As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.

References

References
1.
Yelin
,
E.
,
Murphy
,
L.
,
Cisternas
,
M. G.
,
Foreman
,
A. J.
,
Pasta
,
D. J.
, and
Helmick
,
C. G.
,
2007
, “
Medical Care Expenditures and Earnings Losses Among Persons With Arthritis and Other Rheumatic Conditions in 2003, and Comparisons With 1997
,”
Arthritis Rheum.
,
56
(
5
), pp.
1397
1407
.10.1002/art.22565
2.
Buckwalter
,
J. A.
,
Saltzman
,
C.
, and
Brown
,
T.
,
2004
, “
The Impact of Osteoarthritis: Implications for Research
,”
Clin. Orthop. Relat. Res.
,
427
(
Suppl
), pp.
S6
S15
.10.1097/01.blo.0000143938.30681.9d
3.
Englund
,
M.
,
Guermazi
,
A.
,
Gale
,
D.
,
Hunter
,
D. J.
,
Aliabadi
,
P.
,
Clancy
,
M.
, and
Felson
,
D. T.
,
2008
, “
Incidental Meniscal Findings on Knee MRI in Middle-Aged and Elderly Persons
,”
N. Engl. J. Med.
,
359
(
11
), pp.
1108
1115
.10.1056/NEJMoa0800777
4.
Carlsson
,
G. E.
,
1999
, “
Epidemiology and Treatment Need for Temporomandibular Disorders
,”
J. Orofacial Pain
,
13
(
4
), pp.
232
237
.
5.
Samuels
,
J.
,
Krasnokutsky
,
S.
, and
Abramson
,
S. B.
,
2008
, “
Osteoarthritis: A Tale of Three Tissues
,”
Bull. NYU Hosp. Jt. Dis.
,
66
(
3
), pp.
244
250
.
6.
Revell
,
C. M.
, and
Athanasiou
,
K. A.
,
2008
, “
Success Rates and Immunologic Responses of Autogenic, Allogenic, and Xenogenic Treatments to Repair Articular Cartilage Defectst
,”
Tissue Eng. Part B
,
15
(1), pp.
1
5
.
7.
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
.10.1002/jor.1100090304
8.
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
.10.1002/jor.1100150404
9.
Sweigart
,
M. A.
, and
Athanasiou
,
K. A.
,
2005
, “
Tensile and Compressive Properties of the Medial Rabbit Meniscus
,”
Proc. Inst. Mech. Eng., Part H
,
219
(
5
), pp.
337
347
.10.1243/095441105X34329
10.
Paschos
,
N. K.
,
Makris
,
E. A.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2014
, “
Topographic Variations in Biomechanical and Biochemical Properties in the Ankle Joint: An In Vitro Bovine Study Evaluating Native and Engineered Cartilage
,”
Arthroscopy
,
30
(
10
), pp.
1317
1326
.10.1016/j.arthro.2014.05.025
11.
Detamore
,
M. S.
, and
Athanasiou
,
K. A.
,
2003
, “
Tensile Properties of the Porcine Temporomandibular Joint Disc
,”
ASME J. Biomech. Eng.
,
125
(
4
), pp.
558
565
.10.1115/1.1589778
12.
Murphy
,
M. K.
,
Arzi
,
B.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2013
, “
Tensile Characterization of Porcine Temporomandibular Joint Disc Attachments
,”
J. Dent. Res.
,
92
(
8
), pp.
753
758
.10.1177/0022034513494817
13.
Kempson
,
G. E.
,
Tuke
,
M. A.
,
Dingle
,
J. T.
,
Barrett
,
A. J.
, and
Horsfield
,
P. H.
,
1976
, “
The Effects of Proteolytic Enzymes on the Mechanical Properties of Adult Human Articular Cartilage
,”
Biochim. Biophys. Acta
,
428
(
3
), pp.
741
760
.10.1016/0304-4165(76)90205-1
14.
Kim
,
K. W.
,
Wong
,
M. E.
,
Helfrick
,
J. F.
,
Thomas
,
J. B.
, and
Athanasiou
,
K. A.
,
2003
, “
Biomechanical Tissue Characterization of the Superior Joint Space of the Porcine Temporomandibular Joint
,”
Ann. Biomed. Eng.
,
31
(
8
), pp.
924
930
.10.1114/1.1591190
15.
Sweigart
,
M. A.
,
Zhu
,
C. F.
,
Burt
,
D. M.
,
DeHoll
,
P. D.
,
Agrawal
,
C. M.
,
Clanton
,
T. O.
, and
Athanasiou
,
K. A.
,
2004
, “
Intraspecies and Interspecies Comparison of the Compressive Properties of the Medial Meniscus
,”
Ann. Biomed. Eng.
,
32
(
11
), pp.
1569
1579
.10.1114/B:ABME.0000049040.70767.5c
16.
