0
Research Papers

Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

[+] Author and Article Information
Sijia Zhang

Department of Bioengineering,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104
e-mail: sijiaz@seas.upenn.edu

Xuan Cao

Department of Materials
Science and Engineering,
University of Pennsylvania,
3231 Walnut Street,
Philadelphia, PA 19104
e-mail: xuancao@seas.upenn.edu

Alec M. Stablow

Department of Bioengineering,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104
e-mail: stablowa@seas.upenn.edu

Vivek B. Shenoy

Department of Bioengineering,
University of Pennsylvania,
3231 Walnut Street,
Philadelphia, PA 19104;
Department of Materials
Science and Engineering,
University of Pennsylvania,
3231 Walnut Street,
Philadelphia, PA 19104;
Department of Mechanical Engineering and
Applied Mechanics,
University of Pennsylvania,
3231 Walnut Street,
Philadelphia, PA 19104
e-mail: vshenoy@seas.upenn.edu

Beth A. Winkelstein

Mem. ASME
Department of Bioengineering,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104;
Department of Neurosurgery,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104
e-mail: winkelst@seas.upenn.edu

1Corresponding author.

Manuscript received August 5, 2015; final manuscript received October 21, 2015; published online January 27, 2016. Editor: Victor H. Barocas.

J Biomech Eng 138(2), 021013 (Jan 27, 2016) (12 pages) Paper No: BIO-15-1392; doi: 10.1115/1.4031975 History: Received August 05, 2015; Revised October 21, 2015

Excessive loading of ligaments can activate the neural afferents that innervate the collagenous tissue, leading to a host of pathologies including pain. An integrated experimental and modeling approach was used to define the responses of neurons and the surrounding collagen fibers to the ligamentous matrix loading and to begin to understand how macroscopic deformation is translated to neuronal loading and signaling. A neuron-collagen construct (NCC) developed to mimic innervation of collagenous tissue underwent tension to strains simulating nonpainful (8%) or painful ligament loading (16%). Both neuronal phosphorylation of extracellular signal-regulated kinase (ERK), which is related to neuroplasticity (R2 ≥ 0.041; p ≤ 0.0171) and neuronal aspect ratio (AR) (R2 ≥ 0.250; p < 0.0001), were significantly correlated with tissue-level strains. As NCC strains increased during a slowly applied loading (1%/s), a “switchlike” fiber realignment response was detected with collagen reorganization occurring only above a transition point of 11.3% strain. A finite-element based discrete fiber network (DFN) model predicted that at bulk strains above the transition point, heterogeneous fiber strains were both tensile and compressive and increased, with strains in some fibers along the loading direction exceeding the applied bulk strain. The transition point identified for changes in collagen fiber realignment was consistent with the measured strain threshold (11.7% with a 95% confidence interval of 10.2–13.4%) for elevating ERK phosphorylation after loading. As with collagen fiber realignment, the greatest degree of neuronal reorientation toward the loading direction was observed at the NCC distraction corresponding to painful loading. Because activation of neuronal ERK occurred only at strains that produced evident collagen fiber realignment, findings suggest that tissue strain-induced changes in the micromechanical environment, especially altered local collagen fiber kinematics, may be associated with mechanotransduction signaling in neurons.

FIGURES IN THIS ARTICLE
<>
Copyright © 2016 by ASME
Your Session has timed out. Please sign back in to continue.

