CN1939543A - Composite stand materials of polylactic acid base/nano-hydroxy-apatite and its production - Google Patents
Composite stand materials of polylactic acid base/nano-hydroxy-apatite and its production Download PDFInfo
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Abstract
A porous scaffold material for tissue engineering is the composition of a polylactic acid type polymer, such as poly-L-lactic acid (PLLA), poly-D, L-lactic acid (PDLLA) and poly-L-lactic acid / hydroxyacetic acid copolymer (PLGA), and a modified nano-class hydroxyapatite (NHA). It is prepared by the thermal phase separation technique.
Description
Technical Field
The invention belongs to the technical field of high polymer materials and biomedical engineering, and particularly relates to a polylactic acid-based/nano-hydroxyapatite composite scaffold material and a preparation method thereof.
Technical Field
Bone repair and regeneration is a common and complex clinical problem in orthopedic surgery, with millions of people worldwide suffering from orthopedic-type diseases due to trauma and many people dying due to lack of ideal substitute materials. The bone grafting material at present mainly comprises autogenous bone, allogeneic bone, specially treated xenogeneic bone and human bone synthetic bone material. However, autologous bone is of limited source and requires secondary surgery, post-transplant complications of up to 8% and other health problems may arise. The search for ideal bone tissue substitute materials is the key to solve orthopedic diseases, so that the construction of artificial synthetic materials similar to natural bone structures has become the focus of attention.
The natural hydroxyapatite in the organism exists in the form of nano crystal. The hydroxyapatite is a crystal part of natural bone, has no toxic or teratogenic or carcinogenic side effects, has good biocompatibility and osteoconductivity, can be directly bonded with bone to induce cell growth and division, and generates bone matrix collagen to form bone tissue. The biological characteristics of the hydroxyapatite are closely related to the particle size of the hydroxyapatite, according to the theory of nanometer effect, the surface area of the nanometer particles of unit mass is obviously larger than that of the micron particles, so that the number of atoms on the surfaces of theparticles is obviously increased, the activity of the particles is improved, and the combination of tissues is very facilitated, therefore, the nanometer hydroxyapatite has unique biological activity. However, HA is too brittle, and the resulting material is prone to fracture, HAs poor mechanical properties, and does not have sufficient strength and fatigue resistance.
In order to prepare a more ideal bone tissue engineering substitute material, researchers developed a plurality of nano-hydroxyapatite composite materials similar to natural bone structures in recent years. The polylactic acid has good biocompatibility and degradability and moderate mechanical property, and the bone tissue engineering scaffold material is prepared from the polylactic acid and the nano-hydroxyapatite by a proper preparation method, so that the mechanical property and the bone formation guiding property of the polylactic acid can be improved, the biodegradation of the nano-hydroxyapatite can be controlled, and the bone tissue recovery speed is ensured to be consistent with the material degradation speed. Therefore, the polylactic acid/nano hydroxyapatite composite porous scaffold material has been adopted by many scholars at home and abroad.
However, the composite materials have the defects, such as simple chemical structure of the polylactic acid material; and the nano-hydroxyapatite is not uniformly dispersed in the polylactic acid. Therefore, the preparation of bone tissue engineering scaffold materials similar to natural bone structures, the improvement of mechanical properties and biological compatibility, and the improvement and control of the dispersion condition of hydroxyapatite in the scaffold are important research points of bone tissue engineering.
Disclosure of Invention
The invention aims to provide a polylactic acid-based/nano-hydroxyapatite scaffold material which has excellent mechanical property, good biocompatibility, communicated pore diameter and degradation rate and is matched with the growth of bone tissues, and a preparation method thereof.
The polylactic acid-based/nano hydroxyapatite composite scaffold material provided by the invention is a composite of polylactic acid polymer and modified Nano Hydroxyapatite (NHA) according to the weight ratio of 100: 1-100: 30, wherein the content of the nano hydroxyapatite can be less than 1, even 0. The pore size range is 100-450 mu m, the interior is a communicated and regular macroporous structure, and the porosity is 78-98%.
In the present invention, the polylactic acid polymer may be poly L-lactic acid (PLLA), poly D, L-lactic acid (PDLLA) or poly L-lactic acid-glycolic acid copolymer (PLGA).
According to the polylactic acid-based/nano-hydroxyapatite composite scaffold material provided by the invention, the nano-hydroxyapatite is modified hydroxyapatite of which the surface is grafted with a polylactic acid polymer, so that the nano-hydroxyapatite and the polylactic acid polymer have good compatibility and can be uniformly dispersed in a matrix of the polylactic acid polymer.
