Wireless implantable sensor for non-invasive, longitudinal quantification of axial strain across rodent long bone defects

Bone development, maintenance, and regeneration are remarkably sensitive to mechanical cues. Consequently, mechanical stimulation has long been sought as a putative target to promote endogenous healing after fracture. Given the transient nature of bone repair, tissue-level mechanical cues evolve rapidly over time after injury and are challenging to measure non-invasively. The objective of this work was to develop and characterize an implantable strain sensor for non-invasive monitoring of axial strain across a rodent femoral defect during functional activity. Herein, we present the design, characterization, and in vivo demonstration of the device’s capabilities for quantitatively interrogating physiological dynamic strains during bone regeneration. Ex vivo experimental characterization of the device showed that it exceeded the technical requirements for sensitivity, signal resolution, and electromechanical stability. The digital telemetry minimized power consumption, enabling long-term intermittent data collection. Devices were implanted in a rat 6 mm femoral segmental defect model and after three days, data were acquired wirelessly during ambulation and synchronized to corresponding radiographic videos, validating the ability of the sensor to non-invasively measure strain in real-time. Lastly, in vivo strain measurements were utilized in a finite element model to estimate the strain distribution within the defect region. Together, these data indicate the sensor is a promising technology to quantify local tissue mechanics in a specimen specific manner, facilitating more detailed investigations into the role of the mechanical environment in dynamic skeletal healing and remodeling.

[1]  Keat Ghee Ong,et al.  Implantable Sensors for Regenerative Medicine. , 2017, Journal of biomechanical engineering.

[2]  Toby King,et al.  The burden of musculoskeletal diseases in the United States. , 2016, Seminars in arthritis and rheumatism.

[3]  T. Einhorn,et al.  Epidemiology of Fracture Nonunion in 18 Human Bones. , 2016, JAMA surgery.

[4]  J. Barralet,et al.  Biomaterial‐Stabilized Soft Tissue Healing for Healing of Critical‐Sized Bone Defects: the Masquelet Technique , 2016, Advanced healthcare materials.

[5]  Elizabeth Gibney,et al.  The inside story on wearable electronics , 2015, Nature.

[6]  Hilmi Volkan Demir,et al.  Implantable microelectromechanical sensors for diagnostic monitoring and post‐surgical prediction of bone fracture healing , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[7]  L. Gerstenfeld,et al.  Mechanical microenvironments and protein expression associated with formation of different skeletal tissues during bone healing , 2015, Biomechanics and modeling in mechanobiology.

[8]  Ralph Müller,et al.  Mechanical Regulation of Bone Regeneration: Theories, Models, and Experiments , 2014, Front. Endocrinol..

[9]  E. Zelzer,et al.  A mechanical Jack-like Mechanism drives spontaneous fracture healing in neonatal mice. , 2014, Developmental cell.

[10]  John F. Drazan,et al.  Elementary Implantable Force Sensor: For Smart Orthopaedic Implants. , 2013, Advances in biosensors and bioelectronics.

[11]  R. Guldberg,et al.  Effects of in vivo mechanical loading on large bone defect regeneration , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[12]  M. Allen,et al.  A Microfabricated Wireless RF Pressure Sensor Made Completely of Biodegradable Materials , 2012, Journal of Microelectromechanical Systems.

[13]  R. Guldberg,et al.  Mechanical regulation of vascular growth and tissue regeneration in vivo , 2011, Proceedings of the National Academy of Sciences.

[14]  A Ignatius,et al.  Small animal bone healing models: standards, tips, and pitfalls results of a consensus meeting. , 2011, Bone.

[15]  G. Duda,et al.  Time kinetics of bone defect healing in response to BMP-2 and GDF-5 characterised by in vivo biomechanics. , 2011, European cells & materials.

[16]  Lutz Claes,et al.  Internal forces and moments in the femur of the rat during gait. , 2010, Journal of biomechanics.

[17]  Daniel L. Bellin,et al.  Correlations between local strains and tissue phenotypes in an experimental model of skeletal healing. , 2010, Journal of biomechanics.

[18]  G N Duda,et al.  Mechanobiology of bone healing and regeneration: in vivo models , 2010, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[19]  T. Wright,et al.  Cancellous bone osseointegration is enhanced by in vivo loading. , 2010, Tissue engineering. Part C, Methods.

[20]  Xuebin B. Yang,et al.  Long bone defect models for tissue engineering applications: criteria for choice. , 2010, Tissue engineering. Part B, Reviews.

[21]  Young-Hui Chang,et al.  High-speed X-ray video demonstrates significant skin movement errors with standard optical kinematics during rat locomotion , 2010, Journal of Neuroscience Methods.

[22]  L. Claes,et al.  Monitoring the Mechanical Properties of Healing Bone , 2009, Clinical orthopaedics and related research.

[23]  E. Morgan,et al.  Measurement of fracture callus material properties via nanoindentation. , 2008, Acta biomaterialia.

[24]  David J Mooney,et al.  Quantitative assessment of scaffold and growth factor‐mediated repair of critically sized bone defects , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  Kensall D. Wise,et al.  Integrated sensors, MEMS, and microsystems: Reflections on a fantastic voyage , 2007 .

[26]  Thomas A Einhorn,et al.  Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation , 2003, Journal of cellular biochemistry.

[27]  H. Frost From Wolff's law to the Utah paradigm: Insights about bone physiology and its clinical applications , 2001, The Anatomical record.

[28]  D Kaspar,et al.  Effects of Mechanical Factors on the Fracture Healing Process , 1998, Clinical orthopaedics and related research.

[29]  L. Claes,et al.  Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. , 1998, Journal of biomechanics.

[30]  J Kenwright,et al.  The influence of induced micromovement upon the healing of experimental tibial fractures. , 1985, The Journal of bone and joint surgery. British volume.

[31]  A. T. Berman,et al.  The use of the Hickman catheter in orthopaedic infections. Brief note. , 1985, The Journal of bone and joint surgery. American volume.

[32]  Brett S. Klosterhoff,et al.  Material and Mechanobiological Considerations for Bone Regeneration , 2017 .

[33]  G. Duda,et al.  Mechanical load modulates the stimulatory effect of BMP2 in a rat nonunion model. , 2013, Tissue engineering. Part A.

[34]  David J Mooney,et al.  An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. , 2011, Biomaterials.

[35]  Engin Ozcivici,et al.  Mechanical signals as anabolic agents in bone , 2010, Nature Reviews Rheumatology.

[36]  L. Lanyon Functional strain as a determinant for bone remodeling , 2006, Calcified Tissue International.

[37]  G A Ilizarov,et al.  The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. , 1989, Clinical orthopaedics and related research.

[38]  W C Van Buskirk,et al.  A continuous wave technique for the measurement of the elastic properties of cortical bone. , 1984, Journal of biomechanics.

[39]  Perren Sm,et al.  Physical and biological aspects of fracture healing with special reference to internal fixation. , 1979, Clinical orthopaedics and related research.