Because of the heterogeneous nature of articular cartilage tissue, penetration of potential therapeutic molecules for osteoarthritis (OA) through the articular surface (AS) is complex, with many factors that affect transport of these solutes within the tissue. Therefore, the goal of this study is to investigate how the size of antibody (Ab) variants, as well as application of cyclic mechanical loading, affects solute transport within healthy cartilage tissue. Penetration of fluorescently tagged solutes was quantified using confocal microscopy. For all the solutes tested, fluorescence curves were obtained through the articular surface. On average, diffusivities for the solutes of sizes 200 kDa, 150 kDa, 50 kDa, and 25 kDa were 3.3, 3.4, 5.1, and 6.0 μm2/s from 0 to 100 μm from the articular surface. Diffusivities went up to a maximum of 16.5, 18.5, 20.5, and 23.4 μm2/s for the 200 kDa, 150 kDa, 50 kDa, and 25 kDa molecules, respectively, from 225 to 325 μm from the surface. Overall, the effect of loading was very significant, with maximal transport enhancement for each solute ranging from 2.2 to 3.4-fold near 275 μm. Ultimately, solutes of this size do not diffuse uniformly nor are convected uniformly, through the depth of the cartilage tissue. This research potentially holds great clinical significance to discover ways of further optimizing transport into cartilage and leads to effective antibody-based treatments for OA.
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
.http://content.iospress.com/articles/biorheology/bir1512.
Bang
, L. M.
, and Keating
, G. M.
, 2004
, “A Review of Its Use in Rheumatoid Arthritis
,” Biodrugs
, 18
(2
), pp. 121
–139
.3.
Nestorov
, I.
, 2005
, “Clinical Pharmacokinetics of TNF Antagonists: How Do They Differ?
,” Semin. Arthritis Rheum.
, 34
(Suppl. 1
), pp. 12
–18
.4.
Feldmann
, M.
, and Maini
, R. N.
, 2001
, “Anti-TNFα Therapy of Rheumatoid Arthritis: What Have We Learned?
,” Annu. Rev. Immunol.
, 19
(1
), pp. 163
–196
.5.
Goldring
, M. B.
, 2001
, “Anticytokine Therapy for Osteoarthritis
,” Expert Opin. Biol. Ther.
, 1
(5
), pp. 817
–829
.6.
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.
, 16
(1
), pp. 81
–92
.7.
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
.8.
Martel-Pelletier
, J.
, 1998
, “Pathophysiology of Osteoarthritis
,” Osteoarthritis Cartilage
, 6
(6
), pp. 374
–376
.9.
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
.10.
Gerwin
, N.
, Hops
, C.
, and Lucke
, A.
, 2006
, “Intraarticular Drug Delivery in Osteoarthritis
,” Adv. Drug Delivery Rev.
, 58
(2
), pp. 226
–242
.11.
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
.12.
Poole
, A.
, Kojima
, T.
, Yasuda
, T.
, Mwale
, F.
, Kobayashi
, M.
, and Laverty
, S.
, 2001
, “Composition and Structure of Articular Cartilage: A Template for Tissue Repair
,” Clin. Orthop. Relat. Res.
, 1
(Suppl. 391
), pp. S26
–S33
.13.
Maroudas
, A.
, 1975
, “Biophysical Chemistry of Cartilaginous Tissues With Special Reference to Solute and Fluid Transport
,” Biorheology
, 12
(3–4
), pp. 233
–248
.14.
Maroudas
, A.
, Bullough
, P.
, Swanson
, S. A. V.
, and Freeman
, R.
, 1968
, “The Permeability of Articular Cartilage
,” J. Bone Jt. Surg.
, 50B
(1
), pp. 166
–177
.http://bjj.boneandjoint.org.uk/content/50-B/1/16615.
Hwang
, W. S.
, Li
, B.
, Jin
, L. H.
, Ngo
, K.
, Schachar
, N. S.
, and Hughes
, G. N.
, 1992
, “Collagen Fibril Structure of Normal, Aging, and Osteoarthritic Cartilage
,” J. Pathol.
, 167
(4
), pp. 425
–433
.16.
Maroudas
, A.
, 1970
, “Distribution and Diffusion of Solutes in Articular Cartilage
,” Biophys. J.
, 10
(5
), pp. 365
–379
.17.
Torzilli
, P. A.
, Arduino
, J. M.
, Gregory
, J. D.
, and Bansal
, M.
, 1997
, “Effect of Proteoglycan Removal on Solute Mobility in Articular Cartilage
,” J. Biomech.
, 30
(9
), pp. 895
–902
.18.
Zhang
, L.
, and Szeri
, A. Z.
, 2008
, “Transport of Neutral Solute in Articular Cartilage: Effect of Microstructure Anisotropy
,” J. Biomech.
, 41
(2
), pp. 430
–437
.19.
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
.20.
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
.21.
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
.22.
Lima
, E. G.
, Bian
, L.
, Ng
, K. W.
, Mauck
, R. L.
, Byers
, B. A.
, Tuan
, R. S.
, Ateshian
, G. A.