The preparation method of the polylactic acid-based/nano-hydroxyapatite composite scaffold material comprises the following steps of firstly synthesizing a polylactic acid polymer and nano-hydroxyapatite, grafting the polylactic acid polymer on the surface of the nano-hydroxyapatite, and then preparing the polylactic acid-based/nano-hydroxyapatite composite scaffold by adopting a thermally induced phase separation method, wherein the preparation method comprises the following specific steps:
1. preparation of polylactic acid polymer
Carrying out vacuum melting, ring opening andpolymerization on L-lactide and glycolide for 4-10 hours at 120-160 ℃ according to the molar ratio of 50: 50-90: 10 to prepare poly L-lactic acid-glycolic acid copolymer (PLGA), wherein the weight average molecular weight is 100,000-200,000; preparing polylactic acid materials poly L-lactic acid (PLLA) and poly D, L-lactic acid (PDLLA) from L-lactide and D, L-lactide under the same conditions, wherein the weight average molecular weight is 100,000-300,000; carrying out vacuum melt polymerization on L-lactide and polyethylene glycol (PEG) for 4-10 h at 120-160 ℃ to obtain a polylactic acid material PLA-PEG, wherein the number average molecular weight of the PEG is 2000-10000, the molar ratio of the L-lactide to the PEG is 1: 4-4: 1, and the molecular weight of the PLA-PEG is 50,000-100,000.
2. Synthesis of nano-hydroxyapatite
Firstly, calcium nitrate and diammonium phosphate are weighed according to the Ca/P ratio of 1.67, then aqueous solution is prepared, the temperature is controlled to be room temperature, the pH value of a reaction system is 10-11, chemical reaction is carried out on the aqueous solution, colloid HA precipitate is generated, PEG aqueous solution with the weight concentration of 0.01-0.1% is added as a surfactant after the reaction is finished, the mixture is aged for 10-20 hours at room temperature, filtering and washing are carried out repeatedly, then drying is carried out, and the nano-hydroxyapatite is obtained, wherein the reaction equation is as follows:
3. modification of nano-hydroxyapatite
The preparation method comprises the following steps of carrying out solution polymerization on L-lactide or a mixture of the L-lactide and glycolide according to a molar ratio of 50: 50-90: 10 in a xylene solvent in an environment where nano-hydroxyapatite exists, grafting a polyester chain segment to the surface of the nano-hydroxyapatite to improve the interfacial compatibility of the nano-hydroxyapatite and polylactic acid, and generating strong interfacial adhesion between HA and polylactic acid polymers to facilitate the dispersion of the HA in a polymer solution, thereby facilitating the dispersion of the HA in the polymer scaffold and improving the mechanical property of the porous scaffold. The method comprises the following specific steps:
(1) weighing a mixture of nano hydroxyapatite and L-lactide or a mixture of L-lactide and glycolide according to a mass ratio of 1: 0.5-1: 2, wherein the molar ratio of the former to the latter in the mixture of L-lactide and glycolide is 50: 50-90: 10; dissolving L-lactide or a mixture of L-lactide and glycolide in a xylene solution at 40-55 ℃ to obtain a solution A; dispersing the nano hydroxyapatite in a xylene solution in a device for refluxing, condensing, stirring and introducing nitrogen to obtain a suspension B.
(2) And dropwise adding the solution A into the suspension B, and reacting for 8-24 h at 100-130 ℃.
(3) And dissolving and washing the reaction product for several times by using chloroform, precipitating, and drying to obtain the modified nano-hydroxyapatite.
4. Preparation of polylactic acid base/nano hydroxyapatite porous scaffold by thermally induced phase separation method
The process for preparing the polylactic acid-based/nano hydroxyapatite porous scaffold by the thermally induced phase separation method is shown in figure 4. The solvent is a mixed solvent of dioxane and water, wherein the volume ratio of dioxane to water is 87/13. The specific implementation steps are as follows:
(1) weighing a polylactic acid polymer (such as PLLA, PDLLA or PLGA) and modified nano hydroxyapatite according to the mass ratio of 100: 1-100: 30, and preparing a dioxane-water solution of the polymer according to the weight concentration of the polylactic acid polymer of 5-10%.
