Abstract
Deformational loading represents a primary component of the chondrocyte physical environment in vivo. This review summarizes our experience with physiologic deformational loading of chondrocyte-seeded agarose hydrogels to promote development of cartilage constructs having mechanical properties matching that of the parent calf tissue, which has a Young's modulus E Y = 277 kPa and unconfined dynamic modulus at 1 Hz G*=7 MPa. Over an 8-week culture period, cartilage-like properties have been achieved for 60 × 106 cells/ml seeding density agarose constructs, with E Y = 186 kPa, G*=1.64 MPa. For these constructs, the GAG content reached 1.74% ww and collagen content 2.64% ww compared to 2.4% ww and 21.5% ww for the parent tissue, respectively. Issues regarding the deformational loading protocol, cell-seeding density, nutrient supply, growth factor addition, and construct mechanical characterization are discussed. In anticipation of cartilage repair studies, we also describe early efforts to engineer cylindrical and anatomically shaped bilayered constructs of agarose hydrogel and bone (i.e., osteochondral constructs). The presence of a bony substrate may facilitate integration upon implantation. These efforts will provide an underlying framework from which a functional tissue-engineering approach, as described by Butler and coworkers (2000), may be applied to general cell-scaffold systems adopted for cartilage tissue engineering.
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1Ahsan, T., A. C. Chen, L. Chin, V. W. Wong, R. A. Bank, N. Verzijl, R. L. Sah, and A. Ratcliffe. Effects of long term growth on tissue engineered cartilage. Trans. Orthop. Res. Soc. 28:309, 2003.
2Ahsan, T., and R. L. Sah. Biomechanics of integrative cartilage repair. Osteoarthritis Cartilage 7:29-40, 1999.
3Armstrong, C., W. Lai, and V. Mow. An analysis of the unconfined compression of articular cartilage. J. Biomech. Eng. 106:165-173, 1984.
4Ateshian, G. A., and C. T. Hung. Functional properties of native articular cartilage. In: Functional Tissue Engineering, edited by F. Guilak and D. Butler. New York: Springer, 2003.
5Ateshian, G. A., W. M. Lai, W. B. Zhu, and V. C. Mow. A biphasic model for contact in diarthrodial joints. Adv. Bioeng. ASME BED 22:191-194, 1992.
6Aydelotte, M. B., R. Schleyerbach, B. J. Zeck, and K. E. Kuettner. Articular chondrocytes cultured in agarose gel for study of chondrocytic chondrolysis. In: Articular Cartilage Biochemistry, edited by K. Kuettner. New York: Raven Press, 1986, pp. 235-256.
7Bellamkonda, R., J. P. Ranieri, N. Bouche, and P. Aebischer. Hydrogel-based three-dimensional matrix for neural cells. J. Biomed. Mater. Res. 29:663-671, 1995.
8Benya, P. D., and S. R. Padilla. Dihydrocytochalasin B enhances transforming growth factor-beta-induced reexpression of differentiated chondrocyte phenotype without stimulation of collagen synthesis. Exp. Cell Res. 204:268-277, 1993.
9Benya, P. D., and J. D. Shaffer. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30:215-224, 1982.
10Bonassar, L. J., A. J. Grodzinsky, E. H. Frank, S. G. Davila, N. R. Bhaktav, and S. B. Trippel. The effect of dynamic compression on the response of articular cartilage to insulin like growth factor I. J. Orthop. Res. 19:11-17, 2001.
11Bonassar, L. J., A. J. Grodzinsky, A. Srinivasan, S. G. Davila, and S. B. Trippel. Mechanical and physiochemical regulation of the action of insulin-like growth factor-1 on articular cartilage. Arch. Biochem. Biophys. 379:57-63, 2000.
12Brittberg, M., A. Nilsson, A. Lindahl, C. Ohlsson, and L. Peterson. Rabbit articular cartilage defects treated with autologous cultured chondrocytes. Clin. Orthop. 326:270-283, 1996.
13Brown, T. D., and D. T. Shaw. In vitro contact stress distributions in the natural human hip. J. Biomech. 16:373-384, 1983.
14Bryant, S. J., and K. S. Anseth. The effects of scaffold thickness on cartilage engineered cartilage in photocrosslinked poly(ethylene oxide) hydrogels. Biomaterials 22:619-626, 2001.
15Bujia, L., P. Pitzke, E. Kastenbauer, E. Wilmes, and C. Hammer. Effect of growth factors on matrix synthesis by human nasal chondrocytes cultured in monolayer and agar. Eur. Arch. Otorhinolaryngol. 253:336-340, 1996.
