Corey P Neu

Purdue University, West Lafayette, IN, United States

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Publications (41)130.15 Total impact

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    ABSTRACT: Nuclear structure and mechanics play a critical role in diverse cellular functions, such as organizing direct access of chromatin to transcriptional regulators. Here, we use a new, to our knowledge, hybrid method, based on microscopy and hyperelastic warping, to determine three-dimensional strain distributions inside the nuclei of single living cells embedded within their native extracellular matrix. During physiologically relevant mechanical loading to tissue samples, strain was transferred to individual nuclei, resulting in submicron distributions of displacements, with compressive and tensile strain patterns approaching a fivefold magnitude increase in some locations compared to tissue-scale stimuli. Moreover, nascent RNA synthesis was observed in the interchromatin regions of the cells studied and spatially corresponded to strain patterns. Our ability to measure large strains in the interchromatin space, which reveals that movement of chromatin in the nucleus may not be due to random or biochemical mechanisms alone, but may result from the transfer of mechanical force applied at a distant tissue surface.
    Biophysical Journal 11/2013; 105(10):2252-2261. · 3.67 Impact Factor
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    ABSTRACT: Biomechanical factors play an important role in the growth, regulation, and maintenance of engineered biomaterials and tissues. While physical factors (e.g. applied mechanical strain) can accelerate regeneration, and knowledge of tissue properties often guide the design of custom materials with tailored functionality, the distribution of mechanical quantities (e.g. strain) throughout native and repair tissues is largely unknown. Here, we directly quantify distributions of strain using noninvasive magnetic resonance imaging (MRI) throughout layered agarose constructs, a model system for articular cartilage regeneration. Bulk mechanical testing, giving both instantaneous and equilibrium moduli, was incapable of differentiating between the layered constructs with defined amounts of 2% and 4% agarose. In contrast, MRI revealed complex distributions of strain, with strain transfer to softer (2%) agarose regions, resulting in amplified magnitudes. Comparative studies using finite element simulations and mixture (biphasic) theory confirmed strain distributions in the layered agarose. The results indicate that strain transfer to soft regions is possible in vivo as the biomaterial and tissue changes during regeneration and maturity. It is also possible to modulate locally the strain field that is applied to construct-embedded cells (e.g. chondrocytes) using stratified agarose constructs.
    Journal of biomechanics 10/2013; · 2.66 Impact Factor
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    ABSTRACT: Cells remarkably are capable of large deformations during motility and when subjected to mechanical force. Measurement of mechanical deformation (i.e. displacements, strain) is critical to understand functional changes in cells and biological tissues following disease, and to elucidate basic relationships between applied force and cellular biosynthesis. Microscopy-based imaging modalities provide the ability to noninvasively visualize small cell or tissue structures and track their motion over time, often using two-dimensional (2D) digital image (texture) correlation algorithms. For the measurement of complex and nonlinear motion in cells and tissues, implementation of texture correlation algorithms with high order approximations of displacement mapping terms are needed to minimize error. Here, we extend a texture correlation algorithm with up to third-order approximation of displacement mapping terms for the measurement of cell and tissue deformation. We additionally investigate relationships between measurement error and image texture, defined by subset entropy. Displacement measurement error is significantly reduced when the order of displacement mapping terms in the texture correlation algorithm matches or exceeds the order of the deformation observed. Displacement measurement error is also inversely proportional to subset entropy, with well-defined cell and tissue structures leading to high entropy and low error. For cell and tissue studies where complex or nonlinear displacements are expected, texture correlation algorithms with high order terms are required to best characterize the observed deformation.
    Journal of biomechanics 08/2013; · 2.66 Impact Factor
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    ABSTRACT: The advancement of spectroscopy methods attained through increases in sensitivity, and often with the coupling of complementary techniques, has enabled real-time structure and function measurements of single cells. The purpose of this review is to illustrate, in light of advances, the strengths and the weaknesses of these methods. Included also is an assessment of the impact of the experimental setup and conditions of each method on cellular function and integrity. A particular emphasis is placed on noninvasive and nondestructive techniques for achieving single cell detection, including nuclear magnetic resonance, in addition to physical, optical, and vibrational methods.
