Disclosure of Invention
The embodiment of the invention provides a shape memory nasal sinus stent and a preparation method thereof, wherein the shape memory nasal sinus stent has good compatibility with a human body, and the structure of the stent main body has good fitting property with the nasal cavity structure of the human body, so that the stent is not easy to shift or discharge.
The invention provides a shape memory sinus support, which comprises a support main body, and a nano medicine carrying fiber membrane and a hydrogel medicine carrying fiber membrane which are sequentially coated on the surface of the support main body, wherein the support main body is composed of a top fixed point and a plurality of support bars which are uniformly arranged along the circumferential direction of the top fixed point, one end of each support bar is connected with the top fixed point, and the other end of each support bar is diffused to the periphery of the direction far away from the extension line of the top fixed point, so that the support main body is in a bionic octopus structure;
The support main body includes temporary shape and initial shape, temporary shape with initial shape is bionical octopus structure, the size of initial shape's support main body is greater than the size of temporary shape's support main body, shape memory nasal sinus support can be changed into initial shape from temporary shape when receiving external stimulus.
Preferably, each support bar is composed of a first circular arc close to the top fixing point and a second circular arc far away from the top fixing point, the arc top of the second circular arc faces the extending line direction of the top fixing point, and the arc top of the first circular arc faces opposite to the arc top of the second circular arc.
Preferably, the chord lengths of the first arcs in the adjacent two support bars are different, and the chord lengths of the second arcs are also different.
Preferably, the bracket main body further comprises a plurality of top connecting pieces, wherein the top connecting pieces are positioned between two adjacent supporting bars and are connected with the top fixing points.
Preferably, the support body further comprises a plurality of absorbing parts, and the annular absorbing parts are arranged on the supporting bars and used for enhancing the adsorptivity of the support body and the nasal cavities.
More preferably, the absorbing member is composed of an annular absorbing disc and a columnar protrusion, and the columnar protrusion structure is located in the central area of the annular absorbing disc and connected with the supporting bar.
Preferably, the degradation rates of the nano drug-loaded fiber membrane, the hydrogel drug-loaded fiber membrane and the stent body are different from each other.
More preferably, the degradation rates of the hydrogel drug-loaded fiber membrane, the nano drug-loaded fiber membrane and the stent body are sequentially reduced.
Preferably, the preparation raw materials of the stent main body comprise shape memory racemized polylactic acid, biomedical polymer materials and plasticizers, wherein the biomedical polymer materials are polylactic acid, glycolic acid-lactic acid copolymer, polycaprolactone, polyethylene glycol, poly succinic acid co-succinate, polyglycolic acid, poly trimethylene carbonate, poly para-dioxanone or polyvinyl alcohol, and the plasticizers are vegetable oil-based plasticizers, vegetable-based plasticizers, bio-based plasticizers or citric acid ester plasticizers.
More preferably, the preparation raw material of the bracket main body further comprises a driving agent, and the driving agent is hollow copper sulfide particles.
Preferably, the nano drug-carrying fiber membrane is prepared from the raw materials of shape memory racemized polylactic acid, biomedical polymer materials, additives and therapeutic drugs, wherein the additives are at least one of centella asiatica, onion extracts, chitosan, silk fibroin or chitin, and the therapeutic drugs are at least one of mometasone furoate, triamcinolone acetonide, budesonide, fluticasone propionate or beclomethasone propionate.
More preferably, the hydrogel drug-loaded fibrous membrane comprises natural polymer materials and therapeutic drugs, wherein the natural polymer materials are at least one of chitosan, silk fibroin, sodium alginate, gelatin, hyaluronic acid, chitin or collagen.
In a second aspect, the present invention provides a method for preparing a shape memory sinus stent according to any one of the first aspect, the method comprising the steps of:
(1) Constructing a three-dimensional structure model of the initial shape of the stent main body according to the shape and the size of the nasal sinus structure;
(2) Mixing shape memory racemized polylactic acid, biomedical high molecular material and a thermal driving agent to prepare a shape memory polymer, and performing 4D printing according to the three-dimensional structure model by taking the shape memory polymer as a printing line to obtain a bracket main body with an initial shape;
(3) Preparing a nano drug-carrying fiber membrane and a hydrogel drug-carrying fiber membrane respectively by using an electrostatic spinning method, and sequentially coating the nano drug-carrying fiber membrane and the hydrogel drug-carrying fiber membrane on the surface of the stent main body to obtain the shape memory sinus stent with an initial shape;
(4) And heating the initial shape of the shape memory sinus support to a temperature above the glass transition temperature, applying a load, and cooling and shaping to obtain the temporary shape memory sinus support.
