CN113499476B - Conductive hydrogel scaffold material for treating and promoting bone regeneration in cooperation with osteosarcoma, preparation method and application thereof - Google Patents

Conductive hydrogel scaffold material for treating and promoting bone regeneration in cooperation with osteosarcoma, preparation method and application thereof Download PDF

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CN113499476B
CN113499476B CN202110784475.4A CN202110784475A CN113499476B CN 113499476 B CN113499476 B CN 113499476B CN 202110784475 A CN202110784475 A CN 202110784475A CN 113499476 B CN113499476 B CN 113499476B
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pvp
ppy
gelma
osteosarcoma
scaffold material
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CN113499476A (en
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赵庆华
侯田会
胡硕
吴小峰
周承豪
王刚阳
宋滇文
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Shanghai First Peoples Hospital
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Abstract

The invention discloses a conductive hydrogel scaffold material for treating and promoting bone regeneration in cooperation with osteosarcoma, a preparation method and application thereof, wherein the scaffold material comprises the following components in parts by weight: GelMA/oxide hydrogel, PVP-PPy conductive polymer, mechanical property enhancing particles and bone growth promoting elements; wherein, according to the mass ratio GelMA/oxide hydrogel: PVP-PPy conductive polymer: mechanical property-enhancing particles: bone growth promoting elements (11-40): (0.01-1): (0.5-2): (0.5 to 3). The GelMA/oxide hydrogel, the MMT-Sr particles and the PVP-PPy conducting polymer are polymerized, the GelMA/oxide hydrogel can load drugs, the PVP-PPy conducting polymer has excellent photo-thermal conversion performance, and the material can be used as a preparation material for a scaffold for promoting bone tissue regeneration.

Description

Conductive hydrogel scaffold material for treating and promoting bone regeneration in cooperation with osteosarcoma, preparation method and application thereof
Technical Field
The invention relates to the field of biological materials, in particular to a conductive hydrogel scaffold material for treating osteosarcoma and promoting bone regeneration, a preparation method and application thereof.
Background
Osteosarcoma is the most common primary malignant bone tumor, a common cancer type in children and adolescents. Osteosarcoma is a malignant tumor that originates from mesenchymal tissue, and malignant spindle-shaped stromal cells can produce osteoid tissue. Surgery allows direct resection of the tumor, but does not avoid recurrence or bone defects caused by osteosarcoma. The rise of combined surgery and chemotherapy reduces the risk of recurrence in osteosarcoma patients to some extent. Chemotherapy has long been the standard treatment for osteosarcoma. However, the rapid metabolism of small molecule drugs, side effects of chemotherapy, such as allergy, gastrointestinal toxicity, lead to poor therapeutic efficacy. In addition, osteosarcoma and surgical resection may result in exceeding the limits of bone self-repair, which poses significant challenges for reconstructing structural and functional integrity. Therefore, there is a need to simultaneously meet the practical requirements of tumor tissue resection and provide an osteogenic microenvironment. Currently, clinical treatment of malignant bone tumors still faces challenges. There is an urgent need to develop a new conductive hydrogel scaffold material that synergizes osteosarcoma treatment and promotes bone regeneration, to reduce side effects of chemotherapeutic drugs for osteosarcoma treatment and simultaneously promote bone tissue regeneration.
Disclosure of Invention
The invention aims to reduce side effects of chemotherapeutic drugs for osteosarcoma treatment and promote bone tissue regeneration, and provides a conductive hydrogel scaffold material for cooperating osteosarcoma treatment and bone regeneration promotion, a preparation method and application thereof.
In order to achieve the above objects, the present invention provides a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion, comprising: GelMA/oxide hydrogel, PVP-PPy conductive polymer, mechanical property enhancing particles and bone growth promoting elements; wherein, according to the mass ratio GelMA/oxide hydrogel: PVP-PPy conductive polymer: mechanical property-enhancing particles: bone growth promoting elements (11-40): (0.01-1): (0.5-2): (0.5 to 3).
Optionally, the mechanical property enhancing particles are any one or more of montmorillonite nanoparticles, hectorite nanoparticles, halloysite nanotubes and sepiolite nanoparticles.
Optionally, the bone growth promoting element is any one of strontium and silicon, or a combination of strontium and silicon.
Optionally, the conductive hydrogel scaffold material is loaded with drugs for treating osteosarcoma on the surface and/or inside.