    Methods 07/2013; · 3.64 Impact Factor
  • Deva D Chan, Corey P Neu
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    ABSTRACT: PURPOSE: Noninvasive assessment of tissue mechanical behavior could enable insights into tissue function in healthy and diseased conditions and permit the development of effective tissue repair treatments. Measurement of displacements under applied loading with MRI (dualMRI) has the potential for such biomechanical characterization on a clinical MRI system. METHODS: dualMRI was translated from high-field research systems to a 3T clinical system. Precision was calculated using repeated tests of a silicone phantom. dualMRI was demonstrated by visualizing displacements and strains in an intervertebral disc and compared to T2 measured during cyclic loading. RESULTS: The displacement and strain precisions were 24 µm and 0.3% strain, respectively, under the imaging parameters used in this study. Displacements and strains were measured within the intervertebral disc, but no correlations were found with the T2 values. CONCLUSION: The translation of dualMRI to a 3T system unveils the potential for in vivo studies in a myriad of tissue and organ systems. Because of the importance of mechanical behavior to the function of a variety of tissues, it's expected that dualMRI implemented on a clinical system will be a powerful tool in assessing the interlinked roles of structure, mechanics, and function in both healthy and diseased tissues. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 05/2013; · 3.27 Impact Factor
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    ABSTRACT: We present the coupling of atomic force microscopy (AFM) and nuclear magnetic resonance (NMR) technologies to enable topographical, mechanical, and chemical profiling of biological samples. Here, we fabricate and perform proof-of-concept testing of radiofrequency planar microcoils on commercial AFM cantilevers. The sensitive region of the coil was estimated to cover an approximate volume of 19.4 × 103 μm3 (19.4 pl). Functionality of the spectroscopic module of the prototype device is illustrated through the detection of 1Η resonance in deionized water. The acquired spectra depict combined NMR capability with AFM that may ultimately enable biophysical and biochemical studies at the single cell level.
    Applied Physics Letters 04/2013; 102(14). · 3.79 Impact Factor
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    ABSTRACT: PURPOSE: Medical imaging has the potential to noninvasively diagnose early disease onset and monitor the success of repair therapies. Unfortunately, few reliable imaging biomarkers exist to detect cartilage diseases before advanced degeneration in the tissue. METHOD: In this study, we quantified the ability to detect osteoarthritis (OA) severity in human cartilage explants using a multicontrast magnetic resonance imaging (MRI) approach, inclusive of novel displacements under applied loading by MRI, relaxivity measures, and standard MRI. RESULTS: Displacements under applied loading by MRI measures, which characterized the spatial micromechanical environment by 2D finite and Von Mises strains, were strong predictors of histologically assessed OA severity, both before and after controlling for factors, e.g., patient, joint region, and morphology. Relaxivity measures, sensitive to local macromolecular weight and composition, including T1ρ , but not T1 or T2 , were predictors of OA severity. A combined multicontrast approach that exploited spatial variations in tissue biomechanics and extracellular matrix structure yielded the strongest relationships to OA severity. CONCLUSION: Our results indicate that combining multiple MRI-based biomarkers has high potential for the noninvasive measurement of OA severity and the evaluation of potential therapeutic agents used in the treatment of early OA in animal and human trials. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 03/2013; · 3.27 Impact Factor
  • Deva D Chan, Corey P Neu
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    ABSTRACT: Osteoarthritis (OA) is a debilitating disease that reflects a complex interplay of biochemical, biomechanical, metabolic and genetic factors, which are often triggered by injury, and mediated by inflammation, catabolic cytokines and enzymes. An unmet clinical need is the lack of reliable methods that are able to probe the pathogenesis of early OA when disease-rectifying therapies may be most effective. Non-invasive quantitative magnetic resonance imaging (qMRI) techniques have shown potential for characterizing the structural, biochemical and mechanical changes that occur with cartilage degeneration. In this paper, we review the background in articular cartilage and OA as it pertains to conventional MRI and qMRI techniques. We then discuss how conventional MRI and qMRI techniques are used in clinical and research environments to evaluate biochemical and mechanical changes associated with degeneration. Some qMRI techniques allow for the use of relaxometry values as indirect biomarkers for cartilage components. Direct characterization of mechanical behaviour of cartilage is possible via other specialized qMRI techniques. The combination of these qMRI techniques has the potential to fully characterize the biochemical and biomechanical states that represent the initial changes associated with cartilage degeneration. Additionally, knowledge of in vivo cartilage biochemistry and mechanical behaviour in healthy subjects and across a spectrum of osteoarthritic patients could lead to improvements in the detection, management and treatment of OA.