Compared with the prior art, the invention has at least the following beneficial effects:
According to the invention, the structure of the support main body is designed into a bionic octopus structure, the dimensional parameters of the support main body structure are adjusted according to the human body nasal sinus structure, so that the problem of displacement or discharge of the support main body can be effectively avoided, then, the nanometer medicine carrying fiber membranes and the hydrogel medicine carrying fiber membranes for bearing different treatment effects are sequentially arranged on the surface of the support main body, sequential medicine feeding and intelligent controlled release medicine feeding can be realized, the structure can be used for feeding medicine at the first time after operation, the hydrogel medicine carrying fiber membranes are firstly contacted with the inner wall of a human body nasal sinus when in use, the uncomfortable feeling and foreign body feeling of the human body can be greatly reduced, meanwhile, the problem of displacement or discharge of the support main body can be effectively avoided due to certain adhesiveness, the support main body has shape memory performance, the support main body is small in size and convenient to implant when in a temporary shape, the support main body can be converted from the temporary shape to the larger initial shape, and the shape memory effect of the inner wall of the nasal sinus can be completely reduced due to the influence of the inner wall of the nasal sinus in the shape memory process, and the nasal sinus feeling can be completely attached to the inner wall of a patient.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments, and all other embodiments obtained by those skilled in the art without making any inventive effort based on the embodiments of the present invention are within the scope of protection of the present invention.
As shown in fig. 1 to 4, the invention provides a shape memory sinus support, which comprises a support main body 100, and a nano medicine carrying fibrous membrane 200 and a hydrogel medicine carrying fibrous membrane 300 which are sequentially coated on the surface of the support main body 100, wherein the support main body 100 is composed of a top fixed point 101 and a plurality of support bars 102 which are uniformly arranged along the circumferential direction of the top fixed point 101, one end of each support bar 102 is connected with the top fixed point 101, and the other end of each support bar 102 is diffused towards the periphery far away from the extending line direction of the top fixed point 101, so that the support main body 100 is in a bionic octopus structure;
The support main body 100 comprises a temporary shape and an initial shape, the temporary shape and the initial shape are both bionic octopus structures, the size of the support main body 100 in the initial shape is larger than that of the support main body 100 in the temporary shape, and the shape memory sinus support can be converted from the temporary shape to the initial shape when being stimulated by the outside.
In the embodiment of the invention, firstly, the structure of the bracket main body 100 is designed into a bionic octopus structure, and the dimensional parameters of the structure of the bracket main body 100 are adjusted according to the structure of the human paranasal sinuses, so that the bracket main body 100 can be well attached to the inner wall of the human paranasal sinuses, and the problem of displacement or discharge of the bracket main body 100 is effectively avoided, and then, the electrostatic spinning nano medicine carrying fiber membrane 200 and the hydrogel medicine carrying fiber membrane 300 for carrying different therapeutic medicines are sequentially arranged on the surface of the bracket main body 100, wherein the electrostatic spinning nano medicine carrying fiber membrane 200 has a larger specific surface area and a unique reticular structure, so that the controlled release function of medicines can be realized, and the hydrogel medicine carrying fiber membrane 300 has high water content, high elasticity and high specific surface area, so that the uncomfortable feeling and foreign body feeling of the human bodies can be greatly reduced, and meanwhile, the problem of displacement or discharge of the bracket main body can be effectively avoided due to certain adhesiveness can be also effectively avoided, and the sequential medicine administration and intelligent controlled release medicines can be realized through the design of the structure.
Further, the stent body 100 has shape memory properties, and when the stent is in a temporary shape, the stent body 100 is small in size and convenient to implant, and when the stent body is stimulated by the outside, the stent body 100 can be changed from the temporary shape to an initial shape with large size, and in the shape memory recovery process, the stent body is influenced by resistance of the inner wall of the nasal sinus, so that the shape memory nasal sinus stent can be completely attached to the inner wall of the nasal sinus, and foreign body sensation of a patient is reduced.
As shown in fig. 2, according to some preferred embodiments, each support bar 102 is composed of a first arc 1021 near the top fixing point 101 and a second arc 1022 far from the top fixing point 101, wherein the arc top of the second arc 1022 faces the extension line direction of the top fixing point 101, and the arc top of the first arc 1021 faces opposite to the arc top of the second arc 1022.