16Bursac, P. M., T. W. Obitz, S. R. Eisenberg, and D. Stamenovic. Confined and unconfined stress relaxation of cartilage: A transversely isotropic analysis. Adv. Bioeng. 36:157-158, 1997.
17Burton-Wurster, N., M. Vernier-Singer, T. Farquhar, and G. Lust. Effect of compressive loading and unloading on the synthesis of total protein, PG, and fibronectin by canine cartilage explants. J. Orthop. Res. 11:717-729, 1993.
18Buschmann, M. D., Y. A. Gluzband, A. J. Grodzinsky, and E. B. Hunziker. Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose cultures. J. Cell Sci. 108:1497-1508, 1995.
19Buschmann, M. D., Y. A. Gluzband, A. J. Grodzinsky, J. H. Kimura, and E. B. Hunziker. Chondrocytes in agarose culture synthesize a mechanically functional extracellular matrix. J. Orthop. Res. 10:745-758, 1992.
20Buschmann, M. D., Y.-J. Kim, M. Wong, E. Frank, E. B. Hunziker, and A. J. Grodzinsky. Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow. Arch. Biochem. Biophys. 366:1-7, 1999.
21Butler, D. L., S. A. Goldstein, and F. Guilak. Functional tissue engineering: The role of biomechanics. J. Biomech. Eng. 122:570-575, 2000.
22Cao, X., and M. S. Shoichet. Photoimmobilization of biomolecules within a 3-dimensional hydrogel matrix. J. Biomater. Sci. Polym. Ed. 13:623-636, 2002.
23Carver, S. E., and C. A. Heath. Increasing extracellular matrix production in regenerating cartilage with intermittent physiological pressure. Biotechnol. Bioeng. 63:166-174, 1999.
24Carver, S. E., and C. A. Heath. Influence of intermittent pressure, fluid flow, and mixing on the regenerative properties of articular chondrocytes. Biotechnol. Bioeng. 65:274-281, 1999.
25Carver, S. E., and C. A. Heath. Semi-continuous perfusion system for delivering intermittent physiological pressure to regenerating cartilage. Tissue Eng. 5:1-11, 1999.
26Chang, S. C. N., J. A. Rowley, G. Tobias, N. G. Genes, A. K. Roy, D. J. Mooney, C. A. Vacanti, and L. J. Bonassar. Injection molding of chondrocyte/alginate constructs in the shape of facial implants. J. Biomed. Mater. Res. 55:503-511, 2001.
27Chen, H., and J. Lawler. Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. J. Biol. Chem. 275:26538-26544, 2001.
28Chen, H., and J. Lawler. Cartilage oligomeric matrix protein. In: Encyclopedia of Molecular Medicine. New York: Wiley, 2002.
29Cohen, B., W. M. Lai, G. S. Chorney, H. M. Dick, and V. C. Mow. Unconfined compression of transversely-isotropic biphasic tissue. Adv. Bioeng. BED 19:187-190, 1992.
30Cook, J. L., N. Williams, J. M. Kreeger, J. T. Peacock, and J. L. Tomlinson. Biocompatibility of three-dimensional chondrocyte grafts in large tibial defects of rabbits. Am. J. Vet. Res. 64:12-20, 2003.
31Cooney, W. P., and E. Y. S. Chao. Biomechanical analysis of static forces in the thumb during hand functions. J. Bone Joint Surg. 59A:27-36, 1977.
32Davisson, T., S. Kunig, A. Chen, R. Sah, and A. Ratcliffe. Static and dynamic compression modulate matrix metabolism in tissue engineered cartilage. J. Orthop. Res. 20:842-848, 2002.
33Dudhia, J., M. T. Bayliss, and T. E. Hardingham. Human link protein structure and transcription pattern in chondrocytes. Biochem. J. 303:329-333, 1994.
34Dunkelman, N. S., M. P. Zimber, R. G. LeBaron, R. Pavelec, M. Kwan, and A. F. Purchio. Cartilage production by rabbit articular chondrocytes on polyglycolic acid scaffolds in a closed bioreactor system. Biotech. Bioeng. 46:299-305, 1995.
35Eberhardt, A. W., L. M. Keer, and J. L. Lewis. An analytical model of joint contact. J. Biomech. Eng. 112:407-413, 1990.
36Eckstein, F., M. Tieschky, and S. Faber. In vivo quantification of patellar cartilage volume and thickness changes after strenuous dynamic physical activity—a magnetic resonance imaging study. Trans. Orthop. Res. Soc. 23:486, 1998.
37Eyre, D. R., S. Apone, J. J. Wu, L. H. Ericsson, and K. A. Walsh. Collagen type IX: Evidence for covalent linkages to type II collagen in cartilage. FEBS Lett. 220:337-341, 1987.
