| Bone not only plays a role of movement and support for the human body,but also can be connected into a cavity to protect the important internal tissues and organs.The health of bone is directly related to human health.Bone resorption and bone defect caused by inflammation,tumor,trauma and osteoporosis have seriously affected the physical and mental health of patients.Traditional treatment methods include distraction osteogenesis,guided tissue regeneration,autograft,allograft,and artificial bone graft.Although they promote bone healing to a certain extent,they still have their own limitations,such as implant loosening caused by immune rejection,infection or stress interruption,insufficient donor,and high cost.For these reasons,nanocomposites with high biocompatibility,interfacial compatibility and structural compatibility have become a research hotspot in the field of bone tissue repair.Based on the above background,in this paper,drug-loaded hollow polydopamine nanoparticles were constructed and applied to the surface modification of 3D-printed titanium scaffolds,and the modified titanium scaffolds were further applied to jaw bone defect repair.This paper focuses on its biocompatibility in vitro and in vivo,biological activity,osteogenic ability and osteogenic mechanism.In the second chapter,hollow polydopamine nanoparticles(HPDA NPs)were prepared by coordination competition induced polymerization(CCIP)using metal-organic framework structure ZIF-8 as template.HPDA NPs has a hollow regular dodecahedron structure,and its large specific surface area and pore structure are favorable for drug loading.Four drugs with osteogenic function,aspirin,ascorbic acid,tacrolimus and simvastatin,can be loaded in HPDA NPs to construct drug-loaded nanoparticles,and the morphology of nanoparticles has no obvious change before and after drug loading.And the loaded drug can be released continuously outside the body for up to 30 days.In cell experiments,due to the release and efficacy of drugs,the expressions of osteogenic related genes Runx2,ALP,sp-7,Col I and BMP2 in rBMSCs co-cultured with four drug-loaded nanoparticles were significantly up-regulated,ALP activity was significantly increased,calcium nodules content was significantly increased,and cell mineralization ability was enhanced.In the third chapter,based on the different kinds of drug-loaded nanoparticles constructed in the second chapter,we locally implanted them into tooth extraction fossa of rats.At different time points after operation,the effect of drug-loaded nanoparticles on promoting bone formation in the rat tooth extraction fossa bone defect model was studied,and the safety of the experiment was also explored.Micro CT images at different time points after operation showed that the amount of new bone in tooth extraction fossa in each drug-loaded nanoparticle group was significantly higher than that in the control group,and H&E staining of the mandibles also showed more new bone tissue in the drug-loaded nanoparticle group.All the four drug-loaded nanoparticles could effectively promote bone regeneration in the tooth extraction fossa of rats.At the end of the experiment,the liver and kidney functions of the rats were normal,and the histological morphology and structure of the major organs were normal,indicating that the experiment had good biocompatibility and low toxicity.This way of locally implanting drug-loaded nanoparticles at the bone defect site can shorten the time of bone regeneration and improve the effect of bone regeneration,has a good application prospect.In addition,it is worth noting that Tacrolimus@HPDA NPs has the best effect among the four drug-loaded nanoparticles and is worthy of further application.In the fourth chapter,we use the viscosity of polydopamine to deposit Tacrolimus@HPDA NPs on the surface of 3D-printed porous titanium scaffold and prepare the surface modified porous titanium metal composite scaffold material(Ti/Tacrolimus@HPDA NPs).The modification of porous titanium scaffold surface by Tacrolimus@HPDA NPs significantly improved the surface hydrophilicity of scaffold.The improvement of hydrophilicity and the nanoscale rough structure on the surface of the scaffold were conducive to promoting the adhesion and proliferation of rBMSCs.The sustained release of tacrolimus by drug-loaded nanoparticles in scaffolds significantly upregulated the expressions of osteogenic genes Runx2,Col I and OCN in rBMSCs,and enhanced the activity of ALP and matrix mineralization of cells.In the rabbit mandibular defect model,Ti/Tacrolimus@HPDA NPs scaffold can effectively promote the repair of bone defect,and the scaffold material has strong ability to promote bone formation in vivo,and has good biological safety.Ti/Tacrolimus@HPDA NPs scaffolds provide a new idea for the surface modification of traditional titanium scaffolds and the construction of composite biomaterials for bone repair.In the fifth chapter,we investigated the signaling pathways involved in Tacrolimus@HPDA NPs promoting osteogenic differentiation of rBMSCs.Tacrolimus@HPDA NPs can effectively promote the expression of p-FAK and p-ERK in rBMSCs.The expression of p-ERK in rBMSCs was decreased after the introduction of FAK inhibitors.After the introduction of ERK inhibitor,the expression of osteogenic related genes in rBMSCs,the activity of ALP and the ability of matrix mineralization were also significantly reduced.FAK/ERK signaling pathway plays an important role in mediating tacrolimus to promote the osteogenic differentiation of rBMSCs.Tacrolimus@HPDA NPs promotes bone differentiation through activation of FAK/ERK signaling pathway. |
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