As can be seen from fig. 2, in the embodiment of the present invention, by further setting the structure of each support bar 102, the support bar 102 is made up of two sections of circular arcs that are connected to each other, and the directions of the arc tops of the two sections of circular arcs are set to opposite directions, which is not only beneficial to making the support body better play the roles of supporting the paranasal sinuses, keeping the paranasal sinuses unobstructed, preventing the paranasal sinuses from adhering, keeping the sinus orifice open, continuously inhibiting inflammatory reaction, reducing postoperative adhesion, and the like, but also beneficial to ensuring the better fit between the support body and the inner wall of the paranasal sinuses of the human body.
According to some preferred embodiments, the chord lengths of the first arc 1021 and the second arc 1022 in two adjacent support bars 102 are different.
In the embodiment of the present invention, with continued reference to fig. 2 or fig. 3, the chord lengths corresponding to the two sections of arcs in the two adjacent support bars 102 are different, and further, in the two adjacent support bars 1023 and 1024, the chord length corresponding to the first arc 1021 near the top fixing point 101 in the support bar 1023 is smaller than the chord length corresponding to the first arc 1021 near the top fixing point 101 in the support bar 1024, and the chord length corresponding to the first arc 1021 far from the top fixing point 101 in the support bar 1023 is greater than the chord length corresponding to the first arc 1021 far from the top fixing point 101 in the support bar 1024, so that the fitting degree of the support main body 100 and the inner wall of the paranasal sinus of the human body is further enhanced.
It should be noted that, when the number of the supporting bars 102 in the bracket main body 100 is 6-12, the bracket main body 100 has excellent supporting performance under the condition of having better fitting degree with the inner wall of the nasal sinuses of the human body.
As shown in fig. 5, according to some preferred embodiments, the bracket body 100 further includes a plurality of top connectors 103, and the top connectors 103 are located between two adjacent support bars 102 and connected to the top fixing points 101.
In the embodiment of the invention, the top connecting pieces 103 are further arranged on the bracket main body 100, the number of the top connecting pieces 103 is less than the number of the supporting bars 102, and the top connecting pieces 103 are positioned at one end of the first arc 1021 of two adjacent supporting bars 102 and connected with the top fixing points 101, so that the upper end of the bracket main body 100 is designed in an umbrella shape, the mechanical property of the top end of the bracket main body 100 can be enhanced, and the supporting bars 102 are prevented from being broken.
Meanwhile, in order to make the stent main body 100 conform to the size of the human paranasal sinuses and have a better supporting effect on the paranasal sinuses inner wall, and simultaneously, the drugs in the two layers of drug-carrying fiber membranes on the surface of the stent main body 100 after being implanted into the human paranasal sinuses inner wall can be uniformly released to the paranasal sinuses inner wall, and the maximum diameter of the umbrella-shaped structure formed after the top connecting piece 103 in the embodiment of the invention is connected with each supporting bar 102 is 10mm.
With continued reference to fig. 5, according to some preferred embodiments, the stent body further includes a plurality of adsorbing members 104, where the adsorbing members 104 are disposed on the supporting bar 102 and used for enhancing the adsorptivity of the stent body to the nasal cavity, and the adsorbing members 104 are composed of an annular adsorption disk 1041 and a columnar boss 1042, and the columnar boss 1042 is structurally located in a central area of the annular adsorption disk 1041 and connected to the supporting bar 102.
In the embodiment of the present invention, further, by arranging the adsorption piece 104 comprising the annular adsorption disk 1041 and the columnar protrusion located in the central area of the annular adsorption disk 1041 on the support bar 102, not only the support main body 100 and the nano drug-carrying fiber membrane 200 and the hydrogel drug-carrying fiber membrane 300 can be better fixedly connected together, but also the support main body 100 and the inner wall of the paranasal sinus can still have better adsorptivity after the two layers of drug-carrying fiber membranes on the surface of the support main body 100 are degraded, so that the support main body 100 better supports the inner wall of the paranasal sinus to prevent falling. In the embodiment of the invention, the adsorption members 104 are arranged in the middle areas of at least four support bars 102 to achieve a better adsorption effect, and meanwhile, in order to avoid foreign body sensation of a human body, the annular adsorption plate 1041 and the cylindrical protrusions 1042 are 0.4mm-0.8mm higher than the surfaces of the support bars 102.
According to some preferred embodiments, the degradation rates of the nano drug-loaded fiber membrane, the hydrogel drug-loaded fiber membrane and the stent body are different from each other, and the degradation rates of the hydrogel drug-loaded fiber membrane, the nano drug-loaded fiber membrane and the stent body are sequentially reduced and sequentially degraded in vivo.
