Research Papers

Cyclic Mechanical Loading Enhances Transport of Antibodies Into Articular Cartilage

[+] Author and Article Information
Chris D. DiDomenico

Meinig School of Biomedical Engineering,
Cornell University,
145 Weill Hall,
Ithaca, NY 14853
e-mail: cdd72@cornell.edu

Zhen Xiang Wang

Meinig School of Biomedical Engineering,
Cornell University,
145 Weill Hall,
Ithaca, NY 14853
e-mail: zw55@cornell.edu

Lawrence J. Bonassar

Meinig School of Biomedical Engineering,
Sibley School of Mechanical
and Aerospace Engineering,
Cornell University,
149 Weill Hall,
Ithaca, NY 14853
e-mail: lb244@cornell.edu

1Corresponding author.

Manuscript received June 13, 2016; final manuscript received November 2, 2016; published online November 30, 2016. Assoc. Editor: Jeffrey Ruberti.

J Biomech Eng 139(1), 011012 (Nov 30, 2016) (7 pages) Paper No: BIO-16-1253; doi: 10.1115/1.4035265 History: Received June 13, 2016; Revised November 02, 2016

The goal of this study was to characterize antibody penetration through cartilage tissue under mechanical loading. Mechanical stimulation aids in the penetration of some proteins, but this effect has not characterized molecules such as antibodies (>100 kDa), which may hold some clinical value for treating osteoarthritis (OA). For each experiment, fresh articular cartilage plugs were obtained and exposed to fluorescently labeled antibodies while under cyclic mechanical load in unconfined compression for several hours. Penetration of these antibodies was quantified using confocal microscopy, and finite element (FE) simulations were conducted to predict fluid flow patterns within loaded samples. Transport enhancement followed a linear trend with strain amplitude (0.25–5%) and a nonlinear trend with frequency (0.25–2.60 Hz), with maximum enhancement found to be at 5% cyclic strain and 1 Hz, respectively. Regions of highest enhancement of transport within the tissue were associated with the regions of highest interstitial fluid velocity, as predicted from finite-element simulations. Overall, cyclic compression-enhanced antibody transport by twofold to threefold. To our knowledge, this is the first study to test how mechanical stimulation affects the diffusion of antibodies in cartilage and suggest further study into other important factors regarding macromolecular transport.

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Grahic Jump Location
Fig. 1

Schematic of experimental procedure. The left shows the experimental setup of an individual well and the right shows a radial fluorescence profile of an individual sample. Cylindrical samples are bisected, and that cut surface is imaged under the confocal microscope. Only the middle 50% of the sample is shown in the confocal image.

Grahic Jump Location
Fig. 2

Normalized fluorescence intensity versus radial depth from the sample edge for a representative middle portion of loaded and passive sample exposed to the antibody solution for 3 h. The loaded sample was exposed to loading at 5% cyclic strain at 1 Hz. Solid lines denote a radial 1D diffusion curve derived from Fick's second law, while dotted lines denote experimental data. Diffusivities and goodness of fits from each sample are shown.

Grahic Jump Location
Fig. 3

Transport enhancement versus strain amplitude at 1 Hz (a) and transport enhancement versus loading frequency at 2.5% strain (b). Enhancement was found to be linearly correlated with the strain amplitude (at 1 Hz) for both neonatal bovine tissue (slope: 0.30) and mature equine tissue (slope: 0.24) (R2 > 0.93). The two correlations were forced to have an intercept of one and were not statistically different from one another (p = 0.11). All strain amplitudes were statistically different from a value of one (p < 0.05), except for 0.25% strain. The maximum enhancement was found to be at 1 Hz. All loading frequencies were statistically different from a value of one (p < 0.05), except for 0.25 Hz.

Grahic Jump Location
Fig. 4

Predicted fluid velocities for different strains at 1 Hz (a) and frequencies at 2.5% cyclic strain (b) versus radial depth into the tissue. Experimental local transport enhancement from neonatal cartilage experiments for different strains at 1 Hz (c) and frequencies at 2.5% strain (d). A normalized radius of one corresponds to the sample radial edge. Local diffusivity curves closely followed the curvature of fluid velocity profiles. The highest transport enhancement was found near the edge, near areas of highest fluid flow. Normalized radii of at least 0.925, 0.875, and 0.900 correspond to enhancements greater than one for 1.25% 2.5%, and 5.0%, respectively (p < 0.05, ANOVA). Normalized radii of at least 0.8750, 0.8750, and 0.9375 correspond to enhancements greater than one for 0.25 Hz, 1 Hz, and 2.6 Hz, respectively (p < 0.05, ANOVA). All fluid velocity profiles were obtained at steady-state conditions (occurred within 10 min).

Grahic Jump Location
Fig. 5

Correlative plot of enhancement ratio and maximum fluid velocity for various loading conditions that were previously analyzed. The best fit line is forced to have an intercept of one; the correlation was statistically significant (p < 0.001). Artifacts from lift-off could have caused transport enhancements from higher loading amplitudes (5%) and frequencies (2.6 Hz) to have data points higher than expected. However, correlations between individual loading regimes were not significantly different from one another.



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