References

Kallakuri, S. , Li, Y. , Chen, C. , and Cavanaugh, J. M. , 2012, “ Innervation of Cervical Ventral Facet Joint Capsule: Histological Evidence,” World J. Orthop., 3(2), pp. 10–14. [CrossRef] [PubMed]
Yahia, L. H. , and Newman, N. , 1991, “ Innervation of Spinal Ligaments of Patients With Disc Herniation. An Immunohistochemical Study,” Pathol. Res. Pract., 187(8), pp. 936–938. [CrossRef] [PubMed]
Petrie, S. , Collins, J. G. , Solomonow, M. , Wink, C. , Chuinard, R. , and D'Ambrosia, R. , 1998, “ Mechanoreceptors in the Human Elbow Ligaments,” J. Hand Surg. Am., 23(3), pp. 512–518. [CrossRef] [PubMed]
Schultz, R. A. , Miller, D. C. , Kerr, C. S. , and Micheli, L. , 1984, “ Mechanoreceptors in Human Cruciate Ligaments. A Histological Study,” J. Bone Joint Surg. Am., 66(7), pp. 1072–1076. [PubMed]
Solomonow, M. , 2004, “ Ligaments: A Source of Work-Related Musculoskeletal Disorders,” J. Electromyogr. Kinesiol., 14(1), pp. 49–60. [CrossRef] [PubMed]
Winkelstein, B. A. , 2011, “ How Can Animal Models Inform on the Transition to Chronic Symptoms in Whiplash?” Spine, 36(Suppl. 25), pp. S218–225. [CrossRef] [PubMed]
Kallakuri, S. , Singh, A. , Lu, Y. , Chen, C. , Patwardhan, A. , and Cavanaugh, J. M. , 2008, “ Tensile Stretching of Cervical Facet Joint Capsule and Related Axonal Changes,” Eur. Spine J., 17(4), pp. 556–563. [CrossRef] [PubMed]
Chen, C. , Lu, Y. , Kallakuri, S. , Patwardhan, A. , and Cavanaugh, J. M. , 2006, “ Distribution of A-Delta and C-Fiber Receptors in the Cervical Facet Joint Capsule and Their Response to Stretch,” J. Bone Joint Surg. Am., 88(8), pp. 1807–1816. [CrossRef] [PubMed]
Kras, J. V. , Tanaka, K. , Gilliland, T. M. , and Winkelstein, B. A. , 2013, “ An Anatomical and Immunohistochemical Characterization of Afferents Innervating the C6-C7 Facet Joint After Painful Joint Loading in the Rat,” Spine, 38(6), pp. E325–331. [CrossRef] [PubMed]
Lu, Y. , Chen, C. , Kallakuri, S. , Patwardhan, A. , and Cavanaugh, J. M. , 2005, “ Neural Response of Cervical Facet Joint Capsule to Stretch: A Study of Whiplash Pain Mechanism,” Stapp Car Crash J., 49, pp. 49–65. [PubMed]
Crosby, N. D. , Gilliland, T. M. , and Winkelstein, B. A. , 2014, “ Early Afferent Activity From the Facet Joint After Painful Trauma to Its Capsule Potentiates Neuronal Excitability and Glutamate Signaling in the Spinal Cord,” Pain, 155(9), pp. 1878–1887. [CrossRef] [PubMed]
Lee, K. E. , and Winkelstein, B. A. , 2009, “ Joint Distraction Magnitude is Associated With Different Behavioral Outcomes and Substance P Levels for Cervical Facet Joint Loading in the Rat,” J. Pain, 10(4), pp. 436–445. [CrossRef] [PubMed]
Lee, K. E. , Davis, M. B. , and Winkelstein, B. A. , 2008, “ Capsular Ligament Involvement in the Development of Mechanical Hyperalgesia After Facet Joint Loading: Behavioral and Inflammatory Outcomes in a Rodent Model of Pain,” J. Neurotrauma, 25(11), pp. 1383–1393. [CrossRef] [PubMed]
Quinn, K. P. , Dong, L. , Golder, F. J. , and Winkelstein, B. A. , 2010, “ Neuronal Hyperexcitability in the Dorsal Horn After Painful Facet Joint Injury,” Pain, 151(2), pp. 414–421. [CrossRef] [PubMed]
Quinn, K. P. , Lee, K. E. , Ahaghotu, C. C. , and Winkelstein, B. A. , 2007, “ Structural Changes in the Cervical Facet Capsular Ligament: Potential Contributions to Pain Following Subfailure Loading,” Stapp Car Crash J., 51, pp. 169–187. [PubMed]
Quinn, K. P. , Bauman, J. A. , Crosby, N. D. , and Winkelstein, B. A. , 2010, “ Anomalous Fiber Realignment During Tensile Loading of the Rat Facet Capsular Ligament Identifies Mechanically Induced Damage and Physiological Dysfunction,” J. Biomech., 43(10), pp. 1870–1875. [CrossRef] [PubMed]
