CN117771433A - Bone repair composite material with gelatin microspheres capable of slowly releasing medicine and preparation method thereof - Google Patents
Bone repair composite material with gelatin microspheres capable of slowly releasing medicine and preparation method thereof Download PDFInfo
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- CN117771433A CN117771433A CN202311829044.0A CN202311829044A CN117771433A CN 117771433 A CN117771433 A CN 117771433A CN 202311829044 A CN202311829044 A CN 202311829044A CN 117771433 A CN117771433 A CN 117771433A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
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- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 claims description 3
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Landscapes
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a bone repair composite material with gelatin microspheres capable of slowly releasing drugs and a preparation method thereof, comprising the following steps: preparing a microfluidic channel by 3D printing and adopting tetramethyl disiloxane to carry out surface modification on the microfluidic channel; adding gelatin into phosphate buffer solution, dissolving, then adding antibiotics, and stirring uniformly to obtain a water phase; uniformly mixing mineral oil and a dispersing agent to obtain an oil phase; simultaneously feeding the water phase and the oil phase into the modified micro-fluid channel to obtain the drug-loaded gelatin microspheres; adding cross-linking agent into the medicine-carrying gelatin microsphere, freeze-drying to obtain gelatin medicine-packaging microparticle carrier for packaging medicine, mixing with calcium phosphate bone cement and solidifying so as to obtain the invented medicine-carrying gelatin microsphere.
Description
Technical Field
The invention belongs to the technical field of biomedical orthopaedics, and in particular relates to a bone repair composite material with gelatin microspheres capable of slowly releasing medicines and a preparation method thereof.
Background
Osteomyelitis refers to a disease in which bone tissue is infected with microorganisms to cause a series of inflammatory reactions, thereby destroying the bone tissue itself. At present, the total amount of patients with traumatic open fracture tends to rise year by year, and most of open wounds or bone surgery have the probability of suffering infection, once the patients are infected with osteomyelitis, as bacteria are easy to attach in bone nails or bone plates and artificial joints, the sites receiving bone surgery cannot completely kill the bacteria, so that the patients cannot achieve a successful healing effect, and thus the patients become a great difficulty in clinical treatment of orthopedics.
Treatment of osteomyelitis generally requires the use of antibiotic therapy for a long period of time. In injection or oral administration, systemic side effects that may be caused by the drug need to be considered, and it is difficult for the drug to penetrate ischemic or necrotic tissue to reach the site of infection. In order to avoid osteomyelitis, required antibiotic medicines are added to bone substitute materials during bone surgery, and after the materials are implanted into a human body, the antibiotics can maintain local areas at high concentration levels above the lower treatment limit for a long time at a sustained and slow release rate, so that osteomyelitis can be effectively prevented or treated.
Gelatin is a linear biopolymer polymerized from amino acids and can be extracted by boiling animal skin, tendons, ligaments, bones, etc. When water is added, the gelatin powder swells to form a solution, gradually changes from a sol to a gel (physical gel) during cooling, and returns after heating. Gelatin is often used as a drug release microparticle carrier due to its good biocompatibility and low cost, and according to previous clinical research experience, gelatin is easily soluble in water and has a high swelling degree, so that the drug microparticle carrier coated with gelatin is generally only suitable for release of short-acting drugs. To overcome this problem, chemical cross-linking agents are commonly used in clinic to cross-link gelatin microparticle carriers to control their overrun and hydrolysis rate, thereby achieving drug release and long-lasting effects.
Whereas calcium phosphate has good biocompatibility and is similar to the composition of human hard tissue and is being studied extensively. Wherein Calcium Phosphate Cement (CPC) is prepared by mixing a powder of tetracalcium phosphate and anhydrous dicalcium phosphate with water or an acidic solution to form a paste. The operation is convenient, and the bone defect area can be tightly filled with the bone defect. At normal body temperature, a hydration reaction similar to Portland Cement (Portland Cement) is performed in 5 to 60 minutes without generating exotherm, forming a bone filler material very similar to hydroxyapatite in human bone. After implanted in vivo, it can form good combination with bone tissue, and has good biocompatibility and degradability.
The conventional method for manufacturing microchip, such as engraving method, photolithography method, etc., can only be used for manufacturing planar or simple curved surface structure, and has rather limited manufacturing precision, high material cost and relatively slow manufacturing process.