38Farndale, R. W., D. J. Buttle, and A. J. Barrett. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochem. Biophys. Acta 173-177, 1986.
39Farndale, R. W., C. A. Sayers, and A. J. Barrett. A direct spectrophotometric microassay for sulfated glycosaminoglycans in cartilage cultures. Connect. Tissue Res. 9:247-248, 1982.
40Felson, D. T. In: Stepping Away From OA: A Scientific Conference on the Prevention of Onset, Progression, and Disability of Osteoarthritis. National Institutes of Health, 1999.
41Felson, D. T., R. C. Lawrence, P. A. Dieppe, R. Hirsch, C. G. Helmick, J. M. Jordan, R. S. Kingston, N. E. Lane, M. C. Nevitt, Y. Zhang, M. F. Sow, T. McAlindon, T. D. Spector, A. R. Poole, S. Z. Yanovski, G. A. Ateshian, J. A. Sharma, J. A. Buckwalter, K. Brandt, and J. F. Fries. Osteoarthritis—New insights. Part I: The disease and its risk factors. Ann. Intern. Med. 133:635-646, 2000.
42Freed, L. E., G. Vunjak-Novakovic, and R. Langer. Cultivation of cell-polymer cartilage implants in bioreactors. J. Cell. Biochem. 51:257-264, 1993.
43Freeman, P. M., R. N. Natarajan, J. H. Kimura, and T. P. Andriacchi. Chondrocyte cells respond mechanically to compressive loads. J. Orthop. Res. 12:311-320, 1994.
44Garrett, J. C. Osteochondral allografts for reconstruction of articular defects of the knee. AAOS Instr. Course Lect. 47:517-522, 1998.
45Giannoni, P., M. Siegrist, E. B. Hunziker, and M. Wong. The mechanosensitivity of cartilage oligomeric matrix protein (COMP). Biorheology 40:101-109, 2003.
46Giurea, A., M. A. DiMicco, W. H. Akeson, and R. L. Sah. Mechanisms of cartilage integration at different stages of bovine development: Roles of biosynthesis and existing matrix. Trans. Orthop. Res. Soc. 27:444, 2002.
47Gooch, K. J., T. Blunk, D. L. Courter, A. L. Sieminski, P. M. Bursac, G. Vunjak-Novakovic, and L. E. Freed. IGF-I and mechanical environment interact to modulate engineered cartilage development. Biochem. Biophys. Res. Commun. 286:909-915, 2001.
48Gray, M. L., A. M. Pizzanelli, A. J. Grodzinsky, and R. C. Lee. Mechanical and physiocochemical determinants of the chondrocyte biosynthetic response. J. Orthop. Res. 6:777-792, 1988.
49Guerne, P.-A., F. Blanco, A. Kaelin, A. Desgeorges, and M. Lotz. Growth factor responsiveness of human articular chondrocytes in aging and development. Arthritis. Rheum. 38:960-968, 1995.
50Guilak, F., D. L. Butler, and S. A. Goldstein. Functional tissue engineering: The role of biomechanics in articular cartilage repair. Clin. Orthop. 391:S295-S305, 2001.
51Guilak, F., W. R. Jones, H. P. Ting-Beall, and G. M. Lee. The deformation behavior and mechanical properties of chondrocytes in articular cartilage. Osteoarthritis Cartilage 7:59-70, 1999.
52Guilak, F., B. C. Meyer, A. Ratcliffe, and V. C. Mow. The effects of matrix compression on PG metabolism in articular cartilage explants. Osteoarthritis Cartilage 2:91-101, 1994.
53Guilak, F., R. Sah, and L. Setton. In: Physical regulation of cartilage metabolism. In: Basic Orthopaedic Biomechanics, edited by V. C. Mow and W. C. Hayes. Philadelphia: Lippincott-Raven, 1997, pp. 179-207.
54Hall, A. C., J. P. G. Urban, and K. A. Gehl. The effects of hydrostatic pressure on matrix synthesis in articular cartilage. J. Orthop. Res. 9:1-10, 1991.
55Hangody, L., P. Feczko, L. Bartha, G. Bodo, and G. Kish. Mosaicplasty for treatment of articular defects of the knee and ankle. Clin. Orthop. 391:S328-S336, 2001.
56Hangody, L., Z. Karpati, and I. Szerb. Autologous osteochondral mosaic-like graft technique for replacing weight-bearing cartilage defects. In: 7th Congress of the ESSK. Budapest: Hungary, 1996.
57Hardingham, T. E. The role of link protein in the structure of cartilage PG aggregates. Biochem. J. 177:237-247, 1979.