The invention also provides a preparation method of the conductive hydrogel scaffold material for treating and promoting bone regeneration in cooperation with osteosarcoma, which comprises the following steps:
step 1, preparing montmorillonite-strontium particles: ultrasonically dispersing montmorillonite into distilled water, adding strontium chloride hexahydrate to obtain montmorillonite-strontium solution, stirring and centrifuging to obtain montmorillonite-strontium particles; wherein, in the montmorillonite-strontium solution, the mass concentration of the montmorillonite is 0.5-2.0%, and the mass concentration of the strontium chloride is 1.0-5.0%;
step 2, preparing a PVP-PPy conductive polymer: dissolving PVP in distilled water, adding an oxidant and pyrrole at a low temperature, oxidizing the pyrrole into polypyrrole to obtain a PVP-PPy solution, and stirring and centrifuging to obtain a PVP-PPy conducting polymer; wherein, in the PVP-PPy solution, the mass concentration of PVP is 0.1-2.0%, and the mass concentration of an oxidant is 1.0-10.0%;
step 3, preparing the conductive hydrogel scaffold for treating and promoting bone regeneration in cooperation with osteosarcoma: montmorillonite-strontium particles, PVP-PPy conductive polymer, GelMA, oxide and photoinitiator are dissolved in distilled water, and then ultraviolet light irradiation is carried out to obtain the conductive hydrogel scaffold material for treating osteosarcoma and promoting bone regeneration.
Optionally, the low temperature state in the step 2 is 2-6 ℃.
Alternatively, the molecular weight of PVP is 300-400 kDa.
Optionally, in step 3, the mass concentration of GelMA is 10.0-30.0%, the mass concentration of Ode is 1.0-10.0%, the mass concentration of montmorillonite-strontium particles is 1.0-5.0%, the mass concentration of PVP-PPy conductive polymer is 0.01-1.0%, and the mass concentration of photoinitiator is 0.1-2.0%.
Optionally, in step 3, the photoinitiator is 2-hydroxy-4- (2-hydroxyethoxy) -2-methyl propiophenone.
The conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion can be used for osteosarcoma treatment.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the invention, the oxide and GelMA react to form a double network through Schiff base, and the double bond of GelMA is polymerized to form a double network under the condition of an initiator without additional finishing, so that the hydrogel has good mechanical properties;
(2) the GelMA/oxide hydrogel formed by crosslinking GelMA and oxide has a three-dimensional network structure, can efficiently load drug molecules and control the release speed of the drug molecules, and further achieves the effect of inhibiting tumor recurrence in a long period of time;
(3) the GelMA/oxide hydrogel is compounded with the PVP-PPy conducting polymer, the GelMA/oxide hydrogel can load drugs, the PVP-PPy conducting polymer has excellent photo-thermal conversion performance, and the combination of the GelMA/oxide hydrogel and the PVP-PPy conducting polymer can be applied to photo-thermal treatment of osteosarcoma.
Drawings
FIG. 1 is an SEM representation of the GelMA/Ode/MMT-Sr/PVP-PPy scaffold material of the present invention.
Fig. 2 is an SEM characterization of the PVP-PPy conductive polymer of the present invention.
FIG. 3 is a stress-strain curve for GelMA/Ode/MMT-Sr/PVP-PPy scaffold materials and GelMA/Ode/PVP-PPy scaffold materials of the present invention.
FIG. 4 is a graph comparing the temperature and time changes in aqueous solution and physiological saline of GelMA/Ode/MMT-Sr/PVP-PPy scaffold materials under different laser power densities. Fig. 4 a is a temperature change curve of the GelMA/Ode/MMT-Sr/PVP-PPy stent material in physiological saline under different laser power densities; b in FIG. 4 is a photo-thermal imaging diagram of the GelMA/Ode/MMT-Sr/PVP-PPy stent in physiological saline at different laser power densities; FIG. 4 c is a temperature profile of GelMA/Ode/MMT-Sr/PVP-PPy stent material in water solution at different laser power densities; FIG. 4 d is a photo-thermal image of GelMA/Ode/MMT-Sr/PVP-PPy scaffold in aqueous solution at different laser power densities; FIG. 4 e is a graph of the UV-Vis-NIR absorption spectrum of the hydrogel precursor solution; FIG. 4 f is a graph of photothermal cycling curves for GelMA/Ode/MMT-Sr/PVP-PPy scaffold material for 6 on/off laser cycles at 808 nm; FIG. 4 g is the steady state photothermal curve for GelMA/Ode/MMT-Sr/PVP-PPy scaffold material.