(2) Adding the prepared polymer dioxane-water solution, nano-hydroxyapatite and PLA-PEG copolymer or NaCl into a test tube, heating to 45-50 ℃, and dissolving and ultrasonically dispersing the polymer to uniformly disperse the nano-hydroxyapatite in the polymer solution.
(3) Pouring the uniformly dispersed polymer solution into a mold, placing the mold at the temperature of minus 20 ℃ to 30 ℃ for coarsening for 10min to 3h, freezing the polymer solution at the temperature of minus 100 ℃ to minus 10 ℃ for 10min to 1h after coarsening, and then placing the polymer solution in a freeze dryer for drying for 48h to 96h at the temperature of minus 50 ℃. And then annealing for 1-10 h at 20-40 ℃ to improve the strength of the scaffold, thereby obtaining the polymer/nano hydroxyapatite porous scaffold with better mechanical property.
(4) And washing the NaCl-containing polymer/nano-hydroxyapatite scaffold with deionized water, and then annealing to remove the pore-forming agent in the polymer scaffold.
In step 4(3), the initialization can be performed in two cases:
(1) the initialization is carried out in two steps, the initialization is carried out for 10min to 1h at the temperature of between 5 and 30 ℃ and then for 10min to 2h at the temperature of between 20 ℃ below zero and 5 ℃,
(2) the initialization is carried out in one step, and the initialization is carried out for 10min to 3h at the temperature of between 20 ℃ below zero and 30 ℃.
Drawings
1. XRD pattern of nano-hydroxyapatite.
2. Transmission Electron Microscope (TEM) image of nano hydroxyapatite.
3. Infrared spectrogram of the nano hydroxyapatite before and after modification.
4. A flow chart of a thermally induced phase separation method for preparing a stent.
5. TEM image of PLGA/HA porous scaffolds. Wherein a is the SEM picture of the stent initialized by PLGA/HA (PLGA: HA is 100: 5) solution at 5 ℃ for 1h and initialized at 0 ℃ for 2h, and b is the SEM picture of the stent initialized by PLGA/HA (PLGA: HA is 100: 5) solution at 5 ℃ for 1h and initialized at 0 ℃ for 1 h.
Detailed Description
In example 1, calcium nitrate and diammonium phosphate were weighed to Ca/P of 1.67 and each prepared as an aqueous solution, the aqueous solution of diammonium phosphate was added dropwise to the aqueous solution of calcium nitrate, the temperature was controlled at room temperature and the pH of the reaction system was 10 to 11, a chemical reaction was caused to occur, a colloidal HA precipitate was produced, and after the reaction was completed, an aqueous solution of PEG2000 having a weight concentration of 0.1% was added as a surfactant. Aging at room temperature for 10-20 h, repeatedly filtering, washing and drying to obtain the nano-hydroxyapatite. Putting the prepared dimethylbenzene solution of the nano-hydroxyapatite into a device which is filled with condensing, refluxing, nitrogen protection and stirring, then dropwise adding the dimethylbenzene solution of lactide into the device, wherein the mass ratio of the lactide to the nano-hydroxyapatite is 1: 1, reacting for 16 hours at 120 ℃, repeatedly washing a reaction product with chloroform after the reaction is finished, and drying to obtain the modified nano-hydroxyapatite. Lactide and glycolide react for 10 hours at 140 ℃ in the presence of stannous octoate as a catalyst according to the molar ratio of 75: 25 to obtain polylactic acid-glycolic acid copolymer (PLGA) with the molecular weight of 120,000. Weighing the PLGA and the modified nano-hydroxyapatite according to the weight ratio of 100: 5, wherein NaCl is 1 percent of the weight of the PLGA, dissolving the PLGA and the modified nano-hydroxyapatite in a dioxane-water solution system with the volume ratio of 87/13, wherein the concentration of the PLGA is 9 percent, initializing for 2h at-10 ℃, then curing for 10min, freeze-drying for 72h, soaking in deionized water for 3 days, and annealing for 6h at 30 ℃ to obtain the PLGA (75/25)/HA composite porous tissue engineering scaffold.