Crosby, N. D. , Weisshaar, C. L. , and Winkelstein, B. A. , 2013, “ Spinal Neuronal Plasticity is Evident Within 1 Day After a Painful Cervical Facet Joint Injury,” Neurosci. Lett., 542, pp. 102–106. [CrossRef] [PubMed]
Kras, J. V. , Kartha, S. , and Winkelstein, B. A. , 2015, “ Intra-Articular Nerve Growth Factor Regulates Development, But Not Maintenance, of Injury-Induced Facet Joint Pain & Spinal Neuronal Hypersensitivity,” Osteoarthritis and Cartilage, 23(11) pp. 1999–2008. [CrossRef] [PubMed]
Rosso, F. , Giordano, A. , Barbarisi, M. , and Barbarisi, A. , 2004, “ From Cell-ECM Interactions to Tissue Engineering,” J. Cell. Physiol., 199(2), pp. 174–180. [CrossRef] [PubMed]
Barros, C. S. , Franco, S. J. , and Müller, U. , 2011, “ Extracellular Matrix: Functions in the Nervous System,” Cold Spring Harbor Perspect. Biol., 3(1), p. a005108.
Spedden, E. , White, J. D. , Naumova, E. N. , Kaplan, D. L. , and Staii, C. , 2012, “ Elasticity Maps of Living Neurons Measured by Combined Fluorescence and Atomic Force Microscopy,” Biophys. J., 103(5), pp. 868–877. [CrossRef] [PubMed]
Wenger, M. P. E. , Bozec, L. , Horton, M. A. , and Mesquida, P. , 2007, “ Mechanical Properties of Collagen Fibrils,” Biophys. J., 93(4), pp. 1255–1263. [CrossRef] [PubMed]
Lopez-Garcia, M. D. C. , Beebe, D. J. , and Crone, W. C. , 2010, “ Young's Modulus of Collagen at Slow Displacement Rates,” Biomed. Mater. Eng., 20(6), pp. 361–369. [PubMed]
Tower, T. T. , Neidert, M. R. , and Tranquillo, R. T. , 2002, “ Fiber Alignment Imaging During Mechanical Testing of Soft Tissues,” Ann. Biomed. Eng., 30(10), pp. 1221–1233. [CrossRef] [PubMed]
Quinn, K. P. , and Winkelstein, B. A. , 2009, “ Vector Correlation Technique for Pixel-Wise Detection of Collagen Fiber Realignment during Injurious Tensile Loading,” J. Biomed. Opt., 14(5),p. 054010. [CrossRef] [PubMed]
Sander, E. A. , Stylianopoulos, T. , Tranquillo, R. T. , and Barocas, V. H. , 2009, “ Image-Based Multiscale Modeling Predicts Tissue-Level and Network-Level Fiber Reorganization in Stretched Cell-Compacted Collagen Gels,” Proc. Natl. Acad. Sci. U.S.A., 106(42), pp. 17675–17680. [CrossRef] [PubMed]
Quinn, K. P. , and Winkelstein, B. A. , 2008, “ Altered Collagen Fiber Kinematics Define the Onset of Localized Ligament Damage During Loading,” J. Appl. Physiol., 105(6), pp. 1881–1888. [CrossRef] [PubMed]
Dong, L. , Quindlen, J. C. , Lipschutz, D. E. , and Winkelstein, B. A. , 2012, “ Whiplash-Like Facet Joint Loading Initiates Glutamatergic Responses in the DRG and Spinal Cord Associated With Behavioral Hypersensitivity,” Brain Res., 1461, pp. 51–63. [CrossRef] [PubMed]
Schenck, R. C. , Kovach, I. S. , Agarwal, A. , Brummett, R. , Ward, R. A. , Lanctot, D. , and Athanasiou, K. A. , 1999, “ Cruciate Injury Patterns in Knee Hyperextension: A Cadaveric Model,” Arthroscopy, 15(5), pp. 489–495. [CrossRef] [PubMed]
Panjabi, M. M. , Cholewicki, J. , Nibu, K. , Grauer, J. , and Vahldiek, M. , 1998, “ Capsular Ligament Stretches During In Vitro Whiplash Simulations,” J. Spinal Disord., 11(3), pp. 227–232. [CrossRef] [PubMed]
Noyes, F. R. , DeLucas, J. L. , and Torvik, P. J. , 1974, “ Biomechanics of Anterior Cruciate Ligament Failure: An Analysis of Strain-Rate Sensitivity and Mechanisms of Failure in Primates,” J. Bone Jt. Surg. Am., 56(2), pp. 236–253.
Vader, D. , Kabla, A. , Weitz, D. , and Mahadevan, L. , 2009, “ Strain-Induced Alignment in Collagen Gels,” PLoS One, 4(6), p. e5902. [CrossRef] [PubMed]