In the embodiment of the invention, the arrangement sequence of the bracket main body, the hydrogel medicine-carrying fiber membrane and the nano medicine-carrying fiber membrane and the degradation rate of each layer are designed, so that the hydrogel medicine-carrying fiber membrane and the nano medicine-carrying fiber membrane in the nasal sinus bracket can realize sequential medicine administration and intelligent controlled release medicine in different periods respectively. The method comprises the steps of firstly, carrying out a first time after the implantation of a nasal sinus stent, carrying out a drug-carrying fiber membrane on the outermost layer by using a soft hydrogel, wherein the drug-carrying fiber membrane on the outermost layer can realize accurate and low-dose effective drug administration at the first time after the operation so as to reduce the occurrence of postoperative inflammation, and can finish degradation in one month at the earliest, carrying out a drug-carrying nanofiber membrane on the middle layer in the second time after the implantation of the nasal sinus stent, further releasing the drug so as to treat the scar hyperplasia, and then finishing degradation in two months, and finally, carrying out the degradation of the two layers of drug-carrying fiber membranes on the surface of a stent main body, wherein the stent main body still can play the roles of supporting the inner wall of the nasal sinus to keep the nasal cavity smooth, preventing the adhesion of the nasal cavity, opening the sinus holding mouth, continuously inhibiting inflammatory reaction, reducing postoperative adhesion and intervention and the like, and finally finishing the degradation in three months.
To sum up, through the control to the design and degradation rate of each layer in the nasal sinus support to can make the nasal sinus support fully play effect in each period, and the nasal sinus support can degrade in the human body gradually, can not leave the nasal sinus support for a long time in the nasal sinus, reduce or eliminate the risk that potential complication formed, safer to the human body, also avoided the secondary operation to take out the support simultaneously, can effectively alleviate the illness, bring better experience.
According to some preferred embodiments, the preparation raw materials of the stent main body comprise shape memory racemized polylactic acid, biomedical high polymer materials and plasticizers, wherein the biomedical high polymer materials are polylactic acid, glycolic acid-lactic acid copolymer, polycaprolactone, polyethylene glycol, poly succinic acid co-succinate, polyglycolic acid, poly trimethylene carbonate, poly para-dioxanone or polyvinyl alcohol, the plasticizers are plant oil-based plasticizers, plant-based plasticizers, bio-based plasticizers or citric acid ester plasticizers, and the preparation raw materials of the stent main body further comprise driving agents, and the driving agents are hollow copper sulfide particles.
In the embodiment of the invention, the medical grade shape memory racemized polylactic acid is selected as the main material of the bracket main body to be mixed with the biomedical polymer material, so that the bracket main body has better shape memory performance and better compatibility with human body, and can reduce the occurrence of inflammatory reaction, thereby reducing foreign body sensation and uncomfortable feeling generated after the bracket main body is implanted into the human body. Considering that the glass transition temperature of the shape memory racemic polylactic acid is higher when the shape memory sinus stent is driven in a light-driven or heat-driven mode, the glass transition temperature of the stent main body is reduced to 40-42 ℃ by selecting the safe, nontoxic and degradable material as the plasticizer and mixing the plasticizer with the shape memory racemic polylactic acid and the biomedical polymer material in the embodiment of the invention, so that the uncomfortable feeling to a human body when the sinus stent is stimulated can be relieved. Meanwhile, when the light is used for driving, in order to enable the stent body to have a light response shape memory effect, hollow copper sulfide nano particles with high light-heat conversion efficiency are added into the preparation material of the stent body, and a light source for driving the shape memory sinus stent can select near infrared light.
It should be noted that, in the embodiment of the present invention, the sinus support may be converted by different external stimulus modes, and different driving modes include, but are not limited to, one or more of thermal driving, electric driving, magnetic driving, optical driving, acoustic driving, solution driving, ph driving, etc., where, considering comfort to a human body, the thermal driving or the optical driving mode is preferably selected as the driving mode of the sinus support.
According to some preferred embodiments, the shape memory racemic polylactic acid content in the stent body is 70-90% (e.g., may be 70%, 80% or 90%), the biomedical polymer material content is 10-30% (e.g., may be 10%, 20% or 30%), the plasticizer content is 5-20% (e.g., may be 5%, 10%, 15% or 20%), and the additive amount of the driving agent in the stent body is 0.2-0.5g (e.g., may be 0.2g, 0.3g, 0.4g or 0.5 g).
