymer prepared in example 3 was weighed into a clean glass vial, 4mL of chloroform was added as a solvent, and dissolved by magnetic stirring to obtain an oil phase. And taking a clean bottle, and preparing 1.25mL of ammonium bicarbonate solution with the mass volume concentration of 0.05g/mL, wherein the solvent is deionized water, and the ammonium bicarbonate solution is used as an internal water phase. Mixing the internal water phase and the oil phase together under the condition of ice bath, homogenizing for three minutes at the maximum rotation speed of a homogenizer to obtain a primary emulsion, pouring the homogenized primary emulsion into 150mL of PVA deionized water solution with the mass volume concentration of 0.001g/mL, and stirring for four hours to obtain a secondary emulsion. And in the process of secondary emulsification, obtaining porous microspheres, repeatedly washing the obtained microspheres with distilled water, and freeze-drying to obtain the alkylated lignin grafted polylactic acid-caprolactone random copolymer microspheres.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The lignin grafted polymer is alkylated lignin grafted polylactic acid, or alkylated lignin grafted polycaprolactone, or alkylated lignin grafted polylactic acid-caprolactone random copolymer.
2. A lignin graft polymer according to claim 1, comprising the structure of formula I:
wherein R is1Is selected from C5-15An alkyl group; r2Selected from polylactic acid, polycaprolactone or polylactic acid-caprolactone random copolymer.
3. The lignin graft polymer of claim 2, wherein R is1Is selected from C10-12An alkyl group; r2Selected from polylactic acid, polycaprolactone or polylactic acid-caprolactone random copolymer;
preferably, R1Is dodecyl; r2Selected from polylactic acid, polycaprolactone or polylactic acid-caprolactone random copolymer.
4. The method for preparing the lignin graft polymer according to any one of claims 1 to 3, comprising the steps of:
(1) alkylation reaction: mixing halogenated alkane, alkali, a reaction solvent and lignin, stirring and refluxing, centrifuging after the reaction is finished, discarding the supernatant to obtain a solid, washing with a polar solvent and drying to obtain alkylated lignin;
(2) polymerization reaction: and (2) removing water from the alkylated lignin obtained in the step (1) by using anhydrous toluene, adding a catalyst and a monomer under the protection of inert gas, and initiating the monomer to polymerize to obtain the alkylated lignin graft polymer.
5. The production method according to claim 4, wherein the reaction solvent is a mixed solution of water and an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, such as isopropanol; preferably, the water is ultrapure water; the volume ratio of water to organic solvent is 1:1-5:1, such as 4: 1;
preferably, the alkylation reaction is stirred and refluxed for more than 20 hours, such as more than 60 hours;
preferably, the polar solvent is one or more of n-pentane, n-hexane, n-heptane, cyclohexane or petroleum ether, preferably n-hexane;
preferably, the mass ratio of haloalkane to lignin is (0.8-14) to 1, e.g. 1: 1;
preferably, the molar ratio of haloalkane to active phenolic hydroxyl groups in the lignin is (1.2-10) to 1, e.g. 1.5: 1;
preferably, the mass ratio of the alkylated lignin to the grafting monomer is 1:13.7, 1:62.5 and 1: 139.7;
preferably, the monomer is selected from at least one of levorotatory lactide (L-LA), dextrorotatory lactide monomer (D-LA) or caprolactone monomer;
preferably, the catalyst is stannous octoate;
preferably, the water removal is performed by azeotropic water removal at 135 ℃ for three times or more, so that the water content is less than or equal to 0.4 ppm.
6. A lignin graft polymer copolymer microsphere comprising the lignin graft polymer according to any one of claims 1 to 3.
7. The preparation method of the copolymerization microsphere as claimed in claim 6, which comprises dissolving the alkylated lignin graft polymer in a solvent to obtain an oil phase, and mixing the oil phase with a pore-forming agent solution to obtain a primary emulsion; and adding the primary emulsion into an emulsifier solution, stirring to obtain a secondary emulsion, washing with distilled water, and freeze-drying to obtain the alkylated lignin graft polymer copolymer microspheres.
Preferably, the solvent is dichloromethane or chloroform;
preferably, the pore-forming agent is ammonium bicarbonate, and the mass concentration of the pore-forming agent solution is 0-0.1g/mL, such as 0.05 g/mL;
preferably, the solvent used by the pore-forming agent solution is deionized water;
preferably, the emulsifier is polyvinyl alcohol (PVA), and the mass concentration of the emulsifier is 0-0.01g/mL, such as 0.001 g/mL;
preferably, the solvent used by the emulsifier solution is deionized water;
preferably, the mass to volume ratio of the alkylated lignin polymer to the solvent is from 0.05 to 0.1g/mL, such as 0.0625 g/mL.
8. A microsphere porous scaffold material is characterized by comprising lignin grafted polymer copolymer microspheres, wherein the lignin grafted polymer copolymer microspheres are lignin grafted polylactic acid copolymer microspheres or lignin grafted polycaprolactone copolymer microspheres or lignin grafted polylactic acid-caprolactone random copolymers; preferably, the lignin-grafted polymer copolymer microspheres are the lignin-grafted polymer copolymer microspheres according to claim 6.
9. Use of a lignin graft polymer according to claims 1 to 3, characterized in that it is used in tissue engineering, and the alkylated lignin graft polymer co-polymeric microspheres may or may not contain a drug for therapy.
10. The use of the copolymeric microspheres of claim 6, wherein said alkylated lignin-grafted polymer copolymeric microspheres comprise a therapeutic agent or do not comprise a therapeutic agent, for use in tissue engineering.
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