FIG. 5 is a graph showing a comparison of the hemolysis rate of red blood cells incubated with GelMA/Ode/MMT-Sr/PVP-PPy solutions at different concentrations.
FIG. 6 is a graph comparing results of blood compatibility experiments for GelMA/Ode/MMT-Sr/PVP-PPy scaffold material.
FIG. 7 is a graph comparing the viability of L929 cells cocultured at different concentrations of GelMA/Ode/MMT-Sr/PVP-PPy.
FIG. 8 is a Dead/Live stain image of L929 cells cocultured at different concentrations of GelMA/Ode/MMT-Sr/PVP-PPy.
FIG. 9 is a graph of the in vitro drug release profile of GelMA/Ode/MMT-Sr/PVP-PPy scaffold material of the present invention.
FIG. 10 is a graph comparing the viability of 143B cells co-cultured with a control group, GelMA/Ode/MMT-Sr/PVP-PPy scaffold, DOX @ GOM scaffold, and DOX @ GOMP scaffold according to the present invention.
FIG. 11 is a Dead/Live staining image of 143B cells co-cultured with a control group, GelMA/Ode/MMT-Sr/PVP-PPy scaffold, DOX @ GOM scaffold, and DOX @ GOMP scaffold according to the present invention.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings and examples.
The invention provides a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion, which comprises: GelMA/oxide hydrogel, PVP-PPy conductive polymer, mechanical property enhancing particles and bone growth promoting elements; wherein, according to the mass ratio GelMA/oxide hydrogel: PVP-PPy conductive polymer: mechanical property-enhancing particles: bone growth promoting elements (11-40): (0.01-1): (0.5-2): (0.5 to 3).
Optionally, the mechanical property enhancing particles are any one or more of montmorillonite nanoparticles, hectorite nanoparticles, halloysite nanotubes and sepiolite nanoparticles.
Optionally, the bone growth promoting element is any one of strontium and silicon, or a combination of strontium and silicon.
The methacrylamidoaminated gelatin (GelMA) is a high polymer with good biocompatibility and biodegradability, GelMA/oxide hydrogel formed by crosslinking with oxidized dextran (oxide) has a three-dimensional network structure, the surface and/or the interior of the three-dimensional network structure can be loaded with anti-tumor drugs, and the loaded drugs can be released continuously, so that the problem of rapid diffusion of small-molecule drugs is solved, and the strong side effect of chemotherapeutic drugs is relieved. In addition, soft hydrogels have good plasticity and can be filled in any irregularly shaped frame, compared to hard scaffolds that require pre-forming.
Polypyrrole (PPy) is a common conductive polymer, has good biocompatibility, conductivity and photothermal conversion performance, can be used as a photothermal therapy (PTT) material, under the irradiation of an external light source, the PPy can convert light energy into heat energy to kill cancer cells, and has the characteristics of low cost and low side effect. However, PPy has poor dispersibility and is not easy to disperse in hydrogel, the invention compounds polyvinylpyrrolidone (PVP) and PPy, and the PVP modifies the PPy to better disperse in GelMA/oxide hydrogel.
Montmorillonite (MMT) is a natural mineral of silicate, and the effect of enhancing the mechanical property of hydrogel can be achieved by adding montmorillonite (MMT) into GelMA/oxide hydrogel.
Strontium (Sr) can regulate differentiation of MSCs (mesenchymal stem cells) into osteoblasts, promote synthesis and precipitation of bone matrix protein, and promote osteoblast differentiation and osteogenesis.
The GelMA/oxide hydrogel is compounded with the PVP-PPy conductive polymer, the GelMA/oxide hydrogel can load drugs, the PVP-PPy conductive polymer has excellent photo-thermal conversion performance, and the conductive hydrogel support material (GelMA/oxide/MMT-Sr/PVP-PPy support material) which is used for treating osteosarcoma and promoting bone regeneration is prepared. Meanwhile, the GelMA/oxide/MMT-Sr/PVP-PPy stent material is further evaluated for the photothermal effect, and the result shows that the material has high photothermal conversion efficiency and can be used as an ideal photothermal treatment stent material.
