CN113476660A - Preparation method of highly-bionic composite scaffold simulating tendon-bone interface - Google Patents
Preparation method of highly-bionic composite scaffold simulating tendon-bone interface Download PDFInfo
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- CN113476660A CN113476660A CN202110568305.2A CN202110568305A CN113476660A CN 113476660 A CN113476660 A CN 113476660A CN 202110568305 A CN202110568305 A CN 202110568305A CN 113476660 A CN113476660 A CN 113476660A
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Abstract
The invention discloses a preparation method of a simulated tendon-bone interface-based highly-bionic composite scaffold, and belongs to the technical field of preparation of tissue engineering bone scaffold materials. According to the invention, a highly bionic composite scaffold is constructed by combining the characteristics of a tendon-bone interface continuous gradient structure and a tissue engineering method, different growth factors are loaded on different simulation phases, and mesenchymal stem cells are planted to promote repair. Wherein the first layer adopts a porous bracket loaded with BMP-2-gelatin microspheres to simulate the bone phase of a tendon-bone interface and promote the regeneration of bone tissues; the second layer adopts composite hydrogel of sodium alginate loaded with TGF-beta 3 and collagen to simulate the gradual change phase of the tendon-bone interface; the outermost layer adopts polylactic acid oriented nano fiber to simulate tendon phase at the interface of the tendon and the bone, and has the functions of preventing tissue adhesion and resisting bacteria. The composite scaffold prepared by the method realizes the specific change of the aponeurosis interface heterotypic cell population and the matrix, shows the graded mechanical property and tissue induction property, and has application prospect in bone tissue engineering.
Description
Technical Field
The invention relates to a composite scaffold based on tissue composition of a tendon-bone interface and characteristics of a tissue engineering method, belongs to the technical field of preparation of tissue engineering bone scaffold materials, and particularly relates to a highly bionic scaffold constructed by simulating a tendon-bone interface continuous gradual change structure, which is expected to be used for regeneration and repair of tendon-bone tissues.
Background
Repair and reconstruction of large bone defects caused by trauma, infection, tumor, etc. are common problems in clinical medicine, while large bone defects are often accompanied by severe tendon and ligament tissue damage. The tendon-bone interface is a special transition region for transforming soft tissue into bone, and is composed of four layers of tissues including tendon, uncalcified fibrocartilage, calcified fibrocartilage and bone, and reconstruction and repair of the tendon-bone interface are slow and difficult due to the complex composition structure and special biomechanical function of the tendon-bone interface. Clinically, conventional conservative treatments or surgery are ineffective in achieving tendon healing and regeneration due to the lack of repair of the tendon to bone transition. The bioactive artificial bone which adopts a tissue engineering method to construct compound seed cells, scaffold materials and growth factors is considered to be one of the most effective methods for regenerating and repairing the tendon and bone tissues. However, at present, the types and the number of tissue engineering products which can be used in clinic are very limited, the functions and the structures of the products are relatively simple, and particularly, a highly bionic tissue engineering scaffold material which can simulate the continuous gradual change of a tendon-bone interface tissue structure and the diversity of cell differentiation is lacked, so that the prior art method cannot effectively reconstruct and integrate the scaffold material. We aim to prepare a multilayer bioactive scaffold simulating a tendon-bone interface continuous gradual change structure, and can realize high-degree biochemical simulation of the structure and the function, so that the regeneration and repair of tendon and bone tissues can be quickly and effectively realized.
The purpose of the invention is as follows: provides a preparation method of a highly bionic multilayer bioactive scaffold simulating a tendon-bone interface continuous gradual change structure.
The conception of the invention is as follows: based on the characteristics of the tissue composition and the tissue engineering method of a tendon-bone interface, the constructed scaffold material mainly comprises three layers: the first layer is a bone phase, is prepared by polylactic-co-glycolic acid (PLGA) and nano-hydroxyapatite (nHA), is added with gelatin microspheres loaded with BMP-2 and is planted with inter-marrow rechargeable stem cells (BMSCs), can provide mechanical support for large-section bone defect and induce cell osteogenic differentiation at the same time, and promotes bone regeneration; the second layer is a tendon phase, adopts a composite gel material prepared from collagen and sodium alginate and loads TGF-beta, and provides extracellular matrix and induction factors for the growth and differentiation of the planted tendon cells; the outermost layer is supposed to adopt a directionally arranged levorotatory polylactic acid (PLLA) nanofiber membrane to induce the directional differentiation of tenocytes, and has the functions of preventing tissue adhesion and resisting bacteria. Finally, the three layers are compounded to construct a multilayer bioactive scaffold simulating a tendon-bone interface continuous gradual change structure, so that the scaffold can comprehensively promote the repair and regeneration of the tendon-bone interface from structure, function and the like.