In addition, the physical gelling process of the gelatin itself makes the preparation of gelatin microspheres more difficult.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention aims to provide a bone repair composite material with gelatin microspheres capable of slowly releasing drugs and a preparation method thereof, wherein the micro-fluid channel has low cost and high yield and is used for generating the gelatin microspheres with uniform particle size and drug release function. And further develops a novel slow-release medicament integrating three functions of orthopedic repair, treatment and regeneration, namely the gelatin microsphere and CPC bone cement stent composite material.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the preparation method of the bone repair composite material with the gelatin microspheres capable of slowly releasing the medicine comprises the following steps:
1) Preparing a microfluidic channel by 3D printing and adopting tetramethyl disiloxane to carry out surface modification on the microfluidic channel;
adding gelatin into phosphate buffer solution, dissolving, then adding antibiotics, and stirring uniformly to obtain a water phase;
uniformly mixing mineral oil and a dispersing agent to obtain an oil phase;
2) Simultaneously feeding the water phase and the oil phase into the modified micro-fluid channel to obtain the drug-loaded gelatin microspheres;
3) Adding a cross-linking agent into the drug-loaded gelatin microspheres, and freeze-drying to obtain a gelatin drug-encapsulated particulate carrier for encapsulating the drug;
4) Mixing the gelatin drug encapsulation particle carrier for encapsulating the drug with calcium phosphate bone cement, and solidifying to obtain the bone repair composite material with the gelatin microspheres capable of slowly releasing the drug.
Further, the specific process of carrying out surface modification on the micro-fluid channel by adopting tetramethyl disiloxane is as follows: the liquid tetramethyl disiloxane is brought into the reaction chamber by argon, plasma reaction is carried out under the action of plasma discharge, the tetramethyl disiloxane is decomposed into gaseous monomers, and the gaseous monomers form a plasma polymerized film on the microfluidic channel through polymerization reaction.
Further, the mass ratio of the gelatin, the phosphate buffer solution and the antibiotics is 0.5-1.5 g: 25-30 ml: 5-200 mg.
Further, the gelatin is pigskin gelatin or cow hide gelatin, and the antibiotic is vancomycin; the dissolution is carried out at 50-60 ℃; the mineral oil is paraffin oil, and the dispersing agent is Span 80 or Span60.
Further, the dosage ratio of the paraffin oil to the dispersant is 90-100 ml: 3-10 ml.
Further, the flow rates of the aqueous phase and the oil phase were set to 40. Mu.l/min and 100. Mu.l/min, respectively.
Further, the particle size of the drug-loaded gelatin microsphere is 50-300 mu m.
Further, the cross-linking agent is glutaraldehyde or geniposide.
Further, the dosage is 6-18 ml, and the concentration is 25%; the mixing mass ratio of the gelatin particles to the CPC bone cement is 1:1.
a bone repair composite having gelatin microspheres with sustained release drug prepared according to the method described above.
Compared with the prior art, the invention has the following beneficial technical effects:
compared with the traditional manufacturing of a micro-fluid channel for preparing gelatin microspheres, the preparation of the high-resolution micro-structure can be realized by adopting the photo-curing 3D printing technology, the size, the shape and the internal structure of a micro-fluid device can be accurately controlled, and the consistency and the accuracy of the medicine-carrying gelatin microspheres are ensured. The flexible design and rapid device preparation of the preparation method make the realization of the production of microspheres with different sizes easier, shorten the preparation time, improve the production efficiency, reduce the complexity and cost of the preparation process, and have the advantages of more flexibility, convenience, rapidness and low cost for the production of the drug-loaded gelatin microspheres. The invention uses tetramethyl disiloxane (TMDSO) to carry out surface modification on the micro-fluid channel, which can well overcome the physical gel process of gelatin, thereby making the preparation of the medicine-carrying gelatin microsphere with uniform particle size smoother.
The composite material prepared by the invention combines the advantages of the carrier microsphere and CPC bone cement, has good drug release capability, and can continuously release the drug for at least 30 days, thereby improving the treatment effect, simplifying the medication mode, reducing the toxic and side effects, ensuring that the material has the effect of drug treatment while repairing bone defects, and providing the space required by cell regeneration for the size of the holes generated after the degradation of the carrier microsphere.
