Wireless Measurements Using Electrical Impedance Spectroscopy to Monitor Fracture Healing

There is an unmet need for improved, clinically relevant methods to longitudinally quantify bone healing during fracture care. Here we develop a smart bone plate to wirelessly monitor healing utilizing electrical impedance spectroscopy (EIS) to provide real-time data on tissue com-position within the fracture callus. To validate our technology, we created a 1-mm rabbit tibial defect and fixed the bone with a standard veterinary plate modified with a custom-designed housing that included two impedance sensors capable of wireless transmission. Impedance magnitude and phase measurements were transmitted every 48-hours for up to 10-weeks. Bone healing was assessed by X-ray, μCT, and histomorphometry. Our results indicated the sensors successfully incorporated into the fracture callus and did not impede repair. Electrical impedance, resistance, and reactance increased steadily from weeks 3 to 7—corresponding to the transition from hematoma to cartilage to bone within the fracture gap—then plateaued as the bone began to consolidate. These three electrical readings significantly correlated with traditional measurements of bone healing and successfully distinguished between union and not healed fractures, with the strongest relationship found with impedance magnitude. These results suggest that our EIS smart bone plate can provide continuous and highly sensitive quantitative tissue measurements throughout the course of fracture healing to better guide personalized clinical care.

[1]  G. Slobogean,et al.  Bone turnover markers as surrogates of fracture healing after intramedullary fixation of tibia and femur fractures , 2022, Bone & joint research.

[2]  M. Provencher,et al.  Collagen X Longitudinal Fracture Biomarker Suggests Staged Fixation in Tibial Plateau Fractures Delays Rate of Endochondral Repair , 2022, Journal of orthopaedic trauma.

[3]  J. Davies,et al.  The Sigmoidal Nature of Bone Anchorage. , 2022, The International journal of oral & maxillofacial implants.

[4]  T. Verma,et al.  Monitoring the Progress of Treatment in Fracture Non-Union: The Role of Alkaline Phosphatase and Ultrasonography , 2021, Revista brasileira de ortopedia.

[5]  G. Kazakia,et al.  A timeseries analysis of the fracture callus extracellular matrix proteome during bone fracture healing. , 2021, Journal of life sciences.

[6]  Paolo Dario,et al.  A Novel Capacitive Measurement Device for Longitudinal Monitoring of Bone Fracture Healing , 2021, Sensors.

[7]  F. Di Puccio,et al.  In silico re-foundation of strain-based healing assessment of fractures treated with an external fixator. , 2021, Journal of the mechanical behavior of biomedical materials.

[8]  J. Barcik,et al.  Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time? , 2021, Biomedicines.

[9]  W. Walsh,et al.  'SMART' implantable devices for spinal implants: a systematic review on current and future trends. , 2021, Journal of spine surgery.

[10]  T. Murakami,et al.  Quantitative bone single-photon emission computed tomography imaging for uninfected nonunion: comparison of hypertrophic nonunion and non-hypertrophic nonunion , 2020, Journal of Orthopaedic Surgery and Research.

[11]  M. Provencher,et al.  The Life of a Fracture: Biologic Progression, Healing Gone Awry, and Evaluation of Union. , 2020, JBJS reviews.

[12]  Maria del Sol Pèrez-Lago,et al.  Value of SPECT/CT in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures. , 2020, The British journal of radiology.

[13]  T. Miclau,et al.  A quantitative serum biomarker of circulating collagen X effectively correlates with endochondral fracture healing , 2020, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[14]  Xingjia Mao,et al.  A global bibliometric and visualized analysis in the status and trends of subchondral bone research , 2020, Medicine.

[15]  L. Massari,et al.  Pulsed Electromagnetic Field Stimulation of Bone Healing and Joint Preservation: Cellular Mechanisms of Skeletal Response , 2020, Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews.

[16]  H. Dailey,et al.  Imaging Modalities to Assess Fracture Healing , 2020, Current Osteoporosis Reports.

[17]  Wing Kong Chiu,et al.  Towards a Non-Invasive Technique for Healing Assessment of Internally Fixated Femur , 2019, Sensors.

[18]  B. Gabbe,et al.  Incidence, Costs and Predictors of Non-Union, Delayed Union and Mal-Union Following Long Bone Fracture , 2018, International journal of environmental research and public health.

[19]  R. Marcucio,et al.  Cellular biology of fracture healing , 2018, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[20]  Monica C. Lin,et al.  Smart bone plates can monitor fracture healing , 2018, bioRxiv.

[21]  H. Dailey,et al.  Tibial Fracture Nonunion and Time to Healing After Reamed Intramedullary Nailing: Risk Factors Based on a Single-Center Review of 1003 Patients , 2018, Journal of orthopaedic trauma.

[22]  A. Pitsillides,et al.  The Chondro-Osseous Continuum: Is It Possible to Unlock the Potential Assigned Within? , 2018, Front. Bioeng. Biotechnol..

[23]  M. Aiona,et al.  A degradation fragment of type X collagen is a real-time marker for bone growth velocity , 2017, Science Translational Medicine.

[24]  Meir Marmor,et al.  New opportunities for fracture healing detection: Impedance spectroscopy measurements correlate to tissue composition in fractures , 2017, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  Sunny J. Gandhi,et al.  Bone Scan in Detection of Biological Activity in Nonhypertrophic Fracture Nonunion , 2017, Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India.

[26]  R. Reis,et al.  Evaluation of bone turnover markers and serum minerals variations for predicting fracture healing versus non-union processes in adult sheep as a model for orthopedic research. , 2017, Injury.

[27]  P. Giannoudis,et al.  Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): A systematic review and meta-analysis. , 2017, Injury.

