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.
Issue Section:
Research Papers
Keywords:
Biomechanics
References
1.
Fernandes
, J. C.
, Martel-Pelletier
, J.
, and Pelletier
, J.-P.
, 2002
, “The Role of Cytokines in Osteoarthritis Pathophysiology
,” Biorheology
, 39
(1–2
), pp. 237
–246
.2.
Martel-Pelletier
, J.
, 1998
, “Pathophysiology of Osteoarthritis
,” Osteoarthritis Cartilage
, 6
(6
), pp. 374
–376
.3.
Moos
, V.
, Fickert
, S.
, Müller
, B.
, Weber
, U.
, and Sieper
, J.
, 1999
, “Immunohistological Analysis of Cytokine Expression in Human Osteoarthritic and Healthy Cartilage
,” J. Rheumatol.
, 26
(4
), pp. 870
–879
.4.
Steiner
, G.
, Tohidast-Akrad
, M.
, Witzmann
, G.
, Vesely
, M.
, Studnicka-Benke
, A.
, Gal
, A.
, Kunaver
, M.
, Zenz
, P.
, and Smolen
, J. S.
, 1999
, “Cytokine Production by Synovial T Cells in Rheumatoid Arthritis
,” Rheumatology
, 38
(3
), pp. 202
–213
.5.
Feldmann
, M.
, Brennan
, F. M.
, and Maini
, R. N.
, 1996
, “Role of Cytokines in Rheumatoid Arthritis
,” Annu. Rev. Immunol.
, 14
(1
), pp. 397
–440
.6.
Owen
, S. G.
, Francis
, H. W.
, and Roberts
, M. S.
, 1994
, “Disappearance Kinetics of Solutes From Synovial Fluid After Intra-Articular Injection
,” Br. J. Clin. Pharmacol.
, 38
(4
), pp. 349
–355
.7.
Gerwin
, N.
, Hops
, C.
, and Lucke
, A.
, 2006
, “Intraarticular Drug Delivery in Osteoarthritis
,” Adv. Drug Delivery Rev.
, 58
(2
), pp. 226
–242
.8.
Allen
, K. D.
, Adams
, S. B.
, and Setton
, L. A.
, 2010
, “Evaluating Intra-Articular Drug Delivery for the Treatment of Osteoarthritis in a Rat Model
,” Tissue Eng. Part B. Rev.
, 16
(1
), pp. 81
–92
.9.
Maroudas
, A.
, 1975
, “Biophysical Chemistry of Cartilaginous Tissues With Special Reference to Solute and Fluid Transport
,” Biorheology
, 12
(3–4
), pp. 233
–248
.10.
Maroudas
, A.
, 1976
, “Transport of Solutes Through Cartilage: Permeability to Large Molecules
,” J. Anat.
, 122
(2
), pp. 335
–347
.11.
Garcia
, A. M.
, Lark
, M. W.
, Trippel
, S. B.
, and Grodzinsky
, A. J.
, 1998
, “Transport of Tissue Inhibitor of Metalloproteinases-1 Through Cartilage: Contributions of Fluid Flow and Electrical Migration
,” J. Orthop. Res.
, 16
(6
), pp. 734
–742
.12.
Garcia
, A. M.
, Frank
, E. H.
, Grimshaw
, P. E.
, and Grodzinsky
, A. J.
, 1996
, “Contributions of Fluid Convection and Electrical Migration to Transport in Cartilage: Relevance to Loading
,” Arch. Biochem. Biophys.
, 333
(2
), pp. 317
–325
.13.
Bonassar
, L. J.
, Grodzinsky
, A. J.
, Frank
, E. H.
, Davila
, S. G.
, Bhaktav
, N. R.
, and Trippel
, S. B.
, 2001
, “The Effect of Dynamic Compression on the Response of Articular Cartilage to Insulin-Like Growth Factor-I
,” J. Orthop. Res.
, 19
(1
), pp. 11
–17
.14.
Albro
, M. B.
, Banerjee
, R. E.
, Li
, R.
, Oungoulian
, S. R.
, Chen
, B.
, del Palomar
, A. P.
, Hung
, C. T.
, and Ateshian
, G. A.
, 2011
, “Dynamic Loading of Immature Epiphyseal Cartilage Pumps Nutrients out of Vascular Canals
,” J. Biomech.
, 44
(9
), pp. 1654
–1659
.15.
Winalski
, C. S.
, Aliabadi
, P.
, Wright
, R. J.
, Shortkroff
, S.
, Sledge
, C. B.
, and Weissman
, B. N.
, 1993
, “Enhancement of Joint Fluid With Intravenously Administered Gadopentetate Dimeglumine: Technique, Rationale, and Implications
,” Radiology
, 187
(1
), pp. 179
–185
.16.
Ballyns
, J. J.
, and Bonassar
, L. J.