In the embodiment of the invention, the stent main body is prepared by mixing the shape memory racemized polylactic acid with proper types and proper contents, the biomedical polymer material and the plasticizer, so that the stent main body with good shape memory performance, biocompatibility and proper degradation rate can be prepared.
According to some preferred embodiments, the preparation raw materials of the nano drug-loaded fiber membrane comprise shape memory racemic polylactic acid, biomedical polymer materials, additives and therapeutic drugs, wherein the additives are at least one of centella asiatica, onion extracts, chitosan, silk fibroin or chitin, and the therapeutic drugs are at least one of mometasone furoate, triamcinolone acetonide, budesonide, fluticasone propionate or beclomethasone propionate.
In the embodiment of the invention, the special types of additives and therapeutic drugs are added into the nano drug-loaded fiber membrane in a period of postoperative wound healing, and the additives of the types can enable the nasal sinus stent to have excellent effects of promoting wound healing, resisting inflammation, resisting scar, inhibiting proliferation of fiber cells, promoting wound healing, promoting epithelialization and the like, and the nano drug-loaded fiber membrane can controllably release the therapeutic drugs in a postoperative recovery process so as to realize the treatment of nasosinusitis.
It should be noted that in the embodiment of the present invention, the additives and the therapeutic agents include, but are not limited to, the above-mentioned types, and the types may be selected according to the actual therapeutic effects.
According to some preferred embodiments, the content of the shape memory racemic polylactic acid in the nano drug-loaded fiber membrane is 80-95% (for example, 80%, 90% or 95%), the content of the biomedical polymer material is 5-20% (for example, 5%, 15% or 20%), the content of the additive is 5-10% (for example, 5%, 8% or 10%), and the content of the therapeutic drug in the nano drug-loaded fiber membrane is 350-450 μg (for example, 350 μg, 400 μg or 500 μg).
In the embodiment of the invention, the nanometer medicine carrying fiber membrane is prepared by adopting the shape memory racemized polylactic acid, biomedical polymer material, additive and therapeutic drug with proper types and proper content and adopting an electrostatic spinning method, thereby being beneficial to preparing the nanometer medicine carrying fiber membrane with better biocompatibility, simultaneously being beneficial to realizing controllable release of the drug in proper degradation time of the nanometer medicine carrying fiber membrane, thereby treating the scar hyperplasia period and playing the roles of resisting scar and inhibiting inflammation.
According to some preferred embodiments, the hydrogel drug-loaded fibrous membrane is prepared from natural polymer materials and therapeutic drugs, wherein the natural polymer materials are at least one of chitosan, silk fibroin, sodium alginate, gelatin, hyaluronic acid, chitin or collagen.
In the embodiment of the invention, the hydrogel drug-carrying fiber membrane is firstly contacted with the inner wall of the nasal sinuses in the inflammatory phase in the postoperative wound healing process, and is softer, so that the discomfort and foreign body sensation of postoperative patients can be relieved to a great extent, and the natural polymer material is added in the preparation process of the hydrogel drug-carrying fiber membrane, so that the nasal sinuses bracket has the excellent effects of stopping bleeding, accelerating wound healing of human bodies, reducing postoperative inflammation, preventing postoperative adhesion and the like, and better adhesion can be given to the nasal sinuses bracket, thereby further avoiding the problems of shifting or discharging the nasal sinuses bracket.
According to some preferred embodiments, the content of the natural polymer material in the hydrogel drug-loaded fibrous membrane is 80-100% (e.g., 80%, 90% or 100%), and the content of the therapeutic drug in the hydrogel drug-loaded fibrous membrane is 200-300 μg (e.g., 200 μg, 250 μg or 300 μg).
In the embodiment of the invention, the hydrogel drug-loaded fiber membrane is prepared by mixing natural polymer materials with proper types and proper contents and therapeutic drugs, so that the hydrogel drug-loaded fiber membrane with good biocompatibility and adhesion performance is prepared. Meanwhile, the hydrogel drug-loaded fibrous membrane is beneficial to realizing controllable release of drugs in a proper degradation time, so that the hydrogel drug-loaded fibrous membrane is used for treating an inflammatory phase, and has the effects of stopping bleeding, accelerating wound healing of a human body, reducing inflammation after an operation, preventing postoperative adhesion and the like.
Meanwhile, in the embodiment of the invention, a certain amount of additive can be added into the hydrogel drug-loaded fiber membrane according to actual treatment requirements, the additive can be at least one of centella asiatica, onion extract, chitosan, silk fibroin or chitin, and the content of the additive can be 5-20%.