Drawings
FIG. 1 is a flow chart for preparing a microfluidic channel;
FIG. 2 is a flow chart for preparing gelatin microspheres;
FIG. 3 is a pictorial view of a photo-cured 3D printing microfluidic channel;
FIG. 4 is a graph showing the contact angle before and after surface modification, wherein (a) is before modification and (b) is after modification;
FIG. 5 is a schematic illustration of monodisperse emulsion droplets;
FIG. 6 is an appearance of an orthopedic scaffold material after mixing gelatin microspheres with CPC bone cement prepared in this experiment; wherein, (a) is the shape of gelatin microspheres, and (b) is the shape of orthopedic scaffold materials after the gelatin microspheres and CPC bone cement are mixed;
FIG. 7 is a graph of absorbance at 280nm for vancomycin at various concentrations;
FIG. 8 is a graph of drug release rate of an orthopedic composite with drug-loaded gelatin microspheres and CPC bone cement formulated with drug-loaded gelatin microspheres over 24 hours and 30 days; wherein (a) is 24 hours and (b) is 30 days.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The invention discloses a preparation method of a bone repair composite material with gelatin microspheres capable of slowly releasing drugs based on an LCD photo-curing 3D printing micro-fluidic channel technology, which specifically relates to the following preparation process:
1) Microfluidic channels were prepared by 3D printing and surface modified. Wherein the type of 3D printing is LCD photo-curing 3D printing. Tetramethyl disiloxane (TMDSO) was used as the surface modified material.
Specifically, 1. Preparation of microfluidic channel:
the size and shape of the microfluidics were first determined and designed on demand using CAD2022 software.
The designed 3D model is exported as stl file (assuming name stl_1), the chiu BOX software is opened, stl_1 file is imported, print angle is selected, support is set, and exported again as stl file (assuming name stl_2).
And opening the HALOT BOX software, importing the stl_2 file, setting printing parameters and printing number, and slicing. And after confirming the error, leading out the cut file to the U disk, inserting the U disk to a photo-curing 3D printer (HALOT-SKY 2022), and selecting the corresponding file to start printing.
Taking out the micro-channel after printing, soaking in alcohol for 3-10min to remove residual photosensitive resin in the micro-channel, taking out and removing the support, putting into a curing washer (UW-02) to perform secondary curing (positive and negative curing for 5-10 min) to increase the hardness, and taking out after curing is finished.
2. Surface modification of microfluidic channels
The presence of gelatin results in poor wetting of the microfluidics by the gelatin due to the physical gelling process. When the water column of the dispersed phase (aqueous phase) is generated, it will adhere to the wall surface of the flow channel once it deviates from the center line of the flow channel, resulting in failure to continue to generate W/O type droplets. It is therefore desirable to surface modify microfluidic channels by:
the invention uses argon as carrier gas and tetramethyl disiloxane (TMDSO) as plasma polymerized material. The reaction chamber of the PECVD device is carried with the liquid TMDSO monomer raw material by argon, the current is regulated to enable the power to reach 100w-200w, and the plasma reaction is generated under the action of high-power plasma discharge, so that the TMDSO is decomposed into gaseous monomers (such as methyl and silicon dioxide). These gaseous monomers are transferred onto a substrate placed in a room temperature vacuum chamber, and a pinhole-free plasma polymerized film having an insulating property and a hydrophobic property is formed in a microfluidic channel by polymerization, which lasts about 30 minutes to 60 minutes.
2) Adding a certain amount of gelatin into phosphate buffer solution, mixing and dissolving at a certain temperature, adding a certain amount of vancomycin, stirring for a period of time to enable the vancomycin medicine to be uniformly dispersed in the gelatin solution, and filling the obtained solution into a syringe 1 to obtain a water phase.
Wherein the gelatin is pig skin gelatin (or cow hide gelatin) with a Bloom number of 150-300, and the dosage is 0.5-1.5 g. The amount of phosphate buffer used is 25-30 ml. The mixing temperature is 50-60 ℃. The dosage of vancomycin is 5-200 mg.
3) A solution obtained by uniformly mixing a certain amount of paraffin oil (or other mineral oil) with a dispersing agent is filled into the syringe 2 as an oil phase.
Wherein the dosage of paraffin oil is 90-100 ml. The dispersant is Span 80 (or other Span series such as Span 60) in an amount of 3-10 ml.
