3D-printed Bifunctional Bioceraminc Scaffolds With Photothemral Effect For Tumor Therapy And Bone Regeneration

Bone is the most favored tissue for metastatic cancer because of their special microenvironment.Current treatment of bone tumor in clinic comprise surgery and chemo/radiotherapy.However,surgery causes large bone defects,which is difficult to be healed by themselves.Meanwhile,surgery is difficult to eliminate tumor cells completely,and chemo/radiotherapy would bring severe side-effect.Therefore,it is of great importance to design and fabricate novel biomaterials to kill the possible residual bone-tumor cells,and simultaneously to heal the large bone defect after surgery.In recent years,photothermal therapy as a noninvasive,effective and low-toxic strategy to kill tumor cells via hyperthermia has attracted more and more attentions.Therefore,we put forward to combine tissue engineering and photothermal therapy to develop a bifunctional bioceramic scaffold,which has the ability of killing tumor cells and osteogenic activity.In this dissertation,via 3D printing technique,there kinds of bifunctional scaffolds,based on inorganic,organic,and metal photothermal agents respectively,were fabricated.Their photothermal effect and therapeutic effect in vitro and in vivo were evaluated.The in vitro and in vivo osteogenesis of bifunctional scaffols were also investigated.The main results are described as follows:(1)A bifunctional graphene oxide(GO)-modified β-tricalcium phosphate(GO-TCP)scaffold was fabricated by 3D-printing and surface-modification strategies.The prepared GO-TCP scaffolds exhibited excellent photothermal effects under the irradiation of 808nm near infrared laser(NIR)even at an ultra-low power density of 0.36W/cm2,while no photothermal effects were observed for pure β-TCP scaffolds.The photothermal temperature of GO-TCP scaffolds could be effectively modulated in the range of 40～90℃ by controlling the used GO concentrations,surface-modification times and power densities of NIR.The distinct photothermal effect of GO-TCP scaffolds induced more than 90%of cell death for osteosarcoma cells(MG-63)in vitro,and further effectively inhibited tumor growth in mice.Meanwhile,the prepared GO-TCP scaffolds possessed the improved capability to stimulate the osteogenic differentiation of rabbit bone mesenchymal stem cells(rBMSCs)by upregulating bone-related gene expression,and significantly promoted new bone formation in the bone defects of rabbits as compared to pure β-TCP scaffolds.These results successfully demonstrated that the prepared GO-TCP scaffolds have bifunctional properties of photothermal therapy and bone regeneration,have the potential value in the application of bone tumor therapy and regeneration.(2)We fabricated a 3D-printed bioceramic scaffold with a uniformly self-assembled Ca-P/poly dopamine nanolayer surface.Taking advantage of biocompatibility,biodegradability and the excellent photothermal effect of polydopamine,the bifunctional scaffolds with mussel-inspired nanostructures could be used as a satisfactory and controllable photothermal agent,which effectively induced tumor cell death in vitro,and significantly inhibited tumor growth in mice.In addition,owing to the nanostructured surface,the prepared polydopamine-modified bioceramic scaffolds could support the attachment and proliferation of rabbit bone mesenchymal stem cells(rBMSCs),and significantly promoted the formation of new bone tissues in rabbit bone defects even under photothermal treatment.Therefore,the mussel-inspired nanostructures in 3D-printed bioceramic exhibited a remarkable capability for both cancer therapy and bone regeneration,offering a promising strategy to construct bifunctional biomaterials which could be widely used for therapy of tumor-induced tissue defects.(3)We designed Fe-CaSiO3 composite scaffolds(30CS)via 3D printing technique.Firstly,30CS composite scaffolds possessed high compressive strength to provide sufficient mechanical support in bone cortical defects,Secondly,a synergistic therapy of photothermal and ROS achieved enhanced tumor therapeutic effect in vitro and in vivo.Last but not least,the presence of CaSiO3 in the composite scaffolds enforced the degradation performance and stimulated proliferation and differentiation of rBMSCs and further promoted bone forming in vivo.Such 30CS scaffolds with high compressive strength can function as versatile and efficient biomaterials for the future regeneration of cortical bone defects and therapy of bone cancer.In conclusion,with inorganic ceramic scaffolds as base material,from the perspective of different applications,three types of photothermal agents:inorganic,organic,metal,were chosen,to prepare bifunctional scaffolds and their properties were characterized.Such bifunctional scaffolds pave the way to design and fabricate novel implanting biomaterials in combination of therapy and regeneration fucntionls and represent a universal platform for material science and tissue enginnering and tumor therapy.