The Research Of Bioactive Glasses Used For Bone Augmentation And Macrophages Related Immunomodulation

Bioactive glass is one kind of inorganic nonmetallic bone repair material and has excellent osteoconduction and osteoinduction properties,which has attracted great attention from the research community of biomaterials.The focus of current research of bioactive glass is the repair effect of different types of bone defects.However,it is not clear whether bioactive glass has the ability for bone augmentation without making any bone defect.Unlike the intramembranous osteogenesis in bone defects repair,the bone augmentation occurs outside the cortical bone and the osteoprogenitor cells show the reversed migration.The application of bone augmentation is mainly used for alveolar ridge elevation and plastic surgery which need to increase bone mass.Previous studies needed to add biomolecules or establish blood express way with jaw by making bone defects which would not be suitable in clinic application or may result in additional trauma.Therefore,the focus of this paper is to explore whether BG has the ability for bone augmentation without making any bone defect and the osteogenesis mechanism.As the mechanical strength of bioactive glass scaffolds is generally weak,it is necessary to enhance the scaffolds by necessary measures.In addition,in recent years,studies have found that the immune system plays a key role in the process of bone formation.Therefore,from the perspective of osteoimmunomodulation,a more comprehensive understanding of the process of bone mass increase and related mechanisms is necessary.Moreover,the mucosal tension will increase when bioactive glass is implanted bone augmentation position.Therefore,some measures to promote early vascularization of implants is necessary to avoid tissue necrosis.In this work,we firstly prepared bioactive glass scaffolds and enhanced the mechanical property of scaffolds.Secondly,bone augmentation performance of bioactive glass scaffolds was evaluated by directly implanting the scaffolds outside the cortical bone.The macrophage-related immune regulation was further studied.Third,the promoting early angiogenesis effect of strontium-contained bioactive glasses through regulating macrophage phenotypes was studied.Finally,based on previous studies,a novel dental implant design was designed,and the restoration effect of the implant system was also studied.The specific research work and corresponding conclusions are as follows:（1）The 3D printed enhanced scaffolds were fabricated through a self-crosslinking process of alginate by bioactive glass microspheres provided Ca²⁺completely,without any organic solvent,crosslinking agent or binder.The results showed that uniform films could be obtained on the surface as well as abundant of crosslinking bridges in the interior of scaffolds.The rapidly released Ca²⁺from bioactive glass could be temporarily stored in alginate,which achieved the controlling release.The scaffolds,with porosities of 75–57%,got a compressive strength in the range of human trabecular bone.At the same time,they presented an excellent apatite formation ability in vitro.In vitro cellular study confirmed that the alginate films temporarily separated cells from bioactive glass which promoting early cell adhesion and all the groups showed good cell proliferation and ALP activity.（2）The bone augmentation ability of bioactive glass scaffolds in an intramembranous microenvironment was evaluated by implanting in the skull subcutaneous of rats without making any bone defect.Active osteogenesis could be observed at 6 weeks,and the osteoblasts were derived from the reverse migration of cranial cells by comparing with BG implanting in back subcutaneous.Furthermore,immunomodulation effects were further studied by simulating the state of inflammation in vivo.We find that the pro-inflammatory environment derived from BGS significantly promotes preosteoblasts migration and osteogenic differentiation.It was also confirmed that the anti-inflammatory environment together with BGS significantly increased osteogenic differentiation and bone formation in vitro and in vivo.（3）The promoting early angiogenesis effect of strontium-contained bioactive glasses through regulating macrophage phenotypes was further studied.After being stimulated with SrBGM in vitro,RAW264.7 cells（macrophages）presented a trend towards to M2 phenotype and expressed high level of platelet-derived growth factor-BB（PDGF-BB）.Moreover,the RAW264.7 conditioned medium of SrBGM significantly enhanced the angiogenic capacity of HUVECs.The in vivo early vascularization studies showed that significant new vessels were observed at the center of SrBGM-based scaffolds after implantation for 1 week in a bone defect model of rats,suggesting their enhanced early vascularization.This study demonstrates that SrBGM could enhance the early angiogenesis through immune regulation effect and have wide application in ischemic tissue regeneration.（4）On the basis of the previous work,we developed a novel dental implant design:sub-scaffold dental implant system（SDIS）,which composed of metal implant and bioactive glass scaffold.Metal implant was used to connect dentures and bioactive glass scaffold was used to form new bone on alveolar ridge and augment vertical bone at the same time.We implanted SDIS in sub-epicranial aponeurosis of SD rats for 6 weeks.SDIS was combined closely with the skull without any mobility and denture could bear certain lateral force.In addition,active osteogenesis process could be observed without adding any biomolecules or destroying the alveolar ridge.This novel sub-scaffold dental implant system has great potential for clinical applications of atrophic alveolar ridge.