The embodiment of the invention also provides a preparation method of the shape memory sinus stent, which comprises the following steps:
(1) Constructing a three-dimensional structural model of the initial shape of the stent main body according to the specific structural shape and size of the nasal sinuses of the patient;
(2) Mixing shape memory racemized polylactic acid with biomedical high molecular materials to prepare a shape memory polymer, and performing 4D printing according to the three-dimensional structure model by taking the shape memory polymer as a printing line to obtain a stent main body with an initial shape;
(3) Preparing a nano drug-carrying fiber membrane and a hydrogel drug-carrying fiber membrane respectively by using an electrostatic spinning method, and sequentially coating the nano drug-carrying fiber membrane and the hydrogel drug-carrying fiber membrane on the surface of the stent main body to obtain the shape memory sinus stent with an initial shape;
(4) And heating the initial shape of the shape memory sinus support to a temperature above the glass transition temperature, applying a load, and cooling and shaping to obtain the temporary shape memory sinus support.
In the embodiment of the invention, in the use process, before the shape memory nasal sinus stent is implanted into the nasal cavity, temperature, electromagnetic or illumination stimulus is applied to the shape memory nasal sinus stent (shown in fig. 3 or 5) with an initial shape, the nasal sinus stent with a larger size is converted into the nasal sinus stent with a smaller size and a temporary shape through external force (shown in fig. 4 or 6), then the nasal sinus stent with a temporary shape is implanted into the nasal sinus, and external stimulus is applied to the nasal sinus stent with a temporary shape, so that the nasal sinus stent with a temporary shape is converted into the nasal sinus stent with an initial shape until the nasal sinus stent is attached to the nasal mucosa of a human body.
According to some preferred embodiments, the preparation method of the nano drug-loaded fiber membrane comprises the steps of adding the shape memory racemized polylactic acid and biomedical polymer material into an organic solvent, stirring and mixing uniformly to obtain a mixed solution, sequentially adding an additive and a therapeutic drug into the mixed solution, stirring and mixing uniformly to obtain a spinning solution, injecting the spinning solution into a syringe, and preparing the nano drug-loaded fiber membrane by using an electrostatic spinning method, wherein the organic solvent is dichloromethane;
The preparation method of the hydrogel drug-loaded fiber membrane comprises the following steps of adding a natural polymer material into an organic solvent, stirring and mixing uniformly to obtain a mixed solution, adding a therapeutic drug into the mixed solution, stirring and mixing uniformly to obtain a spinning solution, injecting the spinning solution into an injector, and preparing the natural hydrogel by using an electrostatic spinning method;
Adding a synthetic polymer material (freeze-dried gelatin-hydroxy benzene propionic acid) into an organic solvent, stirring and mixing uniformly to obtain a mixed solution, adding a therapeutic drug into the mixed solution, stirring and mixing uniformly to obtain a spinning solution, injecting the spinning solution into a syringe, and preparing into a synthetic hydrogel by using an electrostatic spinning method;
And mixing and crosslinking the natural hydrogel and the synthetic hydrogel at room temperature to obtain the hydrogel drug-loaded fiber membrane.
In the embodiment of the invention, the nano drug-carrying fiber membrane and the hydrogel drug-carrying fiber membrane are prepared by adopting an electrostatic spinning process in the prior art, and parameters in the 4D printing process are regulated according to practical application. However, when the hydrogel drug-loaded fiber membrane is prepared by using the electrostatic spinning method, the crosslinking reaction of related chemical groups in the fiber can be promoted by mixing the synthetic hydrogel fiber with the natural hydrogel fiber, so that the problem that the mechanical property of the obtained hydrogel drug-loaded fiber membrane is poor due to the fact that the natural polymer material is added into the preparation material of the hydrogel drug-loaded fiber membrane can be effectively avoided.
It should be noted that the freeze-dried gelatin-hydroxy phenylpropionic acid in the examples of the present invention can be obtained by purchase.
Meanwhile, considering the differences of treatment periods and drug loading, the thickness of the hydrogel drug-loaded fiber membrane is smaller than that of the nano drug-loaded fiber membrane in the embodiment of the invention, more specifically, the thickness of the hydrogel drug-loaded fiber membrane is 0.2-0.3mm, and the thickness of the nano drug-loaded fiber membrane is 0.4-0.5mm.
In order to more clearly illustrate the technical scheme and advantages of the invention, a shape memory sinus stent and a preparation method thereof are described in detail below through several embodiments.