, 2011
, “Dynamic Compressive Loading of Image-Guided Tissue Engineered Meniscal Constructs
,” J. Biomech.
, 44
(3
), pp. 509
–516
.17.
Maroudas
, A.
, 1968
, “Physicochemical Properties of Cartilage in the Light of Ion Exchange Theory
,” Biophys. J.
, 8
(5
), pp. 575
–595
.18.
Schinagl
, R. M.
, Gurskis
, D.
, Chen
, A. C.
, and Sah
, R. L.
, 1997
, “Depth-Dependent Confined Compression Modulus of Full-Thickness Bovine Articular Cartilage
,” J. Orthop. Res.
, 15
(4
), pp. 499
–506
.19.
Crank
, J.
, 1975
, The Mathematics of Diffusion
, Clarendon Press
, London, UK
.20.
Fannjiang
, A.
, and Papanicolaou
, G.
, 1997
, “Convection-Enhanced Diffusion for Random Flows
,” J. Stat. Phys.
, 88
(5–6
), pp. 1033
–1076
.21.
Lebrun
, L.
, and Junter
, G. A.
, 1994
, “Diffusion of Dextran Through Microporous Membrane Filters
,” J. Memb. Sci.
, 88
(2–3
), pp. 253
–261
.22.
Scherer
, P. W.
, Shendalman
, L. H.
, and Greene
, N. M.
, 1972
, “Simultaneous Diffusion and Convection in a Single Breath Lung Washout
,” Math. Biophys.
, 34
(3
), pp. 393
–412
.23.
Taylor
, J. R.
, 1997
, An Introduction to Error Analysis: The Study of Uncertainties in Physical Measurements
, University Science Books
, Sausalito, CA
.24.
Carr
, E. J.
, and Turner
, I. W.
, 2016
, “A Semi-Analytical Solution for Multilayer Diffusion in a Composite Medium Consisting of a Large Number of Layers
,” Appl. Math. Model.
, 40
(15–16), pp. 7034
–7050
.25.
Maas
, S. A.
, Ellis
, B. J.
, Ateshian
, G. A.
, and Weiss
, J. A.
, 2012
, “FEBio: Finite Elements for Biomechanics
,” ASME J. Biomech. Eng.
, 134
(1
), p. 11005
.26.
Mow
, V. C.
, Holmes
, M. H.
, and Lai
, W. M.
, 1984
, “Fluid Transport and Mechanical Properties of Articular Cartilage: A Review
,” J. Biomech.
, 17
(5
), pp. 377
–394
.27.
Armstrong
, C. G.
, Lai
, W. M.
, and Mow
, V. C.
, 1984
, “An Analysis of the Unconfined Compression of Articular Cartilage
,” ASME J. Biomech. Eng.
, 106
(2
), pp. 165
–173
.28.
Eckstein
, F.
, Hudelmaier
, M.
, and Putz
, R.
, 2006
, “The Effects of Exercise on Human Articular Cartilage
,” J. Anat.
, 208
(4
), pp. 491
–512
.29.
Armstrong
, J. K.
, Wenby
, R. B.
, Meiselman
, H. J.
, and Fisher
, T. C.
, 2004
, “The Hydrodynamic Radii of Macromolecules and Their Effect on Red Blood Cell Aggregation
,” Biophys. J.
, 87
(6
), pp. 4259
–4270
.30.
Maroudas
, A.
, 1970
, “Distribution and Diffusion of Solutes in Articular Cartilage
,” Biophys. J.
, 10
(5
), pp. 365
–379
.31.
Bonassar
, L. J.
, Grodzinsky
, A. J.
, Srinivasan
, A.
, Davila
, S. G.
, and Trippel
, S. B.
, 2000
, “Mechanical and Physicochemical Regulation of the Action of Insulin-Like Growth Factor-I on Articular Cartilage
,” Arch. Biochem. Biophys.
, 379
(1
), pp. 57
–63
.32.
O'Hara
, B. P.
, Urban
, J. P.
, and Maroudas
, A.
, 1990
, “Influence of Cyclic Loading on the Nutrition of Articular Cartilage
,” Ann. Rheum. Dis.
, 49
(7
), pp. 536
–539
.33.
Athanasiou
, K. A.
, Agarwal
, A.
, Muffoletto
, A.
, Dzida
, F. J.
, Constantinides
, G.
, and Clem
, M.
, 1995
, “Biomechanical Properties of Hip Cartilage in Experimental Animal Models
,” Clin. Orthop. Relat. Res.
, 316
, pp. 254
–266
.34.
Athanasiou
, K. A.
, Rosenwasser
, M. P.
, Buckwalter
, J. A.
, Malinin
, T. I.
, and Mow
, V. C.
, 1991
, “Interspecies Comparisons of In Situ Intrinsic Mechanical Properties of Distal Femoral Cartilage
,” J. Orthop. Res.