    Journal of The Royal Society Interface 01/2013; 10(78):20120608. · 4.91 Impact Factor
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    ABSTRACT: OBJECTIVE: To noninvasively assay the mechanical and structural characteristics of articular cartilage from patients with osteoarthritis (OA) by magnetic resonance imaging (MRI), and to further relate spatial patterns of MRI-based mechanical strain to joint (depth-wise, regional) locations and disease severity. METHODS: Cylindrical osteochondral explants harvested from human tissue obtained during total knee replacement surgery were loaded in unconfined compression and 2D deformation data was acquired at 14.1T using a displacements under applied loading by MRI (dualMRI) approach. After imaging, samples were histologically assessed for OA severity. Strains were determined by depth, and statistically analyzed for dependence on region in the joint and OA severity. RESULTS: Von Mises, Axial, and Transverse strains were highly depth-dependent. After accounting for other factors, Von Mises, Axial, and Shear strains varied significantly by region, with largest strain magnitudes observed in explants harvested from the tibial plateau and anterior condyle near exposed bone. Additionally, in all cases, strains in late-stage OA were significantly greater than either early- or mid-stage OA. Transverse strain in mid-stage OA explants, measured near the articular surface, was significantly higher than early-stage OA explants. CONCLUSION: dualMRI was demonstrated in human OA tissue to quantify the effects of depth, joint region, and OA severity, on strains resulting from mechanical compression. These data suggest dualMRI may possess a wide range of utility, such as validating computational models of soft tissue deformation, assaying changes in cartilage function over time, and perhaps, once implemented for cartilage imaging in vivo, as a new paradigm for diagnosis of early- to mid-stage OA.
    Osteoarthritis and Cartilage 11/2012; · 4.26 Impact Factor
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    ABSTRACT: Biomimetic scaffolds that promote regeneration and resist proteolysis are required as a tissue engineering solution to repair or replace a broad range of diseased tissues. Native corrosive environments, such as the richly enzymatic milieu of diseased articular cartilage, degrade the local extracellular matrix structure, so an implantable replacement must both replicate the healthy structure and demonstrate substantial proteolytic immunity, yet promote regeneration, if long-term functional success is to be achieved. Here, we combine magnetically aligned collagen with peptidoglycans, biosynthetic molecules that mimic proteoglycan activity but lack core proteins susceptible to proteases, to develop cartilage scaffold analogs with tailored functionality. With the incorporation of the aggrecan mimic, we demonstrate an ability to enhance bulk mechanical properties and prevent cytokine-induced degradation. Furthermore, fiber alignment in collagen scaffolds enhanced the gene expression of aggrecan, indicating cell responsiveness to anisotropy that also better replicates the natural environment of cartilage. Finally, the expression of type II collagen is enhanced with both alignment and incorporation of the aggrecan mimic, showing synergism between fiber alignment and incorporation of the aggrecan mimic. The work presented here identified a mechanistic synergy of matrix molecules and organization to prevent proteolysis while simultaneously upregulating protein expression.
    Acta biomaterialia 08/2012; · 5.09 Impact Factor
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    ABSTRACT: Boundary lubrication is characterized by sliding surfaces separated by a molecularly thin film that reduces friction and wear of the underlying substrate when fluid lubrication cannot be established. In this study, the wear and replenishment rates of articular cartilage were examined in the context of friction coefficient changes, protein loss, and direct imaging of the surface ultrastructure, to determine the efficiency of the boundary lubricant (BL) layer. Depletion of cartilage lubricity occurred with the concomitant loss of surface proteoglycans. Restoration of lubrication by incubation with synovial fluid was much faster than incubation with culture media and isolated superficial zone protein. The replenishment action of the BL layer in articular cartilage was rapid, with the rate of formation exceeding the rate of depletion of the BL layer to effectively protect the tissue from mechanical wear. The obtained results indicate that boundary lubrication in articular cartilage depends in part on a sacrificial layer mechanism. The present study provides insight into the natural mechanisms that minimize wear and resist tissue degeneration over the lifetime of an organism.