Turner
,
A. S.
,
Athanasiou
,
K. A.
,
Zhu
,
C. F.
,
Alvis
,
M. R.
, and
Bryant
,
H. U.
,
1997
, “
Biochemical Effects of Estrogen on Articular Cartilage in Ovariectomized Sheep
,”
Osteoarthritis Cartilage
,
5
(
1
), pp.
63
69
.10.1016/S1063-4584(97)80032-5
17.
Athanasiou
,
K. A.
,
Fleischli
,
J. G.
,
Bosma
,
J.
,
Laughlin
,
T. J.
,
Zhu
,
C. F.
,
Agrawal
,
C. M.
, and
Lavery
,
L. A.
,
1999
, “
Effects of Diabetes Mellitus on the Biomechanical Properties of Human Ankle Cartilage
,”
Clin. Orthop. Relat. Res.
,
368
, pp.
182
189
.10.1097/00003086-199911000-00022
18.
Athanasiou
,
K. A.
,
Thoma
,
B. S.
,
Lanctot
,
D. R.
,
Shin
,
D.
,
Agrawal
,
C. M.
, and
LeBaron
,
R. G.
,
1999
, “
Development of the Cytodetachment Technique to Quantify Mechanical Adhesiveness of the Single Cell
,”
Biomaterials
,
20
(
23–24
), pp.
2405
2415
.10.1016/S0142-9612(99)00168-4
19.
Leipzig
,
N. D.
, and
Athanasiou
,
K. A.
,
2008
, “
Static Compression of Single Chondrocytes Catabolically Modifies Single-Cell Gene Expression
,”
Biophys. J.
,
94
(
6
), pp.
2412
2422
.10.1529/biophysj.107.114207
20.
Leipzig
,
N. D.
,
Eleswarapu
,
S. V.
, and
Athanasiou
,
K. A.
,
2006
, “
The Effects of TGF-Beta1 and IGF-I on the Biomechanics and Cytoskeleton of Single Chondrocytes
,”
Osteoarthritis Cartilage
,
14
(
12
), pp.
1227
1236
.10.1016/j.joca.2006.05.013
21.
Koay
,
E. J.
,
Ofek
,
G.
, and
Athanasiou
,
K. A.
,
2008
, “
Effects of TGF-Beta1 and IGF-I on the Compressibility, Biomechanics, and Strain-Dependent Recovery Behavior of Single Chondrocytes
,”
J. Biomech.
,
41
(
5
), pp.
1044
1052
.10.1016/j.jbiomech.2007.12.006
22.
Scott
,
C. C.
, and
Athanasiou
,
K. A.
,
2006
, “
Design, Validation, and Utilization of an Articular Cartilage Impact Instrument
,”
Proc. Inst. Mech. Eng., Part H
,
220
(
8
), pp.
845
855
.10.1243/09544119JEIM97
23.
Natoli
,
R. M.
,
Scott
,
C. C.
, and
Athanasiou
,
K. A.
,
2008
, “
Temporal Effects of Impact on Articular Cartilage Cell Death, Gene Expression, Matrix Biochemistry, and Biomechanics
,”
Ann. Biomed. Eng.
,
36
(
5
), pp.
780
792
.10.1007/s10439-008-9472-5
24.
Blumberg
,
T. J.
,
Natoli
,
R. M.
, and
Athanasiou
,
K. A.
,
2008
, “
Effects of Doxycycline on Articular Cartilage GAG Release and Mechanical Properties Following Impact
,”
Biotechnol. Bioeng.
,
100
(
3
), pp.
506
515
.10.1002/bit.21778
25.
Natoli
,
R. M.
, and
Athanasiou
,
K. A.
,
2008
, “
P188 Reduces Cell Death and IGF-I Reduces GAG Release Following Single-Impact Loading of Articular Cartilage
,”
ASME J. Biomech. Eng.
,
130
(
4
), pp.
93
102
.10.1115/1.2939368
26.
Athanasiou
,
K. A.
,
Singhal
,
A. R.
,
Agrawal
,
C. M.
, and
Boyan
,
B. D.
,
1995
, “
In Vitro Degradation and Release Characteristics of Biodegradable Implants Containing Trypsin Inhibitor
,”
Clin. Orthop. Relat. Res.
,
315
, pp.
272
281
.10.1097/00003086-199506000-00033
27.
Thompson
,
D. E.
,
Agrawal
,
C. M.
, and
Athanasiou
,
K. A.
,
1996
, “
The Effects of Dynamic Compressive Loading on Biodegradable Implants of 50–50% Polylactic Acid-Polyglycolic Acid
,”
Tissue Eng.
,
2
(
1
), pp.
61
74
.10.1089/ten.1996.2.61
28.
Agrawal
,
C. M.
, and
Athanasiou
,
K. A.
,
1997
, “
Technique to Control pH in Vicinity of Biodegrading PLA-PGA Implants
,”
J. Biomed. Mater. Res.
,
38
(
2
), pp.