Cullen, D. K. , Simon, C. M. , and LaPlaca, M. C. , 2007, “ Strain Rate-Dependent Induction of Reactive Astrogliosis and Cell Death in Three-Dimensional Neuronal-Astrocytic Co-Cultures,” Brain Res., 1158, pp. 103–115. [CrossRef] [PubMed]
Geddes, D. M. , Cargill, R. S. , and LaPlaca, M. C. , 2003, “ Mechanical Stretch to Neurons Results in a Strain Rate and Magnitude-Dependent Increase in Plasma Membrane Permeability,” J. Neurotrauma, 20(10), pp. 1039–1049. [CrossRef] [PubMed]
Delmas, P. , Hao, J. , and Rodat-Despoix, L. , 2011, “ Molecular Mechanisms of Mechanotransduction in Mammalian Sensory Neurons,” Nat. Rev. Neurosci., 12(3), pp. 139–153. [CrossRef] [PubMed]
Martinac, B. , 2004, “ Mechanosensitive Ion Channels: Molecules of Mechanotransduction,” J. Cell Sci., 117(Pt 12), pp. 2449–2460. [CrossRef] [PubMed]
Raoux, M. , Rodat-Despoix, L. , Azorin, N. , Giamarchi, A. , Hao, J. , Maingret, F. , Crest, M. , Coste, B. , and Delmas, P. , 2007, “ Mechanosensor Channels in Mammalian Somatosensory Neurons,” Sensors (Basel), 7(9), pp. 1667–1682. [CrossRef]
Hemphill, M. A. , Dabiri, B. E. , Gabriele, S. , Kerscher, L. , Franck, C. , Goss, J. A. , Alford, P. W. , and Parker, K. K. , 2011, “ A Possible Role for Integrin Signaling in Diffuse Axonal Injury,” PLoS One, 6(7), p. e22899. [CrossRef] [PubMed]
Chaturvedi, L. S. , Gayer, C. P. , Marsh, H. M. , and Basson, M. D. , 2008, “ Repetitive Deformation Activates Src-Independent FAK-Dependent ERK Motogenic Signals in Human Caco-2 Intestinal Epithelial Cells,” Am. J. Physiol. Cell Physiol., 294(6), pp. C1350–1361. [CrossRef] [PubMed]
Samarakoon, R. , and Higgins, P. J. , 2003, “ Pp60c-Src Mediates ERK Activation/Nuclear Localization and PAI-1 Gene Expression in Response to Cellular Deformation,” J. Cell. Physiol., 195(3), pp. 411–420. [CrossRef] [PubMed]
Neary, J. T. , Kang, Y. , Willoughby, K. A. , and Ellis, E. F. , 2003, “ Activation of Extracellular Signal-Regulated Kinase by Stretch-Induced Injury in Astrocytes Involves Extracellular ATP and P2 Purinergic Receptors,” J. Neurosci., 23(6), pp. 2348–2356. [PubMed]
Stamboulian, S. , Choi, J.-S. , Ahn, H.-S. , Chang, Y.-W. , Tyrrell, L. , Black, J. A. , Waxman, S. G. , and Dib-Hajj, S. D. , 2010, “ ERK1/2 Mitogen-Activated Protein Kinase Phosphorylates Sodium Channel Na(V)1.7 and Alters Its Gating Properties,” J. Neurosci., 30(5), pp. 1637–1647. [CrossRef] [PubMed]
Cheng, J.-K. , and Ji, R.-R. , 2008, “ Intracellular Signaling in Primary Sensory Neurons and Persistent Pain,” Neurochem. Res., 33(10), pp. 1970–1978. [CrossRef] [PubMed]
Gao, Y.-J. , and Ji, R.-R. , 2009, “ c-Fos and pERK, Which is a Better Marker for Neuronal Activation and Central Sensitization After Noxious Stimulation and Tissue Injury?” Open Pain J., 2(1), pp. 11–17. [CrossRef] [PubMed]
Ji, R. R. , Baba, H. , Brenner, G. J. , and Woolf, C. J. , 1999, “ Nociceptive-Specific Activation of ERK in Spinal Neurons Contributes to Pain Hypersensitivity,” Nat. Neurosci., 2(12), pp. 1114–1119. [CrossRef] [PubMed]
Kras, J. V. , Weisshaar, C. L. , Quindlen, J. , and Winkelstein, B. A. , 2013, “ Brain-Derived Neurotrophic Factor is Upregulated in the Cervical Dorsal Root Ganglia and Spinal Cord and Contributes to the Maintenance of Pain From Facet Joint Injury in the Rat,” J. Neurosci. Res., 91(10), pp. 1312–1321. [CrossRef] [PubMed]
Sander, E. A. , Tranquillo, R. T. , and Barocas, V. H. , 2009, “ Image-Based Multiscale Structural Models of Fibrous Engineered Tissues,” Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2009), Minneapolis, MN, Sept. 3–6, pp. 4270–4272.
Lake, S. P. , and Barocas, V. H. , 2011, “ Mechanical and Structural Contribution of Non-Fibrillar Matrix in Uniaxial Tension: A Collagen-Agarose Co-Gel Model,” Ann. Biomed. Eng., 39(7), pp. 1891–1903. [CrossRef] [PubMed]