Example 1:
(1) Constructing a three-dimensional structure model of the initial shape of the stent main body by using modeling software Solidworks according to the shape and the size of the nasal sinus structure, and slicing the model by using Cura software to obtain a 3D printing structure model capable of performing printing operation;
(2) Adding 85g of shape memory racemic polylactic acid, 5g of plasticizer (tributyl citrate) and 10g of biomedical polymer material (polycaprolactone) into an extruder, uniformly mixing to obtain a shape memory polymer, preheating the extruder to 160 ℃, adjusting the speed of a tractor, pulling out an extrusion line with a wire diameter of 1.75mm, mounting the collected extrusion line onto a 3D printer, introducing a constructed 3D printing structure model file into the 3D printer, performing printing operation by using the FDM printer, and setting printing parameters (the temperature is 190 ℃, the speed is 50% and the fan speed is 100%) to obtain a bracket main body with a 4D printing initial shape;
(3) Preparing a nano medicine carrying fibrous membrane, namely adding 8g of shape memory racemic polylactic acid, 1.5g of biomedical polymer material (polycaprolactone) and 0.5g of additive (centella asiatica) into an organic solvent (dichloromethane), stirring and uniformly mixing for 12 hours to prepare a mixed solution with the concentration of 13wt%, adding 400 mu g of therapeutic medicine (mometasone furoate) into 100mL of the organic solvent (dichloromethane), stirring and uniformly mixing to obtain a medicine solution, and stirring the medicine solution and the mixed solution for 4 hours to obtain a medicine carrying spinning solution with uniform mixing. And pouring 10mL of drug-loaded spinning solution into the injector, starting a power supply, setting the voltage to be 14kV, the propulsion speed to be 3mL/h, the receiving distance to be 20cm, the temperature to be 25 ℃ and the humidity to be 20%, and obtaining the nano drug-loaded fiber membrane.
Preparing a hydrogel drug-loaded fiber membrane:
Dissolving 1.5g of synthetic polymer material (freeze-dried gelatin-hydroxy phenylpropionic acid) in 10mL of mixed solvent of hexafluoroisopropanol and ultrapure water (9:1) to obtain a mixed solution, adding 250 mug of therapeutic drug (mometasone furoate) into the mixed solution, mixing to obtain an electrostatic spinning solution, placing the electrostatic spinning solution in a 10mL syringe installed on a microinjection pump, setting the voltage at 18kV at a rate of 3mL/h, and placing a drum collector (diameter 10cm, width 20cm and rotating speed 1000 n/min) at a position 18cm away from a nozzle of the injector to collect random microfibers to obtain synthetic hydrogel;
Dissolving 1.5g of natural polymer material (freeze-dried gelatin) in 10mL of mixed solvent of hexafluoroisopropanol and ultrapure water (9:1) to obtain a mixed solution, adding 250 mug of therapeutic drug (mometasone furoate) into the mixed solution, mixing to obtain an electrostatic spinning solution, placing the electrostatic spinning solution in a 10mL syringe installed on a microinjection pump, setting the voltage at 18kV,3mL/h, placing a drum collector (with the diameter of 10cm, the width of 20cm and the rotating speed of 1000 n/min) at the position 18cm away from a nozzle of an oil sprayer to collect random microfibers to obtain natural hydrogel, and mixing and crosslinking the synthesized hydrogel and the natural hydrogel at room temperature for 3 hours to obtain the hydrogel drug-carrying fiber membrane.
Sequentially coating the nano drug-carrying fiber membrane and the hydrogel drug-carrying fiber membrane on the surface of the stent main body to obtain the shape memory sinus stent with an initial shape;
(4) The initial shape of the shape memory sinus support is heated to be above the glass transition temperature Tg by the rising temperature, when the surface temperature of the sinus support is higher than the Tg, the support body is softened, at the moment, load is applied to the softened sinus support, the sinus support is folded to a temporary shape towards the middle, the heat source is separated, the surface temperature of the sinus support is reduced to be below the Tg, the shape of the sinus support can be fixed after the load is removed after the sinus support is kept stand for a few minutes, and the temporary shape of the shape memory sinus support is obtained.