    Journal of biomechanics 08/2012; 45(14):2426-31. · 2.66 Impact Factor
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    ABSTRACT: Drug delivery requires precise intradermal and subcutaneous injections of formulations to clinically relevant penetration depths. However, penetration depth is confounded by skin deflection, which occurs prior to and during penetration as the skin surface deforms axially with the needle, and which varies profoundly due to differing intrinsic mechanical (e.g. viscoelastic) tissue properties, disease state, aging, and ethnicity. Herein, an ex vivo model was utilized to study factors that affect skin deflection and the efficacy of injection, including prestress applied at the tissue surface, needle gauge, velocity, and actuation depth. The application of prestress minimized skin deflection during needle penetration and allowed for needle actuation to the targeted penetration depths with minimum variability. The force required to achieve target penetration depths was found to increase with prestress and decrease with needle gauge. Our findings emphasize the need for prestress applied to the skin surface to minimize variation in skin properties and administer formulations for intradermal and subcutaneous treatments with maximum precision.
    Journal of biomechanics 02/2012; 45(7):1176-9. · 2.66 Impact Factor
  • Deva D Chan, David Toribio, Corey P Neu
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    ABSTRACT: Displacement and strain are fundamental quantities that describe the normal and pathological mechanical function of soft biological materials. Non-invasive imaging techniques, including displacement-encoded magnetic resonance imaging (MRI), enable the direct calculation of biomaterial displacements during the application of extrinsic mechanical forces. However, because strain is derived from measured MRI-based displacements, data processing must be accomplished to minimise the propagation and amplification of errors. Here, we evaluate smoothing methods (including averaging filters, splines, finite impulse response filters and wavelets) that enable the calculation of strain in biomaterials from MRI-based displacements for minimal error, defined in terms of bias and precision. Displacement and strain precisions were improved using all smoothing methods studied. Precision generally increased with the number of smoothing iterations (i.e. repeated applications) of a chosen smoothing method. The bias depended on the smoothing method and tended to increase with the number of smoothing iterations. A Gaussian filter characterised complex and heterogeneous strain fields with maximum precision and minimum bias. The results suggest that the optimal choice of smoothing method to compute strain for a given biomaterial or tissue application depends on a careful consideration of trade-offs between the improved precision (with increased data smoothing) and the trending increase in bias.
    Computer Methods in Biomechanics and Biomedical Engineering 01/2012; · 1.39 Impact Factor
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    Deva D Chan, Corey P Neu
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    ABSTRACT: Characterization of spatiotemporal deformation dynamics and material properties requires non-destructive methods to visualize mechanics of materials and biological tissues. Displacement-encoded magnetic resonance imaging (MRI) has emerged as a noninvasive and non-destructive technique used to quantify deformation and strains. However, the techniques are not yet applicable to a broad range of materials and load-bearing tissues. In this paper, we visualize transient and internal material deformation through the novel synchrony of external mechanical loading with rapid displacement-encoded MRI. We achieved deformation measurements in silicone gel materials with a spatial resolution of 100 µm and a temporal resolution (of 2.25 ms), set by the repetition time (TR) of the rapid MRI acquisition. Displacement and strain precisions after smoothing were 11 µm and 0.1%, respectively, approaching cellular length scales. Short (1/2 TR) echo times enabled visualization of in situ deformation in a human tibiofemoral joint, inclusive of multiple variable T(2) biomaterials. Moreover, the MRI acquisitions achieved a fivefold improvement in imaging time over previous technology, setting the stage for mechanical imaging in vivo. Our results provide a general approach for noninvasive and non-destructive measurement, at high spatial and temporal resolution, of the dynamic mechanical response of a broad range of load-bearing materials and biological tissues.
