Lessons from (patho)physiological tissue stiffness and their implications for drug screening, drug delivery and regenerative medicine

Advanced Drug Delivery Reviews

Volumn 63, Issue 4, 2011, Pages 269-276

  Chen, Wen Li Kelly ^a   Simmons, Craig A ^a,b  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

Biomaterials; Biomechanics; Cancer biology; Elasticity; Mechanobiology; Stem cells; Substrate stiffness

Indexed keywords

BIOCHEMICAL SIGNAL; BIOLOGICAL FUNCTIONS; CANCER BIOLOGY; CELL FUNCTIONS; CONTROL MATERIALS; DISEASED TISSUES; DRUG SCREENING; EXTRACELLULAR MATRICES; IN-VITRO; IN-VIVO; MECHANICAL STIFFNESS; MECHANO-BIOLOGY; MOLECULAR THERAPY; ORGAN FAILURE; REGENERATIVE MEDICINE; SIGNALING CASCADES; TISSUE ENGINEERING APPLICATIONS; TISSUE FUNCTION; TISSUE STIFFNESS; TISSUE STRUCTURE;

BIOMATERIALS; CELL CULTURE; DRUG DELIVERY; ELASTICITY; SIGNALING; STEM CELLS; STIFFNESS; STIFFNESS MATRIX; TISSUE; TISSUE ENGINEERING;

BIOMECHANICS;

BIOMATERIAL;

BIOMECHANICS; CARCINOGENESIS; CELL DIFFERENTIATION; CELL FUNCTION; CELL TRANSFORMATION; CYTOLOGY; CYTOPATHOLOGY; DRUG DELIVERY SYSTEM; DRUG SCREENING; ELASTICITY; EXTRACELLULAR MATRIX; GENOMIC INSTABILITY; HUMAN; IN VITRO STUDY; MALIGNANT TRANSFORMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; REGENERATIVE MEDICINE; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; TISSUE ENGINEERING; TISSUE STIFFNESS; TUMOR CELL; TUMOR MICROENVIRONMENT;

ANIMALS; BIOCOMPATIBLE MATERIALS; CELL CULTURE TECHNIQUES; DRUG DELIVERY SYSTEMS; ELASTICITY; EXTRACELLULAR MATRIX; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; REGENERATIVE MEDICINE; STEM CELLS; TISSUE ENGINEERING;

EID: 79957778562     PISSN: 0169409X     EISSN: 0169409X     Source Type: Journal    
DOI: 10.1016/j.addr.2011.01.004     Document Type: Review

References (97)

1. Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F., Csiszar K., Giaccia A., Weninger W., Yamauchi M., Gasser D.L., Weaver V.M. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139:891-906.
2. Boyd N.F., Dite G.S., Stone J., Gunasekara A., English D.R., McCredie M.R., Giles G.G., Tritchler D., Chiarelli A., Yaffe M.J., Hopper J.L. Heritability of mammographic density, a risk factor for breast cancer. N. Engl. J. Med. 2002, 347:886-894.
3. Rutter C.M., Mandelson M.T., Laya M.B., Seger D.J., Taplin S. Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. Jama 2001, 285:171-176.
4. Boyd N., Martin L., Stone J., Greenberg C., Minkin S., Yaffe M. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Current Oncology Reports, Current Medicine Group LLC 2001, 314-321.
5. Butcher D.T., Alliston T., Weaver V.M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 2009, 9:108-122.
6. Reilly G.C., Engler A.J. Intrinsic extracellular matrix properties regulate stem cell differentiation. J. Biomech. 2009, 43:55-62.
7. Wong J.Y., Leach J.B., Brown X.Q. Balance of chemistry, topography, and mechanics at the cell-biomaterial interface: issues and challenges for assessing the role of substrate mechanics on cell response. Surf. Sci. Biosurf. V Funct. Polym. Surf. Biotechnol. 2004, 570:119-133.
8. Pelham R.J., Wang Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl. Acad. Sci. USA 1997, 94:13661-13665.
9. Flanagan L.A., Ju Y.E., Marg B., Osterfield M., Janmey P.A. Neurite branching on deformable substrates. NeuroReport 2002, 13:2411-2415.
10. Engler A.J., Griffin M.A., Sen S., Bonnemann C.G., Sweeney H.L., Discher D.E. Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J. Cell Biol. 2004, 166:877-887.
11. Engler A., Bacakova L., Newman C., Hategan A., Griffin M., Discher D. Substrate compliance versus ligand density in cell on gel responses. Biophys. J. 2004, 86:617-628.
12. Engler A.J., Carag-Krieger C., Johnson C.P., Raab M., Tang H.Y., Speicher D.W., Sanger J.W., Sanger J.M., Discher D.E. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J. Cell Sci. 2008, 121:3794-3802.
13. Jacot J.G., McCulloch A.D., Omens J.H. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 2008, 95:3479-3487.
14. Shapira-Schweitzer K., Seliktar D. Matrix stiffness affects spontaneous contraction of cardiomyocytes cultured within a PEGylated fibrinogen biomaterial. Acta Biomater. 2007, 3:33-41.
15. Hsiong S.X., Carampin P., Kong H.J., Lee K.Y., Mooney D.J. Differentiation stage alters matrix control of stem cells. J. Biomed. Mater. Res. A 2008, 85:145-156.
16. Khatiwala C.B., Peyton S.R., Metzke M., Putnam A.J. The regulation of osteogenesis by ECM rigidity in MC3T3-E1 cells requires MAPK activation. J. Cell. Physiol. 2007, 211:661-672.
17. Genes N.G., Rowley J.A., Mooney D.J., Bonassar L.J. Effect of substrate mechanics on chondrocyte adhesion to modified alginate surfaces. Arch. Biochem. Biophys. 2004, 422:161-167.
18. Li L., Sharma N., Chippada U., Jiang X., Schloss R., Yarmush M.L., Langrana N.A. Functional modulation of ES-derived hepatocyte lineage cells via substrate compliance alteration. Ann. Biomed. Eng. 2008, 36:865-876.
19. Semler E.J., Lancin P.A., Dasgupta A., Moghe P.V. Engineering hepatocellular morphogenesis and function via ligand-presenting hydrogels with graded mechanical compliance. Biotechnol. Bioeng. 2005, 89:296-307.
20. Solon J., Levental I., Sengupta K., Georges P.C., Janmey P.A. Fibroblast adaptation and stiffness matching to soft elastic substrates. Biophys. J. 2007, 93:4453-4461.
21. Yeung T., Georges P.C., Flanagan L.A., Marg B., Ortiz M., Funaki M., Zahir N., Ming W., Weaver V., Janmey P.A. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskeleton 2005, 60:24-34.
22. Alcaraz J., Xu R., Mori H., Nelson C.M., Mroue R., Spencer V.A., Brownfield D., Radisky D.C., Bustamante C., Bissell M.J. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 2008, 27:2829-2838.
23. Paszek M.J., Zahir N., Johnson K.R., Lakins J.N., Rozenberg G.I., Gefen A., Reinhart-King C.A., Margulies S.S., Dembo M., Boettiger D., Hammer D.A., Weaver V.M. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005, 8:241-254.