Example 2, the synthesis and modification of nano-hydroxyapatite were the same as in example 1. Lactide and glycolide react for 10 hours at 140 ℃ in the presence of stannous octoate as a catalyst according to the molar ratio of 85: 15 to obtain polylactic acid-glycolic acid copolymer (PLGA) with the molecular weight of 130,000. Weighing the PLGA and the modified nano-hydroxyapatite according to the weight ratio of 100: 5, wherein NaCl is 1 percent of the weight of the PLGA, dissolving the PLGA and the modified nano-hydroxyapatite in a dioxane-water solution system with the volume ratio of 87/13, wherein the PLGA concentration is 9 percent, initializing for 2h at-10 ℃, then solidifying for 10min, freeze-drying for 72h, and annealing for 6h at 30 ℃ to obtain the PLGA (85/15)/HA composite porous tissue engineering scaffold.
Example 3 synthesis and modification of nano-hydroxyapatite and synthesis of PLGA (75/25) the same as in example 1. Weighing the PLGA (75/25) and the modified nano-hydroxyapatite according to the weight ratio of 100: 5, dissolving the PLGA and the modified nano-hydroxyapatite in a dioxane-water solution system with the volume ratio of 87/13, wherein the PLGA concentration is 9%, coarsening the PLGA at 5 ℃ for 1h, then coarsening the PLGA at 0 ℃ for 2h by adopting a step-by-step initialization method, solidifying the PLGA for 30min, freeze-drying the PLGA for 72h, and annealing the PLGA at 30 ℃ for 6h to obtain the PLGA/HA composite porous scaffold engineering scaffold, wherein the SEM picture of the PLGA/HA composite porous scaffold engineering scaffold is shown in fig. 5 (a.
Example 4 synthesis and modification of nano-hydroxyapatite and synthesis of PLGA (75/25) the same as in example 1. Weighing the PLGA (75/25) and the modified nano-hydroxyapatite according to the weight ratio of 100: 5, dissolving the PLGA in a dioxane-water solution system with the volume ratio of 87/13, wherein the PLGA concentration is 9%, adopting a step-by-step initialization method to coarsen the PLGA at 5 ℃ for 1h, then coarsen the PLGA at 0 ℃ for 1h, solidifying the PLGA for 30min, freeze-drying the PLGA for 72h, and annealing the PLGA at 30 ℃ for 6h to obtain the PLGA/HA composite porous scaffold engineering scaffold, wherein the SEM picture of the PLGA/HA composite porous scaffold engineering scaffold is shown in figure 5 (b).
Example 5 Synthesis and modification of nano-hydroxyapatite and Synthesis of PLGA (75/25) the same as in example 1. Weighing the PLGA and the modified nano-hydroxyapatite according to the weight ratio of 100: 5, wherein the PLA-PEG (molecular weight of 40,000) accounts for 1 percent of the weight of the PLGA, dissolving the PLGA and the modified nano-hydroxyapatite in a dioxane-water solution system with the volume ratio of 87/13, wherein the PLGA concentration is 9 percent, carrying out initialization for 2 hours at-10 ℃, then carrying out solidification for 10 minutes, carrying out freeze drying for 72 hours, and carrying out annealing for 6 hours at 30 ℃ to obtain the PLGA (85/15)/HA compositeporous tissue engineering scaffold.
Example 6 PLGA (75/25) was synthesized as in example 1. PLGA (75/25) is dissolved in a dioxane-water solution system with the volume ratio of 87/13, the concentration of the PLGA is 9 percent, the PLGA is coarsened for 20min at 10 ℃ by adopting stepwise initialization, then the coarsening is carried out for 10min at 5 ℃, the solidification is carried out for 10min, the freeze drying is carried out for 72h, and the annealing at 30 ℃ is carried out for 6h, thus obtaining the PLGA (85/15)/HA composite porous tissue engineering scaffold.
Claims (4)
1. A polylactic acid-based/nano-hydroxyapatite composite scaffold material is characterized in that a composite of a polylactic acid polymer and modified nano-hydroxyapatite according to a weight ratio of 100: 1-100: 30 has a pore size of 100-450 μm, a communicated and regular macroporous structure inside, and a porosity of 78-98%.
2. The polylactic acid-based/nano-hydroxyapatite composite scaffold material according to claim 1, wherein the polylactic acid-based polymer is poly-L-lactic acid, poly-D, L-lactic acid or poly-L-lactic acid-glycolic acid copolymer.