105
114
.10.1002/(SICI)1097-4636(199722)38:2<105::AID-JBM4>3.0.CO;2-U
29.
Athanasiou
,
K. A.
,
Korvick
,
D.
, and
Schenck
,
R.
,
1997
, “
Biodegradable Implants for the Treatment of Osteochondral Defects in a Goat Model
,”
Tissue Eng.
,
3
(
4
), pp.
363
373
.10.1089/ten.1997.3.363
30.
Chu
,
C. R.
,
Coutts
,
R. D.
,
Yoshioka
,
M.
,
Harwood
,
F. L.
,
Monosov
,
A. Z.
, and
Amiel
,
D.
,
1995
, “
Articular Cartilage Repair Using Allogeneic Perichondrocyte-Seeded Biodegradable Porous Polylactic Acid (PLA): A Tissue-Engineering Study
,”
J. Biomed. Mater. Res.
,
29
(
9
), pp.
1147
1154
.10.1002/jbm.820290915
31.
Chu
,
C. R.
,
Dounchis
,
J. S.
,
Yoshioka
,
M.
,
Sah
,
R. L.
,
Coutts
,
R. D.
, and
Amiel
,
D.
,
1997
, “
Osteochondral Repair Using Perichondrial Cells. A 1-Year Study in Rabbits
,”
Clin. Orthop. Relat. Res.
,
340
, pp.
220
229
.10.1097/00003086-199707000-00029
32.
Caterson
,
E. J.
,
Li
,
W. J.
,
Nesti
,
L. J.
,
Albert
,
T.
,
Danielson
,
K.
, and
Tuan
,
R. S.
,
2002
, “
Polymer/Alginate Amalgam for Cartilage-Tissue Engineering
,”
Ann. N.Y. Acad. Sci.
,
961
, pp.
134
138
.10.1111/j.1749-6632.2002.tb03066.x
33.
Moutos
,
F. T.
,
Freed
,
L. E.
, and
Guilak
,
F.
,
2007
, “
A Biomimetic Three-Dimensional Woven Composite Scaffold for Functional Tissue Engineering of Cartilage
,”
Nat. Mater.
,
6
(
2
), pp.
162
167
.10.1038/nmat1822
34.
Fortier
,
L. A.
,
Nixon
,
A. J.
,
Mohammed
,
H. O.
, and
Lust
,
G.
,
1997
, “
Altered Biological Activity of Equine Chondrocytes Cultured in a Three-Dimensional Fibrin Matrix and Supplemented With Transforming Growth Factor Beta-1
,”
Am. J. Vet. Res.
,
58
(
1
), pp.
66
70
.
35.
van Osch
,
G. J.
,
van der Veen
,
S. W.
,
Buma
,
P.
, and
Verwoerd-Verhoef
,
H. L.
,
1998
, “
Effect of Transforming Growth Factor-Beta on Proteoglycan Synthesis by Chondrocytes in Relation to Differentiation Stage and the Presence of Pericellular Matrix
,”
Matrix Biol.
,
17
(
6
), pp.
413
424
.10.1016/S0945-053X(98)90101-9
36.
van Osch
,
G. J.
,
van den Berg
,
W. B.
,
Hunziker
,
E. B.
, and
Hauselmann
,
H. J.
,
1998
, “
Differential Effects of IGF-1 and TGF beta-2 on the Assembly of Proteoglycans in Pericellular and Territorial Matrix by Cultured Bovine Articular Chondrocytes
,”
Osteoarthritis Cartilage
,
6
(
3
), pp.
187
195
.10.1053/joca.1998.0111
37.
Luyten
,
F. P.
,
Yu
,
Y. M.
,
Yanagishita
,
M.
,
Vukicevic
,
S.
,
Hammonds
,
R. G.
, and
Reddi
,
A. H.
,
1992
, “
Natural Bovine Osteogenin and Recombinant Human Bone Morphogenetic Protein-2B are Equipotent in the Maintenance of Proteoglycans in Bovine Articular Cartilage Explant Cultures
,”
J. Biol. Chem.
,
267
(
6
), pp.
3691
3695
.
38.
Gooch
,
K. J.
,
Blunk
,
T.
,
Courter
,
D. L.
,
Sieminski
,
A. L.
,
Vunjak-Novakovic
,
G.
, and
Freed
,
L. E.
,
2002
, “
Bone Morphogenetic Proteins−2, −12, and −13 Modulate In Vitro Development of Engineered Cartilage
,”
Tissue Eng.
,
8
(
4
), pp.
591
601
.10.1089/107632702760240517
39.
Smith
,
P.
,
Shuler
,
F. D.
,
Georgescu
,
H. I.
,
Ghivizzani
,
S. C.
,
Johnstone
,
B.
,
Niyibizi
,
C.
,
Robbins
,
P. D.
, and
Evans
,
C. H.
,
2000
, “
Genetic Enhancement of Matrix Synthesis by Articular Chondrocytes: Comparison of Different Growth Factor Genes in the Presence and Absence of Interleukin-1
,”
Arthritis Rheum.
