Study On The Electrical-Responsive Potassium Sodium Niobate System Implant Material And Its Biological Property

Osteosarcoma is the most common primary malignant bone tumor and has become one of the major diseases in bone surgery.Clinically,tumor resection surgery is the most commonly used and effective method for osteosarcoma treatment.However,the surgical resection often produces bone defects,and cancer recurrence is easily caused by residual tumor cells due to incomplete resection.The development and application of bone implant materials is of great significance to repair bone defect after tumor resection.But traditional implant materials ignore the recurrence and metastasis caused by residual tumor cells.Postoperative patients still need to combine chemotherapy to solve the problem.However,chemotherapy drugs have great limitations,side effects and poor specificity,which causes serious harm to patients'physical and mental health.In addition,the interface infection of implant material in the defect is also one of the major complications after tumor resection.Once the infection occurs after implantation,it is often necessary to inject a large number of antibiotics for treatment,and severe cases will result in amputation or even death of the patient.Therefore,in order to kill residual tumor cells and prevent and eliminate surface infection of implant material,the development of an implant material with both anti-tumor and antibacterial functions has become an effective way for the clinical treatment of large bone defects after tumor resection.With the discovery of bioelectricity in human body,electrical stimulation has been widely used in clinical practice,such as restoring some systolic functions of human body by means of electrical stimulation,and treating Parkinson's disease.Studies have shown that stimulation of external electrical signals can induce some pathological changes,such as the enhancement of tumor cell membrane permeability and mitochondrial membrane potential polarization,which will kill tumor cells.The electric stimulation can also promote the production of a large number of reactive oxygen species through electrolysis of water to kill bacteria.In addition,electrical signals can regulate the proliferation and differentiation of bone cells and promote bone tissue repair with piezoelectric response.However,various external devices that exert electrical signals need extra power supply,which are inconvenient to carry and difficult to be implanted into the body.It is also easy to cause infection of surrounding tissues when devices are implanted,which limits their further development.Therefore,based on the killing effect of electrical signals on tumor cells and bacteria,as well as the piezoelectric properties of bone tissue itself,this paper proposes the idea to use the piezoelectric materials with electrical signals response to bionic construct endogenous electric field to promote ion transport targeting to cells and bacteria to design bone implant materials with both anti-tumor and antibacterial properties.The effects of passive electrical signal assisted ion transport generated by copper doped potassium sodium niobate implantation materials on the mechanism of anti-tumor and bactericidal mechanisms were studied,which has important scientific research value and clinical significance for tumor recurrence and metastasis and the elimination of implant infection after surgical resection for osteosarcoma.The following work was carried out in this study:?1?In view of the clinical problems of tumor recurrence and metastasis caused by residual tumor cells and interface infection of implant materials at the defect after resection,the idea was put forward that the endogenoous electric field?EEF?forming between polarized piezoelectric implant materials and charged cells or bacteria transported charged ions to target cells or bacteria to kill tumor cells and inhibit or eliminate bacterial infection.A new type of copper doped potassium sodium niobate implant material with electrical signal response characteristics was designed and fabricated.The polarized piezoelectric implant was constructed by the method of external electric field polarization.In vitro cell biological experiments showed that EEF can promote the proliferation and spread of BMSCs,which proved that piezoelectric implants have good biocompatibility.On the one hand,EEF intensity also directly affected the metabolism of osteosarcoma cells,in which high-intensity EEF has the most obvious killing effect on osteosarcoma cells?the cell survival rate is only16%?.In specifically,under the effect of high-intensity EEF,cell membrane potential depolarization enhanced membrane permeability,and then copper ions in the solution entered into the cell easily to cause mitochondrial membrane potential depolarization and thus promote cell apoptosis.On the other hand,piezoelectric implants with low,medium and high surface potential can form low,medium and high intensity EEF with bacterial cell membrane.Firstly,the plate colony count method was used to show that the implant with high surface potential has the best killing effect on bacteria,and antibacterial rate can reach 100%.Furthermore,by measuring the amount of ions in bacteria,it was found that under the action of high-intensity EEF,the amount of ions targeting bacteria was the largest,which was about140%higher than that of low-intensity EEF.EEF forming between the polarized piezoelectric implant and the charged living body provides a new way for the clinical design of bone implants with anti-tumor and anti-bacterial.?2?Based on the characteristics that piezoelectric particles can generate electrical signals in response to external ultrasonic stimulation,the idea of constructing high-intensity nano electric field?NEF?is further proposed to achieve remote control to kill tumor cells.The copper doped potassium sodium niobate piezoelectric particles with electrical signal response were prepared by solid-phase sintering method incorporated hydrothermal treatment technology.Under the condition of external electric field,piezoelectric particles were polarized by a personalized mold.The electrical signal of piezoelectric particles response under ultrasonic stimulation was collected by a digital signal amplifier.The results showed that the electric signal response of polarized piezoelectric particles was the strongest,which could reach 120 m V.The results of cell experiments in vitro showed that the killing effect of high-intensity NEF on osteosarcoma cells was the most obvious?the cell survival rate was only 20.8%?.In vivo animal experiments further proved the anti-tumor effect of high-intensity NEF.Therefore,according to the above preliminary exploration experiment of ultrasonic stimulation to enhance the electrical signal response of piezoelectric particles,passive high-intensity NEF provides a new method for early local treatment of osteosarcoma.?3?Based on the multi-level structure of piezoelectric collagen fiber in bone tissue,the ideaof constructing micro-zonal structure with different electric signal response intensity on the surface of potassium sodium niobate piezoelectric implant material was proposed.Firstly,the micropatterned piezoelectric K_0.5Na_0.5Nb O₃?MPK?was constructed by laser induced phase transition.Two types of piezoelectric micro-zones on polarized MPK showed different charge densities,namely,higher charge density zone?H-zone?and lower charge density zone?L-zone?.The micro-zonal piezoelectric difference on negatively polarized MPK?N-MPK?was ascertained by scanning Kelvin probe force microscopy?SKPM?.The micro-zonal structure with different piezoelectricity can indirectly reflect the different electric signal intensity of two areas forming periodic micro-zonal electric field on the surface of implanted material to simulate the micro-zonal electric field environment of bone tissue.In vitro biomimetic mineralization experiments showed that microstructure with different intensity of electrical signal response could regulate the deposition of apatite,and more apatite was deposited in H-zone with high charge density.This preliminary exploratory experiment provides a good foundation for piezoelectric implant materials to have good osteogenic property.The idea of bionic micro-zonal electric field also provides a new thought for the design of implant materials.