Nair, A. , Baker, B. M. , Trappmann, B. , Chen, C. S. , and Shenoy, V. B. , 2014, “ Remodeling of Fibrous Extracellular Matrices by Contractile Cells: Predictions From Discrete Fiber Network Simulations,” Biophys. J., 107(8), pp. 1829–1840. [CrossRef] [PubMed]
Aghvami, M. , Barocas, V. H. , and Sander, E. A. , 2013, “ Multiscale Mechanical Simulations of Cell Compacted Collagen Gels,” ASME J. Biomech. Eng., 135(7), p. 071004. [CrossRef]
Hadi, M. F. , Sander, E. A. , Ruberti, J. W. , and Barocas, V. H. , 2012, “ Simulated Remodeling of Loaded Collagen Networks Via Strain-Dependent Enzymatic Degradation and Constant-Rate Fiber Growth,” Mech. Mater., 44, pp. 72–82. [CrossRef] [PubMed]
Evans, M. C. , and Barocas, V. H. , 2009, “ The Modulus of Fibroblast-Populated Collagen Gels is Not Determined by Final Collagen and Cell Concentration: Experiments and an Inclusion-Based Model,” ASME J. Biomech. Eng., 131(10), p. 101014. [CrossRef]
Dong, L. , Guarino, B. B. , Jordan-Sciutto, K. L. , and Winkelstein, B. A. , 2011, “ Activating Transcription Factor 4, A Mediator of the Integrated Stress Response, is Increased in the Dorsal Root Ganglia Following Painful Facet Joint Distraction,” Neuroscience, 193, pp. 377–386. [CrossRef] [PubMed]
Bonner, T. J. , Newell, N. , Karunaratne, A. , Pullen, A. D. , Amis, A. A. M. J. , Bull, A. , and Masouros, S. D. , 2015, “ Strain-Rate Sensitivity of the Lateral Collateral Ligament of the Knee,” J. Mech. Behav. Biomed. Mater., 41, pp. 261–270. [CrossRef] [PubMed]
Crisco, J. J. , Moore, D. C. , and McGovern, R. D. , 2002, “ Strain-Rate Sensitivity of the Rabbit MCL Diminishes at Traumatic Loading Rates,” J. Biomech., 35(10), pp. 1379–1385. [CrossRef] [PubMed]
Patel, T. P. , Man, K. , Firestein, B. L. , and Meaney, D. F. , 2015, “ Automated Quantification of Neuronal Networks and Single-Cell Calcium Dynamics Using Calcium Imaging,” J. Neurosci. Methods., 243, pp. 26–38. [CrossRef] [PubMed]
MacArthur, M. W. , and Thornton, J. M. , 1993, “ Conformational Analysis of Protein Structures Derived From NMR Data,” Proteins, 17(3), pp. 232–251. [CrossRef] [PubMed]
Miller, K. S. , Connizzo, B. K. , and Soslowsky, L. J. , 2012, “ Collagen Fiber Re-Alignment in a Neonatal Developmental Mouse Supraspinatus Tendon Model,” Ann. Biomed. Eng., 40(5), pp. 1102–1110. [CrossRef] [PubMed]
Weisshaar, C. L. , Dong, L. , Bowman, A. S. , Perez, F. M. , Guarino, B. B. , Sweitzer, S. M. , and Winkelstein, B. A. , 2010, “ Metabotropic Glutamate Receptor-5 and Protein Kinase C-Epsilon Increase in Dorsal Root Ganglion Neurons and Spinal Glial Activation in an Adolescent Rat Model of Painful Neck Injury,” J. Neurotrauma, 27(12), pp. 2261–2271. [CrossRef] [PubMed]
Lee, K. E. , Franklin, A. N. , Davis, M. B. , and Winkelstein, B. A. , 2006, “ Tensile Cervical Facet Capsule Ligament Mechanics: Failure and Subfailure Responses in the Rat,” J. Biomech., 39(7), pp. 1256–1264. [CrossRef] [PubMed]
Kras, J. V , Dong, L. , and Winkelstein, B. A. , 2014, “ Increased Interleukin-1α and Prostaglandin E2 Expression in the Spinal Cord at 1 Day After Painful Facet Joint Injury: Evidence of Early Spinal Inflammation,” Spine, 39(3), pp. 207–212. [CrossRef] [PubMed]
Zhang, S. , Nicholson, K. J. , Smith, J. R. , Gilliland, T. M. , Syré, P. P. , and Winkelstein, B. A. , 2013, “ The Roles of Mechanical Compression and Chemical Irritation in Regulating Spinal Neuronal Signaling in Painful Cervical Nerve Root Injury,” Stapp Car Crash J., 57, pp. 219–242. [PubMed]