3. The preparation method of the polylactic acid-based/nano-hydroxyapatite composite scaffold material according to claim 1, wherein the polylactic acid-based polymer and the nano-hydroxyapatite are firstly synthesized, the polylactic acid-based polymer is grafted on the surface of the nano-hydroxyapatite, and then the polylactic acid-based/nano-hydroxyapatite composite scaffold is prepared by adopting a thermally induced phase separation method, and the preparation method specifically comprises the following steps:
(1) preparation of polylactic acid polymer
Carrying out vacuum melting ring-opening polymerization on L-lactide and glycolide for 4-10 hours at 120-160 ℃ according to the molar ratio of 50: 50-90: 10 to prepare a poly L-lactic acid-glycolic acid copolymer, wherein the weight average molecular weight is 100,000-200,000; preparing polylactic acid materials poly L-lactic acid and poly D, L-lactic acid from L-lactide and D, L-lactide under the same conditions, wherein the weight average molecular weight is 100,000-300,000; and carrying out vacuum melt polymerization on L-lactide and polyethylene glycol for 4-10 hours at 120-160 ℃ to obtain the polylactic acid material poly L-lactide-polyethylene glycol, wherein the number average molecular weight of the polyethylene glycol is 2000-10000, the molar ratio of the L-lactide to the polyethylene glycol is 1: 4-4: 1, and the molecular weight of the poly L-lactide-polyethylene glycol is 50,000-100,000.
(2) Synthesis of nano-hydroxyapatite
Weighing calcium nitrate and diammonium phosphate according to the Ca/P ratio of 1.67 to prepare an aqueous solution, controlling the temperature to be room temperature and the pH value of a reaction system to be 10-11, carrying out chemical reaction on the aqueous solution to generate a colloidal HA precipitate, adding a polyethylene glycol aqueous solution with the weight concentration of 0.01-0.1% as a surfactant after the reaction is finished, aging the mixture at room temperature for 10-20 hours, repeatedly filtering, washing and drying the mixture to obtain nano hydroxyapatite;
(3) modification of nano-hydroxyapatite
① weighing nano-hydroxyapatite and L-lactide or a mixture of L-lactide and glycolide according to the mass ratio of 1: 0.5-1: 2, wherein the molar ratio of the former to the latter in the mixture of L-lactide and glycolide is 50: 50-90: 10, dissolving the L-lactide or the mixture of L-lactide and glycolide in a xylene solution at 40-55 ℃ to obtain a solution A, and dispersing the nano-hydroxyapatite in the xylene solution in a device for refluxing, condensing, stirring and introducing nitrogen to obtain a suspension B;
②, dropwise adding the solution A into the suspension B, and reacting for 8-24 h at 100-130 ℃;
③ dissolving and washing the reaction product with chloroform for several times, precipitating, and oven drying to obtain modified nanometer hydroxyapatite;
(4) preparation of polylactic acid base/nano hydroxyapatite porous scaffold by thermally induced phase separation method
The adopted solvent is a mixed solvent of dioxane and water, wherein the volume ratio of dioxane to water is 87/13,
①, weighing the polylactic acid polymer prepared in the step (1) and the modified nano-hydroxyapatite prepared in the step (3) according to the mass ratio of 100: 1-100: 30, and preparing a dioxane-water solution of the polymer according to the weight concentration of the polylactic acid polymer of 5-10%.
② adding the prepared polymer dioxane-water solution, nano-hydroxyapatite and poly L-lactide-polyethylene glycol copolymer or NaCl into a test tube, heating to 45-50 ℃ to dissolve the polymer and ultrasonically disperse the polymer, so that the nano-hydroxyapatite is uniformly dispersed in the polymer solution;
③ pouring the uniformly dispersed polymer solution into a mould, placing the mould at-20 ℃ to 30 ℃ for coarsening for 10min to 3h, then freezing the mould at-100 ℃ to-10 ℃ for 10min to 1h, then placing the mould in a freeze drier for drying for 48h to 96h at-50 ℃, and annealing the mould at 20 ℃ to 40 ℃ for 1h to 10h to obtain the polymer/nano-hydroxyapatite porous scaffold;
④ the polymer/nano hydroxyapatite bracket containing NaCl is washed with deionized water and then annealed to remove the pore-forming agent in the polymer bracket.
4. The method for preparing a polylactic acid-based/nano-hydroxyapatite composite scaffold material according to claim 3, characterized in that two cases are initially divided in the steps (4) - ③:
(1) the initialization is carried out in two steps, the initialization is carried out for 10min to 1h at the temperature of 5 ℃ to 30 ℃ and then for 10min to 2h at the temperature of minus 20 ℃ to 5 ℃;
(2) the initialization is carried out in one step, and the initialization is carried out for 10min to 3h at the temperature of between 20 ℃ below zero and 30 ℃.
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