4) The injector 1 (water phase) and the injector 2 (oil phase) are arranged on a digital injection pump (micro injection pump), and the solution is sent into a micro fluid channel through a pipeline under the pushing of the injection pump by controlling the flow rate of the two phases, so as to generate the drug-carrying gelatin microsphere with a certain size.
Wherein the flow rates of the aqueous phase and the oil phase were set to 40. Mu.l/min and 100. Mu.l/min, respectively. The particle size of the drug-loaded gelatin microsphere is 50-300 mu m.
5) Transferring the collected liquid drops into ice bath with a certain temperature, adding a certain amount of cross-linking agent for cross-linking reaction for 60-70min, then adopting isopropanol for cleaning, collecting, and freeze-drying at-80 ℃ for 24-36h to obtain the gelatin drug encapsulation particle carrier for encapsulating the vancomycin drug.
Wherein the temperature of the ice bath is 3-5 ℃. The cross-linking agent is glutaraldehyde solution (or geniposide solution) with mass concentration of 25%, and the dosage is 6-18 ml.
6) Uniformly mixing a gelatin drug encapsulation particle carrier coated with a vancomycin drug with CPC (calcium phosphate bone cement) according to a certain proportion, and obtaining the bone repair composite material with gelatin microspheres capable of slowly releasing the drug after the bone cement is solidified.
Wherein, the mixing mass ratio of the gelatin particles and CPC bone cement is 1:1.
the invention can obtain the bone repair composite material with good drug slow release capability, can simplify the medication mode, reduce toxic and side effects, and has the effect of drug treatment while repairing bone defects.
Example 1
The preparation of bone repair composite material with gelatin microspheres capable of releasing drug involves the following processes.
1) Fabrication of microfluidic channels:
referring to fig. 1, the size and shape of the microfluidics is first determined and designed on demand using CAD2022 software.
Exporting the designed 3D model as a stl file (assuming that the name is stl_1), opening CHITU BOX software, importing the stl_1 file, selecting a good printing angle, setting a CHITU BOX support, and exporting the model as the stl file again (assuming that the name is stl_2).
And opening the HALOT BOX software, importing the stl_2 file, setting printing parameters and printing number, and performing HALOT BOX slicing. And after confirming the error, leading out the cut file to the U disk, inserting the U disk to a photo-curing 3D printer (HALOT-SKY 2022), and selecting the corresponding file to start printing.
And taking out the micro-channel after printing, soaking in alcohol for 5min to remove residual photosensitive resin in the micro-channel, fishing out and removing the support, putting the micro-channel into a curing cleaning machine (UW-02) for secondary curing (each of front and back surfaces is cured for 5 min) to increase the hardness of the micro-channel, and taking out the micro-channel after curing.
2) Surface modification of microfluidic channels
The presence of gelatin results in poor wetting of the microfluidics by the gelatin due to the physical gelling process. When the water column of the dispersed phase (aqueous phase) is generated, it will adhere to the wall surface of the flow channel once it deviates from the center line of the flow channel, resulting in failure to continue to generate W/O type droplets. It is therefore desirable to surface modify microfluidic channels by:
argon was used as carrier gas and tetramethyl disiloxane (TMDSO) was used as material for plasma polymerization. The liquid TMDSO monomer raw material is brought into a reaction chamber by argon, then the TMDSO liquid is changed into a gaseous monomer after evaporation and pyrolysis, and then the gaseous monomer is deposited for 30 minutes in a room temperature vacuum chamber by a plasma auxiliary effect, so that the pinhole-free plasma polymerized film with insulating property and hydrophobic property is formed.
3) Preparation of drug-loaded gelatin
First, 1.0 g of pigskin gelatin of 300Bloom number was added to 25 ml of Phosphate Buffer (PBS) and dissolved at 50℃to obtain a gelatin solution.
Then, 0.2 g of vancomycin drug (antibiotic) is added to the gelatin solution in a constant temperature water tank at 50 ℃ and mixed and stirred for a period of time, so that the vancomycin drug can be uniformly dispersed in the gelatin solution.
Then the gelatin solution (aqueous phase) containing the vancomycin drug is filled into the syringe 1 for use.
Referring to fig. 2, 100 ml of paraffin oil was uniformly mixed with 3 ml of dispersant Span 80 (oil phase), and then filled into a syringe 2 for use.