58Hardingham, T. E., M. T. Bayliss, V. Rayan, and D. P. Noble. Effects of growth factors and cytokines on PG turnover in articular cartilage. Br. J. Rheum. 31(Suppl. 1):1-6, 1992.
59Horowitz, M. C., and G. Friedlaender. The immune response to bone grafts. In: Bone and Cartilage Allografts, edited by G. Friedlaender and V. M. Goldberg. Park Ridge: AAOS, 1991, p. 85-101.
60Huang, C.-Y. C., P. M. Reuben, G. D'Ippolito, and H. S. Cheung. Chondrogenesis of human bone-marrow derived mesenchymal stem cells in agarose culture. Trans. Orthop. Res. Soc. 28:865, 2003.
61Huberti, H. H., and W. C. Hayes. Patellofemoral contact pressures. J. Bone Joint Surg. 66A: 715-724, 1984.
62Hung, C. T., E. G. Lima, R. L. Mauck, E. Takai, M. A. LeRoux, H. H. Lu, R. G. Stark, X. E. Guo, and G. A. Ateshian. Anatomically shaped osteochondral constructs for articular cartilage repair. J. Biomech. 36:1853-1864, 2003.
63Hunziker, E. B. Articular cartilage repair: Are the intrinsic biological constraints undermining this process insuperable? Osteoarthritis Cartilage 7:15-28, 1999.
64Jadin, K. D., B. L. Wong, K. W. Li, W. C. Bae, A. K. Williamson, B. L. Schumacher, J. H. Price, and R. L. Sah. Depth-associated variation in chondrocyte density in bovine articular cartilage during growth and maturation. Trans. Orthop. Res. Soc. 28:469, 2003.
65Jones, I. L., A. Klamfeldt, and T. Sanstrom. The effect of continuous mechanical pressure upon the turnover of articular cartilage PGs in vitro. Clin. Orthop. 165:283-289, 1982.
66Jurvelin, J., M. Buschmann, and E. Hunziker. Optical and mechanical determination of Poisson's ratio of adult bovine humeral articular cartilage. J. Biomech. 30:235-241, 1997.
67Keaveny, T. M., R. E. Borchers, L. J. Gibson, and W. C. Hayes. Trabecular bone modulus and strength can depend on specimen geometry. J. Biomech. 26:991-1000, 1993.
68Kim, Y. J., R. L. Sah, J. Y. Doong, and A. J. Grodzinsky. Fluorometric assay of DNA in cartilage explants using hoecsht 33258. Anal. Biochem. 174:168-176, 1988.
69Kim, Y. J., R. L. Sah, A. J. Grodzinsky, A. H. Plaas, and J. D. Sandy. Mechanical regulation of cartilage biosynthetic behavior: Physical stimuli. Arch. Biochem. Biophys. 311:1-12, 1994.
70Knight, M. M., J. van de Breevaart Bravenboer, D. A. Lee, G. J. V. M. van Osch, H. Weinans, and D. L. Bader. Cell and nucleus deformation in compressed chondrocyte-alginate constructs: Temporal changes and calculation of cell modulus. Biochimica et Biophysica Acta 1570:1-8, 2002.
71Krishnan, R., S. Park, F. Eckstein, and G. A. Ateshian. Inhomogeneous cartilage properties enhance superficial interstitial fluid support and frictional properties, but do not provide a homogeneous state of stress. J. Biomech. Eng.
72Lee, D. A., and D. L. Bader. The development and characterisation of an in vitro system to study strain-induced cell deformation in isolated chondrocytes. In Vitro Cell Dev. Biol. Anim. 31:828-835, 1995.
73Lee, D. A., and D. L. Bader. Compressive strains at physiological frequencies influence the metabolism of chondrocytes seeded in agarose. J. Orthop. Res. 15:181-188, 1997.
74Lee, D. A., S. P. Frean, P. Lees, and D. L. Bader. Dynamic mechanical compression influences nitric oxide production by articular chondrocytes seeded in agarose. Biochem. Biophys. Res. Commun. 251:580-585, 1998.
75Lee, D. A., T. Noguchi, S. P. Frean, P. Lees, and D. L. Bader. The influence of mechanical loading on isolated chondrocytes seeded in agarose constructs. Biorheology 37:149-161, 2000.
76Lima, E. G., R. L. Mauck, S. Park, S. Gasinu, K. W. Ng, and C. T. Hung. Material properties of osteochondral constructs and biphasic finite element models of dynamic loading for articular cartilage tissue engineering. Proceedings of the 2003 Summer bioengineering conference, 1129-1130, Key Biscayne, FL, 2003.
