Journal of Cell Science eateto iegneig nvriyo enyvna 1 ot 3dSre,Piaepi,P 90,USA 19104, PA Philadelphia, Street, 33rd South 210 Pennsylvania, of Chen* University Bioengineering, S. of Christopher Department and Baker M. Brendon culture cues 3D cellular how alter – microenvironments dimension third the Deconstructing Commentary iial,mmayeihla el meddi 3D a acinar in into assemble embedded division, cells uncontrolled the halt epithelial 1982). and environment Shaffer, mammary shape and (Benya cell Similarly, markers cartilaginous including of phenotype, expression when physiological restores chondrocytes function For their dedifferentiated environment. and of culture encapsulation form (3D) instance, three-dimensional physiological a their in cell embedded regain these of divide some can Interestingly, Mark 1992). types flatter, al., der et (von Petersen progressively 1977; phenotype al., differentiated become et their lose culture, and cell aberrantly the planar capture faithfully into not vivo. might in model cells of 2D behavior the physiological understanding with that come to caveat have 2D findings the approaches these of but simplicity phenomena reductionist cellular the individual enabled sword: vivo has double-edged in a culture the been and has culture scenario monolayer striking traditional The between factors. interact cell-secreted disparity that of medley populations a and cell and complex heterotypically mixed a components, (ECM) within extracellular matrix multiple embedded contains exist that environment However, primarily information-rich substrates. cells glass vivo, or in plastic on cultured (2D) cells two-dimensional of based populations flat, homogenous is of processes studies biological on many largely of understanding current Our Introduction ( Sachs Frederick and Sukharev Sergei words: by Key adhesion, principles’ unifying and diversity structure, – channels ion by cell systems. transduction force 2D ‘Molecular ( traditional 3061-3073). influence Gardel i L. exploring in – Margaret that link observed and weakest that Schwarz the been ways ‘Finding articles: related have in is ( see ( studying systems please al. not Labouesse culture reading, function et where further Roca-Cusachs would For examples 3D Pere on Mechanotransduction. cellular by that on discuss culture which pathways’ Minifocus molecular be overall and a insights in of biology, part regulate will provided scenarios is cell cell article context – experimental This Commentary studying 3D for describe turn this 3D engineering a will in materials of in we in – focus cells of Additionally, advances which formats. recent the highlight culture factors, features Thus, relevant, 2D soluble particularly microenvironments. traditional to fundamental 3D from three- response dramatically in complex, in material depart the it operative biologists, signaling processes, topographically are cellular among and describing fundamental the factors work mechanotransduction studying the which and for cross-disciplinary and towards systems exactly much surfaces efforts culture define encouraged identifying substantial more-physiological flat towards to spurred has move has these crucial and we This environments is As between vivo. engineers. the biomimetic in dissimilarity tissue recently 3D operate and more the vitro scientists routinely However, cells in surfaces. appreciate force- which plastic of and to in or differentiation development glass environments migration, come (2D) extracellular as two-dimensional has (3D) such on dimensional functions, field cultured cellular cells biology underlie studying that from cell mechanisms garnered biological been the has of sensing understanding our of Much Summary ( correspondence for *Author o:10.1242/jcs.079509 doi: 3015–3024 125, ß Science Cell of Journal 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. ned aycl ye,we sltdfo ise n placed and tissues from isolated when types, cell many Indeed, .Cl Sci. Cell J. Dcluemdl,Cl dein iesoaiy ehntasuto,Mconiomn,Slbefactors Soluble Microenvironment, Mechanotransduction, Dimensionality, adhesion, Cell models, culture 3D 125 [email protected] 0934) Uie esad–itgaigteatnctseeo n elmti dein nclua ehntasuto’b lihS. Ulrich by mechanotransduction’ cellular in adhesions cell–matrix and cytoskeleton actin the integrating – stand we ‘United 3039-3049). , .Cl Sci. Cell J. 125 0136) Mcaoestv ehnssi rncitoa euain yAioMmooe l ( al. et Mammoto Akiko by regulation’ transcriptional in mechanisms ‘Mechanosensitive 3051-3060). , .Cl Sci. Cell J. ) 125 0533) Sgaln hog ehnclipt oriae rcs’b umnZagadMichel and Zhang Huimin by process’ coordinated a – inputs mechanical through ‘Signalling 3025-3038). , ifsbefcos–adhwsc usmyb rsne n3D physiological in appropriate presented and be providing may forces Beyond cues culture. mechanical such 2D how adhesions, versus and cell – to – factors known diffusible are function cues cell microenvironmental impact which by avenues main traditional more from what differs exactly that settings. cells demystify 2D the to to of provides strive features culture salient and 3D the setting understand and experimental factor identify each must dimensionality we a contexts. play, that these at concluding of is each simply to than originate inherent rather instead are Thus, that consequences features functional finer culture, the shape from or dimensional cell overall the the the of and than systems between Rather culture differences two- 3D setting. monolayer, physiological potential 2D a versus many in culture entails traditional blanket three-dimensionality what difference a for become i.e. single statement has dimensionality a states, Presently, dimensionality. into two of wary drives comparisons be between must monolayer these we However, culture in state. oversimplifying 3D physiological whereas more cells dedifferentiation, a the elicits or culturing to function and cell determinant, that abnormal fate crucial impression a is vague cultured are 1992). cells al., which et Petersen 1984; al., et Lee (Emerman 1977; membrane Pitelka, basement and novo de a establish and structures ihti oli id hsCmetr ileaiethe examine will Commentary this mind, in goal this With in dimension the that notion the to led have observations These .Cl Sci. Cell J. tgi-eitdmechanical ntegrin-mediated 125 .Cl Sci. Cell J. 3075-3083). , 3015 125 , Journal of Cell Science uiggsrlto,teagoei potn fbodvessels, blood occurs of that sprouting folding angiogenic tissue the collective and the gastrulation, generation example, during For force might substrates. migration, that 2D cell responses on biological observable be facilitates not also culture 3D cues, 3016 B A C remodeling synthesis and Matrix cues Soluble ora fCl cec 2 (13) 125 Science Cell of Journal cues ECM-bound Soluble and cues Topographical Chondrogenesis Metastasis Angiogenesis Migration ECM-bound cues Soluble and remodeling Matrix cues Adhesive cues Mechanical reorganization Multicellular Repolarization cues Adhesive adhesion Cell-cell Migration cues Topographical Proliferation Polarization cues Mechanical Proliferation remodeling Matrix cues Mechanical flow Interstitial n irto Wzike l,20;Wbre l,21;Ore al., et fundamental Orr 2011; al., many et are Weber regulate 2004; al., that to et (Wozniak migration signals order and proliferation in differentiation, understood survival, of including cell behaviors, better cellular the number the by and among integrated and composition shape are cell organization, adhesions define the The cells with neighboring organization. interactions and ECM adhesive surrounding cells, anchorage-dependent For structure conduct. and we adhesion studies Cell the and be pose identify should we to that questions seeks