4) Preparation of medicine-carrying gelatin microsphere with uniform particle size
Syringe 1 (aqueous phase) and syringe 2 (oil phase) were placed on a microinjection pump and the solution was sent into the microfluidic channel through the tubing by pushing the syringe pump.
The collected beads were transferred to an ice bath at 4 degrees celsius, and 10 ml of a glutaraldehyde solution as a crosslinking agent was added to perform a crosslinking reaction for 65 minutes. And then removing the degreasing agent through an isopropanol cleaning step, collecting powder, and freeze-drying at-80 ℃ for 32 hours to obtain the gelatin drug encapsulation particle carrier for encapsulating the vancomycin drug.
5) Preparation of orthopaedics bracket material of gelatin microsphere and CPC bone cement
The prepared gelatin microparticles were mixed with medical grade biocompatible Calcium Phosphate Cement (CPC). When mixing, the microspheres and the bone cement are mixed according to the same proportion, and then the preparation of the material is completed after the bone cement is cured.
6. Drug release assay
Analysis was performed using an ultraviolet spectrometer. The antibiotic used in this experiment was vancomycin with an optimal detection wavelength of 280nm. Vancomycin solution at a concentration of 50mg/ml was used as a stock solution, and the solution at this concentration was diluted to 20, 40, 60, 80, 100, 150, 200, 300 and 400mg/ml (ppm). The linear relationship between concentration and absorbance can be obtained by measuring absorbance at 280nm absorption wavelength with ultraviolet spectrometer. The concentration of the released antibiotic drug can be calculated by the detection line formula.
Referring to fig. 3, it can be seen that the photo-cured 3D printing microfluidic channel is a physical image in which the inner channel width and depth are both 1mm.
Referring to fig. 4 (a) and (b), it can be seen that the contact angle before surface modification is 63.43 ° and the contact angle after surface modification is 90 °.
Referring to fig. 5, it can be seen that the formation of monodisperse droplets is a rapid formation of gelatin microspheres with uniform particle size by shearing action of the oil phase at both ends in the channels of the cross-junctions.
Referring to fig. 6 (a) and (b), it can be seen that the particle size of the gelatin microsphere morphology is 200 μm, the bone repair composite material after mixing the gelatin microsphere and CPC bone cement is spherical, and other shapes can be prepared, wherein the light yellow points in the figure are drug-loaded gelatin particles, and the white parts are CPC bone cement.
Referring to fig. 7, it can be seen that the detection line formula is y=0.004x+0.035, and the drug release concentration (x value) can be calculated from the absorbance value (y value) of 280nm carried over into the detection line formula by ultraviolet absorption spectrometry of released drug.
Referring to fig. 8 (a) and (b), it can be seen that the drug release rate profile of the orthopedic composite material with drug-loaded gelatin microspheres and CPC bone cement-loaded gelatin microspheres within 24 hours and 30 days is known: the release rate of the medicine of the orthopaedics composite material is lower than that of the single medicine carrying gelatin microsphere, which means that the release time of the medicine is longer than that of the single medicine carrying microsphere. The reason is that vancomycin released by the composite material can have bond decomposition with hydroxyapatite in bone cement, so that the drug release time is delayed, and the sustained performance of the drug release can last for at least 30 days.
Example 2
The preparation of bone repair composite material with gelatin microspheres capable of releasing drug involves the following processes.
1) Fabrication of microfluidic channels:
as in example 1;
2) Surface modification of microfluidic channels
As in example 1;
3) Preparation of drug-loaded gelatin
First, 0.5 g of pigskin gelatin of 300Bloom number was added to 28 ml of Phosphate Buffer (PBS) and dissolved at 50℃to obtain a gelatin solution.
Then, 0.1 g of vancomycin drug (antibiotic) is added to the gelatin solution in a constant temperature water tank at 60 ℃ and mixed and stirred for a period of time, so that the vancomycin drug can be uniformly dispersed in the gelatin solution.
Then the gelatin solution (aqueous phase) containing the vancomycin drug is filled into the syringe 1 for use.
Referring to fig. 2, 97 ml of paraffin oil was uniformly mixed with 8 ml of dispersant Span 80 (oil phase), and then filled into a syringe 2 for use.
