Remote Tuning Of Built-In Magnetoelectric Microenvironment To Promote Bone Regeneration

BackgroundThe repair of large osseous defects remains a major clinical challenge.The dynamic balance of bone tissue is regulated by many biological,chemical and physical environmental factors.Employing biomimetic materials to simulate the microenvironment under the physiological status of bone tissue is an important development direction of tissue engineering in recent years.With the in-depth study,it has been found that when bone get injured,the surrounding magnetoelectric microenvironment will be damaged.Therefore,providing a magnetoelectric microenvironment that simulates physiological status will promote bone regeneration.In the early-stage studies of magnetic and electrical stimulation-guided bone repair,applying an electromagnetic field was mostly used.However,the applied electromagnetic field could not be accurately located to the injury site;The intensity of electromagnetic field was also difficult to be precisely controlled.Therefore,these limit its application in clinical treatment.In recent years,for implant materials that can achieve in-situ stimulation,piezoelectric materials are used by more and more researchers,mainly for restoring the electrical microenvironment.The effects of magnetic fields in physiological status are ignored.In addition,after the piezoelectric material is implanted in the defect area,the surfacepotential is generally decreased,and the surface potential of the material cannot be controlled postimplantation.It's difficult to achieve the well effect of bone repair in long-term if the implant materials can't be dynamically controlled.In order to make up the shortcoming of piezoelectric materials,researchers have focused on magneto electric materials.The magnetoelectric composite is composed of piezoelectric and magnetostrictive components.Due to the magnetoelectric effect,once a magnetic field is applied to the composite,the electrical polarization is induced.Thus,the surface potential of the material can be dynamically controlled.Therefore,how to construct the magneto electric composites that can provide the magneto electric microenvironment required for bone regeneration through remote tuning has become a key scientific problem in current research.ObjectivesIn view of the exiting problems,this study used cobalt ferrite(CoFe2O4)and polyvinylidene fluoride trifluoroethylene(P(VDF-TrFE))to construct magneto electric composite,which can be remotely tuned by external magnetic field.Molecular dynamics simulation was used to predict the optimal material systems for attaining the greatest protein adsorption.To explore the effect of magnetoelectric microenvironment constructed by selected material system on osteoimmunomodulatory and bone regeneration.Provide guidance for the design and development of synthetic bone biomaterials in the future.MethodsFirstly,CoFe2O4 nanoparticles were used as fillers and the P(VDF-TrFE)was used as the matrix in this study.The CoFe2O4/P(VDF-TrFE)magnetoelectric nanocomposite with different proportion of CoFe2O4 nanoparticles were prepared by the casting process.The external magnetic field was employed for remote tuning of the magneto electric microenvironment constructed by the magnetoelectric nanocomposite.Next,molecular dynamics was used to simulate the adsorption of fibronectin on magneto electric nanocomposite with different different proportion of CoFe2O4 nanoparticles.The osteoinductive ability of materials was predicted according to the results of molecular dynamics.These predictions were validated by in vitro experiments.Then,the influence of the magnetoelectric microenvironment on the behavior of stem cells and immune cells and the related mechanisms were tested through the indirect co-culture of bone marrow mesenchymal stem cells(BMSCs)and macrophages,under the selected materials system.Finally,the rat calvarial defects were employed for evaluating the osteoimmunomodulatory and bone regeneration in vivo.ResultsCoFe2O4/P(VDF-TrFE)magnetoelectric nanocomposite was prepared by solution casting method.By loading an external magnetic field,the remote tuning of the magnetoelectric microenvironment is realized.According to molecular dynamics simulation,it is predicted thatthe 10 wt%CoFe2O4/P(VDF-TrFE)magnetoelectric nanocomposite has the optimal osteoinductive ability.The results of in vitro experiments confirmed the accuracy of the prediction.The magnetoelectric microenvironment constructed by the 10 wt%CoFe2O4/P(VDF-TrFE)magnetoelectric nanocomposite and the external magnetic field can promote BMSCs osteogenic differentiation by activating mechanical transduction related signaling pathways.This magnetoelectric microenvironment can induce macrophages M2 polarization by activating PI3 K/Akt signaling pathway and inhibiting the activation of NF-?B.The magnetoelectric microenvironment constructed by the 10 wt%CoFe2O4/P(VDF-TrFE)magnetoelectric nanocomposite and the external magnetic field could activate the initial immune response and accelerate the transition from M1 to M2 phenotype to further promote bone regeneration in vivo.ConclusionBy regulating the CoFe2O4/P(VDF-TrFE)magneto electric nanocomposite with an external magnetic field,it can realize the remote tuning of the build-in magnetoelectric microenvironment.The tuned magneto electric microenvironment can directly induce the osteogenic differentiation of BMSCs,and can also promote bone regeneration by regulating the osteoimmunomodulatory.This study provides a strategy to precisely tune the magnetoelectric microenvironment in the bone defect area to accelerate bone repair.This study also offers a novel perspective and direction of regulation of the microenvironment in bone regeneration area by biomimetic materials for promoting bone regeneration.