,
43
(
5
), pp.
1156
1164
.10.1002/1529-0131(200005)43:5<1156::AID-ANR26>3.0.CO;2-M
40.
Flechtenmacher
,
J.
,
Huch
,
K.
,
Thonar
,
E. J.
,
Mollenhauer
,
J. A.
,
Davies
,
S. R.
,
Schmid
,
T. M.
,
Puhl
,
W.
,
Sampath
,
T. K.
,
Aydelotte
,
M. B.
, and
Kuettner
,
K. E.
,
1996
, “
Recombinant Human Osteogenic Protein 1 is a Potent Stimulator of the Synthesis of Cartilage Proteoglycans and Collagens by Human Articular Chondrocytes
,”
Arthritis Rheum.
,
39
(
11
), pp.
1896
1904
.10.1002/art.1780391117
41.
Sah
,
R. L.
,
Chen
,
A. C.
,
Grodzinsky
,
A. J.
, and
Trippel
,
S. B.
,
1994
, “
Differential Effects of BFGF and IGF-I on Matrix Metabolism in Calf and Adult Bovine Cartilage Explants
,”
Arch. Biochem. Biophys.
,
308
(
1
), pp.
137
147
.10.1006/abbi.1994.1020
42.
Blunk
,
T.
,
Sieminski
,
A. L.
,
Gooch
,
K. J.
,
Courter
,
D. L.
,
Hollander
,
A. P.
,
Nahir
,
A. M.
,
Langer
,
R.
,
Vunjak-Novakovic
,
G.
, and
Freed
,
L. E.
,
2002
, “
Differential Effects of Growth Factors on Tissue-Engineered Cartilage
,”
Tissue Eng.
,
8
(
1
), pp.
73
84
.10.1089/107632702753503072
43.
Fortier
,
L. A.
,
Lust
,
G.
,
Mohammed
,
H. O.
, and
Nixon
,
A. J.
,
1999
, “
Coordinate Upregulation of Cartilage Matrix Synthesis in Fibrin Cultures Supplemented With Exogenous Insulin-Like Growth Factor-I
,”
J. Orthop. Res.
,
17
(
4
), pp.
467
474
.10.1002/jor.1100170403
44.
Darling
,
E. M.
, and
Athanasiou
,
K. A.
,
2005
, “
Growth Factor Impact on Articular Cartilage Subpopulations
,”
Cell Tissue Res.
,
322
(
3
), pp.
463
473
.10.1007/s00441-005-0020-4
45.
Jenniskens
,
Y. M.
,
Koevoet
,
W.
,
de Bart
,
A. C.
,
Weinans
,
H.
,
Jahr
,
H.
,
Verhaar
,
J. A.
,
DeGroot
,
J.
, and
van Osch
,
G. J.
,
2006
, “
Biochemical and Functional Modulation of the Cartilage Collagen Network by IGF1, TGFbeta2 and FGF2
,”
Osteoarthritis Cartilage
,
14
(
11
), pp.
1136
1146
.10.1016/j.joca.2006.04.002
46.
Mauck
,
R. L.
,
Soltz
,
M. A.
,
Wang
,
C. C.
,
Wong
,
D. D.
,
Chao
,
P. H.
,
Valhmu
,
W. B.
,
Hung
,
C. T.
, and
Ateshian
,
G. A.
,
2000
, “
Functional Tissue Engineering of Articular Cartilage Through Dynamic Loading of Chondrocyte-Seeded Agarose Gels
,”
ASME J. Biomech. Eng.
,
122
(
3
), pp.
252
260
.10.1115/1.429656
47.
Pei
,
M.
,
Solchaga
,
L. A.
,
Seidel
,
J.
,
Zeng
,
L.
,
Vunjak-Novakovic
,
G.
,
Caplan
,
A. I.
, and
Freed
,
L. E.
,
2002
, “
Bioreactors Mediate the Effectiveness of Tissue Engineering Scaffolds
,”
FASEB J.
,
16
(
12
), pp.
1691
1694
.10.1096/fj.02-0083fje
48.
Carver
,
S. E.
, and
Heath
,
C. A.
,
1999
, “
Increasing Extracellular Matrix Production in Regenerating Cartilage With Intermittent Physiological Pressure
,”
Biotechnol. Bioeng.
,
62
(
2
), pp.
166
174
.10.1002/(SICI)1097-0290(19990120)62:2<166::AID-BIT6>3.0.CO;2-K
49.
Carver
,
S. E.
, and
Heath
,
C. A.
,
1999
, “
Semi-Continuous Perfusion System for Delivering Intermittent Physiological Pressure to Regenerating Cartilage
,”
Tissue Eng.
,
5
(
1
), pp.
1
11
.10.1089/ten.1999.5.1
50.
Takahashi
,
K.