    PLoS ONE 01/2012; 7(3):e33463. · 3.73 Impact Factor
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    ABSTRACT: The noninvasive measurement of finite strains in biomaterials and tissues by magnetic resonance imaging (MRI) enables mathematical estimates of stress distributions and material properties. Such methods allow for non-contact and patient-specific modeling in a manner not possible with traditional mechanical testing or finite element techniques. Here, we employed three constitutive (i.e. linear Hookean, and nonlinear Neo-Hookean and Mooney-Rivlin) relations with known loading conditions and MRI-based finite strains to estimate stress patterns and material properties in the articular cartilage of tibiofemoral joints. Displacement-encoded MRI was used to determine two-dimensional finite strains in juvenile porcine joints, and an iterative technique estimated stress distributions and material properties with defined constitutive relations. Stress distributions were consistent across all relations, although the stress magnitudes varied. Material properties for femoral and tibial cartilage were found to be consistent with those reported in literature. Further, the stress estimates from Hookean and Neo-Hookean, but not Mooney-Rivlin, relations agreed with finite element-based simulations. A nonlinear Neo-Hookean relation provided the most appropriate model for the characterization of complex and spatially dependent stresses using two-dimensional MRI-based finite strain. These results demonstrate the feasibility of a new and computationally efficient technique incorporating MRI-based deformation with mathematical modeling to non-invasively evaluate the mechanical behavior of biological tissues and materials.
    Journal of biomechanics 09/2011; 44(15):2667-72. · 2.66 Impact Factor
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    ABSTRACT: Mechanostasis describes a complex and dynamic process where cells maintain equilibrium in response to mechanical forces. Normal physiological loading modes and magnitudes contribute to cell proliferation, tissue growth, differentiation and development. However, cell responses to abnormal forces include compensatory apoptotic mechanisms that may contribute to the development of tissue disease and pathological conditions. Mechanotransduction mechanisms tightly regulate the cell response through discrete signaling pathways. Here, we provide an overview of links between pro- and anti-apoptotic signaling and mechanotransduction signaling pathways, and identify potential clinical applications for treatments of disease by exploiting mechanically-linked apoptotic pathways.
    Progress in Biophysics and Molecular Biology 08/2011; 106(3):517-24. · 2.91 Impact Factor
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    ABSTRACT: Friction and adhesion of articular cartilage from high- and low-load-bearing regions of bovine knee joints were examined with a tribometer under various loads and equilibration times. The effect of trapped lubricants was investigated by briefly unloading the cartilage sample before friction testing, to allow fluid to reflow into the contact interface and boundary lubricants to rearrange. Friction and adhesion of high-load-bearing joint regions were consistently lower than those of low-load-bearing regions. This investigation is the first to demonstrate the regional variation in the friction and adhesion properties of articular cartilage. Friction coefficient decreased with increasing contact pressure and decreasing equilibration time. Briefly unloading cartilage before the onset of sliding resulted in significantly lower friction and adhesion and a loss of the friction dependence on contact pressure, suggesting an enhancement of the cartilage tribological properties by trapped lubricants. The results of this study reveal significant differences in the friction and adhesion properties between high- and low-load-bearing joint regions and elucidate the role of trapped lubricants in cartilage tribology.
    Journal of biomechanics 06/2011; 44(11):2015-20. · 2.66 Impact Factor
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    ABSTRACT: Articular cartilage is the load bearing soft tissue that covers the contacting surfaces of long bones in articulating joints. Healthy cartilage allows for smooth joint motion, while damaged cartilage prohibits normal function in debilitating joint diseases such as osteoarthritis. Knowledge of cartilage mechanical function through the progression of osteoarthritis, and in response to innovative regeneration treatments, requires a comprehensive understanding of the molecular nature of interacting extracellular matrix constituents and interstitial fluid. The objectives of this study were therefore to (1) examine the timescale of cartilage stress-relaxation using different mechanistic models and (2) develop and apply a novel (termed "sticky") polymer mechanics model to cartilage stress-relaxation based on temporary binding of constituent macromolecules. Using data from calf cartilage samples, we found that different models captured distinct timescales of cartilage stress-relaxation: monodisperse polymer reptation best described the first second of relaxation, sticky polymer mechanics best described data from ∼1-100 seconds of relaxation, and a model of inviscid fluid flow through a porous elastic matrix best described data from 100 seconds to equilibrium. Further support for the sticky polymer model was observed using experimental data where cartilage stress-relaxation was measured in either low or high salt concentration. These data suggest that a complete understanding of cartilage mechanics, especially in the short time scales immediately following loading, requires appreciation of both fluid flow and the polymeric behavior of the extracellular matrix.