[28]  Brian P. Cunningham,et al.  Fracture healing: A review of clinical, imaging and laboratory diagnostic options. , 2017, Injury.

[29]  C. Garnavos Treatment of aseptic non-union after intramedullary nailing without removal of the nail. , 2017, Injury.

[30]  Enrico Ciulli,et al.  Vibration Testing Procedures for Bone Stiffness Assessment in Fractures Treated with External Fixation , 2016, Annals of Biomedical Engineering.

[31]  P. Kostenuik,et al.  Fracture healing physiology and the quest for therapies for delayed healing and nonunion , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[32]  R. Steen,et al.  Epidemiology of Fracture Nonunion in 18 Human Bones. , 2016, JAMA surgery.

[33]  A. Sanjay,et al.  The Multifaceted Osteoclast; Far and Beyond Bone Resorption , 2016, Journal of cellular biochemistry.

[34]  Tomio Inoue,et al.  SUV measurement of normal vertebrae using SPECT/CT with Tc-99m methylene diphosphonate. , 2016, American journal of nuclear medicine and molecular imaging.

[35]  S. Mehta,et al.  Biological Risk Factors for Nonunion of Bone Fracture , 2016, JBJS reviews.

[36]  M. Bhandari,et al.  Determination of Radiographic Healing: An Assessment of Consistency Using RUST and Modified RUST in Metadiaphyseal Fractures , 2015, Journal of orthopaedic trauma.

[37]  R. Reis,et al.  Bone turnover markers for early detection of fracture healing disturbances: A review of the scientific literature. , 2015, Anais da Academia Brasileira de Ciencias.

[38]  D. Hu,et al.  The Multifaceted Role of the Vasculature in Endochondral Fracture Repair , 2015, Front. Endocrinol..

[39]  M. Richardson,et al.  Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. , 2014, Injury.

[40]  Hamish Simpson,et al.  Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. , 2014, Injury.

[41]  M. Kurosaka,et al.  Comparison of radiographic appearance and bone scintigraphy in fracture nonunions. , 2013, Orthopedics.

[42]  Mohit Bhandari,et al.  Predictors of nonunion and reoperation in patients with fractures of the tibia: an observational study , 2013, BMC Musculoskeletal Disorders.

[43]  D. Hu,et al.  Creating rigidly stabilized fractures for assessing intramembranous ossification, distraction osteogenesis, or healing of critical sized defects. , 2012, Journal of visualized experiments : JoVE.

[44]  Thomas A Einhorn,et al.  The biology of fracture healing. , 2011, Injury.

[45]  D. Hu,et al.  Rejuvenation of the inflammatory system stimulates fracture repair in aged mice , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[46]  G. Duda,et al.  The early fracture hematoma and its potential role in fracture healing. , 2010, Tissue engineering. Part B, Reviews.

[47]  E. Cherkaev,et al.  Electrical impedance spectroscopy as a potential tool for recovering bone porosity , 2009, Physics in medicine and biology.

[48]  Mohit Bhandari,et al.  Study to prospectively evaluate reamed intramedually nails in patients with tibial fractures (S.P.R.I.N.T.): Study rationale and design , 2008, BMC musculoskeletal disorders.

[49]  L. Tagliabue,et al.  Risk factors contributing to fracture non-unions. , 2007, Injury.

[50]  O. Johnell,et al.  An estimate of the worldwide prevalence and disability associated with osteoporotic fractures , 2006, Osteoporosis International.

[51]  Eleftherios Tsiridis,et al.  Bone substitutes: an update. , 2005, Injury.

[52]  A. Parfitt Misconceptions (2): turnover is always higher in cancellous than in cortical bone. , 2002, Bone.

[53]  Kenneth A Buckwalter,et al.  Technical considerations: CT and MR imaging in the postoperative orthopedic patient. , 2002, Seminars in musculoskeletal radiology.

[54]  D. Hu,et al.  Molecular aspects of healing in stabilized and non‐stabilized fractures , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[55]  Christopher L. Davey,et al.  The dielectric properties of biological cells at radiofrequencies : Applications in biotechnology , 1999 .

[56]  R. W. Lau,et al.  The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz. , 1996, Physics in medicine and biology.

[57]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[58]  G. Paiement,et al.  The importance of the blood supply in the healing of tibial fractures. , 1995, Contemporary orthopaedics.

[59]  S M Perren,et al.  A method for making reproducible experimental fractures of the rabbit tibia. , 1982, Injury.

[60]  K. Foster,et al.  Dielectric properties of mammalian tissues from 0.1 to 100 MHz: a summary of recent data. , 1982, Physics in medicine and biology.

[61]  H. Genant,et al.  Bone-seeking radionuclides: an in vivo study of factors affecting skeletal uptake. , 1974, Radiology.

[62]  C. Galasko The pathological basis for skeletal scintigraphy. , 1972, The Journal of bone and joint surgery. British volume.

[63]  W. J. Whitehouse,et al.  Composition of Trabecular Bone in Children and its relation to Radiation Dosimetry , 1968, Nature.

[64]  E. Mackenzie,et al.  Inter-Rater Reliability of the Modified Radiographic Union Score for Diaphyseal Tibial Fractures With Bone Defects , 2019, Journal of orthopaedic trauma.

[65]  A. Vaziri,et al.  Biomechanics and mechanobiology of trabecular bone: a review. , 2015, Journal of biomechanical engineering.

[66]  B. Olsen,et al.  Bone development. , 2015, Bone.

[67]  Janet Austin,et al.  The Burden of Musculoskeletal Diseases in the United States , 2008 .

[68]  The Sprint Investigators Study to prospectively evaluate reamed intramedually nails in patients with tibial fractures (S.P.R.I.N.T.): Study rationale and design , 2008 .