systems the experimental rather, in 3D but, considered of 3D of features in This compilation salient biology 2). for exhaustive some cell and an employed on 1 be literature be to Boxes the intended (see can not vitro that is in methods Commentary cues we for the different evolving, these of technologies guide studying rapidly some are aid that the examine environment also mechanisms because cellular will the into underlying Furthermore, engineering components the processes processes. chemical understanding these associated in and the us these mechanical and Deconstructing 1). adhesive, cell (Fig. microenvironments into higher-order 3D and of inherently 3D stroma cases are all through that are processes cells metastasis, cancerous during of lymphatics migration the and fclst ppoi Wae ta. 02.I lohsbeen has also It 2002). al., et and (Weaver instance, apoptosis geometry sensitivity the For to cell modulate function. cells to in shown cell of stellate been changes has impact a polarity These directly apical-basal assume 2007). – can ECM al., organization migration during 3D et rear cells, to a front (Mseka mesenchymal from in polarize as most only embedded such and for morphology types, when unnatural cell – is some which but for polarity. relevant cells, apical–basal arguably forced epithelial a is that have polarity cells surfaces that This 2D is on this in of cultured spread spreading consequence are and for One support adhere 2). dimension. no can (Fig. have vertical and but the morphology plane flat, in horizontal are the dissimilarity in monolayer freely the a is in 3D grown Cells and 2D in cells system. culture adhesive the foreign by a defined into is that them environment introducing cell– and and cell–cell interactions, in native these ECM biology of cell cells studying stripping Unavoidably, necessitates 2009). vitro al., et Geiger 2006; egbrn acltr lgtbu)ad vnuly omtsaie Drawings scale. towards metastasize. to to migrate not eventually, to and, blue) (green) (light cells vasculature epithelial the neighboring in transformed changes enable structural ECM in and stromal (blue) mechanical fibroblasts Subsequent activate stroma. that surrounding signals the soluble extracellular of cascade or a and genetic initiates proliferation through changes regulate proliferation tightly of the to Misregulation and order apoptosis. cells in neighboring (brown) from membrane cues basement mechanical form and and adhesive tissue requires surrounding the ( invade sprouts. ECM collectively tubular stromal to and and order contacts, (brown) in cell-cell membrane (orange) and basement polarity surrounding their the alter degrade vessel (pink) blood the cells and on endothelial form forces wall, to mechanical flow-induced cells and the factors allow growth ( bound which cartilage. cytokines, cues surrounding of adhesive the form flow, maintain the fluid in interstitial cues forces, soluble compressive and to exposed are they environment. extracellular the cues and ( chemical cells and other and mechanical from homeostasis adhesive, originating tissue by development, conducted in are phenomena disease cellular 3D 1. Fig. A hnrcts(le eiewti pcaie eiellrEM where ECM, pericellular specialized a within reside (blue) Chondrocytes ) n ftems tiigdfeecsosre hncomparing when observed differences striking most the of One C h omto fnra pteilsrcue (pink) structures epithelial normal of formation The ) B nrsos oslbeadmatrix- and soluble to response In ) Journal of Cell Science o xml,o Dsbtae,itgi-eitdadhesion surface. integrin-mediated planar substrates, a on 2D occur on that example, processes quite be For the might al., matrix the from 3D et Indeed, a into 2011). DeForest different extending al., 2008; or just et spreading Klein al., are of 2010; process 3D et cell Burdick, in (Lee and on adhesion Khetan established 2009; cell area be control and to to map insights beginning Methods shape these settings. how of unclear 3D remains to role it culture, apparent 2D in function the Despite 2010). The 2006; h elcnipc t ucin(rc ta. 03 The 2003; al., et circular (Brock function (e.g. its shape impact by assumed can geometric is cell that the the to elongated) addition versus spreading, proliferation, cuboidal In star-shaped, of 2004). al., cell versus al., area et et impact total Chen McBeath 2002; 1994; the can al., al., et et spreading Thomas (Singhvi 1997; cell differentiation altering and that of apoptosis demonstrated have degree others islands and adhesive the cell we micropatterned the substrates, using effective into 2D By propagated on the 2006). better al., is alter et surface (Meyers can cell the that cells from such signaling of ratio, membrane-to-cytoplasm) flattening (i.e. surface-to-volume the that suggested ta. 03 ol ta. 09 eate l,21) cl as 20 bars: 2009). Scale al., 2010). et al., (Kloxin et recently in Legant gels developed 2009; example, been al., For have et systems. light Doyle these to 2003; in in response al., achievable modular in et is often induced that and be diversity tunable can and highly advantage stiffness flexibility are The in ever-expanding gels sites. changes al., the These binding These et dynamic growth-factor- by 2009). Miller or which evidenced 2005). al., 2005; domains best et al., metalloprotease-cleavable Hubbell, are Mata et matrix and Raeber materials as 2003; 2002; such synthetic Zhang, (Lutolf Anseth, functionalities, 2002; these and counterparts additional of al., Burdick of natural common 2001; et inclusion most al., their (Kisiday their et The peptides using (Mann mechanism. self-assembling Figure) crosslinking by and in ‘cell-friendly’ (D 2010) achieved a hydrogels and be (PEG)-based ligands, glycol can cell-binding polyethylene backbone, include than structural properties a possess biological typically materials and also without material porosity. stiffness and over modulate o Additional to size difficulty control impossible 2010). pore the is and al., ligand, it moieties gel adhesive et collagen functional the (Hughes a additional of in incorporate batches example, but density to For between entactin, the systems these independently. substantially these altering and microenvironment origin, modifying the varies laminin cellular of of these collagens, that their features challenge reason, comprises different of factors the same tuning Matrigel include result this growth systems example, For a of natural cells. For As of population by responses. 2007). limitations remodeled uncharacterized cell al., be an certain et readily isolating possesses can (Beacham in and also Figure) activity, disadvantageous in biological prove (Kleinman (C other Matrigel) can fibroblasts and (e.g. systems ligands by membrane basement adhesive synthesized reconstituted possess ECM fibrinogen, inherently of stromal materials cleavage and thrombin function. by 2005) ECMs formed Martin, natural gels how and fibrin of 2003), understanding (Grinnell, our Figure) by in informed (A multicellular been has synt or materials or natural synthetic remodeling of behind be engineering can matrix materials the Such domains. of migration, biological must much and ECM factors cell insoluble but 3D or the origin, soluble occur, biologica where of specific to addition Finally, hydrolysis. experiments this the through or For facilitated surroundings. cleavage be proteolytic In their through can interactions waste of either constraints degradation, peptides. steric and to susceptible the containing Arg–Gly–Asp nutrient are overcome that precursor to enable entities need of structural liquid to contain will cells porous form embedded a c the are of interest, with the addition gels of by begin is ensuing achieved organization in typically is The functionality