, 9
(3
), pp. 330
–340
.35.
Buschmann
, M. D.
, Kim
, Y. J.
, Wong
, M.
, Frank
, E.
, Hunziker
, E. B.
, and Grodzinsky
, A. J.
, 1999
, “Stimulation of Aggrecan Synthesis in Cartilage Explants by Cyclic Loading is Localized to Regions of High Interstitial Fluid Flow
,” Arch. Biochem. Biophys.
, 366
(1
), pp. 1
–7
.36.
Park
, S.
, Hung
, C. T.
, and Ateshian
, G. A.
, 2004
, “Mechanical Response of Bovine Articular Cartilage Under Dynamic Unconfined Compression Loading at Physiological Stress Levels
,” Osteoarthritis Cartilage
, 12
(1
), pp. 65
–73
.37.
Ateshian
, G. A.
, Maas
, S.
, and Weiss
, J. A.
, 2013
, “Multiphasic Finite Element Framework for Modeling Hydrated Mixtures With Multiple Neutral and Charged Solutes
,” ASME J. Biomech. Eng.
, 135
(11
), p. 111001
.38.
Chahine
, N. O.
, Albro
, M. B.
, Lima
, E. G.
, Wei
, V. I.
, Dubois
, C. R.
, Hung
, C. T.
, and Ateshian
, G. A.
, 2009
, “Effect of Dynamic Loading on the Transport of Solutes Into Agarose Hydrogels
,” Biophys. J.
, 97
(4
), pp. 968
–975
.39.
Mauck
, R. L.
, Hung
, C. T.
, and Ateshian
, G. A.
, 2003
, “Modeling of Neutral Solute Transport in a Dynamically Loaded Porous Permeable Gel: Implications for Articular Cartilage Biosynthesis and Tissue Engineering
,” ASME J. Biomech. Eng.
, 125
(5
), pp. 602
–614
.40.
Yao
, H.
, and Gu
, W. Y.
, 2007
, “Convection and Diffusion in Charged Hydrated Soft Tissues: A Mixture Theory Approach
,” Biomech. Model. Mechanobiol.
, 6
(1–2
), pp. 63
–72
.41.
Zhang
, L.
, Gardiner
, B. S.
, Smith
, D. W.
, Pivonka
, P.
, and Grodzinsky
, A.
, 2007
, “The Effect of Cyclic Deformation and Solute Binding on Solute Transport in Cartilage
,” Arch. Biochem. Biophys.
, 457
(1
), pp. 47
–56
.42.
Leddy
, H. A.
, and Guilak
, F.
, 2003
, “Site-Specific Molecular Diffusion in Articular Cartilage Measured Using Fluorescence Recovery After Photobleaching
,” Ann. Biomed. Eng.
, 31
(7
), pp. 753
–760
.43.
Evans
, R. C.
, and Quinn
, T. M.
, 2006
, “Solute Convection in Dynamically Compressed Cartilage
,” J. Biomech.
, 39
(6
), pp. 1048
–1055
.44.
Fortin
, M.
, Soulhat
, J.
, Shirazi-Adl
, A.
, Hunziker
, E. B.
, and Buschmann
, M. D.
, 2000
, “Unconfined Compression of Articular Cartilage: Nonlinear Behavior and Comparison With a Fibril-Reinforced Biphasic Model
,” ASME J. Biomech. Eng.
, 122
(2
), pp. 189
–195
.45.
Chen
, A. C.
, Bae
, W. C.
, Schinagl
, R. M.
, and Sah
, R. L.
, 2001
, “Depth- and Strain-Dependent Mechanical and Electromechanical Properties of Full-Thickness Bovine Articular Cartilage in Confined Compression
,” J. Biomech.
, 34
(1
), pp. 1
–12
.46.
Quinn
, T. M.
, Kocian
, P.
, and Meister
, J. J.
, 2000
, “Static Compression is Associated With Decreased Diffusivity of Dextrans in Cartilage Explants
,” Arch. Biochem. Biophys.
, 384
(2
), pp. 327
–334
.47.
Evans
, R. C.
, and Quinn
, T. M.
, 2005
, “Solute Diffusivity Correlates With Mechanical Properties and Matrix Density of Compressed Articular Cartilage
,” Arch. Biochem. Biophys.
, 442
(1
), pp. 1
–10
.48.
Hayes
, W.
, and Mockros
, L.
, 1971
, “Some Viscoelastic Properties of Human Articular Cartilage
,” J. Appl. Physiol.
, 31
(4
), pp. 562
–538
.49.
Evans
, C. H.
, Kraus
, V. B.
, and Setton
, L. A.
, 2013
, “Progress in Intra-Articular Therapy
,” Nat. Rev. Rheumatol.
, 10
(1
), pp. 11
–22
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