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.

References

References
1.
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
2.
Evans
,
C. H.
,
Kraus
,
V. B.
, and
Setton
,
L. A.
,
2013
, “
Progress in Intra-Articular Therapy
,”
Nat. Rev. Rheumatol.
,
10
(
1
), pp.
11
22
.
3.
Gerwin
,
N.
,
Hops
,
C.
, and
Lucke
,
A.
,
2006
, “
Intraarticular Drug Delivery in Osteoarthritis
,”
Adv. Drug Delivery Rev.
,
58
(
2
), pp.
226
242
.
4.
Bang
,
L. M.
, and
Keating
,
G. M.
,
2004
, “
A Review of Its Use in Rheumatoid Arthritis
,”
Biodrugs
,
18
(
2
), pp.
121
139
.
5.
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
.
6.
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
.
7.
Goldring
,
M. B.
,
2001
, “
Anticytokine Therapy for Osteoarthritis
,”
Expert Opin. Biol. Ther.
,
1
(
5
), pp.
817
829
.
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.
Martel-Pelletier
,
J.
,
2004
, “
Pathophysiology of Osteoarthritis
,”
Osteoarthr. Cartilage
,
12
(
Suppl. A
), pp.
S31
S33
.
10.
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
.
11.
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
.
12.
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
.
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.
, and
Bullough
,
P.
,
1968
, “
Permeability of Articular Cartilage
,”
Nature
,
219
(
5160
), pp.
1260
1261
.
15.
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.
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
.
17.
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.
18.
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
.
19.
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
.
20.
Maroudas
,
A.
,
1968
, “
Physicochemical Properties of Cartilage in the Light of Ion Exchange Theory
,”
Biophys. J
,
8
(
5
), pp.
575
595
.
21.
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
.
22.
Bajpayee
,
A. G.
, and
Grodzinsky
,
A. J.
,
2017
, “
Cartilage-Targeting Drug Delivery: Can Electrostatic Interactions Help?
,”
Nat. Rev. Rheumatol.
,
13
(
3
), pp.
183
193
.
23.
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
.
24.
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
.
25.
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
.
26.
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
.
27.
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
.
28.
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
.
29.
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
.
30.
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
.
31.
Maroudas
,
A.
,
1970
, “
Distribution and Diffusion of Solutes in Articular Cartilage
,”
Biophys. J
,
10
(
5
), pp.
365
379
.
32.
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
.
33.
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
.
34.
Fannjiang
,
A.
, and
Papanicolaou
,
G.
,
1997
, “
Convection-Enhanced Diffusion for Random Flows
,”
J. Stat. Phys.
,
88
(
5–6
), pp.
1033
1076
.
35.
Eckstein
,
F.
,
Hudelmaier
,
M.
, and
Putz
,
R.
,
2006
, “
The Effects of Exercise on Human Articular Cartilage
,”
J. Anat.
,
208
(
4
), pp.
491
512
.
36.
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/
37.
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
.
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
,”
Orthopaedics
,
1
(
6
), pp.
461
468
.
40.
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
.
41.
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
.
42.
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
.
43.
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
.
44.
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
.
45.
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
.
You do not currently have access to this content.