, and Hung
, C. T.
, 2007
, “The Beneficial Effect of Delayed Compressive Loading on Tissue-Engineered Cartilage Constructs Cultured With TGF-β3
,” Osteoarthritis Cartilage
, 15
(9
), pp. 1025
–1033
.23.
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
.24.
DiDomenico
, C. D.
, Wang
, Z. X.
, and Bonassar
, L. J.
, 2016
, “Cyclic Mechanical Loading Enhances Transport of Antibodies Into Articular Cartilage
,” ASME J. Biomech. Eng.
, 139
(1
), p. 11012
.25.
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
.26.
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
.27.
Leddy
, H. A.
, Haider
, M. A.
, and Guilak
, F.
, 2006
, “Diffusional Anisotropy in Collagenous Tissues: Fluorescence Imaging of Continuous Point Photobleaching
,” Biophys. J.
, 91
(1
), pp. 311
–316
.28.
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. 1
–17
.29.
Fannjiang
, A.
, and Papanicolaou
, G.
, 1997
, “Convection-Enhanced Diffusion for Random Flows
,” J. Stat. Phys.
, 88
(5–6
), pp. 1033
–1076
.30.
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
.31.
Evans
, R. C.
, and Quinn
, T. M.
, 2006
, “Solute Convection in Dynamically Compressed Cartilage
,” J. Biomech.
, 39
(6
), pp. 1048
–1055
.32.
Eckstein
, F.
, Hudelmaier
, M.
, and Putz
, R.
, 2006
, “The Effects of Exercise on Human Articular Cartilage
,” J. Anat.
, 208
(4
), pp. 491
–512
.33.
Maroudas
, A.
, 1976
, “Transport of Solutes Through Cartilage: Permeability to Large Molecules
,” J. Anat.
, 122
(2
), pp. 335
–347
.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1231906/34.
Klein
, T. J.
, Chaudhry
, M.
, Bae
, W. C.
, and Sah
, R. L.
, 2007
, “Depth-Dependent Biomechanical and Biochemical Properties of Fetal, Newborn, and Tissue-Engineered Articular Cartilage
,” J. Biomech.
, 40
(1
), pp. 182
–190
.35.
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
.36.
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
.37.
Silverberg
, J. L.
, Barrett
, A. R.
, Das
, M.
, Petersen
, P. B.
, and Bonassar
, L. J.
, 2014
, “Article Structure-Function Relations and Rigidity Percolation in the Shear Properties of Articular Cartilage
,” Biophys. J.
, 107
(7
), pp. 1721
–1730
.38.
Wilson
, W.
, Huyghe
, J. M.
, and Van Donkelaar
, C. C.
, 2007
, “Depth-Dependent Compressive Equilibrium Properties of Articular Cartilage Explained by Its Composition
,” Biomech. Model. Mechanobiol.
, 6
(1–2
), pp. 43
–53
.39.
Sophia Fox
, A. J.
, Bedi
, A.
, and Rodeo
, S. A.
, 2009
, “The Basic Science of Articular Cartilage: Structure, Composition, and Function
,” Sports Health
, 1
(6
), pp. 461
–468
.40.
Maroudas
, A.
, 1968
, “Physicochemical Properties of Cartilage in the Light of Ion Exchange Theory
,” Biophys. J.
, 8
(5
), pp. 575
–595
.41.
Kulmala
, K. M.
, Korhonen
, R. K.
, Julkunen
, P.
, Jurvelin
, J. S.
, Quinn
, T. M.
, Kröger
, H.
, and Töyräs
, J.
, 2010
, “Diffusion Coefficients of Articular Cartilage for Different CT and MRI Contrast Agents
,” Med. Eng. Phys.
, 32
(8
), pp. 878
–882
.42.
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
.43.
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
.44.
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
.45.
Ateshian
, G. A.
, and Weiss
, J. A.
, 2013
, “Finite Element Modeling of Solutes in Hydrated Deformable Biological Tissues
,” Computer Models in Biomechanics
, Springer
, Dordrecht, The Netherlands, pp. 231
–249
.46.
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
.47.
Besier
, T. F.
, Gold
, G. E.
, and Delp
, S. L.
, 2005
, “A Modeling Framework to Estimate Patellofemoral Joint Cartilage Stress In Vivo
,” Med. Sci. Sports Exercise
, pp. 1924
–1930
.48.
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
.49.
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
.50.
Bajpayee
, A. G.
, Wong
, C. R.
, Bawendi
, M. G.
, Frank
, E. H.
, and Grodzinsky
, A. J.
, 2014
, “Avidin as a Model for Charge Driven Transport Into Cartilage and Drug Delivery for Treating Early Stage Post-Traumatic Osteoarthritis
,” Biomaterials
, 35
(1
), pp. 538
–549
.51.
Hayes
, W. C.
, and Mockros
, L. F.
, 1971
, “Viscoelastic Properties of Human Articular Cartilage
,” J. Appl. Physiol.
, 31
(4
), pp. 562
–538
.http://jap.physiology.org/content/31/4/562Copyright © 2017 by ASME
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