Example preparation method of conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion
The embodiment provides a preparation method of a conductive hydrogel scaffold material (GelMA/oxide/MMT-Sr/PVP-PPy scaffold material) for synergistically treating osteosarcoma and promoting bone regeneration, which comprises the following steps:
step 1, preparation of oxidized dextran (Ode): 1.0g NaIO4Dissolving in 10mL of deionized water, and continuously stirring; dissolving 2.0g dextran in 100mL deionized water, mixing the above two solutions, stirring at room temperature in dark for 24h, terminating the reaction with ethylene glycol, dialyzing, and lyophilizing.
Step 2, preparation of methacrylamidoaminated gelatin (GelMA): dissolving 3.0g of gelatin in 30mL of PBS solution at 50 ℃, dropwise adding 0.3mL of methacrylic anhydride, continuously heating and stirring for 3h, dialyzing, and freeze-drying.
Step 3, preparing montmorillonite-strontium particles (MMT-Sr): 1.0g of MMT was weighed and dissolved in 100mL of distilled water by sonication, and 4.0g of SrCl was added2·6H2O, stirring for 12 hours at normal temperature and centrifugingWashing and freeze-drying.
Step 4, preparing a PVP-PPy conductive polymer: weighing 0.2g of PVP with the molecular weight of 360kDa, dissolving the PVP in 40mL of distilled water, and adding 2.48g of an oxidant; 0.14mL of pyrrole is added dropwise at 4 ℃, stirred for 4 hours, centrifuged, washed and freeze-dried.
Step 5, preparing a GelMA/Ode/MMT-Sr/PVP-PPy scaffold material: dissolving 0.01g PVP-PPy and 0.3g MMT-Sr in 10mL of distilled water by ultrasonic, then adding 0.5g of oxide, 2g of GelMA and 0.1g of photoinitiator, heating to 50 ℃ for dissolution, and finally placing under a 365nm ultraviolet lamp for irradiation to obtain the GelMA/oxide/MMT-Sr/PVP-PPy scaffold material.
The aldehyde group of the oxide and the amino group of the GelMA react through Schiff base to form a first heavy network, the reaction condition is mild, the GelMA grafted double bond is polymerized by ultraviolet irradiation in the presence of a photoinitiator to form a second heavy network, and the gelling speed is high; so that the hydrogel has good mechanical properties.
Preferably, GelMA is prepared by gelatin solution which is PBS solution of gelatin, and the mass concentration of the gelatin solution is 5.0-20.0%; the addition amount of the methacrylic anhydride is 5.0-20.0% of the mass of the gelatin, the grafting reaction temperature is 35-65 ℃, and the reaction time is 2-5 h.
Preferably, the mass concentration of the glucan is 1.0-5.0%, the mass concentration of the sodium periodate is 0.1-2.0%, and the oxidation reaction time is 12-36 h.
Preferably, the mass concentration of MMT is 0.5-2.0%, the mass concentration of strontium chloride is 1.0-5.0%, the reaction time is 6-24h, the centrifugation speed is 5000-10000rpm, and the centrifugation time is 5-20 min.
Preferably, the molecular weight of PVP is 360kDa and the mass concentration is 0.1-2.0%.
Preferably, the oxidant is FeCl3·6H2O, by FeCl3·6H2O Oxidation of pyrrole to polypyrrole, FeCl3·6H2The mass concentration of O is 1.0-10.0%, the reaction time is 2-6h, PVP-PPy nano particles are obtained after centrifugation, the centrifugation speed is 13000-21000rpm, and the centrifugation time is 10-30 min.
Preferably, the mass concentration of GelMA is 10.0-30.0%, the mass concentration of oxide is 1.0-10.0%, the mass concentration of MMT-Sr is 1.0-5.0%, the mass concentration of PVP-PPy is 0.01-1.0%, PPy is used as a reduction substance and has certain effect of preventing polymerization, and the content of PVP-PPy influences the gelling speed of hydrogel, so that the content of PVP-PPy in the hydrogel is not suitable to be excessive.
Preferably, the photoinitiator is 2-hydroxy-4- (2-hydroxyethoxy) -2-methyl propiophenone, the mass concentration is 0.1-2.0%, and the dissolution temperature is 40-60 ℃.
Preferably, the invention adopts a magnetic stirrer for stirring, and the rotating speed is 300-.