Atanasov, D. , 2010, “ Two-Phase Linear Regression Model,” MATLAB Central File Exchange, The Mathworks, Natick, MA, http://www.mathworks.com/matlabcentral/fileexchange/26804-two-phase-linear-regression-model
Diniz, C. A. R. , and Brochi, L. C. , 2005, “ Robustness of Two-Phase Regression Tests,” Revstat—Stat. J., 3(1), pp. 1–18.
Koul, H. L. , Qian, L. , and Surgailis, D. , 2003, “ Asymptotics of M-Estimators in Two-Phase Linear Regression Models,” Stochastic Processes Appl., 103(1), pp. 123–154. [CrossRef]
Bain, A. C. , Raghupathi, R. , and Meaney, D. F. , 2001, “ Dynamic Stretch Correlates to Both Morphological Abnormalities and Electrophysiological Impairment in a Model of Traumatic Axonal Injury,” J. Neurotrauma, 18(5), pp. 499–511. [CrossRef] [PubMed]
Hubbard, R. D. , and Winkelstein, B. A. , 2008, “ Dorsal Root Compression Produces Myelinated Axonal Degeneration Near the Biomechanical Thresholds for Mechanical Behavioral Hypersensitivity,” Exp. Neurol., 212(2), pp. 482–489. [CrossRef] [PubMed]
McDonald, J. H. , 2014, Handbook of Biological Statistics, 3rd ed., Sparkly House Publishing, Baltimore, MD.
Schwartz, M. A. , 2010, “ Integrins and Extracellular Matrix in Mechanotransduction,” Cold Spring Harbor Perspect. Biol., 2(12), p. a005066.
Spedden, E. , and Staii, C. , 2013, “ Neuron Biomechanics Probed by Atomic Force Microscopy,” Int. J. Mol. Sci., 14(8), pp. 16124–16140. [CrossRef] [PubMed]
Dong, L. , and Winkelstein, B. A. , 2010, “ Simulated Whiplash Modulates Expression of the Glutamatergic System in the Spinal Cord Suggesting Spinal Plasticity is Associated With Painful Dynamic Cervical Facet Loading,” J. Neurotrauma, 27(1), pp. 163–174. [CrossRef] [PubMed]
Liao, H. , and Belkoff, S. M. , 1999, “ A Failure Model for Ligaments,” J. Biomech., 32(2), pp. 183–188. [CrossRef] [PubMed]
Münster, S. , Jawerth, L. M. , Leslie, B. A. , Weitz, J. I. , Fabry, B. , and Weitz, D. A. , 2013, “ Strain History Dependence of the Nonlinear Stress Response of Fibrin and Collagen Networks,” Proc. Natl. Acad. Sci. U.S.A., 110(30), pp. 12197–12202. [CrossRef] [PubMed]
Roeder, B. A. , Kokini, K. , Sturgis, J. E. , Robinson, J. P. , and Voytik-Harbin, S. L. , 2002, “ Tensile Mechanical Properties of Three-Dimensional Type I Collagen Extracellular Matrices With Varied Microstructure,” ASME J. Biomech. Eng., 124(2), pp. 214–222. [CrossRef]
Lu, Y.-B. , Franze, K. , Seifert, G. , Steinhäuser, C. , Kirchhoff, F. , Wolburg, H. , Guck, J. , Janmey, P. , Wei, E.-Q. , Käs, J. , and Reichenbach, A. , 2006, “ Viscoelastic Properties of Individual Glial Cells and Neurons in the CNS,” Proc. Natl. Acad. Sci. U.S.A., 103(47), pp. 17759–17764. [CrossRef] [PubMed]
Topp, K. S. , and Boyd, B. S. , 2006, “ Structure and Biomechanics of Peripheral Nerves: Nerve Responses to Physical Stresses and Implications for Physical Therapist Practice,” Phys. Ther., 86(1), pp. 92–109. [PubMed]
Xu, B. , Li, H. , and Zhang, Y. , 2013, “ Understanding the Viscoelastic Behavior of Collagen Matrices Through Relaxation Time Distribution Spectrum,” Biomatter, 3(3), p. e24651. [CrossRef] [PubMed]
Silver, F. H. , Seehra, G. P. , Freeman, J. W. , and DeVore, D. , 2002, “ Viscoelastic Properties of Young and Old Human Dermis: A Proposed Molecular Mechanism for Elastic Energy Storage in Collagen and Elastin,” J. Appl. Polym. Sci., 86(8), pp. 1978–1985. [CrossRef]
In't Veld, P. J. , and Stevens, M. J. , 2008, “ Simulation of the Mechanical Strength of a Single Collagen Molecule,” Biophys. J., 95(1), pp. 33–39. [CrossRef] [PubMed]
Laplaca, M. C. , and Prado, G. R. , 2010, “ Neural Mechanobiology and Neuronal Vulnerability to Traumatic Loading,” J. Biomech., 43(1), pp. 71–78. [CrossRef] [PubMed]