24. Banerjee A., Arha M., Choudhary S., Ashton R.S., Bhatia S.R., Schaffer D.V., Kane R.S. The influence of hydrogel modulus on the proliferation and differentiation of encapsulated neural stem cells. Biomaterials 2009, 30:4695-4699.
25. Engler A.J., Sen S., Sweeney H.L., Discher D.E. Matrix elasticity directs stem cell lineage specification. Cell 2006, 126:677-689.
26. Evans N.D., Minelli C., Gentleman E., LaPointe V., Patankar S.N., Kallivretaki M., Chen X., Roberts C.J., Stevens M.M. Substrate stiffness affects early differentiation events in embryonic stem cells. Eur. Cell Mater. 2009, 18:1-13. discussion 13-14.
27. Gilbert P.M., Havenstrite K.L., Magnusson K.E., Sacco A., Leonardi N.A., Kraft P., Nguyen N.K., Thrun S., Lutolf M.P., Blau H.M. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 2010, 329:1078-1081.
28. Huebsch N., Arany P.R., Mao A.S., Shvartsman D., Ali O.A., Bencherif S.A., Rivera-Feliciano J., Mooney D.J. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 2010, 9:518-526.
29. Rowlands A.S., George P.A., Cooper-White J.J. Directing osteogenic and myogenic differentiation of MSCs: interplay of stiffness and adhesive ligand presentation. Am. J. Physiol. Cell Physiol. 2008, 295:C1037-C1044.
30. Chen W.L., Likhitpanichkul M., Ho A., Simmons C.A. Integration of statistical modeling and high-content microscopy to systematically investigate cell-substrate interactions. Biomaterials 2010, 31:2489-2497.
31. Winer J.P., Janmey P.A., McCormick M.E., Funaki M. Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli. Tissue Eng. A 2009, 15:147-154.
32. Stroka K.M., Aranda-Espinoza H. Neutrophils display biphasic relationship between migration and substrate stiffness. Cell Motil. Cytoskeleton 2009, 66:328-341.
33. Irwin E.F., Saha K., Rosenbluth M., Gamble L.J., Castner D.G., Healy K.E. Modulus-dependent macrophage adhesion and behavior. J. Biomater. Sci. Polym. Ed. 2008, 19:1363-1382.
34. Nemir S., West J.L. Synthetic materials in the study of cell response to substrate rigidity. Ann. Biomed. Eng. 2010, 38:2-20.
35. Yip C.Y., Chen J.H., Simmons C.A. Engineering substrate mechanics to regulate cell response. Micro- and Nanoengineering of the Cell Microenvironment: Technologies and Applications 2008, 161-178. Artech House, Boston, London. A. Khademhosseini (Ed.).
36. McDaniel D.P., Shaw G.A., Elliott J.T., Bhadriraju K., Meuse C., Chung K.-H., Plant A.L. The stiffness of collagen fibrils influences vascular smooth muscle cell phenotype. Biophys. J. 2007, 92:1759-1769.
37. Georges P.C., Hui J.J., Gombos Z., McCormick M.E., Wang A.Y., Uemura M., Mick R., Janmey P.A., Furth E.E., Wells R.G. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 293:G1147-G1154.
38. Wells R.G. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J. Clin. Gastroenterol. 2005, 39:S158-S161.
39. Wells R.G. The role of matrix stiffness in regulating cell behavior. Hepatology 2008, 47:1394-1400.
40. Li Z., Dranoff J.A., Chan E.P., Uemura M., Sevigny J., Wells R.G. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007, 46:1246-1256.
41. Zhao R., Sider K.L., Simmons C.A. Measurement of layer-specific mechanical properties in multilayered biomaterials by micropipette aspiration. Acta Biomater. 2010, doi:10.1016/j.actbio.2010.11.004.
42. Chen J.-H., Chen W.L.K., Sider K.L., Yip C.Y.Y., Simmons C.A. {beta}-catenin mediates mechanically regulated, transforming growth factor-{beta}1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler. Thromb. Vasc. Biol. 2010, 10.1161/ATVBAHA.110.220061.
43. Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr. Rheumatol. Rep. 2009, 11:120-126.
44. Yip C.Y., Chen J.H., Zhao R., Simmons C.A. Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler. Thromb. Vasc. Biol. 2009, 29:936-942.
45. Wipff P.J., Rifkin D.B., Meister J.J., Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J. Cell Biol. 2007, 179:1311-1323.
46. Paszek M.J., Weaver V.M. The tension mounts: mechanics meets morphogenesis and malignancy. J. Mammary Gland Biol. Neoplasia 2004, 9:325-342.
47. Varga J., Pasche B. Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr. Opin. Rheumatol. 2008, 20:720-728.
