Bioactive Elements-induced Photothermal Bioactive Materials For Treatment Of Tumorous Bone Defects

For the treatment of tumorous bone defects,it is of great significance to develop bifunctional biomaterials with both bone regeneration and postoperative adjuvant tumor therapy abilities.Because phototherapy has the advantages of high efficacy,low side effects and strong targeting in tumor treatment,the bioactive scaffolds with photothermal effect for bone tumor treatment studied by our team were mainly focused on the modification of the scaffold surface by two-dimensional materials(e.g.graphene,molybdenum disulfide).However,the introduction of these two-dimensional materials may result in the uncontrolled degradation.Considering the degradability and bone repair ability of Ca-Si based bioactive materials,we suppose the preparation of Ca-Sibased bioactive materials with photothermal property for treatment of postoperative tumorous bone defects.In this paper,according to the different types and locations of bone tumors,elements-induced photothermal functionalized bioactive glass-ceramic scaffolds,Mn-doped mesoporous bioactive glass-loaded with chlorin e6,and Co-doped xonotlite nanowires composite hydrogel scaffolds were designed,respectively,for treatments of postoperative tumorous(osteosarcoma and chondrosarcoma)bone defects.The antitumor effects of the above biomaterials were evaluated in vitro and in vivo,respectively;Meanwhile,the osteogenic activity of the three biomaterials was further investigated.The specific conclusions are as follows:1.Based on the excellent photothermal property of transition metal dichalcogenides nanomaterials,we prepared elements(Cu,Fe,Mn and Co)-doped bioactive glass-ceramic powders by the sol-gel method.Elements-doped bioactive glass-ceramic scaffolds were prepared by 3D-printing method.After being treated with 808 nm laser,it was found that all four elements-doped scaffolds displayed photothermal effects,while pure BGC scaffold did not have photothermal performance.By altering the doping element categories,contents and the laser power densities,the photothermal performance of the BGC scaffolds could be well controlled.Under 808 nm laser irradiation,5Cu-BGC,5Fe-BGC and 5Mn-BGC scaffolds could effectively kill osteosarcoma cells both in vitro and in vivo.At the same time,5Fe-BGC and 5MnBGC scaffolds supported the adhesion and proliferation of r BMSCs,and up-regulated the expression levels of osteogenic genes(OCN?BSP?BMP2?OPN?ALP)in r BMSCs.The above results indicate that,compared with other elements-doped scaffolds,5FeBGC and 5Mn-BGC scaffolds have great potential in the treatment of tumorous bone defect.This study,on the one hand,harnesses the photothermal effect of trace elements,and on the other hand,utilizes the biological activity of trace elements.The concept is of great significance for the preparation of bifunctional bioactive scaffolds.2.Considering that the heat shock protein in tumor cells will expand during hyperthermia,in order to further improve the therapeutic effect of osteosarcoma,we combine photothermal therapy with photodynamic therapy for the enhanced treatment of osteosarcoma-induced bone defects.To achieve the target above,we prepared a intelligent bioactive material triggered by 808 nm laser namely: Mn-doped mesoporous bioactive glass-loaded with chlorin e6(5Mn-MBG/Ce6).The 5Mn-MBG,prepared by the EISA method,displayed excellent photothermal performance and high specific surface area,which were beneficial to Ce6 loading and release.Moreover,the photothermal effect of 5Mn-MBG/Ce6 could regulate the release of Ce6,and also enhanced the intracellular uptake of Ce6 by osteosarcoma cells.Compared with single phototherapy,hyperthermia could enhance photodynamic therapy to achieve the optimal osteosarcoma therapeutic effects both in vitro and in vivo.In addition,5MnMBG/Ce6 particles possessed good bioactivity,and could induce the growth of new bone tissue in vivo.The intelligent bioactive 5Mn-MBG/Ce6 provides a novel strategy for the enhanced treatment and repair of osteosarcoma-induced bone defects.3.Based on the characteristics of chondrosarcoma involving bone and cartilage,a multi-functional hydrogel scaffold with chondrosarcoma treatment and bone-cartilage regeneration abilities was designed.The scaffolds of different cobalt-doped xonotlite nanowires composite hydrogel(CS-PVA-0Co,CS-PVA-5Co)were prepared by 3D printing method.Under the 808 nm laser irradiation,the survival rate of human chondrosarcoma cells in CS-PVA-5Co-13.4% and CS-PVA-5Co-16.2% scaffold groups were both less than 2%.At the same time,the encapsulation of nanowires in the hydrogel could significantly improve the adhesion and spreading of r BMSCs and chondrocytes on the hydrogel scaffolds.The cobalt-doped xonotlite nanowires composite hydrogel scaffold may provide a new treatment strategy for postoperative adjuvant treatment of chondrosarcoma.In conclusion,the incorporation of bioactive elements into traditional bone repair biomaterials endowed them with excellent photothermal properties,thus achieving the dual functions of bone tumor therapy and bone defect repair.Bioactive elementsinduced bifunctional Ca-Si-based bioactive materials make up for the deficiency of traditional photothermal reagents in the field of tissue engineering.Based on the different types of bone tumors,we designed three different photothermal functionalized Ca-Si-based bioactive materials for the treatment of tumorous bone defects caused by osteosarcoma and chondrosarcoma,respectively.The research of dual-function Ca-Sibased bioactive materials in this paper provides a simple and effective design idea for creating a universal platform for postoperative treatment of bone tumors.