Technical Brief

The Effect of Charge and Mechanical Loading on Antibody Diffusion Through the Articular Surface of Cartilage

[+] Author and Article Information
Chris D. DiDomenico

Meinig School of Biomedical Engineering,
Cornell University,
Ithaca, NY 14853

Lawrence J. Bonassar

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

1Corresponding author.

Manuscript received April 17, 2018; final manuscript received October 3, 2018; published online November 19, 2018. Assoc. Editor: David Corr.

J Biomech Eng 141(1), 014502 (Nov 19, 2018) (5 pages) Paper No: BIO-18-1187; doi: 10.1115/1.4041768 History: Received April 17, 2018; Revised October 03, 2018

Molecular transport of osteoarthritis (OA) therapeutics within articular cartilage is influenced by many factors, such as solute charge, that have yet to be fully understood. This study characterizes how solute charge influences local diffusion and convective transport of antibodies within the heterogeneous cartilage matrix. Three fluorescently tagged solutes of varying isoelectric point (pI) (4.7–5.9) were tested in either cyclic or passive cartilage loading conditions. In each case, local diffusivities were calculated based on local fluorescence in the cartilage sample, as observed by confocal microscopy. In agreement with past research, local solute diffusivities within the heterogeneous cartilage matrix were highest around 200–275 μm from the articular surface, but 3–4 times lower at the articular surface and in the deeper zones of the tissue. Transport of all 150 kDa solutes was significantly increased by the application of mechanical loading at 1 Hz, but local transport enhancement was not significantly affected by changes in solute isoelectric point. More positively charged solutes (higher pI) had significantly higher local diffusivities 200–275 μm from the tissue surface, but no other differences were observed. This implies that there are certain regions of cartilage that are more sensitive to changes in solute charge than others, which could be useful for future development of OA therapeutics.

Copyright © 2019 by ASME
Your Session has timed out. Please sign back in to continue.