commonly biological systems manner. basic hydrated these ligands, most The self-supporting. and feasible, adhesive cyto-compatible be logistically to a properties be mechanical sufficient in possess to solidifies and experiments exchange, or for gels 2004 Tirrell, which order and (Langer cells, 3D In suspended in interactions 2005). cellular directing, Hubbell, as well and as studying, Lutolf for developed been culture have biomaterials 3D of number overwhelming for An systems and Materials 1. Box mgsi h iuewr dpe ihpriso rmGinl ta. 03() ol ta. 09()adLgn ta. 00()(Grinnell (D) 2010 al., et Legant and (C) 2009 al., et Doyle (A), 2003 al., et Grinnell from permission with adapted were Figure the in Images greater provide to desire the by motivated been has and decade, past the during advanced rapidly has gels synthetic of development The I type collagen purified include materials These biologists. for tool important an as served has sources natural from ECM decades, several For ´ ye l,20;Mhu ta. 09 iine al., et Kilian 2009; al., et Mahmud 2007; al., et ry ABCD olgnNnfbr Fibronectin Nanofibers Collagen ´ ye al., et ry m m. ci-ihetnin,ai ofbols opooyosre in observed morphology fibroblast long lamellipodial to with morphology akin planes, stellate extensions, a opposing actin-rich of favor two in integrin on diminished With formation occurring 2004). al., now et (Beningo binding integrins two both ventral engage between and simultaneously dorsal fibroblasts to gels ‘sandwiched’ For polyacrylamide al. adhesions. ECM-coated of et arise distribution Beningo could spatial culture the 2). example, in 3D (Fig. surface variations versus cell these 2D the from around in all responses or cellular cell the Different matrix of extracellular face one the on form to cell adhesions integrin-mediated Thus, whether extend. rather 2010). to days Burdick, instances, and order some (Khetan in minutes in and, than 3D hours, proteolytically scaffold over In occurs or substrates. physical spreading negotiate restraint-free the often a these must cleave takes on cells process however, time this settings, of Overall period 2005). al., myosin-mediated adhesions short Horwitz, and et focal Lauffenburger Reinhart-King 1988; extension, of 1996; al., et reinforcement Burridge lamellipodial the 1987; (Hynes, and by tension cytoskeletal followed is el sue2 r3 emtislreyo h ai of basis the on largely geometries 3D or 2D assume Cells eosrcigtetiddmnin3017 dimension third the Deconstructing PEG lactivityand hetic sof ell- f ; Journal of Cell Science 3018 Uiest fWsigo,Sate WA). Seattle, Washington, of (University ptal yai rfls irfudc r o sdruieyt rvd rdet fslbegot atr ocls rmrl ostudy to primarily cells, to factors and growth Go temporally soluble Go 2003; al., (F), producing of et 2003 Teixeira in al., gradients et flexibility Teixeira provide and (E), cell to 2009 control routinely stem 2010). greater free simple al., used provide finer mesenchymal from et now design the that (Kim in promote control can are chemotaxis range generators to or devices and that Microfluidics gradient These 2000), used polarization 2007). Scherer, flow-based profiles. be factors al., and can et complex dynamic (Quake (Yu soluble lithography factors more signals spatially soft biological autocrine response. the to amplify on of biological thus, presentation systems based optimize and, resulting spatial are volume diffusion and the culture to that timing effective examine Figure) the the approach and in reduce including simply factors microenvironment, (G,H high-throughput soluble devices soluble the Microfluidic a of of 2008). libraries features used al., High- to defined. et cells have stringently (Huang expose be chondrogenesis co-workers can to environment used and soluble the be Huang which t can by is approaches means systems two screening these provide of throughput microfluidic all the and to tune methods intrinsic to fluid-handling is High-throughput densities designer that crosslinking feature of the different salient number factors A with growing study density. Soluble Figure). a prepared to ligand in and be order and (D as also stiffness stiffness in such can softer substrate hydrogels, of lengths Silicones alter in numerous control differing 2010). to Similarly, formed orthogonal crosslinked and al., 2011). is differentially et al., diameters this be et Fu sub-micrometer can when (Prager-Khoutorsky Figure, systems, of substrate microenvironment in resulting posts cellular (C the silicone the cells of of of on the stiffness properties arrays stiffness restrict ECM mechanical generated 2010). to of the al., have effects alter et we gratings (Salaita to example, membrane, nm-scale receptors used For plasma these employed be materials. from the also colleagues signaling of can alter and positioning features several thereby, Nanometer-scale the Salaita and, using influence receptors example, fabricated can (EPHA2) For roughness be A2 Mechanics receptor and them. can EPH curvature with materials topological of local As multicellular These associated clustering 2010). nano-scale the al., and as adhesions. structures scales, with et movement Anselme cell–matrix nm well and substrates 2004; approaches of al., receptors as stiff the et features geometry (Dalby surface typically Figure) the electrospray and of or are of in size electrospinning attributes scale Figure) roughening, between the (A physical the coupling in chemical and constrain tight architecture chemical (E–F the lithography, to or regulating cytoskeletal including materials in designed methods, factors physical and Nanotopographic are these of function. shape altering that importance and the features cell demonstrating without signaling, in adhesions, instrumental spreading, structure, been integrin-mediated have cell and and of Figure), in adhesion distribution (B organization cell and flat a control size on presented the The precisely 2001; are al., that can et regions (Whitesides protein-adsorption-resistant microenvironment substrates and cell-adhesive These of surface. arrangements defined contain factors. in drawbacks substrates soluble tools experimental Micropatterned of these the delivery adhesion With and cell the provide. culture control and Adhesion can to 3D topography, methods culture for include and requirement 3D Examples mechanics factors). the that microenvironmental matrix without interdependent cues shape, and possible microenvironmental and imaging be specific non-optimal might (e.g. the it phenotype culture harnessing with cellular associated 3D and particular isolating of a in features reconstituting interest the hand, growing capture a to is microenvironments There engineer to How 2. Box h mgsi h iuewr dpe ihpriso rmKla ta. 00() ea ta. 09() ue l,21 C,Btigre al., et Bettinger (C), 2010 al., et Fu (B), 2009 al., et Desai (A), 2010 al., et Kilian from permission with adapted were Figure the in images The ora fCl cec 2 (13) 125 Science Cell of Journal A B ´mez-Sjo br ta. 07.Iae nD oreyo oi hiadCrsohrCe.IaeH orsyo letFolch, Albert of courtsey H, Image Chen. Christopher and Choi Colin of courtesy D, in Images 2007). al., et ¨berg ´mez-Sjo br ta. 07()(iine l,21;Dsie l,20;F ta. 00 etne ta. 2009; al., et Bettinger 2010; al., et Fu 2009; al., et Desai 2010; al., et (Kilian (G) 2007 al., et ¨berg r,21) eedn ntegoer ftepten,sc usrtshv enue odictate to used been have substrates such patterns, the of geometry the on Depending 2010). ´ry, Stiff Stiff C D Soft Soft F E Grating Posts Pits H G he Journal of Cell Science thsbcm ieyapeitdta ehnclfre are forces these that mechanical and surroundings, that their and appreciated cells widely between ever-present become has It 3D the Mechanotransduction of features mechanical and