,
Kubo
,
T.
,
Arai
,
Y.
,
Kitajima
,
I.
,
Takigawa
,
M.
,
Imanishi
,
J.
, and
Hirasawa
,
Y.
,
1998
, “
Hydrostatic Pressure Induces Expression of Interleukin 6 and Tumour Necrosis Factor Alpha mRNAs in a Chondrocyte-Like Cell Line
,”
Ann. Rheum. Dis.
,
57
(
4
), pp.
231
236
.10.1136/ard.57.4.231
51.
Gunja
,
N. J.
,
Uthamanthil
,
R. K.
, and
Athanasiou
,
K. A.
,
2009
, “
Effects of TGF-Beta1 and Hydrostatic Pressure on Meniscus Cell-Seeded Scaffolds
,”
Biomaterials
,
30
(
4
), pp.
565
573
.10.1016/j.biomaterials.2008.10.007
52.
Kato
,
Y.
,
Iwamoto
,
M.
,
Koike
,
T.
,
Suzuki
,
F.
, and
Takano
,
Y.
,
1988
, “
Terminal Differentiation and Calcification in Rabbit Chondrocyte Cultures Grown in Centrifuge Tubes: Regulation by Transforming Growth Factor Beta and Serum Factors
,”
Proc. Ntnl. Acad. Sci. U.S.A.
,
85
(
24
), pp.
9552
9556
.10.1073/pnas.85.24.9552
53.
Stewart
,
M. C.
,
Saunders
,
K. M.
,
Burton-Wurster
,
N.
, and
Macleod
,
J. N.
,
2000
, “
Phenotypic Stability of Articular Chondrocytes In Vitro: The Effects of Culture Models, Bone Morphogenetic Protein 2, and Serum Supplementation
,”
J. Bone Miner. Res.
,
15
(
1
), pp.
166
174
.10.1359/jbmr.2000.15.1.166
54.
Zhang
,
Z.
,
McCaffery
,
J. M.
,
Spencer
,
R. G.
, and
Francomano
,
C. A.
,
2004
, “
Hyaline Cartilage Engineered by Chondrocytes in Pellet Culture: Histological, Immunohistochemical and Ultrastructural Analysis in Comparison With Cartilage Explants
,”
J. Anat.
,
205
(
3
), pp.
229
237
.10.1111/j.0021-8782.2004.00327.x
55.
Sekiya
,
I.
,
Vuoristo
,
J. T.
,
Larson
,
B. L.
, and
Prockop
,
D. J.
,
2002
, “
In Vitro Cartilage Formation by Human Adult Stem Cells From Bone Marrow Stroma Defines the Sequence of Cellular and Molecular Events During Chondrogenesis
,”
Proc. Natl. Acad. Sci. U.S.A.
,
99
(
7
), pp.
4397
4402
.10.1073/pnas.052716199
56.
Reginato
,
A. M.
,
Iozzo
,
R. V.
, and
Jimenez
,
S. A.
,
1994
, “
Formation of Nodular Structures Resembling Mature Articular Cartilage in Long-Term Primary Cultures of Human Fetal Epiphyseal Chondrocytes on a Hydrogel Substrate
,”
Arthritis Rheum.
,
37
(
9
), pp.
1338
1349
.10.1002/art.1780370912
57.
Yoo
,
J. U.
,
Barthel
,
T. S.
,
Nishimura
,
K.
,
Solchaga
,
L.
,
Caplan
,
A. I.
,
Goldberg
,
V. M.
, and
Johnstone
,
B.
,
1998
, “
The Chondrogenic Potential of Human Bone-Marrow-Derived Mesenchymal Progenitor Cells
,”
J. Bone Jt. Surg. Am. Vol.
,
80
(
12
), pp.
1745
1757
.
58.
Penick
,
K. J.
,
Solchaga
,
L. A.
, and
Welter
,
J. F.
,
2005
, “
High-Throughput Aggregate Culture System to Assess the Chondrogenic Potential of Mesenchymal Stem Cells
,”
Biotechniques
,
39
(
5
), pp.
687
691
.10.2144/000112009
59.
Palmer
,
G. D.
,
Steinert
,
A.
,
Pascher
,
A.
,
Gouze
,
E.
,
Gouze
,
J. N.
,
Betz
,
O.
,
Johnstone
,
B.
,
Evans
,
C. H.
, and
Ghivizzani
,
S. C.
,
2005
, “
Gene-Induced Chondrogenesis of Primary Mesenchymal Stem Cells In Vitro
,”
Mol. Ther.
,
12
(
2
), pp.
219
228
.10.1016/j.ymthe.2005.03.024
60.
Nishimura
,
K.
,
Solchaga
,
L. A.
,
Caplan
,
A. I.
,
Yoo
,
J. U.
,
Goldberg
,
V. M.
, and
Johnstone
,
B.
,
1999
, “
Chondroprogenitor Cells of Synovial Tissue
,”
Arthritis Rheum.