Preferably, in step 5, the redispersion of MMT-Sr and PVP-PPy is carried out under ultrasonic pulverization conditions for 10-60min until a uniform solution with good stability is obtained, which is beneficial for the more uniform distribution of the MMT-Sr and the PVP-PPy in the hydrogel scaffold.
Further, if it is desired to load the drug in the GelMA/Ode/MMT-Sr/PVP-PPy scaffold material, the drug may be dissolved in the hydrogel precursor solution prior to adding the photoinitiator at step 5. After the medicine is added, adding a photoinitiator for ultraviolet lamp irradiation to obtain the GelMA/Ode/MMT-Sr/PVP-PPy stent material loaded with the medicine.
After the GelMA/oxide/MMT-Sr/PVP-PPy stent material is prepared, the prepared stent material is further subjected to experiments such as characterization analysis, mechanical property analysis, photothermal effect evaluation and the like, and the material is verified to be an ideal photothermal treatment stent material, and the specific method and the result are as follows:
1. characterization analysis
The surface appearances of the GelMA/Ode/MMT-Sr/PVP-PPy support material and the PVP-PPy conducting polymer are characterized by a scanning electron microscope. As shown in figure 1, the GelMA/Ode/MMT-Sr/PVP-PPy scaffold material has a loose and porous three-dimensional network structure. As shown in fig. 2, the PVP-PPy conductive polymer has a spherical particle structure with a diameter of 100 nm.
2. Analysis of mechanical Properties
Compressive stress strain measurements were made using a universal materials tester (Zwick-Roell Z2.5 TH with a 2.5kN sensor). The GelMA/Ode/MMT-Sr/PVP-PPy stent material is put into a mould with the diameter of 10mm and the depth of 3mm for preparation. GelMA/Ode/MMT-Sr/PVP-PPy was compressed to 50% of the original height at a predetermined compressive strain rate of 1 mm/min. The compressive modulus was read from a linear fit of the stress-strain curve with a strain range of 10-15%.
As shown in FIG. 3, the GelMA/Ode/MMT-Sr/PVP-PPy scaffold material has a larger compressive modulus and more excellent mechanical properties than the GelMA/Ode/PVP-PPy scaffold material. Wherein, GelMA/Ode/PVP-PPy is prepared according to the preparation method, and the difference is that: in step 5, MMT-Sr particles are not added.
3. Assessment of photothermal effects
(1) GelMA/oxide/MMT-Sr/PVP-PPy scaffold material is dispersed in aqueous solution and physiological saline, and 808nm NIR laser (0.2W/cm) with different power densities is used2、0.4W/cm2、0.6W/cm2) Irradiation was continued for 5min, the solution was cooled to room temperature after cessation of irradiation for 5min, and the temperature change over time and corresponding images were recorded using a FLIR E60 thermal infrared imager.
As shown in a-b of FIG. 4, after 5 minutes of laser irradiation, 0.2W/cm2、0.4W/cm2、0.6W/cm2At the laser power density, the GelMA/Ode/MMT-Sr/PVP-Ppy physiological saline solution is respectively increased by 10.43 ℃, 21.57 ℃ and 30.23 ℃, and the temperature of the stent material is increased along with the increase of the laser power density. As shown in c-d of FIG. 4, after 5 minutes of laser irradiation, 0.2W/cm2、0.4W/cm2、0.6W/cm2Under the laser power density, the temperature of the aqueous solution of GelMA/Ode/MMT-Sr/PVP-Ppy is respectively raised by 15.72 ℃, 33.30 ℃ and 51.52 ℃, and the temperature change of GelMA/Ode/MMT-Sr/PVP-Ppy in the aqueous solution is more obvious. When doctors use the GelMA/Ode/MMT-Sr/PVP-Ppy material to perform photothermal therapy on patients, the power density of laser can be adjusted to adjust the temperature of the material, and the best therapeutic effect is achieved.
(2) The spectral properties of the hydrogel precursor solutions were measured in the ultraviolet visible-near infrared (UV-Vis-NIR) range using a UV-Vis-NIR spectrometer. The hydrogel precursor solution is a solution before ultraviolet irradiation without adding a photoinitiator, and already comprises all substances which form the whole scaffold material. As shown in e of fig. 4, the hydrogel precursor solution has a wide absorption wavelength range and can be used as a photothermal therapy material.