tunable structural more environment. afford the might fibrin), over matrices and control synthetic I in collagen progress for (e.g. models recent effects as forward, topographical accessible already Looking these are studying features. ECMs natural nanoscale few a such cell whereas impact through might is culture be 3D might function which and ECM by signaling, mechanism the and important of structure one nature adhesion al., modulating fibrillar et 3D for the (Doyle responsible surfaces words, ECM these flat other micropatterned on In of that 2009). cells strips culturing 2001). narrow suggested by present al., that reproduced has be et can work (Cukierman adhesions follow-up microenvironments by 2D Interestingly, specified differentially the sample. versus is that cell suggested the 3D of non-planar been by cell-derived employed has integrin intensity it on a of and type adhesions described, or in matrix been have 3D size matrices optics challenges, decreased these non-optimal Despite the the or is to contexts of quantitatively 3D adhesions, owing in because emerged, adhesions to focal yet 2010; challenging imaging Approaches not that al., hurdle have 2011). et additional variations Fraley these Horwitz, 3D 2011; describe different and in Yamada, and observed sites and Kubow to variations adhesion (Harunaga the likely variable. to of contexts are highly proteins some topography of are explain recruitment and 3D might the stiffness in to matrix adhesions contribute as that such surprising Factors not is it al., 2005). disease et Provenzano of Ra 2005; al., progression et 2006; ECMs Amatangelo the 2009; during native al., et dynamically of (Levental change structures wide can This fibrillar the that nanometer-scale given adhesions. and, important of particularly function variety integrin-mediated is structure, nanometer-scale architecture of of the the question impacts composition context. that ECM 3D possibly, the suggest a of into results architecture adhesion develop these cell to in of Nonetheless, crucial efforts understanding be infancy, will patterning our its technologies moving 2D spatially in these still occur for to is analogous technology approaches 3D to The in ligands 2004). signaling adhesive al., integrin-clustering-induced et spacing (Arnold ligand for minimum integrin, single the a required determined only colleagues of and binding Arg-Gly-Asp the Arnold with permit coated that particles peptides gold (RGD) 8-nm Using 2007). al., et itiuino dein neligacl a isteai of axis the (The bias spindle can mitotic the cell and a polarity underlying planar adhesions of distribution rmcnrligahso itiuin n2,sc usisare pursuits such largely acquired 2D, have motivated. in remains we well distributions knowledge function adhesion in of controlling and body adhesions from the signaling of given cell distributions but, speculative spatial impact How could 1989). 3D have al., hepatocytes cultures of et function ‘sandwich’ differentiated (Dunn the Similar maintain 2005). to shown al., been et (Langevin vivo itiuin flgn matitgi-eitdahso and adhesion integrin-mediated (The impact spatial function how ligand explain to of begin distributions that studies facilitated have surfaces ie h tutrldvriyo h xrclua environment, extracellular the of diversity structural the Given dacsi u blt ocnrlEMpeetto n2D on presentation ECM control to ability our in Advances ¨sa nnadVhr,21;BahmadCukierman, and Beacham 2010; Vaheri, and ¨nen ´ y 00 egre l,20) o xml,the example, For 2009). al., et Geiger 2010; ry, ´ ye l,20;The 2006; al., et ry ´ ry tfns sntncsaiya nrni rpryo 3D 3D of most property to when consideration common into intrinsic taken feature be should an a that factor a is necessarily and systems it not however, Low 2010). al., environments; adhesions, et is Gilbert maintenance 2005; influence al., and et stiffness Paszek can differentiation 2006; al., cell stiffness et (Engler stem ECM and more-compliant that morphogenesis, gels markedly 2D confirmed soft using between the work has recent disparity tissues, and most the of conditions microenvironment Recognizing 2). artificial in (Fig. supraphysiological these stiffness is that of environment terms mechanical static a in al., cells. impacts et in culture transduction Keely 3D their 1985; that and possibility al., forces gels the mechanical et floating consider in we Parry only Here, 1977; 1995). occur Pitelka, to and found (Emerman were acini formation cell epithelial tubule allowed mammary and were with instance, hence For (attached) and (floating). evidence dish detached contract were the to earliest that to gels bound the in to cultured remained those of cells that comparing contrast gels from some arose in in mechanics cultured surfaces, derived ECM for been However, 2D role a has suggesting on 2006). understanding studies our al., of from et much where (Orr signaling adhesions, adhesion-mediated processes central transduce a cells represent and cell neighbors how their control as of to al., and cells component can ECM et by the experienced Hoffman to that adhere or 2011; they signals generated al., stresses of et Mechanical (Eyckmans 2011). set function crucial and structure a provide forces otdgaso lsi ufc 2)adatpcl3 C,sc scollagen. as such ECM, 3D typical a and (2D) surface plastic and or 2D glass in coated cues soluble and mechanical, 3D. topographical, Adhesive, 2. Fig. y rdtoa Dclueo ls rpatcsbtae lcscells places substrates plastic or glass on culture 2D Traditional Collagen gel(3D) Collagen-coated glass(2D) h usecutrdb elaesrknl ifrn ewe nECM- an between different strikingly are cell a by encountered cues The z

(kPa range) f) Lowstiffness

(GPa range) (GPa f) High stiffness stiffness High f) x absent gradients a) Soluble eosrcigtetiddmnin3019 dimension third the Deconstructing present gradients a) Soluble basal polarity b) Forcedapical- polarity b) Noprescribed dimensions in allthree distributed e) Adhesions x restricted to e) Adhesions - y plane hindered migration sterically d) Spreadingand migration in spreading and d) Unconstrained layer ofmatrix c) Continous matrix fibrils c) Discrete x - y Journal of Cell Science ol eeaesrse ntetases ln ftecell. the of plane transverse the stretch, in under elongate cell stresses they the generate as how is narrow between could this discrepancies matrix culture, example, surrounding 3D For and In 2D case. and constraint. important axis the physical In out-of-plane not or to the condition. in mechanical deform rise of mechanical to free allowed the gives is cell to culture the culture, regards 3D with aside, distinctions cross- materials for approaches need fibrous the modeling engendering engineers. within and thus biologists computational between embedded 2010), collaborations disciplinary al., cells and et combination a on (Niklason experimental require will loads 3D of cellular exogenous in materials of alters complex sense of structurally making intricacies, effects material numerous these (Heo the Given fibrous expression 2011). and gene al., a forces influences et differentially applied in and of deformation orientation anisotropy the (Kurpinski structural that between response observed colleagues divergence cellular and Heo the 2011). the al., on et Nathan architecture effect 2006; matrix al., profound et and a forces applied have with of orientation can direction and 2008). the morphology al., their to cell et respect complexity, experience on (Upton the fibrils depending to collagen fibrocartilage Adding stretch to adhesions of within and proximity amounts directly located different is cell considerably the cells whether example, For as material. neighboring well the fibers by as constrained matrix cell, physically of and/or the organization