,
42
(
12
), pp.
2631
2637
.10.1002/1529-0131(199912)42:12<2631::AID-ANR18>3.0.CO;2-H
61.
Huey
,
D. J.
, and
Athanasiou
,
K. A.
,
2013
, “
Alteration of the Fibrocartilaginous Nature of Scaffoldless Constructs Formed From Leporine Meniscus Cells and Chondrocytes Through Manipulation of Culture and Processing Conditions
,”
Cells Tissues Organs
,
197
(
5
), pp.
360
371
.10.1159/000346252
62.
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2006
, “
A Self-Assembling Process in Articular Cartilage Tissue Engineering
,”
Tissue Eng.
,
12
(
4
), pp.
969
979
.10.1089/ten.2006.12.969
63.
Athanasiou
,
K. A.
,
Eswaramoorthy
,
R.
,
Hadidi
,
P.
, and
Hu
,
J. C.
,
2013
, “
Self-Organization and the Self-Assembling Process in Tissue Engineering
,”
Annu. Rev. Biomed. Eng.
,
15
, pp.
115
136
.10.1146/annurev-bioeng-071812-152423
64.
Ofek
,
G.
,
Revell
,
C. M.
,
Hu
,
J. C.
,
Allison
,
D. D.
,
Grande-Allen
,
K. J.
, and
Athanasiou
,
K. A.
,
2008
, “
Matrix Development in Self-Assembly of Articular Cartilage
,”
PloS One
,
3
(
7
), p.
e2795
.10.1371/journal.pone.0002795
65.
Elder
,
B. D.
, and
Athanasiou
,
K. A.
,
2008
, “
Effects of Temporal Hydrostatic Pressure on Tissue-Engineered Bovine Articular Cartilage Constructs
,”
Tissue Eng. Part A
,
15
(
5
), pp.
1151
1158
.10.1089/ten.tea.2008.0200
66.
Aufderheide
,
A. C.
, and
Athanasiou
,
K. A.
,
2006
, “
A Direct Compression Stimulator for Articular Cartilage and Meniscal Explants
,”
Ann. Biomed. Eng.
,
34
(
9
), pp.
1463
1474
.10.1007/s10439-006-9157-x
67.
Huey
,
D. J.
, and
Athanasiou
,
K. A.
,
2011
, “
Tension-Compression Loading With Chemical Stimulation Results in Additive Increases to Functional Properties of Anatomic Meniscal Constructs
,”
PloS One
,
6
(
11
), p.
e27857
.10.1371/journal.pone.0027857
68.
Elder
,
B. D.
, and
Athanasiou
,
K. A.
,
2009
, “
Hydrostatic Pressure in Articular Cartilage Tissue Engineering: From Chondrocytes to Tissue Regeneration
,”
Tissue Eng. Part B Rev.
,
15
(
1
), pp.
43
53
.10.1089/ten.teb.2008.0435
69.
Natoli
,
R. M.
,
Skaalure
,
S.
,
Bijlani
,
S.
,
Chen
,
K. X.
,
Hu
,
J.
, and
Athanasiou
,
K. A.
, “
Intracellular Na(+) and Ca(2+) Modulation Increases the Tensile Properties of Developing Engineered Articular Cartilage
,”
Arthritis Rheum.
,
62
(
4
), pp.
1097
1107
.10.1002/art.27313
70.
Elder
,
B. D.
, and
Athanasiou
,
K. A.
,
2008
, “
Systematic Assessment of Growth Factor Treatment on Biochemical and Biomechanical Properties of Engineered Articular Cartilage Constructs
,”
Osteoarthritis Cartilage
,
17
(
1
), pp.
114
123
.10.1016/j.joca.2008.05.006
71.
Kalpakci
,
K. N.
,
Kim
,
E. J.
, and
Athanasiou
,
K. A.
,
2011
, “
Assessment of Growth Factor Treatment on Fibrochondrocyte and Chondrocyte Co-Cultures for TMJ Fibrocartilage Engineering
,”
Acta Biomater.
,
7
(
4
), pp.
1710
1718
.10.1016/j.actbio.2010.12.015
72.
Asanbaeva
,
A.
,
Masuda
,
K.
,
Thonar
,
E. J.
,
Klisch
,
S. M.
, and
Sah
,
R. L.
,
2007
, “
Mechanisms of Cartilage Growth: Modulation of Balance Between Proteoglycan and Collagen In Vitro Using Chondroitinase ABC
,”
Arthritis Rheum.
,
56
(
1
), pp.
188
198
.10.1002/art.22298
73.
Natoli
,
R.
,
Revell
,
C. M.
, and
Athanasiou
,
K.
,
2009
, “
Chondroitinase ABC Treatment Results in Increased Tensile Properties of Self-Assembled Tissue Engineered Articular Cartilage
,”
Tissue Eng. Part A
,
15
(10), pp.
3119
3128
.