Disclosure of Invention
The purpose of the invention is mainly realized by the following technical routes:
(1) preparation of tendon-bone interface simulated bone phase: firstly, preparing BMP-2-loaded gelatin microspheres, dissolving gelatin in deionized water at room temperature, and adjusting the pH value of the solution to be neutral by using sodium hydroxide. Adding ethanol under stirring to replace water in gradient to form gelatin granule, adding glyoxal for crosslinking, and removing unreacted aldehyde group with 12% sodium metabisulfite water solution after reaction. The gelatin particles collected by centrifugation were washed twice with deionized water and then freeze-dried. And (3) putting the gelatin granules into an activating solution for activating for 1 h. The activated gelatin granules were dialyzed overnight in deionized water, centrifuged and freeze-dried, and then swollen with added aqueous solution of BMP-2 in PBS to load BMP-2. And finally, centrifuging, collecting, freezing and drying the gelatin microspheres loaded with the BMP-2, and storing for later use. Dissolving PLGA with chloroform, and after the polymer is completely dissolved, sieving chlorine with a predetermined massThe sodium hydroxide and the hydroxyapatite are dispersed in the solution, and a certain amount of gelatin microspheres carrying the BMP-2 are added and mixed evenly. The mixture was poured into a stent mold, left to stand at room temperature for 24 hours, demolded, and dried for 24 hours. The stent was soaked with deionized water for 2 days, with water changed every 4 hours and stirring continuously. And finally, taking out the sample, drying for 24 hours, and then drying for 24 hours in vacuum to obtain the PLGA/nHA porous scaffold carrying the BMP-2 gelatin microspheres. BMSCs cell suspension was seeded on scaffolds and placed at 37 ℃ with 5% CO2The wet culture box is used for culturing.
(2) Preparation of tendon-bone interface simulated tendon-bone gradual phase: sodium alginate with certain concentration is mixed with I type collagen solution by a vortex mixer, and TGF-beta 3 solution is added under the condition of low temperature. And dropwise adding a calcium chloride solution into the mixed solution in a vortex state to gelatinize the mixed solution, and standing the sample at 4 ℃ overnight to prepare the sodium alginate/I type collagen hydrogel. The composite hydrogel is freeze-dried and placed in a cell culture medium, and a Tenocyte (TCs) suspension is inoculated on the hydrogel. Placing at 37 ℃ and 5% CO2The humidified incubator of (1) for cultivation.
(3) Preparation of tendon-bone interface mimic tendon phase: PLLA was dissolved in chloroform to form a PLLA-chloroform solution which was filled into a 10mL syringe fitted with a blunt-ended needle. The resulting PLLA oriented microfiber membrane was spun by an electrospinning apparatus.
(4) Compounding different simulation phase materials: smearing a layer of sodium alginate/I type collagen mixed solution outside the PLGA/nHA porous scaffold carrying the BMP-2 microspheres, wrapping an electrostatic spinning membrane at the outermost part through the viscosity of the mixed solution, dropwise adding a calcium chloride solution to crosslink the calcium chloride solution into gel, turning over the scaffold after standing, dropwise adding calcium chloride to a hydrogel layer to crosslink the calcium chloride solution, and standing to obtain the three-layer composite scaffold.
The application of the invention is as follows: the invention is mainly used for preparing the highly bionic composite scaffold simulating the tendon-bone interface continuous gradual change structure, so that the repair and regeneration of the tendon-bone interface can be comprehensively promoted from the structure, the function and the like.
The invention has the advantages that: the method is simple in preparation process, green, environment-friendly and highly bionic. Each layer of the prepared high-bionic composite scaffold simulating the tendon-bone interface continuous gradual change structure is made of different biological materials to have different properties so as to simulate the structure and composition gradient of the tendon-bone interface, so that the phase specificity change of supporting interface heterotypic cell populations and matrixes is possible, and the graded mechanical properties are shown.