bound of and that scale to the transmitted relative on is depends force which cell in the way to The are 2011). anisotropic tissues Kumar, and and 3D (Pathak heterogeneous most structurally contrast, therefore, By and, manner. strain fibrous occurs affine deformation resulting predictable, cell a and The homogeneous, in membranes. and smooth silicone are fields of ECM-coated adhere effect flat, that the cells stretching to experiments, by 2D investigated is typical deformations tensile in 3D versus example, common 2D in For cells through by clear contexts. experienced are are sensed forces how exogenous there in are differences 2008), whether force (Chen, (Hoffman forces unclear in mechanisms remains level generated mechanotransduction result it cellular internally commonly Although which the and 2011). loads, tissues at al., active deformation et matrix, of and surrounding variety transduction a the experience of compliance 2010). al., et observed (Huebsch not substrates was 2D unknown clustering For on integrin this matrix. on requires 3D that dependency stiff this context and overly reasons, an 3D forces, in abrogated traction a is the cell-exerted in clustering by osteogenesis osteogenesis. FRET-imaging, clustering that using induce integrin found by efficiently also interactions authors substrates cell–ECM both plastic which Probing for response and stiffness, plateau with a intermediate glass suggested response, an Interestingly, studies 2D at bimodal 2010). whereas RGD- maximally on a al., occurring 3D demonstrated et stiffness osteogenesis in (Huebsch differentiation gel differentiation gels MSC of (MSC) alginate 2D influence Huebsch cell modified between the example, stem differ For examined mesenchymal stiffness microenvironments. co-authors sense 3D and to and the that use surfaces possible is still cells it is However, identify gels. mechanisms to rigididty 2D seeking using are or by efforts mechanisms current stiffness the the of sense Our most 3D. cells and and developing, how 2D in of behavior cell understanding between noticed are differences 3020 vnptigtecmlxte fhtrgnos anisotropic heterogeneous, of complexities the putting Even the as such cues, mechanical passive sensing to addition In ora fCl cec 2 (13) 125 Science Cell of Journal h C lohsa nerlrl nrgltn h spatial the growth regulating morphogens, (including oxide) in nitric molecules role and effector oxygen integral soluble as (such and an gases nutrients, has cells, of for distribution also support mechanical ECM and adhesive the an as serving Beyond transport Effector 2010). al., et Legant 2009; transduction al., force in et cell–ECM instrumental of (Maskarinec be understanding will better initial a and measuring allowed achieving differences have in these settings 3D developments of and characterization Recent 2D in contexts. forces traction 3D environments, cellular differently versus 3D forces. quite differences 2D experienced and the be those in 2D also illustrate might in of forces to experienced cell-generated orientation forces stresses the applied the between used on cells. we the depending Although very of could change midline forces mechanical the membrane well transduce through adhesions the travel and to embedded that cells perpendicular How an forces lie stretching in that contrast, result stresses and By to 2). lead 1999; (Fig. will Wang, 2003) cell and (Dembo al., is fibers it et (i.e. stress Tan transmission substrate located force 2D basally to a the leads on and along adhesions) cell the the at of shearing surface adhesions causing focal the to to respect tangential with is stress of orientation the Similarly, nadto ocl est,slt ieadcag l ouaethe modulate all – charge and size solute density, – cell dimensions to gel addition and interconnectivity in size, pore as such ECM, the tumorigenic Mueller- of 2010; production al., et the 1997). (Hirschhaeuser Klieser, for in resistance useful drug hypoxia proved and of have factors and core role tumors, necrotic the actual hypoxic lacks studying of a reminiscent possess also that is size can that sufficient that cells such of tumor- model spheroids example, of 3D support For cell gradients. simple cluster radial can relatively diffusion-mediated simply a capture and pelleted is by ECM factors, A transport or exogenous the soluble gradients. culture down of slows sustained 3D culture, equilibration 2D using a and by on of presence matrices but are created mere overlaying The 2), that days. whether to Box hours gradients ECM, of (see duration require cell the surfaces for as events these sustained 2D such morphogenetic in on events rapidly longer-term migration created chemotactic thereby and short-lived be polarization medium, study can to the gradients contexts throughout Temporary freely mix equilibrating. convectively diffuse factors soluble and added exogenously or ECM secreted maintenance between the adult. to the loop essential in ensuing structures is feedback differentiated transport The of this of effector formation factors). and a the and can to, structure is these contributor gradients, which subsequent development a of as signaling of during well sinks as tissues of, (both distribution result our or and cells of sources presence compartmentalization surrounding as the and and serve vasculature porosity ECM, and structure surrounding of the by the dictated factors is of diffusible and tissue of complex presentation is spatial and tissues Bourillot, The in 1). 2007) and (Fig. 2008) Manjo al., al., (Gurdon 2006; et Schaffer, et development and Saha Otrock early 2001; sprouting cell 2007; during angiogenic as Alitalo, 2008), patterning such al., and processes, et cell (Kay (Adams homing fundamental essential and of are migration regulation gradients the These cytokines). for and hormones factors, hnclsaeecpuae na3 C,srcua etrsof features structural ECM, 3D a in encapsulated are cells When cell- conditions, culture monolayer 2D traditional Under ´ ta. 07 Bollenbach 2007; al., et n Journal of Cell Science ifso ares oprn h epneo DKclsto cells MDCK of response the Comparing barriers. diffusion we this, address To of material. generated effects the direct through of diffusing timing the the signals distinguish in soluble differences to from fact, ECM difficult 3D the In often within encapsulation is 2002). it al., gels, mm- et scale diffusion-limited within embedded (Ramanujan typically are factors cells because soluble of diffusion oul eaoyegot atr(G)in (HGF) factor growth hepatocyte soluble anrt itt h rcs pta oaino potn n3D- in sprouting of location spatial precise patterned autocrine the an in dictate act to that manner morphogens to inhibitory for lead co-workers role can and a Nelson identified effects observed example, diffusion For frequently These responses. differences local settings. surprisingly factors 3D the soluble and of 2D of some between diffusion for the account in tissues might 3D limitations vitro ignored, 2010). in al., often through et diffusion are (Raghavan of than hours effects of the rather although course Thus, the HGF over even gels, of scale phosphorylation rates in elevated ERK robustly diffusion was HGF-induced to Strikingly, sensitive dimensionality. signaling of highly level and timing was the that confirmed we gels, mm-scale utperaoswycl eairdfesbten2 n 3D and 2D often between and differs we different behavior dramatically circumstances, cell be why the can reasons on there multiple mechanisms Depending that and learned effect. cues have specific desired the or a revealing behind to attributing dimensionality, engineering essential of than be effects more will tissue rather nonspecific critical to a microenvironment, a discrepancies endeavors, keep observed the these in all of to In examination mind. findings and in and screens purposes drug 2D regenerative models, robust the more validate towards develop organotypic moving to to continuously setting, is physiological striving biology cell dimension, of field The the remarks Concluding entwined. control closely 2007), can are in signaling al., cells mechanism chemical which another and et but mechanical by which factors, (Wipff means ECM-bound cells a of consumption only by release not active tugging proteolytic or illustrating 1989) as mechanical al., such et (Bashkin through mechanisms, matrix of the be then of variety can degradation factors a Such an through orchestrated. be tightly released to is presentation cells likely spatial to is and factors timing ECM of the the which within by al., mechanism factors et essential of Paralkar 1993; storage al., The et Park 1991). 