74.
Natoli
,
R. M.
,
Responte
,
D. J.
,
Lu
,
B. Y.
, and
Athanasiou
,
K. A.
,
2009
, “
Effects of Multiple Chondroitinase ABC Applications on Tissue Engineered Articular Cartilage
,”
J. Orthop. Res.
,
27
(7), pp.
949
956
.
75.
Makris
,
E. A.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2013
, “
Hypoxia-Induced Collagen Crosslinking as a Mechanism for Enhancing Mechanical Properties of Engineered Articular Cartilage
,”
Osteoarthritis Cartilage/OARS, Osteoarthritis Res. Soc.
,
21
(
4
), pp.
634
641
.10.1016/j.joca.2013.01.007
76.
Makris
,
E. A.
,
MacBarb
,
R. F.
,
Responte
,
D. J.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2013
, “
A Copper Sulfate and Hydroxylysine Treatment Regimen for Enhancing Collagen Cross-Linking and Biomechanical Properties in Engineered Neocartilage
,”
FASEB J.
,
27
(
6
), pp.
2421
2430
.10.1096/fj.12-224030
77.
Responte
,
D. J.
,
Lee
,
J. K.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2012
, “
Biomechanics-Driven Chondrogenesis: From Embryo to Adult
,”
FASEB J.
,
26
(
9
), pp.
3614
3624
.10.1096/fj.12-207241
78.
Elder
,
B. D.
, and
Athanasiou
,
K. A.
,
2008
, “
Synergistic and Additive Effects of Hydrostatic Pressure and Growth Factors on Tissue Formation
,”
PloS One
,
3
(
6
), p.
e2341
.10.1371/journal.pone.0002341
79.
Responte
,
D. J.
,
Arzi
,
B.
,
Natoli
,
R. M.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2012
, “
Mechanisms Underlying the Synergistic Enhancement of Self-Assembled Neocartilage Treated With Chondroitinase-ABC and TGF-Beta1
,”
Biomaterials
,
33
(
11
), pp.
3187
3194
.10.1016/j.biomaterials.2012.01.028
80.
Huey
,
D. J.
, and
Athanasiou
,
K. A.
,
2011
, “
Maturational Growth of Self-Assembled, Functional Menisci as a Result of TGF-Beta 1 and Enzymatic Chondroitinase-ABC Stimulation
,”
Biomaterials
,
32
(
8
), pp.
2052
2058
.10.1016/j.biomaterials.2010.11.041
81.
MacBarb
,
R. F.
,
Makris
,
E. A.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2013
, “
A Chondroitinase-ABC and TGF-Beta1 Treatment Regimen for Enhancing the Mechanical Properties of Tissue-Engineered Fibrocartilage
,”
Acta Biomater.
,
9
(
1
), pp.
4626
4634
.10.1016/j.actbio.2012.09.037
82.
Makris
,
E. A.
,
MacBarb
,
R. F.
,
Paschos
,
N. K.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2014
, “
Combined Use of Chondroitinase-ABC, TGF-Beta1, and Collagen Crosslinking Agent Lysyl Oxidase to Engineer Functional Neotissues for Fibrocartilage Repair
,”
Biomaterials
,
35
(
25
), pp.
6787
6796
.10.1016/j.biomaterials.2014.04.083
83.
Aufderheide
,
A. C.
, and
Athanasiou
,
K. A.
,
2007
, “
Assessment of a Bovine Co-Culture, Scaffold-Free Method for Growing Meniscus-Shaped Constructs
,”
Tissue Eng.
,
13
(
9
), pp.
2195
2205
.10.1089/ten.2006.0291
84.
Higashioka
,
M. M.
,
Chen
,
J. A.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2014
, “
Building an Anisotropic Meniscus With Zonal Variations
,”
Tissue Eng. Part A
,
20
(
1–2
), pp.
294
302
.10.1089/ten.tea.2013.0098
85.
Hoben
,
G. M.
, and
Athanasiou
,
K. A.
,
2008
, “
Creating a Spectrum of Fibrocartilages Through Different Cell Sources and Biochemical Stimuli
,”
Biotechnol. Bioeng.
,
100
(
3
), pp.
587
598
.10.1002/bit.21768
86.
Johns
,
D. E.
, and
Athanasiou
,
K. A.
,
2007
, “
Improving Culture Conditions for Temporomandibular Joint Disc Tissue Engineering
,”
Cells Tissues Organs
,
185
(
4
), pp.
246
257
.10.1159/000102173
87.
Anderson
,
D. E.
, and
Athanasiou
,
K. A.
,
2008
, “
Passaged Goat Costal Chondrocytes Provide a Feasible Cell Source for Temporomandibular Joint Tissue Engineering
,”
Ann. Biomed. Eng.
,
36
(
12
), pp.
1992
2001
.10.1007/s10439-008-9572-2
88.