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. https://www.ncbi.nlm.nih.gov/pubmed/10229409 [PubMed]
Evans, C. H. , Kraus, V. B. , and Setton, L. A. , 2013, “ Progress in Intra-Articular Therapy,” Nat. Rev. Rheumatol., 10(1), pp. 11–22. [CrossRef] [PubMed]
Gerwin, N. , Hops, C. , and Lucke, A. , 2006, “ Intraarticular Drug Delivery in Osteoarthritis,” Adv. Drug Delivery Rev., 58(2), pp. 226–242. [CrossRef]
Bang, L. M. , and Keating, G. M. , 2004, “ A Review of Its Use in Rheumatoid Arthritis,” Biodrugs, 18(2), pp. 121–139. [CrossRef] [PubMed]
Chan, C. E. Z. , Chan, A. H. Y. , Hanson, B. J. , and Ooi, E. E. , 2009, “ The Use of Antibodies in the Treatment of Infectious Diseases,” Singapore Med. J., 50(7), pp. 663–672. [PubMed]
Khawli, L. A. , Goswami, S. , Hutchinson, R. , Kwong, Z. W. , Yang, J. , Wang, X. , Yao, Z. , Sreedhara, A. , Cano, T. , Tesar, D. , Nijem, I. , Allison, D. E. , Wong, P. Y. , Kao, Y. H. , Quan, C. , Joshi, A. , Harris, R. J. , and Motchnik, P. , 2010, “ Charge Variants in IgG1: Isolation, Characterization, In Vitro Binding Properties and Pharmacokinetics in Rats,” mAbs, 2(6), pp. 613–624. [CrossRef] [PubMed]
Goldring, M. B. , 2001, “ Anticytokine Therapy for Osteoarthritis,” Expert Opin. Biol. Ther., 1(5), pp. 817–829. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Martel-Pelletier, J. , 2004, “ Pathophysiology of Osteoarthritis,” Osteoarthr. Cartilage, 12(Suppl. A), pp. S31–S33. [CrossRef]
Owen, S. , Francis, H. , and Roberts, M. , 1994, “ Disappearance Kinetics of Solutes From Synovial Fluid After Intra-Articular Injection,” Br. J. Clin. Pharmacol., 38(4), pp. 349–355. [CrossRef] [PubMed]
Mow, V. C. , Holmes, M. H. , and Michael Lai, W. , 1984, “ Fluid Transport and Mechanical Properties of Articular Cartilage: A Review,” J. Biomech., 17(5), pp. 377–394. [CrossRef] [PubMed]
Poole, A. R. , 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. [CrossRef]
Maroudas, A. , 1975, “ Biophysical Chemistry of Cartilaginous Tissues With Special Reference to Solute and Fluid Transport,” Biorheology, 12(3–4), pp. 233–248. [CrossRef] [PubMed]
Maroudas, A. , and Bullough, P. , 1968, “ Permeability of Articular Cartilage,” Nature, 219(5160), pp. 1260–1261. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
DiDomenico, C. D. , Goodearl, A. , Yarilina, A. , Sun, V. , Mitra, S. , Sterman, A. S. , and Bonassar, L. J. , 2017, “ The Effect of Antibody Size and Mechanical Loading on Solute Diffusion Through the Articular Surface of Cartilage,” ASME J. Biomech. Eng., 139(9), p. 091005. [CrossRef]
DiDomenico, C. D. , and Bonassar, L. J. , 2018, “ How Can 50 Years of Solute Transport Data in Articular Cartilage Inform the Design of Arthritis Therapeutics?,” Osteoarthr. Cartilage, 26(11), pp. 1438–1446.
DiDomenico, C. D. , Lintz, M. , and Bonassar, L. J. , 2018, “ Molecular Transport in Articular Cartilage—What Have We Learned From the Past 50 Years?,” Nat. Rev. Rheumatol., p. 1.
Arbabi, V. , Pouran, B. , Weinans, H. , and Zadpoor, A. A. , 2016, “ Multiphasic Modeling of Charged Solute Transport Across Articular Cartilage: Application of Multi-Zone Finite-Bath Model,” J. Biomech., 49(9), pp. 1510–1517. [CrossRef] [PubMed]
Maroudas, A. , 1968, “ Physicochemical Properties of Cartilage in the Light of Ion Exchange Theory,” Biophys. J, 8(5), pp. 575–595. [CrossRef] [PubMed]
Kokkonen, H. T. , Chin, H. C. , Töyräs, J. , Jurvelin, J. S. , and Quinn, T. M. , 2017, “ Solute Transport of Negatively Charged Contrast Agents Across Articular Surface of Injured Cartilage,” Ann. Biomed. Eng., 45(4), pp. 973–981. [CrossRef] [PubMed]
Bajpayee, A. G. , and Grodzinsky, A. J. , 2017, “ Cartilage-Targeting Drug Delivery: Can Electrostatic Interactions Help?,” Nat. Rev. Rheumatol., 13(3), pp. 183–193. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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,” Osteoarthr. Cartilage, 15(9), pp. 1025–1033. [CrossRef]
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. [CrossRef] [PubMed]
Graham, B. T. , Moore, A. C. , Burris, D. L. , and Price, C. , 2017, “ Sliding Enhances Fluid and Solute Transport Into Buried Articular Cartilage Contacts,” Osteoarthr. Cartilage, 25(12), pp. 2100–2107. [CrossRef]
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.—PubMed—NCBI,” Radiology, 187(1), pp. 179–185. [CrossRef] [PubMed]
DiDomenico, C. D. , Xiang Wang, Z. , and Bonassar, L. J. , 2016, “ Cyclic Mechanical Loading Enhances Transport of Antibodies Into Articular Cartilage,” ASME J. Biomech. Eng., 139(1), p. 011012. [CrossRef]
Bajpayee, A. G. , Quadir, M. A. , Hammond, P. T. , and Grodzinsky, A. J. , 2016, “ Charge Based Intra-Cartilage Delivery of Single Dose Dexamethasone Using Avidin Nano-Carriers Suppresses Cytokine-Induced Catabolism Long Term,” Osteoarthr. Cartilage, 24(1), pp. 71–81. [CrossRef]
Maroudas, A. , 1970, “ Distribution and Diffusion of Solutes in Articular Cartilage,” Biophys. J, 10(5), pp. 365–379. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Carr, E. J. , and Turner, I. W. , 2015, “ 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.
Fannjiang, A. , and Papanicolaou, G. , 1997, “ Convection-Enhanced Diffusion for Random Flows,” J. Stat. Phys., 88(5–6), pp. 1033–1076. [CrossRef]
Eckstein, F. , Hudelmaier, M. , and Putz, R. , 2006, “ The Effects of Exercise on Human Articular Cartilage,” J. Anat., 208(4), pp. 491–512. [CrossRef] [PubMed]
Maroudas, A. , 1976, “ Transport of Solutes Through Cartilage: Permeability to Large Molecules,” J. Anat., 122(Pt. 2), pp. 335–347. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1231906/ [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Sophia Fox, A. J. , Bedi, A. , and Rodeo, S. A. , 2009, “ The Basic Science of Articular Cartilage: Structure, Composition and Function,” Orthopaedics, 1(6), pp. 461–468.
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. [CrossRef] [PubMed]
Silverberg, J. L. , Barrett, A. R. , Das, M. , Petersen, P. B. , Bonassar, L. J. , and Cohen, I. , 2014, “ Structure-Function Relations and Rigidity Percolation in the Shear Properties of Articular Cartilage,” Biophys. J., 107(7), pp. 1721–1730. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Besier, T. F. , Gold, G. E. , Beaupré, G. S. , and Delp, S. L. , 2005, “ A Modeling Framework to Estimate Patellofemoral Joint Cartilage Stress In Vivo,” Med. Sci. Sports Exercise, 37(11), pp. 1924–1930. [CrossRef]
Li, L. P. , Cheung, J. T. M. , and Herzog, W. , 2009, “ Three-Dimensional Fibril-Reinforced Finite Element Model of Articular Cartilage,” Med. Biol. Eng. Comput., 47(6), pp. 607–615. [CrossRef] [PubMed]
Ferguson, S. J. , Bryant, J. T. , Ganz, R. , and Ito, K. , 2000, “ The Acetabular Labrum Seal: A Poroelastic Finite Element Model,” Clin. Biomech., 15(6), pp. 463–468. [CrossRef]