1987; al., et (Vlodavsky collagen factor growth example, transforming actively and For to ECM (TGF- the known factors. in been factors soluble growth long bind have sequester factors, proteoglycans only soluble actively sulfate not of heparin also transport ECM can convective the and but Furthermore, diffusive dimensions 2006). the three limits Swartz, in solute signaling and cell and into (Griffith transduced forces mechanical be which by can mechanical means signals important another between be transport. of might coupling convective transport laws and the the flow fluid by Indeed, interstitial governed deformations directed tissue only in macroscale result not and is gradients Pressure ECM diffusion. death 3D cell the or throughout of hypoxia boundaries of define areas 2008). sharply al., of and et solubility can (Volkmer cells low – the active media to metabolically owing aqueous – in tissues oxygen 3D in gradients oxygen oto vrtesailpeetto fslbefactors soluble of presentation spatial the over Control b a ensont aea fiiytwrstp IV type towards affinity an have to shown been has ) m m -cl pteiltbs(esne l,20) Similarly, 2006). al., et (Nelson tubes epithelial m-scale -ie Dgl ht wn otersalsae lack scale, small their to owing that, gels 3D m-sized m -cl esbtnal beti larger- in absent nearly but gels m-scale m -adtraditional and m- b yeIclae e ceeae eifrnito oad a towards operative The dedifferentiation 1995). al., accelerates et 3D Susante in gel their (van encapsulation phenotype collagen whereas fibroblastic maintain 1982), I agarose Shaffer, type the inert Chondrocytes and biologically (Benya maintain with within gels involved. underlying embedded to distinct when compared functionality the are that employed chondrocytes suggesting in mechanisms are cells, differences of epithelial substantial that mammary phenotype are systems there mentioned differentiated culture that and culture see cell 3D epithelial we complex mammary above, task and numerous, our behavior. chondrocyte as cell govern well the that be and as mechanisms hidden nature Although the transport our light to is effectors. might bring to it the scientists bound as alters involved interdependent, and matrix soluble chemical factors of the of tissue how structure of and availability mechanics respectively, physical elastic gels, linearly flat and and or or stiff plastic passive and greatly culture how differs static ECMs function, the 3D in adhesive in from and transduction and, force of signaling organization mechanical active cytoskeletal cell distribution and influence 3D shape turn, cell and alter how composition domains include future structure, the in examined the be to topics Fruitful contexts. meddi,a ela h ciaino rtoyi ahnr to machinery are proteolytic cells of activation the the and ECM as well hindrance fibrous as steric the In in, cells embedded topography, to which edge 2003). specific the in mechanics on way al., trailing anisotropic depends the 3D et sequence, the in defined Ridley migrate rather of this 1996; to Horwitz, retraction contrast and subsequent (Lauffenburger traction and formation, adhesion several edge, generation through leading assume the progresses of can iteratively instance, extension For steps: surfaces processes settings. 2D 3D on simple and 2D migration Even in 2D forms 1). in different (Fig. processes dramatically these is systems recapitulate it to and culture migration impossible, itself not microenvironment cell if the of difficult, cancer organization 3D and nature. occur, the in alter remodeling, to structural phenomena tissue are the themselves higher-order Morphogenesis, function, responses for cellular cell the allows regulate where also that context cues 3D chemical and setting. mechanical 3D particular perhaps a important that, in cell happenstance from microenvironments by normal but found select were culture restore initially, of 3D to features from needed directly underlying changes not arise vital function the Thus, al., et (Debnath 2003). events morphogenetic basement similar of in top results on al., membrane cells plating not et because is response, 3D this (Debnath in for cells essential formation epithelial mammary encapsulating lumen and fact, In 2005) trigger 2002). al., that et 1997), (Paszek signals al., substrate et apoptotic low-stiffness (Weaver a matrix of the presence within the of IV amount the collagen the contrast, on and By dependent laminin 2010). highly is al., acini et al., mammary Gao of et formation 2006; Beier, (Glowacki and function Woods to sufficient 1983; and is substrate) morphology 3D chondrocyte or 2D restore Thus, a on 2007). (whether adhesion the al., of reducing level Moreover, et adhesion. of Connelly overabundance because an chondrocytes promotes 2005; it for al., non-physiological is et culture Woods monolayer 2000; Langelier 1991; al., al., et et resulted (Mallein-Gerin that maintenance ligands adhesive phenotypic Shaffer, the of in and removal thought, (Benya the shape was initially it cell as Instead, on 1982). not, effects these was exerted 3D that factor in encapsulation of feature pligti cuiiigotokt h xmlsof examples the to outlook scrutinizing this Applying nadto omdltn h ypoyo adhesive, of symphony the modulating to addition In eosrcigtetiddmnin3021 dimension third the Deconstructing Journal of Cell Science etne,C . agr .adBrnti,J T. J. Borenstein, and R. Langer, J., C. Bettinger, E. Cukierman, and A. D. Beacham, ey,P .adSafr .D. J. Shaffer, and D. P. L. Benya, Y. Wang, and M. Dembo, A., K. E. Beningo, Cukierman, and D., M. Amatangelo, A., D. Beacham, Vlodavsky, and J. Folkman, M., C. Svahn, M., Klagsbrun, S., Doctrow, P., Bashkin, Blu R., Glass, A., E. Cavalcanti-Adam, M., Arnold, nem,K,Dvdo,P,Pp,A . izo,M,Lly .adPox L. Ploux, and M. Liley, M., Giazzon, M., A. Popa, P., Davidson, K., Anselme, mtneo .D,Bsi .E,KenSat,A .P n uira,E. Cukierman, and P. J. A. Klein-Szanto, E., D. Bassi, D., K. M. Amatangelo, Alitalo, and H. R. Adams, References of University months. PMC 12 the in after Deposited Ruth release Award. of a Service for Research from Regeneration National support Kirschstein Center financial L. and [grant and acknowledges NIH B.M.B. Cells the GM74048] Pennsylvania. from Engineering HL73305, grants from EB08396, for part EB00262, in supported numbers was work This Funding Michele discussions and suggestions. thoughtful for Trappmann and PA) Britta Pennsylvania, of Stapleton, (University Sarah Wozniak thank authors The the to Acknowledgements left is rest only a The are condition. with 3D, initial themselves. and or us the cells 2D termed of leaves whether terms itself. circle cells, in cultures, 1982), cell controlled our al., and that the full et reminder matrix is humble (Bissell ECM between coming reciprocity’ the interaction ‘dynamic of without two-way origin This the incomplete that behavior