(3) GelMA/Ode/MMT-Sr/PVP-PPy aqueous solution was dispersed in cell culture plates (96 wells) on an NIR laser (0.4W/cm)2808nm) was irradiated for 6 laser on/off cycles (5 minutes each time the laser was turned on, off), and the temperature change of the solution was recorded using a FLIR E60 thermal infrared imager. As shown in f of FIG. 4, the heat generated by GelMA/Ode/MMT-Sr/PVP-PPy is not reduced after multiple laser irradiations.
(4) After the FLIR E60 thermal infrared imager is adopted to record the temperature change, the photothermal conversion efficiency of the GelMA/oxide/MMT-Sr/PVP-PPy support material is calculated according to a formula, wherein the calculation formula of the photothermal conversion efficiency is as follows:
Figure BDA0003158625030000081
wherein eta is the photothermal conversion efficiency, Tmax is the highest temperature of the sample, Tsurr is the ambient temperature, I is the laser power, AλIs the absorbance value, Q, of the sample at the excitation wavelengthdisThe heat change in the reagent blank, h the system heat conversion efficiency, and S the surface area of the vessel. The value of hS is calculated according to the following formula:
Figure BDA0003158625030000082
wherein m is the mass of the solution, CH2OIs the specific heat capacity of water and τ s is the time constant of the system. The value of τ s is calculated according to the following equation:
Figure BDA0003158625030000083
wherein T is the time during the cooling process and T is the instant temperature at time T.
As shown in g of figure 4, GelMA/Ode/MMT-Sr/PVP-PPy has the photothermal conversion efficiency of 31.61% under 808nm radiation, and can be used as an ideal photothermal treatment stent material.
4. Evaluation of blood compatibility
Evaluation of in vitro blood compatibility: blood from KM mice was collected by heart puncture under anesthesia, centrifuged at 3000rpm for 5min, washed 3 times with PBS solution, and a suspension of red blood cells and PBS was prepared at a ratio of 1: 50 (by volume) and stored in a refrigerator at 4 ℃. The following reagents were added to 5 tubes, respectively:
tube 1 (positive control): 0.6mL suspension of erythrocytes and PBS, 2.4mL distilled water tube 2 (negative control): suspension of 0.6mL of erythrocytes and PBS, 2.4mL of PBS
Test tube 3: 0.6mL of a suspension of erythrocytes and PBS, 2.4mL of PBS, 30mg of GelMA/oxide/MMT-Sr/PVP-PPy, in which case the concentration of GelMA/oxide/MMT-Sr/PVP-PPy is 10mg/mL
Test tube 4: 0.6mL of a suspension of erythrocytes and PBS, 2.4mL of PBS, 60mg of GelMA/oxide/MMT-Sr/PVP-PPy, in which case the concentration of GelMA/oxide/MMT-Sr/PVP-PPy is 20mg/mL
Test tube 5: 0.6mL of a suspension of erythrocytes and PBS, 2.4mL of PBS, 150mg of GelMA/oxide/MMT-Sr/PVP-PPy, in which case the concentration of GelMA/oxide/MMT-Sr/PVP-PPy is 50mg/mL
After incubating the tubes at 37 ℃ for 2 hours, the aqueous gel was removed, the red cell suspension was centrifuged for 5min (3000rpm), and the absorbance value of the 541nm supernatant was measured by UV spectroscopy to calculate the hemolysis rate. As shown in FIGS. 5-6, the hemolysis rates of 10mg/mL, 20mg/mL, 50mg/mL GelMA/oxide/MMT-Sr/PVP-PPy treated mouse erythrocytes were below 5%, no significant hemolysis was observed, and the material was proved to have good blood compatibility.
5. GelMA/Ode/MMT-Sr/PVP-PPy in vitro cytotoxicity assay
GelMA/Ode/MMT-Sr/PVP-PPy cytotoxicity was assessed in vitro using CCK-8 and the Dead/Live kit: sterilizing GelMA/oxide/MMT-Sr/PVP-PPy, soaking in DMEM medium (100mg/mL), culturing at 37 deg.C for 24 hr, and storing the leachate in refrigerator at 4 deg.C. L929 fibroblasts were seeded in a 96-well plate, and the medium was replaced with a mixed solution of the leachate and the medium so that the final concentrations of GelMA/Ode/MMT-Sr/PVP-PPy were 0mg/mL, 10mg/mL, 20mg/mL, 50mg/mL and 100mg/mL, respectively. After 1, 3, 5 days of incubation, cells were washed 3 times with PBS.