77Lippiello, L., C. Kaye, T. Neumata, and H. J. Mankin. In vitro metabolic response of articular cartilage segments to low levels of hydrostatic pressure. Connect. Tissue. Res. 13:99-107, 1985.
78Lo, S. S., R. L. Mauck, S. L. Seyhan, G. D. Palmer, V. C. Mow, and C. T. Hung. Mechanical loading modulates gene expression in chondrocyte-seeded agarose hydrogels. Adv. Bioeng. 51:23144, 2001.
79Malemud, C. J., W. Killeen, T. M. Hering, and A. F. Purchio. Enhanced sulfated-PG core protein synthesis by incubation of rabbit chondrocytes with recombinant Transforming Growth Factor-B1. J. Cell Physiol. 149:152-159, 1991.
80Mauck, R. L., M. M. Y. Ho, C. T. Hung, and G. A. Ateshian. Growth factor supplementation and dynamic hydrostatic pressurization for articular cartilage tissue engineering. Adv. Bioeng.:0283.pdf, 2003.
81Mauck, R. L., C. T. Hung, and G. A. Ateshian. Modeling of neutral solute transport in a dynamically loaded porous permeable gel: Implications for articular cartilage biosynthesis and tissue engineering. J. Biomech. Eng. 125:602-614, 2003.
82Mauck, R. L., C. T. Hung, and G. A. Ateshian. Modeling solute transport with mixture theory for dynamically loaded porous permeable gels. Trans. Orthop. Res. Soc.: Paper 662, 2003.
83Mauck, R. L., S. B. Nicoll, S. L. Seyhan, G. A. Ateshian, and C. T. Hung. Synergistic effects of growth factors and dynamic loading for cartilage tissue engineering. Tissue Eng. 9:597-611, 2003.
84Mauck, R. L., S. B. Nicoll, R. Stark, C. T. Hung, and G. A. Ateshian. Joint-specific surface molds for articular cartilage tissue engineering. Trans. Orthop. Res. Soc. 27:251, 2002.
85Mauck, R. L., S. L. Seyhan, G. A. Ateshian, and C. T. Hung. The influence of seeding density and dynamic deformational loading on the developing structure/function relationships of chondrocyte-seeded agarose hydrogels. Ann. Biomed. Eng. 30:1046-1056, 2002.
86Mauck, R. L., S. L. Seyhan, K. V. Jamieson, S. B. Nicoll, G. A. Ateshian, and C. T. Hung. Synergistic effects of growth factors and dynamic loading for cartilage tissue engineering. Trans. Orthop. Res. Soc. 27:213, 2002.
87Mauck, R. L., S. L. Seyhan, S. B. Nicoll, G. A. Ateshian, and C. T. Hung. Transforming growth factor β1 increases the mechanical properties and matrix development of chondrocyte-seeded agarose hydrogels. Adv. Bioeng. 50:691-692, 2001.
88Mauck, R. L., M. A. Soltz, C. C.-B. Wang, D. D. Wong, P.-H. G. Chao, W. B. Valhmu, C. T. Hung, and G. A. Ateshian. Functional tissue engineering of articular cartilage through dynamic loading of chondrocyte-seeded agarose gels. J. Biomech. Eng. 122:252-260, 2000.
89Mauck, R. L., C.-C. B. Wang, F. H. Chen, H. H. Lu, G. A. Ateshian, and C. T. Hung. Dynamic deformational loading of chondrocyte-seeded agarose hydrogels modulates deposition and structural organization of matrix constituents. Preceedings of the 2003 Summer Bioengineering Conference, 531-532, Key Biscayne, FL, 2003.
90Mauck, R. L., C. C.-B. Wang, Q. Cheng, N. Gabriel, E. S. Oswald, G. A. Ateshian, and C. T. Hung. Optimization of parameters for articular cartilage tissue engineering with deformational loading. Trans. Orthop. Res. Soc. 28:305, 2003.
91Mauck, R. L., C.-C. B. Wang, E. S. Oswald, and C. T. Hung. Optimization of cell seeding density and nutrient supply for articular cartilage tissue engineering with deformational loading. Osteoarthritis Cartilage. 11:879-890, 2003.
92Meilander, N. J., X. Yu, N. P. Ziats, and R. V. Bellamkonda. Lipid-based microtubular drug delivery vehicles. J. Control. Release. 71:141-152, 2001.
93Menche, D. S., J. Vangsness, C. T. M. Pitman, A. E. Gross, and L. Peterson. The treatment of isolated articular cartilage lesions in the young individual. AAOS Instr. Course Lect. 47:505-515, 1998.