    Materials Science and Engineering C 05/2011; 31(4):781-788. · 2.40 Impact Factor
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    ABSTRACT: This study evaluated the failure properties of length unstable humerii secured with small or large fragment plates. Two nonlocking plate constructs were examined, a nine-hole 4.5-mm limited contact dynamic compression plate (large fragment group) and a 12-hole 3.5-mm limited contact dynamic compression plate (small fragment group), both on composite humerii with a 1-cm defect to simulate comminution (n = 12 for each group). Each plate construct had similar working lengths and number of fixation points. Mechanical testing was first randomized for stiffness measurements in axial and torsional loads. All constructs were then tested in cyclic axial loads to failure. For axial testing, the large fragment group had a mean stiffness of 1020 ± 195 N/mm compared with 268 ± 67 N/mm in the small fragment group (P < 0.0001). For torsional testing, the large fragment group had a mean stiffness of 1.5 ± 0.05 Nm/degree compared with 0.9 ± 0.04 Nm/degree in the small fragment group (P < 0.0001). Plastic deformation in the large fragment and small fragment groups were 0.09 ± 0.07 mm and 0.20 ± 0.24 mm, respectively (P = 0.1) assessed during cyclic testing up to 300 N. The postcyclic yield force in the large fragment group was 227 ± 30 N and in the small fragment group was 153 ± 5 N (P < 0.0001). The ultimate load in the large fragment and small fragment groups were 800 ± 87 N and 307 ± 15 N, respectively. The results corroborate anticipated plate mechanical behavior with plate stiffness increasing as both plate width and thickness increase. The calculated yield force data suggest that both small and large fragment constructs would experience plastic deformation during bilateral crutch ambulation in a patient weighing 50 kg or more. The large fragment construct is not expected to catastrophically fail when subjected to loads in a patient 90 kg or less. The small fragment construct is predicted to catastrophically fail in patients weighing 70 kg or more.
    Journal of orthopaedic trauma 04/2011; 25(5):300-5. · 1.78 Impact Factor
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    ABSTRACT: Boundary lubrication of articular cartilage by conformal, molecularly thin films reduces friction and adhesion between asperities at the cartilage-cartilage contact interface when the contact conditions are not conducive to fluid film lubrication. In this study, the nanoscale friction and adhesion properties of articular cartilage from typical load-bearing and non-load-bearing joint regions were studied in the boundary lubrication regime under a range of physiological contact pressures using an atomic force microscope (AFM). Adhesion of load-bearing cartilage was found to be much lower than that of non-load-bearing cartilage. In addition, load-bearing cartilage demonstrated steady and low friction coefficient through the entire load range examined, whereas non-load-bearing cartilage showed higher friction coefficient that decreased nonlinearly with increasing normal load. AFM imaging and roughness calculations indicated that the above trends in the nanotribological properties of cartilage are not due to topographical (roughness) differences. However, immunohistochemistry revealed consistently higher surface concentration of boundary lubricant at load-bearing joint regions. The results of this study suggest that under contact conditions leading to joint starvation from fluid lubrication, the higher content of boundary lubricant at load-bearing cartilage sites preserves synovial joint function by minimizing adhesion and wear at asperity microcontacts, which are precursors for tissue degeneration.
    Journal of biomechanics 02/2011; 44(7):1340-5. · 2.66 Impact Factor

Publication Stats

303 Citations
268 Downloads
2k Views
130.15 Total Impact Points

Institutions

  • 2009–2013
    • Purdue University
      • Weldon School of Biomedical Engineering
      West Lafayette, IN, United States
  • 2003–2012
    • University of California, Davis
      • • Center for Comparative Medicine
      • • Department of Orthopaedic Surgery
      Davis, CA, United States