Drawings
FIG. 1. Observation of PLGA/nHA porous scaffold morphology by electron microscope
FIG. 2. Electron microscope observation of morphology of sodium alginate/type I collagen composite hydrogel
FIG. 3 Electron microscopy of PLLA oriented microfiber morphology
FIG. 4 shows morphology electron microscope observation of BMP-2-loaded gelatin microspheres
Figure 5. abstract figure
Detailed Description
The invented highly bionic tissue engineering scaffold is further elaborated in the following by combining the specific examples given by the inventor. However, the present invention is not limited to the scope of the following examples.
Example-preparation of composite scaffold bone phase:
(1) a10% (w/v) PLGA-chloroform solution was prepared by dissolving 0.5g PLGA (molecular weight 10 ten thousand) in 5ml chloroform.
(2) 2.5g of sodium chloride (the volume ratio of the sodium chloride to the PLGA is 5:1) which is sieved (200 mu m) and 0.1g of nano hydroxyapatite are dispersed in chloroform-PLGA solution, and a certain amount of BMP-2 carrying microspheres are added and stirred at high speed for 5 minutes until the mixture is mixed evenly.
(3) The mixture was injected into a scaffold mold and the injection time was not too fast and left to stand at room temperature for 24 hours after injection molding was completed.
(4) Demolding, drying for 24 hr, and volatilizing organic solvent.
(5) The stent was soaked with deionized water for 2 days, with water changed every 4 hours and stirring continuously.
(6) And finally, taking out the sample, drying the sample for 24 hours at 37 ℃ in a forced air dryer, and then placing the sample in a vacuum drying oven for drying for 24 hours at 37 ℃ to obtain the PLGA/nHA porous scaffold carrying the BMP-2 gelatin microspheres.
(7) Placing the support in a super clean bench, sterilizing for 1 hr under ultraviolet irradiation, addingGrowth medium 1 ml. After 1 hour, BMSCs cell suspension (10. mu.l, 1X 10)5Individual cells) are seeded onto the porous scaffold. After 1 hour, 1ml of growth medium was added and placed at 37 ℃ in 5% CO2Cultured in an incubator.
Example preparation of two composite scaffold tendon-bone progressive phases:
(1) weighing sodium alginate, and dissolving with deionized water to obtain 9.1mg/ml sodium alginate solution
(2) Weighing type I collagen, dissolving in 0.02N acetic acid solution to obtain type I collagen solution of 9.1mg/ml
(3) Sodium alginate was mixed with the type I collagen solution by vortex mixer (sodium alginate to type I collagen solution volume ratio 3:2) and pH was adjusted to 7.4 using NaOH (1 mol/L).
(4) TGF-. beta.3 was added at low temperature (4 ℃) and mixed well.
(5) The mixed solution was added dropwise to a calcium chloride solution (0.1mol/L) in a swirling state to gel the mixture.
(6) The samples were left overnight at 4 ℃ and the resulting type I collagen/sodium alginate hydrogel was lyophilized prior to cell inoculation.
(7) Sterilizing the lyophilized hydrogel in a superclean bench under ultraviolet irradiation, and mixing with TCs cell suspension (10 μ l, 1 × 10)5Individual cells) were inoculated onto the hydrogel, medium was added, and the mixture was incubated at 37 ℃ with 5% CO2Culturing in an incubator.
Example preparation of three composite scaffold tendon phases:
(1) 1.3g of PLLA (molecular weight: 30 ten thousand) was weighed and dissolved in 10ml of chloroform to form a 13% (w/v) PLLA-chloroform solution,
(2) the PLLA-chloroform solution was loaded into a 10mL syringe fitted with a 21 gauge blunt-ended needle and the syringe was mounted on an electrospinning device.
(3) The preparation parameters of the electrostatic spinning machine are set as follows: the temperature is 37 ℃, the voltage is 20kV, the flow rate is 1.5mL/h, the distance from the needle point to the electric rotating target is 10cm, and the rotating speed of the electric rotating target is 2000 rpm.
(4) The electrospinning apparatus was turned on for spinning for 10 minutes and the PLLA spinning was received using an electric rotating target. The machine was stopped and oriented PLLA nanofiber membranes were obtained.
