title: Remotely Activated Mechanotransduction via Magnetic Nanoparticles Promotes Mineralization Synergistically With Bone Morphogenetic Protein 2: Applications for Injectable Cell Therapy.
abstract: Bone requires dynamic mechanical stimulation to form and maintain functional tissue, yet mechanical stimuli are often lacking in many therapeutic approaches for bone regeneration. Magnetic nanoparticles provide a method for delivering these stimuli by directly targeting cell-surface mechanosensors and transducing forces from an external magnetic field, resulting in remotely controllable mechanotransduction. In this investigation, functionalized magnetic nanoparticles were attached to either the mechanically gated TREK1 K+ channel or the (integrin) RGD-binding domains of human mesenchymal stem cells. These cells were microinjected into an ex vivo chick fetal femur (embryonic day 11) that was cultured organotypically in vitro as a model for endochondral bone formation. An oscillating 25-mT magnetic field delivering a force of 4 pN per nanoparticle directly against the mechanoreceptor induced mechanotransduction in the injected mesenchymal stem cells. It was found that cells that received mechanical stimuli via the nanoparticles mineralized the epiphyseal injection site more extensively than unlabeled control cells. The nanoparticle-tagged cells were also seeded into collagen hydrogels to evaluate osteogenesis in tissue-engineered constructs: in this case, inducing mechanotransduction by targeting TREK1 resulted in a 2.4-fold increase in mineralization and significant increases in matrix density. In both models, the combination of mechanical stimulation and sustained release of bone morphogenetic protein 2 (BMP2) from polymer microspheres showed a significant additive effect on mineralization, increasing the effectiveness of BMP2 delivery and demonstrating that nanoparticle-mediated mechanotransduction can be used synergistically with pharmacological approaches for orthopedic tissue engineering to maximize bone formation.
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom j.r.henstock@keele.ac.uk.
authors.forename: James R
authors.initials: JR
authors.lastname: Henstock
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Rotherham
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Hassan
authors.initials: H
authors.lastname: Rashidi
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shakesheff
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom; School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: El Haj
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002642:Chick Embryo; D002645:Chickens; D005269:Femur / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D060526:Magnetic Fields; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: Bone marrow stromal cells; Cellular therapy; Clinical translation; Differentiation; Mesenchymal stem cells; Tissue regeneration; Transduction