Miller, K. S. , Connizzo, B. K. , Feeney, E. , Tucker, J. J. , and Soslowsky, L. J. , 2012, “ Examining Differences in Local Collagen Fiber Crimp Frequency Throughout Mechanical Testing in a Developmental Mouse Supraspinatus Tendon Model,” ASME J. Biomech. Eng., 134(4), p. 041004. [CrossRef]
Franchi, M. , Quaranta, M. , Macciocca, M. , Leonardi, L. , Ottani, V. , Bianchini, P. , Diaspro, A. , and Ruggeri, A. , 2010, “ Collagen Fibre Arrangement and Functional Crimping Pattern of the Medial Collateral Ligament in the Rat Knee,” Knee Surg. Sports Traumatol. Arthrosc., 18(12), pp. 1671–1678. [CrossRef] [PubMed]
Sacks, M. S. , 2003, “ Incorporation of Experimentally-Derived Fiber Orientation Into a Structural Constitutive Model for Planar Collagenous Tissues,” ASME J. Biomech. Eng., 125(2), pp. 280–287. [CrossRef]
Cullen, D. K. , Lessing, M. C. , and LaPlaca, M. C. , 2007, “ Collagen-Dependent Neurite Outgrowth and Response to Dynamic Deformation in Three-Dimensional Neuronal Cultures,” Ann. Biomed. Eng., 35(5), pp. 835–846. [CrossRef] [PubMed]
Khalsa, P. S. , Hoffman, A. H. , and Grigg, P. , 1996, “ Mechanical States Encoded by Stretch-Sensitive Neurons in Feline Joint Capsule,” J. Neurophysiol., 76(1), pp. 175–187. [PubMed]
Yamashita, T. , Minaki, Y. , Ozaktay, A. C. , Cavanaugh, J. M. , and King, A. I. , 1996, “ A Morphological Study of the Fibrous Capsule of the Human Lumbar Facet Joint,” Spine, 21(5), pp. 538–543. [CrossRef] [PubMed]
Mommersteeg, T. J. , Blankevoort, L. , Kooloos, J. G. , Hendriks, J. C. , Kauer, J. M. , and Huiskes, R. , 1994, “ Nonuniform Distribution of Collagen Density in Human Knee Ligaments,” J. Orthop. Res., 12(2), pp. 238–245. [CrossRef] [PubMed]
McLain, R. F. , and Pickar, J. G. , 1998, “ Mechanoreceptor Endings in Human Thoracic and Lumbar Facet Joints,” Spine, 23(2), pp. 168–173. [CrossRef] [PubMed]
Cavanaugh, J. M. , Lu, Y. , Chen, C. , and Kallakuri, S. , 2006, “ Pain Generation in Lumbar and Cervical Facet Joints,” J. Bone Jt. Surg. Am., 88(Suppl. 2), pp. 63–67. [CrossRef]
Tang-Schomer, M. D. , Patel, A. R. , Baas, P. W. , and Smith, D. H. , 2010, “ Mechanical Breaking of Microtubules in Axons During Dynamic Stretch Injury Underlies Delayed Elasticity, Microtubule Disassembly, and Axon Degeneration,” FASEB J., 24(5), pp. 1401–1410. [CrossRef] [PubMed]
Jaumard, N. V. , Welch, W. C. , and Winkelstein, B. A. , 2011, “ Spinal Facet Joint Biomechanics and Mechanotransduction in Normal, Injury and Degenerative Conditions,” ASME J. Biomech. Eng., 133(7), p. 071010. [CrossRef]
Magou, G. C. , Pfister, B. J. , and Berlin, J. R. , 2015, “ Effect of Acute Stretch Injury on Action Potential and Network Activity of Rat Neocortical Neurons in Culture,” Brain Res., 1624, pp. 525–535. [CrossRef] [PubMed]
Siddique, R. , and Thakor, N. , 2014, “ Investigation of Nerve Injury Through Microfluidic Devices,” J. R. Soc. Interface, 11(90), p. 20130676. [CrossRef] [PubMed]
Mietto, B. S. , Mostacada, K. , and Martinez, A. M. B. , 2015, “ Neurotrauma and Inflammation: CNS and PNS Responses,” Mediators Inflammation, 2015, p. 251204. [CrossRef]
Cullen, D. K. , Vernekar, V. N. , and LaPlaca, M. C. , 2011, “ Trauma-Induced Plasmalemma Disruptions in Three-Dimensional Neural Cultures are Dependent on Strain Modality and Rate,” J. Neurotrauma, 28(11), pp. 2219–2233. [CrossRef] [PubMed]
Zhang, S. , Barocas, V. H. , and Winkelstein, B. A. , 2014, “ Local Neuronal Loading Modulates Perk Release in a Neuron-Collagen Gel Construct Simulating Facet Capsule Injury,” 7th World Congress of Biomechanics, Boston, MA, July 6–11.