Murphy
,
M. K.
,
Masters
,
T. E.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2013
, “
Engineering a Fibrocartilage Spectrum Through Modulation of Aggregate Redifferentiation
,”
Cell Transplant.
, (preprint). 10.3727/096368913X676204
89.
Darling
,
E. M.
, and
Athanasiou
,
K. A.
,
2005
, “
Rapid Phenotypic Changes in Passaged Articular Chondrocyte Subpopulations
,”
J. Orthop. Res.
,
23
(
2
), pp.
425
432
.10.1016/j.orthres.2004.08.008
90.
Koay
,
E. J.
, and
Athanasiou
,
K. A.
,
2008
, “
Hypoxic Chondrogenic Differentiation of Human Embryonic Stem Cells Enhances Cartilage Protein Synthesis and Biomechanical Functionality
,”
Osteoarthritis Cartilage
,
16
(
12
), pp.
1450
1456
.10.1016/j.joca.2008.04.007
91.
Hoben
,
G. M.
,
Willard
,
V. P.
, and
Athanasiou
,
K. A.
,
2008
, “
Fibrochondrogenesis of hESCs: Growth Factor Combinations and Co-Cultures
,”
Stem Cells Dev.
,
18
(
2
), pp.
283
292
.10.1089/scd.2008.0024
92.
Levenberg
,
S.
,
Huang
,
N. F.
,
Lavik
,
E.
,
Rogers
,
A. B.
,
Itskovitz-Eldor
,
J.
, and
Langer
,
R.
,
2003
, “
Differentiation of Human Embryonic Stem Cells on Three-Dimensional Polymer Scaffolds
,”
Proc. Natl. Acad. Sci. U.S.A,
100
(
22
), pp.
12741
12746
.10.1073/pnas.1735463100
93.
Vats
,
A.
,
Bielby
,
R. C.
,
Tolley
,
N.
,
Dickinson
,
S. C.
,
Boccaccini
,
A. R.
,
Hollander
,
A. P.
,
Bishop
,
A. E.
, and
Polak
,
J. M.
,
2006
, “
Chondrogenic Differentiation of Human Embryonic Stem Cells: The Effect of the Micro-Environment
,”
Tissue Eng.
,
12
(
6
), pp.
1687
1697
.10.1089/ten.2006.12.1687
94.
Hoben
,
G. M.
,
Koay
,
E. J.
, and
Athanasiou
,
K. A.
,
2008
, “
Fibrochondrogenesis in Two Embryonic Stem Cell Lines: Effects of Differentiation Timelines
,”
Stem Cells
,
26
(
2
), pp.
422
430
.10.1634/stemcells.2007-0641
95.
Lee
,
J. K.
,
Responte
,
D. J.
,
Cissell
,
D. D.
,
Hu
,
J. C.
,
Nolta
,
J. A.
, and
Athanasiou
,
K. A.
,
2014
, “
Clinical Translation of Stem Cells: Insight for Cartilage Therapies
,”
Crit. Rev. Biotechnol.
,
34
(
1
), pp.
89
100
.10.3109/07388551.2013.823596
96.
Sanchez-Adams
,
J.
, and
Athanasiou
,
K. A.
,
2012
, “
Dermis Isolated Adult Stem Cells for Cartilage Tissue Engineering
,”
Biomaterials
,
33
(
1
), pp.
109
119
.10.1016/j.biomaterials.2011.09.038
97.
French
,
M. M.
,
Rose
,
S.
,
Canseco
,
J.
, and
Athanasiou
,
K. A.
,
2004
, “
Chondrogenic Differentiation of Adult Dermal Fibroblasts
,”
Ann. Biomed. Eng.
,
32
(
1
), pp.
50
56
.10.1023/B:ABME.0000007790.65773.e0
98.
Deng
,
Y.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2007
, “
Isolation and Chondroinduction of a Dermis-Isolated, Aggrecan-Sensitive Subpopulation With High Chondrogenic Potential
,”
Arthritis Rheum.
,
56
(
1
), pp.
168
176
.10.1002/art.22300
99.
Kalpakci
,
K. N.
,
Brown
,
W. E.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2014
, “
Cartilage Tissue Engineering Using Dermis Isolated Adult Stem Cells: The Use of Hypoxia During Expansion Versus Chondrogenic Differentiation
,”
PloS One
,
9
(
5
), p.
e98570
.10.1371/journal.pone.0098570
100.
Athens
,
A. A.
,
Makris
,
E. A.
, and
Hu
,
J. C.
,
2013
, “
Induced Collagen Cross-Links Enhance Cartilage Integration
,”
PloS One
,
8
(
4
), p.
e60719
.10.1371/journal.pone.0060719
101.
Huey
,
D. J.
,
Hu
,
J. C.
, and
Athanasiou
,
K. A.
,
2012
, “
Unlike Bone, Cartilage Regeneration Remains Elusive
,”
Science
,
338
(
6109
), pp.
917
921
.10.1126/science.1222454
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