94Morales, T. I. Transforming growth factor-beta1 stimulates synthesis of PG aggregates in calf articular cartilage organ cultures. Arch. Biochem. Biophys. 286:99-106, 1991.
95Morales, T. I., and A. B. Roberts. Transforming growth factor beta regulates the metabolism of PGs in bovine cartilage organ cultures. J. Biol. Chem. 263:12828-12831, 1988.
96Morales, T. I., and V. C. Hascall. Factors involved in the regulation of PG metabolism in articular cartilage. Arthritis Rheum. 32:1197-1201, 1989.
97Mow, V. C., S. C. Kuei, W. M. Lai, and C. G. Armstrong. Biphasic creep and stress relaxation of articular cartilage in compression: Theory and experiments. J. Biomech. Eng. 102:73-84, 1980.
98Mow, V., C. Wang, and C. Hung. The extracellular matrix, interstitial fluid and ions as a mechanical signal transducer in articular cartilage. Osteoarthritis Cartilage 7:41-59, 1999.
99Mukherjee, N., D. B. F. Saris, F. M. Schultz, L. J. Berglund, K. N. An, and S. W. O'Driscoll. The enhancement of periosteal chondrogenesis in organ culture by dynamic fluid pressure. J. Orthop. Res. 19:1213, 2001.
100Nixon, A. J., J. T. Lillich, N. Burton-Wurster, G. Lust, and H. O. Mohammed. Differentiated cellular function in fetal chondrocytes cultured with insulin-like growth factor-1 and transforming growth factor-beta. J. Orthop. Res. 16:531-541, 1998.
101O'Driscoll, S. W. Articular cartilage regeneration using periosteum. Clin. Orthop. 367(Suppl.):S186-S203, 1999.
102Palmoski, M. J., and K. D. Brandt. Effect of static and cyclic compressive loading on articular cartilage plugs in vitro. Arthritis Rheum. 27:675-681, 1984.
103Palmoski, M., E. Perricone, and K. D. Brandt. Development and reversal of a PG aggregation defect in normal canine knee cartilage after remobilization. Arthritis Rheum. 22:508-517, 1979.
104Park, S., C. T. Hung, and G. A. Ateshian. Mechanical response of bovine articular cartilage under dynamic unconfined compression loading at physiologic stress levels. Osteoarthritis Cartilage
105Park, S., R. Krishnan, S. B. Nicoll, and G. A. Ateshian. Cartilage interstitial fluid load support in unconfined compression. J. Biomech. 36:1785-1796, 2003.
106Parkkinen, J. J., J. Ikonen, M. J. Lammi, J. Laakkonen, M. Tammi, and H. J. Helminen. Effects of cyclic hydrostatic pressure on PG synthesis in cultured chondrocytes and articular cartilage explants. Arch. Biochem. Biophys. 300:458-465, 1993.
107Parkkinen, J., M. J. Lammi, H. J. Helminen, and M. Tammi. Local stimulation of PG synthesis in articular cartilage explants by dynamic compression in vitro. J. Orthop. Res. 10:610-620, 1992.
108Pazzano, D., K. A. Mercier, J. M. Moran, S. S. Fong, D. D. DiBiasio, J. X. Rulfs, S. S. Kohles, and L. J. Bonassar. Comparison of chondrogensis in static and perfused bioreactor culture. Biotechnol. Prog. 16:893-896, 2000.
109Pelker, R., and G. E. Friedlaender. Biomechanical considerations in osteochondral grafts. In: Bone and Cartilage Allografts, edited by G. E. Friedlaender and V. M. Goldberg, Park Ridge: AAOS, 1991, pp. 155-162.
110Puelacher, W. C., S. W. Kim, J. P. Vacanti, B. Schloo, D. Mooney, and C. A. Vacanti. Tissue-engineered growth of cartilage: Effect of varying the concentration of chondrocytes seeded onto synthetic polymer matrices. Int. J. Oral. Maxillofac. Surg. 23:49-53, 1994.
111Qi, W.-N., and S. P. Scully. Effect of type II collagen in chondrocyte response to TGF-beta1 regulation. Exp. Cell Res. 241:142-150, 1998.
112Ragan, P. M., V. I. Chin, H. H. Hung, K. Masuda, E. J. Thonar, E. C. Arner, A. J. Grodzinsky, and J. D. Sandy. Chondrocyte extracellular matrix synthesis and turnover are influenced by static compression in a new alginate disk culture system. Arch. Biochem. Biophys. 383:256-264, 2000.
