Preparation Of Gadolinium Phosphate/chitosan Composite Scaffold And Its Application In Bone Defect Repair And Tumor Treatment

Bone metastasis is one of the most common distant metastases in cancer patients.There is a huge challenge in the treatment of bone defects caused by tumor resection,bone injury or bone diseases.There is an urgent need to find a new multi-functional biomaterial,which can treat large bone defects and inhibit the growth of cancer cells at the same time.Gadolinium?Gd?is one of the trace rare earth elements in human skeleton.However,the potential mechanism of positive cell response and bone regeneration by Gd is rarely reported.In this paper,chemical precipitation method,hydrothermal method and freeze-drying method were proposed,and granular gadolinium phosphate and rod gadolinium phosphate and their composite scaffolds with chitosan and ferric oxide were prepared.XRD,SEM,TEM,FTIR,cell staining and skull section were used to characterize the morphology,phase,osteogenesis and anti-tumor properties of gadolinium phosphate/chitosan and iron tetroxide-doped composite scaffolds.The mechanism of rare earth in vivo and in vitro was discussed.In this paper,gadolinium phosphate granules?p-GdPO₄?/chitosan?CS?scaffolds were constructed by freeze-drying method.Appropriate macropore and chemical composition improved the bone conductivity of p-GdPO₄/CS scaffold,induced cell proliferation and bone tissue growth in vivo.The release of Gd³⁺ions remained in a safe range and was not toxic to rat bone marrow mesenchymal stem cells?rBMSCS?.It is noteworthy that Gd³⁺in p-GdPO₄/CS scaffolds significantly promotes the osteogenic differentiation of rBMSCS by activating the Smad/Runx2 signaling pathway.Compared with?-TCP/CS scaffolds,p-GdPO₄/CS scaffolds significantly increased the expression levels of ALP,Runx-2,OCN and Col-I.In addition,the rat model of critical skull defect showed that the p-GdPO₄/CS scaffold group was much larger than the?-TCP/CS scaffold group.This exciting discovery reveals the potential mechanism of GdPO₄ nanoparticles enhancing osteogenic activity and provides a promising scaffold for bone regeneration.Based on the study of p-GdPO₄/CS scaffolds,the scaffolds were doped with near infrared response Fe₃O₄ particles,which endowed the scaffolds with multi-function,which could kill tumor cells by photothermal therapy and promote bone formation.In order to investigate the effects of different morphologies of GdPO₄ powder on cell proliferation and osteogenesis,a multifunctional scaffold of gadolinium phosphate nanorods?r-GdPO₄?/chitosan/ferric oxide?Fe₃O₄?was constructed.On the one hand,Fe₃O₄ nanoparticles in r-GdPO₄/CS/Fe₃O₄ scaffolds can significantly improve the near infrared absorption capacity and photothermal conversion efficiency of the materials.Under near infrared laser irradiation,the local temperature around r-GdPO₄/CS/Fe₃O₄ scaffold increased enough to stimulate apoptosis of tumor cells.On the other hand,as a new bioactive component,GdPO₄ nanorods can enhance angiogenesis and osteogenesis.Gd³⁺released from r-GdPO₄/CS/Fe₃O₄ scaffolds can induce M2 polarization of macrophages to form a stable vasculogenic system.The newly formed vessels provide conditions for new bone formation.Moreover,r-GdPO₄/CS/Fe₃O₄ scaffolds promote osteogenic differentiation of rBMSCS by activating BMP-2/Smad/Runx-2 signaling pathway.Compared with the blank group and the control group,r-GdPO₄/CS/Fe₃O₄ stent significantly increased the expression levels of ALP,Runx-2,OCN and BMP-2.Therefore,multifunctional r-GdPO₄/CS/Fe₃O₄ scaffolds bring new hope for the treatment of bone tumors.