As shown in FIG. 7, the viability of L929 cells treated with GelMA/Ode/MMT-Sr/PVP-PPy was not significantly different from that of the control group at 10mg/mL, 20mg/mL, 50mg/mL and 100 mg/mL. As shown in FIG. 8, after staining with the Dead/Live kit, 10mg/mL, 20mg/mL, 50mg/mL and 100mg/mL GelMA/Ode/MMT-Sr/PVP-PPy treated L929 cells were almost stained green, and there was no significant difference from the control group. The results prove that the GelMA/Ode/MMT-Sr/PVP-PPy material has excellent biocompatibility when the concentration is lower than 100 mg/mL.
6. GelMA/Ode/MMT-Sr/PVP-PPy drug release capacity
GelMA/Ode/MMT-Sr/PVP-PPy (100mg) loaded with Doxorubicin (DOX) was loaded into dialysis bags, placed into 50mL centrifuge tubes containing 5mL CBS (pH 5.4) or 5mL PBS (pH 7.4) and shaken in a shaker (T37 ℃ or 50 ℃). At a particular time point, 1mL of DOX-releasing solution was removed from the centrifuge tube, then supplemented with 1mL of fresh buffer solution and shaking was continued. The absorbance of the released buffer solution at 480nm was measured and the released DOX concentration was calculated according to a standard curve.
As shown in FIG. 9, GelMA/Ode/MMT-Sr/PVP-PPy can release DOX continuously within 48 h. Wherein, the DOX release speed is higher within the first 12 h; the rate of DOX release tends to stabilize over the next several hours, and the amount of drug released increases with increasing temperature. The amount of drug released also increased under mildly acidic conditions at pH 5.4. Under mildly acidic and higher temperature conditions, more DOX is released from the GelMA/Ode/MMT-Sr/PVP-PPy scaffold material, possibly due to enhanced molecular motion and solubility. When doctors use the GelMA/Ode/MMT-Sr/PVP-Ppy material to perform photothermal therapy on patients, the temperature and the pH value of the material can be adjusted to achieve the best therapeutic effect.
7. GelMA/Ode/MMT-Sr/PVP-Ppy can inhibit growth of human osteosarcoma cells (143B)
At a rate of 1X 10 per hole4Seeding density of individuals human osteosarcoma cells (143B) were seeded into 96-well cell culture plates. Adding to 4 plates of cell culture plates separatelyThe following reagents:
plate 1: 100 μ L DMEM Medium
Culture plate 2: 100 mu L DMEM medium, 25mg GelMA/Ode/MMT-Sr/PVP-Ppy
Culture plate 3: 100 uL DMEM medium, 25mg DOX-loaded GelMA/Ode/MMT-Sr (DOX @ GOM)
Culture plate 4: 100 mu L DMEM medium, 25mg DOX-loaded GelMA/Ode/MMT-Sr/PVP-Ppy (DOX @ GOMP)
Wherein GelMA/oxide/MMT-Sr is prepared by the method of the embodiment, and the difference is that: no PVP-PPy polymer was added in step 5.
The plates were incubated at 37 ℃ with 5% CO2Culturing for 24h under the condition, and irradiating the GelMA/Ode/MMT-Sr/PVP-Ppy and DOX @ GOMP treatment groups with near infrared laser for 5min (808nm, 0.6W/cm)2) Cell viability was studied using the CCK-8 kit and LIVE/DEAD BacLight kit.
As shown in fig. 10 and 11, the cell activities of the photothermal treatment group and the drug treatment group were significantly decreased compared to the control group. Due to the coexistence of the chemotherapy drugs and the photothermal material, the growth of the cells cultured in the combined treatment group is inhibited, and the survival rate after near-infrared irradiation is reduced to 8.74% +/-6.04%, which indicates that the treatment method of combined chemotherapy and photothermal treatment can obviously inhibit the growth of osteosarcoma cells.
The application method of the GelMA/Ode/MMT-Sr/PVP-Ppy stent material comprises the following steps:
for osteosarcoma postoperative bone defect patients, selecting a mould according to the shape of bone defect of the patients, and preparing a tissue engineering scaffold by adopting a GelMA/Ode/MMT-Sr/PVP-Ppy scaffold material;
the tissue engineering scaffold is implanted into the bone defect of a patient, and the strontium element in the scaffold can promote osteogenesis and osteoblast differentiation; meanwhile, under the irradiation of an external light source, PPy can perform photothermal conversion to further kill residual cancer cells after operation, inhibit the growth of the cancer cells, reduce the recurrence rate of osteosarcoma after operation, and realize the effects of reducing the side effect of chemotherapeutic drugs and promoting the regeneration of bone tissues.