113Rahfoth, B., J. Weisser, F. Sternkopf, T. Aigner, K. von der Mark, and R. Brauer. Transplantation of allograft chondrocytes in agarose gel into cartilage defects in rabbits. Osteoarthritis Cartilage 6:50-65, 1998.
114Ratcliffe, A., C. Hughes, P. R. Fryer, F. Saed-Nejad, and T. E. Hardingham. Immunochemical studies on the synthesis and secretion of link protein and aggregating PG by chondrocytes. Coll. Relat. Res. 7:409-421, 1987.
115Reindel, E. S., A. M. Aryoso, A. C. Chen, D. M. Chun, R. M. Schinagl, and R. L. Sah. Integrative repair of articular carilage in vitro: Adhesive strength of the interface region. J. Orthop. Res. 13:751-760, 1995.
116Roberts, S., M. Knight, D. Lee, and D. Bader. Mechanical compression influences intracellular Ca2+ signaling in chondrocytes seeded in agarose constructs. J. Appl. Physiol. 90(4):1385-1391, 2001.
117Rotter, N., J. Aigner, A. Naumann, H. Planck, C. Hammer, G. Burmester, and M. Sittinger. Cartilage reconstruction in head and neck surgery: Comparison of resorbable polymer scaffolds for tissue engineering of human septal cartilage. J. Biomed. Mater. Res. 42:347-356, 1998.
118Sah, R. L., A. C. Chen, A. J. Grodzinsky, and S. B. Trippel. Differential effects of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. Arch. Biochem. Biophys. 308:137-147, 1994.
119Sah, R. L. Y., J.-Y. H. Doong, A. J. Grodzinsky, A. H. K. Plaas, and J. D. Sandy. Effects of compression on the loss of newly synthesized PGs and proteins from cartilage explants. Arch. Biochem. Biophys. 286:20-29, 1991.
120Sah, R. L. Y., Y. J. Kim, J.-Y. H. Doong, A. J. Grodzinsky, A. H. K. Plaas, and J. D. Sandy. Biosynthetic response of cartilage explants to dynamic compression. J. Orthop. Res. 7:619-636, 1989.
121Sah, R. L., S. B. Trippel, and A. J. Grodzinsky. Differential effects of serum, insulin-like growth factor-1, and fibroblast growth factor-2 on the maintenance of cartilage physical properties during long-term culture. J. Orthop. Res. 14:44-52, 1996.
122Saris, D. B., N. Mukherjee, L. J. Berglund, F. M. Schultz, K. N. An, and S. W. O'Driscoll. Dynamic pressure transmission through agarose gels. Tissue Eng. 6:531-537, 2000.
123Setton, L. A., V. C. Mow, and D. S. Howell. Mechanical behavior of articular cartilage in shear is altered by transection of the anterior cruciate ligament. J. Orthop. Res. 13:473-482, 1995.
124Sittinger, M., J. Bujia, W. W. Minuth, C. Hammer, and G. R. Burmester. Engineering of cartilage tissue using bioresorbable polymer carriers in perfusion culture. Biomaterials 15:451-456, 1994.
125Sittinger, M., J. Bujia, N. Rotter, D. Reitzel, W. W. Minuth, and G. Burmester. Tissue engineering an autologous transplant formation: Practical approaches with resorbable biomaterials and new culture techniques. Biomaterials 17:237-242, 1996.
126Smetana, K. Cell biology of hydrogels. Biomaterials 14:1046-1050, 1993.
127Smith, R. L., J. Lin, M. C. Trindade, G. Kajiyama, T. Vu, A. R. Hoffman, M. C. van der Meulen, S. B. Goodman, D. J. Schurman, and D. R. Carter. Time-dependent effects of intermittent hydrostatic pressure on articular chondrocyte type II collagen and aggrecan mRNA expression. J. Rehabil. Res. Dev. 37:153-161, 2000.
128Smith, R. L., S. F. Rusk, B. E. Ellison, P. Wessells, K. Tsuchiya, D. R. Carter, W. E. Caler, L. J. Sandell, and D. J. Schurman. In vitro stimulation of articular chondrocyte mRNA and extracellular matrix synthesis by hydrostatic pressure. J. Orthop. Res. 14:53-60, 1996.
129Soltz, M. A., and G. A. Ateshian. Experimental verification and theoretical prediction of cartilage interstitial fluid pressurization at an impermeable contact interface in confined compression. J. Biomech. 31:927-934, 1998.
130Soltz, M. A., R. L. Mauck, C. T. Hung, and G. A. Ateshian. Fluid pressurization in agarose hydrogels under mechanical loading. Adv. Bioeng. 43:127-128, 1999.