48. Munger J.S., Huang X., Kawakatsu H., Griffiths M.J.D., Dalton S.L., Wu J., Pittet J.-F., Kaminski N., Garat C., Matthay M.A., Rifkin D.B., Sheppard D. A mechanism for regulating pulmonary inflammation and fibrosis: the integrin [alpha]v[beta]6 binds and activates latent TGF [beta]1. Cell 1999, 96:319-328.
49. Bissell M.J., Labarge M.A. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?. Cancer Cell 2005, 7:17-23.
50. Jacobs T.W., Byrne C., Colditz G., Connolly J.L., Schnitt S.J. Radial scars in benign breast-biopsy specimens and the risk of breast cancer. N. Engl. J. Med. 1999, 340:430-436.
51. Zhao G., Cui J., Qin Q., Zhang J., Liu L., Deng S., Wu C., Yang M., Li S., Wang C. Mechanical stiffness of liver tissues in relation to integrin β1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma. J. Surg. Oncol. 2010, 102:482-489.
52. Cukierman E., Bassi D.E. Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors. Semin. Cancer Biol. 2010, 20:139-145.
53. Erler J.T., Bennewith K.L., Cox T.R., Lang G., Bird D., Koong A., Le Q.-T., Giaccia A.J. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 2009, 15:35-44.
54. Wang H.B., Dembo M., Wang Y.L. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell Physiol. 2000, 279:C1345-C1350.
55. Kostic A., Lynch C.D., Sheetz M.P. Differential matrix rigidity response in breast cancer cell lines correlates with the tissue tropism. PLoS ONE 2009, 4:e6361.
56. Jaalouk D.E., Lammerding J. Mechanotransduction gone awry. Nat. Rev. Mol. Cell Biol. 2009, 10:63-73.
57. Weaver V.M., Petersen O.W., Wang F., Larabell C.A., Briand P., Damsky C., Bissell M.J. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol. 1997, 137:231-245.
58. Chioni A.-M., Grose R. Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis. Fibrogenesis Tissue Repair 2008, 1:8.
59. Fidler I.J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 2003, 3:453-458.
60. Wittekind C., Neid M. Cancer invasion and metastasis. Oncology 2005, 69(Suppl 1):14-16.
61. Sahai E., Marshall C.J. RHO-GTPases and cancer. Nat. Rev. Cancer 2002, 2:133-142.
62. Cross S.E., Jin Y.S., Rao J., Gimzewski J.K. Nanomechanical analysis of cells from cancer patients. Nat. Nanotechnol. 2007, 2:780-783.
63. Suresh S. Biomechanics and biophysics of cancer cells. Acta Biomater. 2007, 3:413-438.
64. von Wichert G., Krndija D., Schmid H., Haerter G., Adler G., Seufferlein T., Sheetz M.P. Focal adhesion kinase mediates defects in the force-dependent reinforcement of initial integrin-cytoskeleton linkages in metastatic colon cancer cell lines. Eur. J. Cell Biol. 2008, 87:1-16.
65. Ayaki M., Komatsu K., Mukai M., Murata K., Kameyama M., Ishiguro S., Miyoshi J., Tatsuta M., Nakamura H. Reduced expression of focal adhesion kinase in liver metastases compared with matched primary human colorectal adenocarcinomas. Clin. Cancer Res. 2001, 7:3106-3112.
66. Kornberg L.J. Focal adhesion kinase and its potential involvement in tumor invasion and metastasis. Head Neck 1998, 20:745-752.
67. Gabriel B., zur Hausen A., Stickeler E., Dietz C., Gitsch G., Fischer D.C., Bouda J., Tempfer C., Hasenburg A. Weak expression of focal adhesion kinase (pp 125FAK) in patients with cervical cancer is associated with poor disease outcome. Clin. Cancer Res. 2006, 12:2476-2483.
68. Luo M., Guan J.L. Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett. 2010, 289:127-139.
69. Klein A., Olendrowitz C., Schmutzler R., Hampl J., Schlag P.M., Maass N., Arnold N., Wessel R., Ramser J., Meindl A., Scherneck S., Seitz S. Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett. 2009, 276:212-220.
70. Chen J.H., Yip C.Y., Sone E.D., Simmons C.A. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am. J. Pathol. 2009, 174:1109-1119.
71. Russo F.P., Alison M.R., Bigger B.W., Amofah E., Florou A., Amin F., Bou-Gharios G., Jeffery R., Iredale J.P., Forbes S.J. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006, 130:1807-1821.
72. Yao Z., Mishra L. Cancer stem cells and hepatocellular carcinoma. Cancer Biol. Ther. 2009, 8:1691-1698.
73. Lazennec G., Jorgensen C. Concise review: adult multipotent stromal cells and cancer: risk or benefit?. Stem Cells 2008, 26:1387-1394.
74. Breitbach M., Bostani T., Roell W., Xia Y., Dewald O., Nygren J.M., Fries J.W.U., Tiemann K., Bohlen H., Hescheler J., Welz A., Bloch W., Jacobsen S.E.W., Fleischmann B.K. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007, 110:1362-1369. 10.1182/blood-2006-12-063412.