Grahic Jump Location
Fig. 1

Cartilage cylinders were bisected and then sliced to obtain a final sample dimension of 4 × 2 × 1.15 mm (A). Samples were loaded in a way that caused fluid flow to be perpendicular to the articular surface (AS) and deep zone (DZ) (B). Representative image from confocal microscopy showing the fluorescence gradient perpendicular to the AS (C). The red box (∼1000 μm wide, 500 μm tall) indicates the region of interest that was examined for this study. Diffusion perpendicular to the deep zone was not examined for this study.

Grahic Jump Location
Fig. 2

Fluorescence curves for all solutes (passive condition) tested (left) and local diffusivities (right), which includes historical data (*) for a neutral antibody from a previous study [16]. Error bars denote standard deviations with n = 5–7 for all solutes. On average, diffusivities for the pI 4.7, pI 5.4, and pI 5.9, were 3.8, 4.5, 4.6 μm2/s at 50 μm, but pI did not affect diffusivity significantly within this region (p = 0.25). Diffusivities increased to a maximum of 15.0, 16.9, and 19.0 μm2/s for the pI 4.7, pI 5.4, and pI 5.9 solutes respectively, between 200 and 275 μm. Calculated diffusivities at 125 μm, 200 μm, and 275 μm were higher than all other diffusivities in the tissue, for all solutes (#: p < 0.001). Diffusivities for pI 5.9 were higher than that of pI 4.7, between 200 and 375 μm (p < 0.02). Values obtained from 50 μm and 425 and 800 μm range were not different from each other, for any solute (p > 0.3).

Grahic Jump Location
Fig. 3

Fluorescence curves for pI 5.9 and 5% cyclic loading (left) and local diffusivities for all solutes at 5% cyclic loading (right). Error bars denote standard deviations with n = 5–7 for all solutes. Orange solid line denotes average passive diffusivity levels in the passive condition for all solutes. Cyclic loading at 5% cyclic strain and at 1 Hz increased fluorescence values between 150 and 400 μm. Solutes did not experience any significant differences in diffusivity values or trends at this loading amplitude (p > 0.1). Additionally, there were no differences between solute diffusivities at 1.25% or 2.5% (shown in supplement). However, maximal transport enhancement increased for all solutes with increasing loading amplitude, as expected.



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