Figures

Grahic Jump Location
Fig. 1

Representative images of the experimental test setup demonstrating (a) the mechanical testing system integrated with the elements of the QPLI system, (b) an NCC in an unloaded reference state and at 8 mm of distraction, (c) the corresponding force–displacement response, and (d) strain map showing both the magnitude and directions of MPS at 8 mm displacement. (e) A schematic overview showing the DFN model as constructed using the confocal images of collagen in elements of the unloaded control NCCs, as well as the boundary conditions simulating experimental conditions for the NCCs.

Grahic Jump Location
Fig. 2

ERK phosphorylation increases with increasing imposed distraction magnitude. (a) Representative confocal images showing neuronal structure labeled for βIII-tubulin (blue), pERK expression (red), and their colocalization (pink) demonstrate increased ERK phosphorylation at 8 mm than at 4 mm but with no difference for loading rate; the scale bar applies to all panels. (b) Quantification of pERK expression in loaded constructs normalized to unloaded controls indicates significant increases in NCCs distracted to 8 mm compared to 4 mm at both the 0.5 mm/s (*p < 0.0001) and 3.5 mm/s (#p = 0.002) distraction rates.

Grahic Jump Location
Fig. 3

Elemental pERK expression is positively related to elemental MPS. (a) Significant positive correlations exist between normalized elemental pERK expression and elemental MPS at both 0.5 mm/s (R2 = 0.200, *p < 0.0001) and 3.5 mm/s (R2 = 0.041, #p = 0.0171) distraction rates. (b) pERK expression is significantly (p < 0.0001) regressed against elemental MPS at both distraction rates. Solid dots () and open triangles (Δ) represent samples in which elevated pERK expression was detected (probability of 1) or not detected (probability of 0) at each strain level for 0.5 mm/s and 3.5 mm/s, respectively. The predicted 50th-percentile thresholds for ERK phosphorylation are 11.7% for 0.5 mm/s rate, 10.2% for 3.5 mm/s; the corresponding 95th-percentile thresholds are 24.9% and 23.7% at the 0.5 mm/s and 3.5 mm/s distraction rates, respectively.

Grahic Jump Location
Fig. 4

Neuronal AR and orientation toward the loading direction depend on NCC displacement and loading rate. (a) Significant correlations are detected between normalized cell AR and MPS for both 0.5 mm/s (*p < 0.0001) and 3.5 mm/s (#p < 0.0001) rates of distraction. (b) Cell orientation angle (α) is measured as the angle between cell's long-axis (dotted line) and the direction of applied tension (arrow). (c) Distributions of cell orientation angles show that cell orientation angle is significantly smaller (p = 0.004) at the slow distraction rate (0.5 mm/s) than at the fast rate (3.5 mm/s).

Grahic Jump Location
Fig. 5

For the 0.5 mm/s loading rate, fiber realignment exhibits a switchlike response. (a) Representative collagen fiber alignment maps in two adjacent elements before (reference) and at maximal distraction (distracted) show different fiber realignment responses depending on both the distraction magnitude and rate. The direction of the orientation vector indicates the average fiber alignment direction measured through the NCC thickness and its length represents the alignment strength in that direction. Fiber reorientation toward the loading direction is apparent by the changes in the length of the orientation vectors and their directions toward the vertical direction, with the most realignment along the lateral edges (indicated by vertically orientated vectors). (b) Quantification of the normalized circular variance measures the degree of fiber realignment in the distracted configuration relative to the unloaded reference and indicates significantly more collagen fiber realignment at 8 mm of distraction at 0.5 mm/s than at either 4 mm at the same rate (*p = 0.009) or 8 mm at the higher distraction rate (+p = 0.040). (c) The mean circular variance of collagen fiber orientation angles during loading at 0.5 mm/s exhibits a biphasic response with increasing applied strain (MPS), with a transition point of 11.3% strain estimated. The insets show representative distributions of collagen fiber alignment angles before (0%) and after (16%) evident fiber realignment occurs.

Grahic Jump Location
Fig. 6

DFN modeling predicts that collagen fiber realignment and fiber strain increase with bulk strain. (a) The distribution of fiber angle indicates more realignment toward the loading direction (±90 deg) at 16% strain, which is different from the uniform distributions that are observed at 0% and 7% strain. Plotting the Chi-squared statistic against the applied bulk strain shows that the fiber angle distribution becomes less uniform with increasing strain above 10%. (b) Visualization of the heterogeneous fiber axial strains during network loading shows more fibers under large tensile strain as more fibers realign toward the loading direction at 16% bulk strain compared to 0% and 7% strains. (c) Distributions of fiber axial strains show that most fibers have strains lower than the applied bulk strain and both compressive and tensile fiber strains increase with increasing bulk strain.

Tables

Errata

Discussions

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging and repositioning the boxes below.

Related Journal Articles
Related eBook Content
Topic Collections

Sorry! You do not have access to this content. For assistance or to subscribe, please contact us:

  • TELEPHONE: 1-800-843-2763 (Toll-free in the USA)
  • EMAIL: asmedigitalcollection@asme.org
Sign In