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Translation of remote control regenerative technologies for bone repair.

Markides, Hareklea; McLaren, Jane S.; Telling, Neil D.; Alom, Noura; Al-Mutheffer, E’atelaf A.; Oreffo, Richard O.C.; Zannettino, Andrew; Scammell, Brigitte E.; White, Lisa J.; El Haj, Alicia J.

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Authors

Hareklea Markides

Jane S. McLaren

Noura Alom

E’atelaf A. Al-Mutheffer

Richard O.C. Oreffo

Andrew Zannettino

Brigitte E. Scammell

Lisa J. White

Alicia J. El Haj



Abstract

The role of biomechanical stimuli, or mechanotransduction, in normal bone homeostasis and repair is understood to facilitate effective osteogenesis of mesenchymal stem cells (MSCs) in vitro. Mechanotransduction has been integrated into a multitude of in vitro bone tissue engineering strategies and provides an effective means of controlling cell behaviour towards therapeutic outcomes. However, the delivery of mechanical stimuli to exogenous MSC populations, post implantation, poses a significant translational hurdle. Here, we describe an innovative bio-magnetic strategy, MICA, where magnetic nanoparticles (MNPs) are used to remotely deliver mechanical stimuli to the mechano-receptor, TREK-1, resulting in activation and downstream signalling via an external magnetic array. In these studies, we have translated MICA to a pre-clinical ovine model of bone injury to evaluate functional bone repair. We describe the development of a magnetic array capable of in vivo MNP manipulation and subsequent osteogenesis at equivalent field strengths in vitro. We further demonstrate that the viability of MICA-activated MSCs in vivo is unaffected 48?h post implantation. We present evidence to support early accelerated repair and preliminary enhanced bone growth in MICA-activated defects within individuals compared to internal controls. The variability in donor responses to MICA-activation was evaluated in vitro revealing that donors with poor osteogenic potential were most improved by MICA-activation. Our results demonstrate a clear relationship between responders to MICA in vitro and in vivo. These unique experiments offer exciting clinical applications for cell-based therapies as a practical in vivo source of dynamic loading, in real-time, in the absence of pharmacological agents.

Journal Article Type Article
Acceptance Date Mar 22, 2018
Publication Date Apr 17, 2018
Journal NPJ Regenerative Medicine
Print ISSN 2057-3995
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 3
Article Number 9
DOI https://doi.org/10.1038/s41536-018-0048-1
Keywords cell signaling; mesenchymal stem cells
Publisher URL https://www.nature.com/articles/s41536-018-0048-1

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