acknowledging be engineer cell and of function regulation to its on would cell discussion and dictate a microenvironment suited Lastly, cellular can purposes. the regenerative that better for in those cell the the even harness such capture be or accurately Through scenario, more will vivo. vivo that different in 2) we by with (Box and microenvironments compared modulated understanding, forces as are cultures they mechanical an 3D how adhesions, and and cell 2D – that – more factors cues is function diffusible microenvironmental it classic cell Instead, the dimensionality. drive of of think matter to environments a productive tissue 3D and simply native being various and modes as culture in cell migration between not cells differences therefore, of for is, variety described It 2003). been large environments. al., have a et 2006; to mechanisms al., Wolf needed that et 2005; Zaman mechanisms surprising 2009; al., of al., et activation et Raeber (Doyle or pores matrix through squeeze the into bore 3022 oorpya h ir-adnnsaet oto elfunction. cell control to nanoscale Engl. and Ed. micro- the at topography 1743. ifrnitdclae hntp hnclue naaoegels. agarose in cultured when phenotype collagen differentiated receptors. matrix 18024-18029. extracellular dorsal of anchorage Fibroblasts. Primary and Biol. Cultured Cell by Produced Matrices Extracellular progression. tumor 329-341. during microenvironments fibroblastic molecules. heparin-like and heparitinase by released is and P. I. J. Spatz, interfaces. and adhesive H. nanopatterned Kessler, M., h neato fclsadbcei ihsrae tutrda h aoer scale. nanometre the at structured surfaces with bacteria Biomater. and Acta cells of interaction The toadrvdtredmninlmtie r eesr n ufcett promote to fibroblasts. sufficient normal and of necessary differentiation are desmoplastic matrices three-dimensional Stroma-derived lymphangiogenesis. ncnlso,teei ra iko vripiyn the oversimplifying of risk great a is there conclusion, In 18) ai irbatgot atrbnst uedteiletaellrmatrix extracellular subendothelial to binds factor growth fibroblast Basic (1989). 48 33 ora fCl cec 2 (13) 125 Science Cell of Journal 5406-5415. , 10.9.1–10.9.21. , 6 3824-3846. , a.Rv o.Cl Biol. Cell Mol. Rev. Nat. 18) eifrnitdcodoye exrs the reexpress chondrocytes Dedifferentiated (1982). 20) oeua euaino nignssand angiogenesis of regulation Molecular (2007). ChemPhysChem 20) toaeei:tecagn aeof face changing the Stromagenesis: (2005). 20) ciaino nernfnto by function integrin of Activation (2004). 8 464-478. , 20) epne ffbolssto fibroblasts of Responses (2004). me,J,Ek . Kantlehner, W., Eck, J., ¨mmel, m .Pathol. J. Am. rc al cd c.USA Sci. Acad. Natl. Proc. 5 383-388. , 20) niern substrate Engineering (2009). ei.Cne Biol. Cancer Semin. Biochemistry 20) rprto of Preparation (2007). Cell ne.Ce.Int. Chem. Angew. 167 475-488. , 30 ur Protoc. Curr. 215-224. , 28 1737- , (2010). (2005). 101 15 , , e,S-. eukr .L,Bkr .M,Si,J-. lit,D .adMauck, and M. D. Elliott, J.-W., Shin, M., B. Baker, L., N. Nerurkar, S.-J., Heo, auaa .S n aaa .M. K. Yamada, and S. J. Harunaga, Y. P. Bourillot, and B. J. Gurdon, rnel . o .H,Tmrz . e,D .adSua G. Skuta, and J. D. Lee, E., Tamariz, C.-H., Ho, F., Grinnell, F. Grinnell, A. M. Swartz, and G. L. Griffith, lwci . rpa,E n oka,J. Folkman, Go and E. Trepman, J., Glowacki, ibr,P . aesrt,K . anso,K .G,Sco . enri .A., N. Leonardi, A., Sacco, G., E. K. Magnusson, L., K. Havenstrite, M., P. Gilbert, olnah . atzs . ihv,A,Bo A., Kicheva, P., Pantazis, G. T., Parry, and Bollenbach, G. H. Hall, J., M. Bissell, egr . pt,J .adBrhdk,A D. A. Bershadsky, and S. P. J. C. Spatz, B., Geiger, Chen, and R. McBeath, L., Gao, udc,J .adAst,K S. K. Anseth, and A. J. Ingber, Burdick, and M. G. Whitesides, X., Jiang, P., LeDuc, C.-C., Ho, E., Chang, A., Brock, u . ag .K,Yn,M . ea,R . u . i,Z n hn .S. C. Chen, and Z. Liu, X., Yu, A., R. Desai, T., M. Yang, Y.-K., Wang, J., Fu, nlr .J,Sn . wee,H .adDshr .E. D. Discher, and L. H. Sweeney, S., Sen, J., R. A. Engler, D. Pitelka, and T. J. Emerman, G. R. Tompkins, and G. H. Koebe, L., M. Yarmush, C., J. Dunn, urde . ah . el,T,Ncol,G n unr C. Turner, and G. Nuckolls, T., Kelly, K., Fath, K., Burridge, rly .I,Fn,Y,Kihauty . i,D-. eeo,A,Longmore, A., Celedon, D.-H., Kim, R., Krishnamurthy, Y., Feng, I., S. Fraley, ent,J,Mtuwm,S .adBug,J S. J. Brugge, and K. S. Muthuswamy, J., Debnath, G. S. A. Curtis, and H. Agheli, S., D. Sutherland, O., M. M. Riehle, K. J., M. Yamada, Dalby, and R. D. Stevens, R., Pankov, E., Cukierman, E. D. Ingber, Garcı and M. T., G. J. Whitesides, Connelly, S., Huang, M., Mrksich, S., C. Chen, S. C. Chen, ykas . odu . u .adCe,C S. C. Chen, and X. Yu, T., Boudou, J., Eyckmans, M. K. Yamada, and K. Matsumoto, W., F. Wang, S. C. D., Chen, and A. F. W. Doyle, Liu, S., Raghavan, L., Gao, A., R. Desai, Y.-L. Wang, and M. Dembo, S. K. Anseth, and D. B. Polizzotti, A., C. DeForest, ent,J,Mls .R,Clis .L,Rgnt,M . uhsay .K and K. S. Muthuswamy, J., M. Reginato, L., N. Collins, R., K. Mills, J., Debnath, ´mez-Sjo .L. R. 30 413 matrices. collagen three-dimensional in fibroblasts Biol. Cell vitro. 8557-8563. 20) estl,flyatmtd irfudccl utr system. culture cell microfluidic automated, fully Versatile, (2007). rf,P,Nue,N . hu,S,Ltl,M .adBa,H M. H. Blau, chondrocytes. and in expression P. M. Lutolf, culture. in S., self-renewal cell Thrun, stem 329 muscle K., skeletal regulates N. elasticity Substrate Nguyen, P., Kraft, oa adhesions. focal N-cadherin. and Rac1 through fate 564-572. myogenic versus chondrogenic ircnatprinting. microcontact E. D. Ju expression? gene direct 21) ehnclrglto fcl ucinwt emtial modulated geometrically with function cell of substrates. regulation elastomeric Mechanical (2010). dein:tasebaejntosbtenteetaellrmti n the and matrix extracellular the between junctions transmembrane adhesions: engineering. tissue bone for 4323. hydrogels PEG RGD-modified iesoa elmotility. cell D. dimensional Wirtz, and D. G. arxahsost h hr dimension. third the to adhesions matrix gels. alginate three-dimensional 1071-1083. RGD-modified in chondrogenesis 3285-3292. mechanobiology. floating specification. on lineage cell stem epithelium directs mammary sandwich dissociated a in membranes. in collagen differentiation culture long-term morphological geometry: matrix extracellular configuration. and function migration. cell fibrillar three-dimensional Biol. underlies topography dimensional E-cadherin. via adhesion cell-cell by triggered microenvironments. cell three-dimensional patterning and Mater. synthesizing for noeei fMF1Ammayeihla cn rw nthree-dimensional in grown acini epithelial cultures. mammary membrane basement MCF-10A of oncogenesis acini. mammary oncogene-expressing and normal within S. J. and Brugge, fibroblasts--methods in mechanotransduction study to perspectives. nanotopography of Use death. and life cell of control Geometric cytoskeleton. oooino fibroblasts. of locomotion lce,F. ¨licher, 363-368. , 797-803. , 1078-1081. , 184 a.Rv o.Cl Biol. Cell Mol. Rev. Nat. 20) emti eemnnso ietoa elmtlt eeldusing revealed motility cell directional of determinants Geometric (2003). 21) ie tec n eretto ouae eecya tmcell stem mesenchymal modulates reorientation and stretch Fiber (2011). 8 br,R,Lya,A . ioe .M,Ce,C .adQae .R. S. Quake, and S. C. Chen, M., D. Pirone, A., A. Leyrat, R., ¨berg, 659-664. , 481-490. , 20) irbatbooyi he-iesoa olgnmatrices. collagen three-dimensional 13 in biology Fibroblast (2003). 20) ehntasuto il uln together? pulling field a - Mechanotransduction (2008). 