In conclusion, the invention provides a conductive hydrogel scaffold material (GelMA/oxide/MMT-Sr/PVP-PPy scaffold material) for cooperating with osteosarcoma treatment and promoting bone regeneration, GelMA/oxide hydrogel, MMT-Sr particles and PVP-PPy conductive polymer are polymerized, GelMA/oxide hydrogel can load medicines, PVP-PPy conductive polymer has excellent photothermal conversion performance, MMT-Sr particles can promote bone tissue regeneration and enhance the mechanical performance of hydrogel, and GelMA/oxide/MMT-Sr/PVP-PPy prepared by combining the GelMA/oxide/MMT-Sr/PVP-PPy scaffold material can be used as a chemotherapeutic medicine carrier, a thermotherapy agent carrier and a preparation material for promoting bone tissue regeneration.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.

Claims (9)

1. An electrically conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion, comprising: GelMA/oxide hydrogel, PVP-PPy conductive polymer, mechanical property enhancing particles and bone growth promoting elements; wherein, according to the mass ratio GelMA/oxide hydrogel: PVP-PPy conductive polymer: mechanical property-enhancing particles: bone growth promoting elements (11-40): (0.01-1): (0.5-2): (0.5 to 3).
2. The electrically conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration of claim 1, wherein said mechanical property enhancing particles are any one or more of montmorillonite nanoparticles, hectorite nanoparticles, halloysite nanotubes and sepiolite nanoparticles.
3. The electrically conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration of claim 1, wherein said bone growth promoting element is any one of strontium and silicon, or a combination of strontium and silicon.
4. The electrically conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration of claim 1, wherein the electrically conductive hydrogel scaffold material is loaded with drugs for osteosarcoma treatment on the surface and/or inside.
5. The method for preparing a conductive hydrogel scaffold material for the synergistic treatment of osteosarcoma and promotion of bone regeneration according to any one of claims 1 to 4, comprising the steps of:
step 1, preparing montmorillonite-strontium particles: ultrasonically dispersing montmorillonite into distilled water, adding strontium chloride hexahydrate to obtain montmorillonite-strontium solution, stirring and centrifuging to obtain montmorillonite-strontium particles; wherein, in the montmorillonite-strontium solution, the mass concentration of the montmorillonite is 0.5-2.0%, and the mass concentration of the strontium chloride is 1.0-5.0%;
step 2, preparing a PVP-PPy conductive polymer: dissolving PVP in distilled water, adding an oxidant and pyrrole at a low temperature, oxidizing the pyrrole into polypyrrole to obtain a PVP-PPy solution, and stirring and centrifuging to obtain a PVP-PPy conducting polymer; wherein, in the PVP-PPy solution, the mass concentration of PVP is 0.1-2.0%, and the mass concentration of an oxidant is 1.0-10.0%;
step 3, preparing the conductive hydrogel scaffold for treating and promoting bone regeneration in cooperation with osteosarcoma: montmorillonite-strontium particles, PVP-PPy conductive polymer, GelMA, oxide and photoinitiator are dissolved in distilled water, and then ultraviolet light irradiation is carried out to obtain the conductive hydrogel scaffold material for treating osteosarcoma and promoting bone regeneration.
6. The method for preparing a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration as claimed in claim 5, wherein the low temperature state in step 2 is 2-6 ℃.
7. The method for preparing a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration as claimed in claim 5, wherein the molecular weight of PVP is 300-400 kDa.
8. The method for preparing a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration promotion as claimed in claim 5, wherein in step 3, the mass concentration of GelMA is 10.0-30.0%, the mass concentration of Ode is 1.0-10.0%, the mass concentration of montmorillonite-strontium particles is 1.0-5.0%, the mass concentration of PVP-PPy conductive polymer is 0.01-1.0%, and the mass concentration of photoinitiator is 0.1-2.0%.
9. The method for preparing a conductive hydrogel scaffold material for synergistic osteosarcoma treatment and bone regeneration as claimed in claim 5, wherein in step 3, the photoinitiator is 2-hydroxy-4- (2-hydroxyethoxy) -2-methyl propiophenone.
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