4) Preparation of medicine-carrying gelatin microsphere with uniform particle size
Syringe 1 (aqueous phase) and syringe 2 (oil phase) were placed on a microinjection pump and the solution was sent into the microfluidic channel through the tubing by pushing the syringe pump. The flow rates of the aqueous phase and the oil phase were set to 40. Mu.l/min and 100. Mu.l/min, respectively.
The collected liquid beads are transferred into an ice bath at 5 ℃, and 18 ml of a cross-linking agent geniposide solution is added for cross-linking reaction for 60min. And then removing the degreasing agent through an isopropanol cleaning step, collecting powder, and freeze-drying at-80 ℃ for 28 hours to obtain the gelatin drug encapsulation particle carrier for encapsulating the vancomycin drug.
5) Preparation of orthopaedics bracket material of gelatin microsphere and CPC bone cement
The prepared gelatin microparticles were mixed with medical grade biocompatible Calcium Phosphate Cement (CPC). When mixing, the microspheres and the bone cement are mixed according to the same proportion, and then the preparation of the material is completed after the bone cement is cured.
Example 3
The preparation of bone repair composite material with gelatin microspheres capable of releasing drug involves the following processes.
1) Fabrication of microfluidic channels:
as in example 1;
2) Surface modification of microfluidic channels
As in example 1;
3) Preparation of drug-loaded gelatin
First, 1.2 g of bovine hide gelatin was added to 27 ml of Phosphate Buffer (PBS) and dissolved at 50 degrees celsius to obtain a gelatin solution.
Then, 0.005 g of vancomycin drug (antibiotic) was added to the gelatin solution in a constant temperature water tank at 55 degrees celsius and mixed and stirred for a period of time so that the vancomycin drug could be uniformly dispersed in the gelatin solution.
Then the gelatin solution (aqueous phase) containing the vancomycin drug is filled into the syringe 1 for use.
Referring to fig. 2, 95 ml of paraffin oil was uniformly mixed with 10 ml of dispersant Span 80 (oil phase), and then filled into a syringe 2 for use.
4) Preparation of medicine-carrying gelatin microsphere with uniform particle size
Syringe 1 (aqueous phase) and syringe 2 (oil phase) were placed on a microinjection pump and the solution was sent into the microfluidic channel through the tubing by pushing the syringe pump. The flow rates of the aqueous phase and the oil phase were set to 40. Mu.l/min and 100. Mu.l/min, respectively.
The collected beads were transferred to an ice bath at 4 degrees celsius, and a crosslinking reaction was performed by adding 6 ml of a crosslinking agent glutaraldehyde solution for 70 minutes. And then removing the degreasing agent through an isopropanol cleaning step, collecting powder, and freeze-drying at-80 ℃ for 36 hours to obtain the gelatin drug encapsulation particle carrier for encapsulating the vancomycin drug.
5) Preparation of orthopaedics bracket material of gelatin microsphere and CPC bone cement
The prepared gelatin microparticles were mixed with medical grade biocompatible Calcium Phosphate Cement (CPC). When mixing, the microspheres and the bone cement are mixed according to the same proportion, and then the preparation of the material is completed after the bone cement is cured.
Example 4
The preparation of bone repair composite material with gelatin microspheres capable of releasing drug involves the following processes.
1) Fabrication of microfluidic channels:
as in example 1;
2) Surface modification of microfluidic channels
As in example 1;
3) Preparation of drug-loaded gelatin
First, 1.5 g of pigskin gelatin of 300Bloom number was added to 30 ml of Phosphate Buffer (PBS) and dissolved at 50℃to obtain a gelatin solution.
Then, in a constant temperature water tank at 53 ℃, 0.05 g of vancomycin drug (antibiotic) is added to the gelatin solution and mixed and stirred for a period of time, so that the vancomycin drug can be uniformly dispersed in the gelatin solution.
Then the gelatin solution (aqueous phase) containing the vancomycin drug is filled into the syringe 1 for use.
Referring to fig. 2, 90 ml of paraffin oil was uniformly mixed with 3 ml of dispersant Span60 (oil phase), and then filled into a syringe 2 for use.
4) Preparation of medicine-carrying gelatin microsphere with uniform particle size
Syringe 1 (aqueous phase) and syringe 2 (oil phase) were placed on a microinjection pump and the solution was sent into the microfluidic channel through the tubing by pushing the syringe pump. The flow rates of the aqueous phase and the oil phase were set to 40. Mu.l/min and 100. Mu.l/min, respectively.