Example preparation of a four composite scaffold:
(1) coating a layer of sodium alginate/I type collagen mixed solution with the thickness of about 1mm on the exterior of the BMP-2 microsphere-loaded PLGA/nHA porous scaffold, and coating the PLLA electrostatic spinning membrane on the outermost part through the viscosity of hydrogel.
(2) And (3) dripping calcium chloride solution (0.8mol/L) into the sodium alginate/I type collagen hydrogel layer for crosslinking, and standing for 5 min.
(3) Turning over the bracket, dripping calcium chloride (0.8mol/L) into the sodium alginate/I type collagen hydrogel layer for crosslinking, and standing for 5 min.
(4) And soaking the composite scaffold in calcium chloride solution for 2 min.
(5) Taking out the bracket, and sucking off the redundant calcium chloride solution on the surface to obtain the calcium chloride-based stent.
Example five preparation of BMP-2 loaded gelatin microspheres:
(1) 200mg of gelatin were dissolved in 20ml of deionized water until a clear solution was obtained. The pH of the solution was adjusted to 7.00 using 0.2mol/L NaOH.
(2) Adding ethanol under stirring to replace water in a gradient manner to form gelatin granules, wherein the final elution mixed solution is 100ml, and the volume ratio of ethanol to water is 65: 35. 50: 50. 35: 65.
(3) adding glyoxal for crosslinking, and stirring at room temperature for 10 h. After the reaction is finished, unreacted aldehyde groups in the glyoxal are removed by using a 12% sodium metabisulfite aqueous solution. Centrifuging at 14000rpm for 90min, washing the centrifuged gelatin granules twice with deionized water, and freeze-drying.
(4) The gelatin granules were activated for 1h in MES buffer (100mM, pH 6) to which N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 4mg/mL) and N-hydroxysulfosuccinimide sodium (NHS, 4mg/mL) had been added.
(5) The activated gelatin granules were dialyzed overnight in deionized water, centrifuged and freeze-dried, and reacted in PBS with added aqueous BMP-2 for 10h to load BMP-2.
(6) And (3) centrifuging, collecting and freeze-drying the gelatin microspheres loaded with the BMP-2 to obtain the gelatin microspheres.
Claims (9)
1. A preparation method of a highly bionic composite scaffold simulating a tendon-bone interface is characterized by comprising the following steps:
(1) preparation of tendon-bone interface simulated bone phase: dissolving PLGA with chloroform, after the polymer is completely dissolved, dispersing sieved sodium chloride and nano hydroxyapatite with preset mass in the solution, adding a certain amount of gelatin microspheres carrying BMP-2, and uniformly mixing. The mixture was injected into a teflon stent mold. After the injection molding was completed, the mixture was left standing at room temperature for 24 hours, and then released from the mold and dried for 24 hours. The scaffolds were soaked with deionized water for 2 days, with water changed every 4 hours and stirring continuously. The porous scaffolds were removed, dried in a forced air dryer for 24 hours, then placed in a vacuum oven for 24 hours, and stored in a vacuum desiccator to avoid degradation. Placing the scaffold into a super clean bench irradiation ultraviolet lamp, and inoculating the bone marrow mesenchymal stem cells (BMSCs) cell suspension onto the scaffold. Placing at 37 ℃ and 5% CO2Culturing in an incubator.
(2) Preparation of tendon-bone interface simulated tendon-bone gradual phase: sodium alginate with the same concentration and the I type collagen solution are mixed evenly by a vortex mixer, and TGF-beta 3 is added under the condition of keeping low temperature. And (3) dropwise adding a calcium chloride solution into the mixed solution in a vortex state to gelatinize the mixed solution, and standing the sample at 4 ℃ overnight to prepare the I type collagen/sodium alginate hydrogel. Placing the lyophilized hydrogel in a superclean ultraviolet lamp, inoculating Tenocyte (TCs) cell suspension onto the hydrogel, placing at 37 deg.C and 5% CO2Culturing in an incubator.
(3) Preparation of tendon-bone interface mimic tendon phase: PLLA was dissolved in chloroform to form a PLLA-chloroform solution, which was filled in a 10mL syringe equipped with a blunt-ended needle and spun by using an electrospinning device. The collected nanofiber membranes of oriented PLLA were heat treated at 60 ℃ for 2 hours.