75. Rehfeldt F., Engler A.J., Eckhardt A., Ahmed F., Discher D.E. Cell responses to the mechanochemical microenvironment-implications for regenerative medicine and drug delivery. Adv. Drug Deliv. Rev. 2007, 59:1329-1339.
76. Lemmon C.A., Sniadecki N.J., Ruiz S.A., Tan J.L., Romer L.H., Chen C.S. Shear force at the cell-matrix interface: enhanced analysis for microfabricated post array detectors. Mech. Chem. Biosyst. 2005, 2:1-16.
77. Fu J., Wang Y.K., Yang M.T., Desai R.A., Yu X., Liu Z., Chen C.S. Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat. Methods 2010, 7:733-736.
78. Tan J.L., Tien J., Pirone D.M., Gray D.S., Bhadriraju K., Chen C.S. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl. Acad. Sci. USA 2003, 100:1484-1489.
79. Buxboim A., Discher D.E. Stem cells feel the difference. Nat. Methods 2010, 7:695-697.
80. Kong H.J., Mooney D.J. Microenvironmental regulation of biomacromolecular therapies. Nat. Rev. Drug Discov. 2007, 6:455-463.
81. Kong H.J., Liu J., Riddle K., Matsumoto T., Leach K., Mooney D.J. Non-viral gene delivery regulated by stiffness of cell adhesion substrates. Nat. Mater. 2005, 4:460-464.
82. Ingber D.E. Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ. Res. 2002, 91:877-887.
83. Wang N., Butler J.P., Ingber D.E. Mechanotransduction across the cell surface and through the cytoskeleton. Science 1993, 260:1124-1127.
84. Treiser M.D., Yang E.H., Gordonov S., Cohen D.M., Androulakis I.P., Kohn J., Chen C.S., Moghe P.V. Cytoskeleton-based forecasting of stem cell lineage fates. Proc. Natl. Acad. Sci. USA 2010, 107:610-615.
85. Moraes C., Wang G., Sun Y., Simmons C.A. A microfabricated platform for high-throughput unconfined compression of micropatterned biomaterial arrays. Biomaterials 2010, 31:577-584.
86. Neuss S., Apel C., Buttler P., Denecke B., Dhanasingh A., Ding X., Grafahrend D., Groger A., Hemmrich K., Herr A., Jahnen-Dechent W., Mastitskaya S., Perez-Bouza A., Rosewick S., Salber J., Woltje M., Zenke M. Assessment of stem cell/biomaterial combinations for stem cell-based tissue engineering. Biomaterials 2008, 29:302-313.
87. Mei Y., Saha K., Bogatyrev S.R., Yang J., Hook A.L., Kalcioglu Z.I., Cho S.W., Mitalipova M., Pyzocha N., Rojas F., Van Vliet K.J., Davies M.C., Alexander M.R., Langer R., Jaenisch R., Anderson D.G. Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells. Nat. Mater. 2010, 9:768-778.
88. Zaari N., Rajagopalan P., Kim S., Engler A., Wong J. Photopolymerization in microfluidic gradient generators: microscale control of substrate compliance to manipulate cell response. Adv. Mater. 2004, 16:2133-2137.
89. Anderson D.G., Levenberg S., Langer R. Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells. Nat. Biotechnol. 2004, 22:863-866.
90. Anderson D.G., Putnam D., Lavik E.B., Mahmood T.A., Langer R. Biomaterial microarrays: rapid, microscale screening of polymer-cell interaction. Biomaterials 2005, 26:4892-4897.
91. Albrecht D.R., Tsang V.L., Sah R.L., Bhatia S.N. Photo- and electropatterning of hydrogel-encapsulated living cell arrays. Lab Chip 2005, 5:111-118.
92. Flaim C.J., Chien S., Bhatia S.N. An extracellular matrix microarray for probing cellular differentiation. Nat. Methods 2005, 2:119-125.
93. Gomez-Sjoberg R., Leyrat A.A., Pirone D.M., Chen C.S., Quake S.R. Versatile, fully automated, microfluidic cell culture system. Anal. Chem. 2007, 79:8557-8563. 10.1021/ac071311w.
94. Moraes C., Chen J.H., Sun Y., Simmons C.A. Microfabricated arrays for high-throughput screening of cellular response to cyclic substrate deformation. Lab Chip 2010, 10:227-234.
95. Cukierman E., Pankov R., Stevens D.R., Yamada K.M. Taking cell-matrix adhesions to the third dimension. Science 2001, 294:1708-1712.
96. Fischbach C., Chen R., Matsumoto T., Schmelzle T., Brugge J.S., Polverini P.J., Mooney D.J. Engineering tumors with 3D scaffolds. Nat. Methods 2007, 4:855-860.
97. Peyton S.R., Kim P.D., Ghajar C.M., Seliktar D., Putnam A.J. The effects of matrix stiffness and RhoA on the phenotypic plasticity of smooth muscle cells in a 3-D biosynthetic hydrogel system. Biomaterials 2008, 29:2597-2607.