Example 2:
(1) Constructing a three-structure model of the initial shape of the stent main body by using modeling software Solidworks according to the shape and the size of the nasal sinus structure, and slicing the model by using Cura software to obtain a 3D printing structure model capable of performing printing operation;
(2) Adding 85g of shape memory racemic polylactic acid, 10g of biomedical polymer material (polycaprolactone), 5g of plasticizer (tributyl citrate) and 0.2g of driving agent (hollow copper sulfide nano particles) into an extruder, uniformly mixing to obtain a shape memory polymer, preheating the extruder to 160 ℃, adjusting the speed of the tractor, pulling out an extrusion line with a wire diameter of 1.75mm, mounting the collected extrusion line on a 3D printer, introducing the constructed 3D printing structure model file into the 3D printer, performing printing operation by using the FDM printer, and setting printing parameters (the temperature is 190 ℃, the speed is 50% and the fan speed is 100%) to obtain a bracket main body with a 4D printing initial shape;
(3) Preparing a nano medicine carrying fibrous membrane, namely adding 8g of shape memory racemic polylactic acid, 1.5g of biomedical polymer material (polycaprolactone) and 0.5g of additive (centella asiatica) into an organic solvent (dichloromethane), stirring and uniformly mixing for 3 hours to prepare a mixed solution with the concentration of 13wt%, adding 500 mu g of therapeutic medicine (mometasone furoate) into 100mL of the organic solvent (dichloromethane), stirring and uniformly mixing to obtain a medicine solution, and stirring the medicine solution and the mixed solution for 4 hours to obtain a medicine carrying spinning solution which is uniformly mixed. And pouring 10mL of drug-loaded spinning solution into the injector, starting a power supply, setting the voltage to be 14kV, the propulsion speed to be 3mL/h, the receiving distance to be 20cm, the temperature to be 25 ℃ and the humidity to be 20%, and obtaining the nano drug-loaded fiber membrane.
Preparing a hydrogel drug-loaded fiber membrane:
1.5g of a synthetic polymer material (freeze-dried gelatin-hydroxy phenylpropionic acid) was dissolved in 10mL of a mixed solvent of hexafluoroisopropanol and ultrapure water (9:1) to obtain a mixed solution, and the electrospinning solution was placed in a10 mL syringe mounted on a microinjection pump, the voltage was set at 18kV, the rate of 3mL/h, and a drum collector (diameter 10cm, width 20cm, rotation speed 1000 n/min) was placed at 18cm from the nozzle of the injector to collect the random microfibers to obtain a synthetic hydrogel;
Dissolving 1.5g of natural polymer material (freeze-dried gelatin) in 10mL of mixed solvent of hexafluoroisopropanol and ultrapure water (9:1) to obtain mixed solution, adding 250 mug of therapeutic drug (mometasone furoate) into the mixed solution, mixing to obtain electrostatic spinning solution, placing the electrostatic spinning solution in a 10mL syringe installed on a microinjection pump, setting the voltage at 18kV,3mL/h, placing a drum collector (diameter 10cm, width 20cm and rotating speed 1000 n/min) at 18cm from a nozzle of an oil sprayer to collect random microfibers to obtain natural hydrogel, mixing and crosslinking the synthesized hydrogel and the natural hydrogel at room temperature for 3h to obtain a hydrogel drug-carrying fiber membrane;
sequentially coating the nano drug-carrying fiber membrane and the hydrogel drug-carrying fiber membrane on the surface of the stent main body to obtain the shape memory sinus stent with an initial shape;
(4) The shape memory sinus support of the initial shape is heated to be above the glass transition temperature Tg through near infrared light irradiation, the support body is softened after the surface temperature of the sinus support is higher than Tg, at the moment, load is applied to the softened sinus support, the sinus support is folded to be in a temporary shape towards the middle, the light source is separated, the surface temperature of the sinus support is reduced to be below Tg, the shape of the sinus support can be fixed after the load is removed after the sinus support is kept stand for a few minutes, and the shape memory sinus support of the temporary shape is obtained.
Experiments show that the shape memory sinus support prepared in the embodiments 1-2 is controllable in degradation rate, the hydrogel drug-carrying fiber membrane at the outermost layer can be degraded in one month at the earliest, the drug-carrying nanofiber membrane at the middle layer can be degraded in the second month, and the support main body at the innermost layer is degraded finally, so that the sinus support fully plays a role in each period, and the sinus support can be gradually degraded in a human body, the sinus support cannot be left in the sinus for a long time, the risk of potential complication formation is reduced or eliminated, the preparation is safer for the human body, the support is prevented from being taken out by a secondary operation, the pain can be effectively relieved, and better experience is brought.
It should be noted that the above-mentioned embodiments are merely for illustrating the technical solution of the present invention, and not for limiting the same, and although the present invention has been described in detail with reference to the above-mentioned embodiments, it should be understood by those skilled in the art that the technical solution described in the above-mentioned embodiments may be modified or some technical features may be equivalently replaced, and these modifications or substitutions do not make the essence of the corresponding technical solution deviate from the spirit and scope of the technical solution of the embodiments of the present invention.