(4) Compounding different simulation phase materials: coating a layer of sodium alginate/I type collagen mixed solution outside the PLGA/nHA porous scaffold carrying the BMP-2 microspheres, and wrapping the electrostatic spinning membrane at the outermost part through the viscosity of the mixed solution. And (3) dropwise adding a calcium chloride solution into the hydrogel layer for crosslinking, and standing for 5 min. Turning over the support, adding calcium chloride dropwise into the hydrogel layer for crosslinking, and standing for 5 min. And (3) soaking the composite stent in a calcium chloride solution for 2min, taking out the stent, and sucking off the redundant calcium chloride solution on the surface to obtain the composite stent.
2. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 1, when the PLGA/nHA porous scaffold is prepared by particle leaching method, the room temperature is 5-40 ℃, the temperature of the vacuum drying oven is 30-40 ℃, the pressure is (0.08 ± 0.01) MPa, and the drying temperature in the forced air dryer is 30-40 ℃.
3. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in the step 1, when PLGA/nHA porous scaffold is prepared by particle leaching method: the molecular weight of PLGA is 5-15 ten thousand, the using amount is 0.1-1.0 g, the concentration of PLGA solution is 5-15% (w/v), the using amount of chloroform is 1.0-10.0 mL, the particle size of NaCl is 100-200 um and 0.3-9.0 g, and the mass ratio of PLGA to NaCl is 1: 3-1: 9
4. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 1, the method for preparing the gelatin microsphere carrying BMP-2 comprises: 200mg of gelatin were dissolved in 20ml of deionized water at room temperature until a clear solution was obtained. The pH of the solution was adjusted to 7.00 using 0.2mol/L NaOH. Adding ethanol under stirring to replace water to form gelatin granule, adding glyoxal for crosslinking, and stirring at room temperature for 10 hr. After the reaction is finished, unreacted aldehyde groups in the glyoxal are removed by using a 12% sodium metabisulfite aqueous solution. The mixture was centrifuged at 14000rpm for 90min, and the centrifuged and collected gelatin particles were washed twice with deionized water and then freeze-dried. BMP-2 gelatin microspheres preparation, gelatin carboxyl groups in the addition of N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 4mg/mL) and N-hydroxysulfosuccinimide sodium (NHS, 4mg/mL) in MES buffer (100mM, pH 6) for 1h activation. The activated gelatin granules were dialyzed overnight in deionized water, centrifuged and freeze-dried, and then swollen for 10h in PBS with added aqueous BMP-2 solution to load BMP-2. Finally, the gelatin microsphere carrying the BMP-2 is collected by centrifugation and freeze-dried. Wherein, in 100ml of final elution mixed liquor, the volume ratio of ethanol to water is 13: 7-7: 13, the dosage of the drug-loaded microspheres is 10-40 mg.
5. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 2, the concentration of the sodium alginate/type I collagen hydrogel is 8.0-10.0 mg/ml, the volume ratio is 2: 3-3: 2, and the pH value of the mixture is adjusted to 7.0-7.6 by adding hydrochloric acid or sodium hydroxide. The experimental temperature is 0-10 ℃, the concentration of calcium chloride is 0.2-1.0 mol/L, and the concentration of TGF is 10-1000 ng/ml.
6. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in steps 1 and 2, the amount of cell suspension used is 100-1000 μ l, and the cell suspension is 1 x 105～2×106And (4) cells.
7. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 3, the technological parameters for preparing the oriented nanofiber membrane by using a coaxial electrospinning method are as follows: the temperature is 30-40 ℃, the voltage difference is 10-30 kV, the number of the needle is 17-25, the flow rate is 1.0-2.0 mL/h, the distance from the needle point to the electric rotating target is 8-30 cm, and the rotating speed of the electric rotating target is 1000-7000 rpm.
8. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 3, when the oriented nanofiber membrane is prepared by using a coaxial electrospinning method: the molecular weight of PLLA is 10-30 ten thousand, and the concentration of PLLA-chloroform solution is 10-20% (w/v).
9. The method for preparing a highly biomimetic composite scaffold simulating tendon-bone interface according to claim 1, wherein in step 4, the volume of the sodium alginate/type I collagen mixed solution used in the composition of different simulation phase materials is 50 to 200 μ L, the length of the electrospun membrane is 20 to 60mm, the width is 5 to 10mm, the thickness is 0.1 to 2mm, and the concentration of the calcium chloride solution is 0.6 to 1.0 mol/L.
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