131Soparkar, C. N., J. F. Wong, J. R. Patrinely, and D. Appling. Growth factors embedded in agarose matrix enhance the rate of porous polyethylene implant biointegration. Ophthal. Plast. Reconstr. Surg. 16:341-346, 2000.
132Soparkar, C. N., J. F. Wong, J. R. Patrinely, J. K. Davidson, and D. Appling. Porous polyethylene implant fibrovascularization rate is affected by tissue wrapping, agarose coating, and insertion site. Ophthal. Plast. Reconstr. Surg. 16:330-336, 2000.
133Soulhat, J., M. D. Buschmann, and A. Shirazi-adl. Non-linear cartilage mechanics in unconfined compression. J. Biomechanics 23:226, 1998.
134Stegeman, H., and K. Stalder. Determination of hydroxyproline. Clin. Chim. Acta 19:267-273, 1967.
135Trippel, S. B. Growth factor actions on articular cartilage. J. Rheumatol. 22(Suppl. 43):129-132, 1995.
136Valhmu, W. B., E. J. Stazzone, N. M. Bachrach, F. Saed-Nejad, S. G. Fischer, V. C. Mow, and A. Ratcliffe. Load-controlled compression of articular cartilage induces a transient stimulation of aggrecan gene expression. Arch. Biochem. Biophys. 353:29-36, 1998.
137van der Kraan, P., E. Vitters, and W. van den Berg. Differential effect of transforming growth factor beta on freshly isolated and culture articular chondrocytes. J. Rheum. 19:140-145, 1992.
138van der Rest, M., and R. Mayne. Type IX collagen PG from cartilage is covalently cross-linked to type II collagen. J. Biol. Chem. 263:1615-1618, 1988.
139van Susante, J. L. C., P. Buma, H. M. van Beuningen, W. B. van den Berg, and R. P. H. Veth. Responsiveness of bovine chondrocytes to growth factors in medium with different serum concentrations. J. Orthop. Res. 18:68-77, 2000.
140Vunjak-Novakovic, G., I. Martin, B. Obradovic, S. Treppo, A. J. Grodzinsky, R. Langer, and L. E. Freed. Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J. Orthop. Res. 17:130-138, 1999.
141Vunjak-Novakovic, G., B. Obradovic, I. Martin, P. Bursac, F. Langer, and L.E. Freed. Dynamic cell seeding of polymer scaffolds for cartilage tissue engineering. Biotechnol. Prog. 14:193-202, 1998.
142Waldman, S. D., C. G. Spiteri, M. D. Grynpas, R. M. Pilliar, and R. A. Kandel. Long-term intermittent shear deformation improves the quality of cartilaginous tissue formed in vitro. J. Orthop. Res. 21:590-596, 2003.
143Wang, N., and X. S. Wu. Preparation and characterization of agarose hydrogel nanoparticles for protein and peptide drug delivery. Pharm. Dev. Technol. 2:135-142, 1997.
144Weisser, J., B. Rahfoth, A. Timmermann, T. Aigner, R. Brauer, and K. von der Mark. Role of growth factors in rabbit articular cartilage repair by chondrocytes in agarose. Osteoarthritis Cartilage 9(Suppl. A):S48-S54, 2001.
145Wong, M., M. Siegrist, and X. Cao. Cyclic compression of articular cartilage explants associated with progressive consolidation and altered expression pattern of extracellular matrix. Matrix Biol. 18:391-399, 1999.
146Wu, J., T. Pietka, M. Weis, and D. Eyre. A newly identified site of cross-linking between collagens IX and II: Insights on molecular assembly in cartilage. Trans. Orthop. Res. Soc. 27:55, 2002.
147Wu, J. J., P. E. Woods, and D. R. Eyre. Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II–type IX molecular relationship and type IX to type IX bonding. J. Biol. Chem. 287:23007-23014, 1992.
148Yang, H., H. Iwata, H. Shimizu, T. Takagi, T. Tsuji, and F. Ito. Comparative studies of in vitro and in vivo function of three different shaped bioartificial pancreases made of agarose hydrogel. Biomaterials 15:113-120, 1994.
149Yu, X., G. P. Dillon, and R. B. Bellamkonda. A laminin and nerve growth factor-laden three-dimensional scaffold for enhanced neurite extension. Tissue Eng. 5:291-304, 1999.
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Hung, C.T., Mauck, R.L., Wang, C.CB. et al. A Paradigm for Functional Tissue Engineering of Articular Cartilage via Applied Physiologic Deformational Loading. Annals of Biomedical Engineering 32, 35–49 (2004). https://doi.org/10.1023/B:ABME.0000007789.99565.42
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DOI: https://doi.org/10.1023/B:ABME.0000007789.99565.42