Study On 4D Printing Intelligent Porous Scaffold With Controllable Release Of Drug Microspheres For Bone Tissue Repair

The development of drug-loaded scaffolds similar to natural bone is one of the main challenges in the field of bone tissue engineering.The traditional drug loading method of bone stent is to embed the drug in the print line,which is easy to damage the efficacy and stent structure and can not regulate the drug release rate according to the condition of the patient.The combination of 4D printing stent and drug microsphere in the treatment of bone defect has become a new way of bone tissue repair.Simvastatin(SIM)can promote osteogenesis,but its bioavailability is low.In addition,the half-life of local injection is short,and local extensive use has toxic side effects.Therefore,it is very important to optimize the route of administration.In this study,the bone repair drug SIM was combined with biopolymer material Poly(lactic acid-glycolic acid)copolymer(PLGA)to prepare SIM/PLGA drug-loaded microspheres.Fabrication of intelligent porous composite scaffolds with folding cover structure by 4D printing technology,Simvastatin microspheres were loaded on the stents to release the drugs from the microspheres through the pores of the stents.The surface of the stent modified by poly dopamine can improve the biocompatibility and realize the near infrared response of the stent.The folding cover of the stent is driven to control the drug release rate.The main results of this paper are as follows:Preparation and properties of microspheres:The blank microspheres and drug-loaded microspheres were successfully prepared by S/O/W solvent evaporation method,and the properties of the microspheres were tested.The experiment shows that PLGA blank microspheres with a diameter of 545.32±103.06 μm and SIM/PLGA drug-loaded microspheres with a particle size of 488.28±93.66 μm can be prepared by S/O/W solvent evaporation.Through the LEXT OLS4500 nano-detection microscope,it was observed that the two kinds of microspheres were regular spherical.There was no agglomeration between the microspheres,and the particle size distribution was uniform.Determination of Spectral Properties of SIM by Ultraviolet Spectrophotometer,SIM has a maximum absorption peak at 240 nm.The entrapment efficiency of SIM/PLGA microspheres is 65.288±3.7%,the drug loading rate is 0.806±0.042%,and the yield is 75.65±3.49%.Compared with free SIM solution,PLGA microspheres can be used as a sustained release carrier of SIM and have a certain sustained release effect.Study on the preparation and performance of 4D printing intelligent porous scaffold:Polylactic acid/hydroxyapatite composites and composite printing lines with different hydroxyapatite content were prepared by physical mixing method using polylactic acid(PLA)as substrate.PLA/HA composites and composite printing lines with different hydroxyapatite(HA)contents were prepared by physical mixing method using PLA as substrate.PLA and PLA/HA intelligent porous scaffolds with folding cover structure were fabricated by 4D printing technology.Dopamine(DA)induced scaffolds were used to prepare PLA/PDA and PLA/HA/PDA smart porous scaffolds with uniform self-assembly,construction of PLA/HA/PDA/microsphere smart porous scaffolds loaded with SIM/PLGA drug microspheres.The scaffolds were analyzed by morphology observation,porosity analysis,photothermal performance characterization,infrared spectrum analysis,thermal performance analysis,thermal stability analysis,dynamic thermomechanical analysis,static mechanical property analysis,in vitro drug release analysis,shape memory performance analysis.The scaffolds were analyzed by morphology observation,porosity,characterization of photothermal properties,infrared spectra,thermal properties,thermal stability,dynamic thermomechanical properties,static mechanical properties,drug release in vitro,shape memory properties and so on.The results show that the fiber diameter of the scaffold is about 300 μm,the pore diameter of the scaffold is about 200 μm,and the porosity is more than 25%.After 150 s of near-infrared light irradiation,the temperature of PLA/HA stents induced by different concentrations of dopamine(2 mg/mL,4 mg/mL,6 mg/mL)increased to 68.4℃,74.23℃ and 79.45℃,respectively.An obvious characteristic absorption peak can be observed by Fourier transform infrared spectroscopy.The Tg,Tm and thermal decomposition temperature of PLA,PLA/PDA and PLA/HA/PDA scaffolds are all around 65℃ and 169℃,respectively.The composite of HA and PDA will increase the storage modulus of the material as a whole,but at low temperature,the storage modulus of the three groups of scaffolds is above 1500 MPa,and the compressive strength of the three groups of scaffolds is above 44.7 MPa.The compressive strength of PLA/HA composite scaffolds with 9%HA content can reach 70.2 MPa,which is higher than that of pure PLA scaffolds.The drug release rates of PLA/HA/PDA/microsphere smart porous scaffolds were different in original shape,temporary shape and deformation,and the maximum cumulative release rates within 168 hours were 54.25%,38.2%and 52.14%,respectively.The folding cover of PLA/HA/PDA porous support can recover within 120 s driven by near infrared light.In vitro study of 4D printing intelligent porous scaffold:The toxicity of 4D printed shape memory PLA、PLA/PDA、PLA/HA/PDA、PLA/HA/PDA/microspheres porous scaffold on L929 fibroblasts and the proliferation of mouse embryonic osteoblast progenitor cells(MC3T3E1)were studied by CCK-8 method.The results showed that different concentrations of stent extract could not produce cytotoxicity,and the prepared porous scaffolds had good biocompatibility.PLA/HA/PDA/microsphere porous scaffolds could significantly promote the proliferation of MC3T3-E1,and the maximum increment rate could reach 418.8%on the 5th day.To sum up,a new type of intelligent porous stent which can control the release rate of drug microsphere was successfully prepared by the combination of 4D printing stent and drug microsphere,and the slow and rapid drug release system was well combined with the biological stent.This method can realize personalized repair according to different conditions of patients,and provides a new idea for accurate treatment and new polymer to control drug release.