The collected beads were transferred to an ice bath at 3 degrees celsius, and a crosslinking reaction was performed by adding 12 ml of a solution of a crosslinking agent glutaraldehyde for 62 minutes. And then removing the degreasing agent through an isopropanol cleaning step, collecting powder, and freeze-drying at-80 ℃ for 24 hours to obtain the gelatin drug encapsulation particle carrier for encapsulating the vancomycin drug.
5) Preparation of orthopaedics bracket material of gelatin microsphere and CPC bone cement
The prepared gelatin microparticles were mixed with medical grade biocompatible Calcium Phosphate Cement (CPC). When mixing, the microspheres and the bone cement are mixed according to the same proportion, and then the preparation of the material is completed after the bone cement is cured.
The foregoing is illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the claims. The present invention is not limited to the above embodiments, and the specific structure thereof is allowed to vary. It is intended that all such variations as fall within the scope of the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Claims (10)
1. The preparation method of the bone repair composite material with the gelatin microspheres capable of slowly releasing the medicine is characterized by comprising the following steps:
1) Preparing a microfluidic channel by 3D printing and adopting tetramethyl disiloxane to carry out surface modification on the microfluidic channel;
adding gelatin into phosphate buffer solution, dissolving, then adding antibiotics, and stirring uniformly to obtain a water phase;
uniformly mixing mineral oil and a dispersing agent to obtain an oil phase;
2) Simultaneously feeding the water phase and the oil phase into the modified micro-fluid channel to obtain the drug-loaded gelatin microspheres;
3) Adding a cross-linking agent into the drug-loaded gelatin microspheres, and freeze-drying to obtain a gelatin drug-encapsulated particulate carrier for encapsulating the drug;
4) Mixing the gelatin drug encapsulation particle carrier for encapsulating the drug with calcium phosphate bone cement, and solidifying to obtain the bone repair composite material with the gelatin microspheres capable of slowly releasing the drug.
2. The method for preparing a bone repair composite material with gelatin microspheres capable of slowly releasing drugs according to claim 1, wherein the specific process of surface modification of the microfluidic channel by adopting tetramethyl disiloxane is as follows: the liquid tetramethyl disiloxane is brought into the reaction chamber by argon, plasma reaction is carried out under the action of plasma discharge, the tetramethyl disiloxane is decomposed into gaseous monomers, and the gaseous monomers form a plasma polymerized film on the microfluidic channel through polymerization reaction.
3. The method for preparing a bone repair composite material with gelatin microspheres capable of slowly releasing drugs according to claim 1, wherein the mass ratio of gelatin, phosphate buffer and antibiotics is 0.5-1.5 g: 25-30 ml: 5-200 mg.
4. The method for preparing a bone repair composite material with gelatin microspheres capable of slowly releasing drugs according to claim 1, wherein the gelatin is pigskin gelatin or cow hide gelatin and the antibiotic is vancomycin; the dissolution is carried out at 50-60 ℃; the mineral oil is paraffin oil, and the dispersing agent is Span 80 or Span60.
5. The method for preparing a bone repair composite material with gelatin microspheres capable of slowly releasing drugs according to claim 1, wherein the dosage ratio of paraffin oil to dispersant is 90-100 ml: 3-10 ml.
6. The method for preparing a bone repair composite with gelatin microspheres having a sustained release drug according to claim 1, wherein the flow rates of the aqueous phase and the oil phase are set to 40 μl/min and 100 μl/min, respectively.
7. The method for preparing a bone repair composite material with gelatin microspheres having sustained release of a drug according to claim 1, wherein the particle size of the drug-loaded gelatin microspheres is in the range of 50-300 μm.
8. The method for preparing a bone repair composite material with gelatin microspheres capable of slowly releasing drugs according to claim 1, wherein the cross-linking agent is glutaraldehyde or geniposide.
9. The method for preparing a bone repair composite material with gelatin microspheres capable of releasing drugs according to claim 1, wherein the dosage is 6-18 ml and the concentration is 25%; the mixing mass ratio of the gelatin particles to the CPC bone cement is 1:1.
10. a bone repair composite with gelatin microspheres of a slow release drug prepared according to the method of any one of claims 1-9.
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