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.

References

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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