264-269. , 20) rcso fteDpgradient. Dpp the of Precision (2008). u.J elBiol. Cell J. Eur. nu e.Cl Biol. Cell Rev. Annu. 20) h oeo ppoi ncetn n anann uia space luminal maintaining and creating in apoptosis of role The (2002). AE J. FASEB a.Rv o.Cl Biol. Cell Mol. Rev. Nat. e.Cell Dev. a .J n eeso,M E. M. Levenston, and J. A. ´a, nVitro In 21) itntv oefrfclahso rtisi three- in proteins adhesion focal for role distinctive A (2010). Langmuir a.Methods Nat. .Ter Biol. Theor. J. 3 a.Cl Biol. Cell Nat. 174-177. , ipy.J. Biophys. 21 rc o.Ep il Med. Biol. Exp. Soc. Proc. 19) tessa h elt-usrt nefc during interface cell-to-substrate the at Stresses (1999). Methods 35-47. , 13 20) htecpuaino sebat ninjectable in osteoblasts of Photoencapsulation (2002). 83 7 316-328. , 20) atrn ope Dtsu hsooyin physiology tissue 3D complex Capturing (2006). 211-224. , 19 20) opoe rdetinterpretation. gradient Morphogen (2001). 159-169. , 21) elmti dein n3D. in adhesions Cell-matrix (2011). 1611-1617. , 4 487-525. , 7 76 733-736. , Cell 99 30 2307-2316. , Science Science 18) o osteetaellrmatrix extracellular the does How (1982). 17) aneac n nuto of induction and Maintenance (1977). 12 31-68. , 256-268. , 10 126 598-604. , 21) tmcl hp euae a regulates shape cell Stem (2010). 21-33. , 20) niomna esn through sensing Environmental (2009). kl . Gonza C., ¨kel, .Cl Sci. Cell J. 677-689. , 18) elsaeadphenotypic and shape Cell (1983). 294 276 20) eunilcikreactions click Sequential (2009). o.Bo.Cell Biol. Mol. Development 21) ichkrsgieto guide hitchhiker’s A (2011). 1708-1712. , 1425-1428. , 20) niiino nvitro in of Inhibition (2007). 20) opoeei and Morphogenesis (2003). 172 Cell 122 20) arxelasticity Matrix (2006). 93-98. , Biomaterials ´lez-Gaita 111 905-911. , 20) elpolarity Cell (2009). 20) aigcell- Taking (2001). 18) Hepatocyte (1989). 135 29-40. , 20) Dendritic (2003). 14 Biomaterials .Cl Sci. Cell J. nl Chem. Anal. tmCells Stem 1137-1146. , 384-395. , 18) Focal (1988). 20) One- (2009). n .and M. ´n, arxBiol. Matrix 23 Science 4315- , (2010). (2004). (1997). Nature Trends .Cell J. 121 Nat. 79 28 28 , , , , Journal of Cell Science upnk,K,Cu . ah,C n i S. Li, and C. Hashi, J., Chu, K., Kurpinski, uo,K .adHriz .R. A. Horwitz, and E. K. Kubow, Kloxin,A.M.,Kasko,A.M.,Salinas,C.N.andAnseth,K.S. R. G. Martin, and K. H. Kleinman, li,F,Rctr . tibl . rn,C . o ryan . eee,M. Wegener, G., Freymann, von M., C. Franz, T., Striebel, B., Richter, F., Klein, iia,J,Jn . uz . ug . eio . hn,S n rdisy .J. A. Grodzinsky, and S. Zhang, C., Semino, H., Hung, B., Kurz, L. M., Jin, N. J., Kisiday, Jeon, and J. H. Kim, S., Kim, iin .A,Bgrj,B,Lh,B .adMkih M. Mrksich, and T. B. Lahn, B., Bugarija, A., K. Kilian, A. J. Burdick, and S. Khetan, el,P . og .M,Zte,M .adSnoo .A. S. Santoro, and M. M. Zutter, M., A. Fong, J., P. Keely, an .K,Gbn .S,Ta,A . cmde,R .adWs,J L. J. West, and H. R. Schmedlen, T., A. Tsai, S., A. Gobin, K., B. Mann, M. Rest, Manjo der van and R. Garrone, F., Mallein-Gerin, a,R . agig,P,Tanr .adHelr O. Hoeller, and D. Traynor, P., Langridge, R., R. Kay, amd . apel .J,Bso,K .M,Kmrv,Y . hg,O,Soh, O., Chaga, A., Y. Komarova, M., J. K. Bishop, J., C. Campbell, G., Mahmud, uhs .S,Psoi,L .adLji,G A. G. Lajoie, and M. L. Postovit, S., C. Hughes, A., S. Bencherif, A., O. Ali, D., Shvartsman, S., A. Mao, R., P. Mauck, Arany, and N., M. E. Huebsch, Shore, L., S. Diamond, A., Stein, A., N. Motlekar, H., A. Huang, uof .P n ubl,J A. J. Hubbell, Fong, T., and J. Erler, P. M., M. Egeblad, N., Lutolf, J. Lakins, L., Kass, H., Chen, and Yu, M. R., G. K. Genin, Levental, M., D. Cohen, L., B. Blakely, S., J. Miller, R., W. Legant, L. J. West, and J. J. Moon, S.-H., Lee, ofa,B . rsof .adShat,M A. M. Schwartz, and C. Grashoff, D., B. Hoffman, e,E . ar,G n isl,M J. M. Bissell, and G. F. Parry, Y., A. E. Horwitz, Lee, and A. D. Lauffenburger, ishaue,F,Mne . ited . et . ule-lee,W n Kunz- and W. Mueller-Klieser, J., West, C., Dittfeld, H., Menne, F., Hirschhaeuser, agvn .M,Bufr,N . agr .J,Itii,J .adHw,A K. A. Howe, and C. J. Iatridis, J., G. Badger, A., N. Bouffard, M., H. Langevin, A. D. Tirrell, D. and M. R. Buschmann, Langer, and U. Aebi, D., C. Hoemann, R., Suetterlin, E., Langelier, eecya tmcells. stem mesenchymal dein n3 matrices. 3D in adhesions properties. chemical and physical of tuning Science dynamic for hydrogels Photodegradable ilgclactivity. biological culture. cell dimensional M. Bastmeyer, and 20) efasmln etd yrglfsescodoyeetaellrmatrix repair. tissue extracellular cartilage USA for chondrocyte Sci. implications fosters division: cell hydrogel and production peptide Self-assembling (2002). rdetdevices. gradient cells. stem mesenchymal 107 of differentiation the directing ellrrmdln n tmcl aewti -iesoa hydrogels. 3-dimensional within fate cell 31 of stem and expression remodeling cells. cellular the mammary by in mRNA morphogenesis integrin 2 and alpha motility, antisense adhesion, collagen-dependent inligtigrlclcl et eurdfrDoohl e morphogenesis. leg Drosophila for dedifferentiating required in death Biol. cell Cell organization local trigger actin signalling with correlated are chondrocytes. synthesis collagen h td fchemotaxis. of study the mohmsl elgot npoooyeie yrgl ihcl deieand adhesive cell with hydrogels photopolymerized in growth cell muscle Smooth A. ratchets. B. micropatterned Grzybowski, on and motions K. cell Kandere-Grzybowska, S., Huda, S., itr eurdfrotmlgot fcl culture. cell of growth optimal for required mixture fate. stem-cell J. control to D. 526. interface cell/matrix Mooney, the of and manipulation J. Rivera-Feliciano, chondrogenesis. L. R. xrclua irevrnet o opoeei ntsu engineering. tissue in morphogenesis for Biotechnol. microenvironments extracellular al. signaling. et integrin W. enhancing Weninger, by A., progression Giaccia, tumor K., forces Csiszar, T., F. S. matrices. dimensional S. 3D C. guided for photolithography scanning laser migration. two-photon cell via hydrogels bioactive 155. rcse eit ellrmechanotransduction. cellular mediate processes os amr pteilclsb h olgnu substrata. collagenous the by cells epithelial mammary mouse acigu again. up catching A. L. Schughart, nertdmlclrprocess. molecular ex integrated stretch tissue subcutaneous vivo. to in response and cytoskeletal vivo fibroblast Dynamic (2005). and structure filaments. cartilage: vimentin articular and mature tubulin, 1307-1320. in actin, of cytoskeleton distribution chondrocyte The (2000). opooyadfbosgn xrsino retdnnfbosmicroenvironments. Eng. nanofibrous oriented Biomed. on Ann. expression gene fibrous and morphology Nature 8228-8234. , n . Sa C., ´n, 4872-4877. , 20) ihtruhu cenn o ouaoso eecya tmcell stem mesenchymal of modulators for screening High-throughput (2008). 21) esrmn fmcaia rcin xre yclsi three- in cells by exerted tractions mechanical of Measurement (2010). 428 324 99 9 487-492. , 57-63. , 59-63. , 23 9996-10001. , nhzHreo .adSzne M. Suzanne, and E. ´nchez-Herrero, u.J elBiol. Cell J. Eur. 47-55. , Biomaterials n.Boe.Eng. Biomed. Ann. nerBo (Camb) Biol Integr m .Pyil elPhysiol. Cell Physiol. J. Am. 21) utclua uo peod:a neetmtdto is tool underestimated an spheroids: tumor Multicellular (2010). .Biotechnol. J. ei.Cne Biol. Cancer Semin. 39 21) w-opnn oye cfod o otoldthree- controlled for scaffolds polymer Two-component (2011). 2780-2790. , a.Methods Nat. a.Rv o.Cl Biol. Cell Mol. Rev. Nat. d.Mtr DefedBahFla.) Beach (Deerfield Mater. Adv. rc al cd c.USA Sci. Acad. Natl. Proc. a.Cl Biol. Cell Nat. 29 21) atrigntoksrcuet ptal control spatially to structure network Patterning (2010). 20) einn aeil o ilg n medicine. and biology for materials Designing (2004). Cell 2962-2968. , 56 21) euigbcgon loecnereveals fluorescence background Reducing (2011). 148 20) argl aeetmmrn arxwith matrix membrane basement Matrigel: (2005). 84 364-373. , 36 7 21) ilgclapiain fmicrofluidic of applications Biological (2010). 20) ytei imtrasa instructive as biomaterials Synthetic (2005). 3-15. , 359-369. , 2 969-971. , 20) he-iesoa irptenn of micropatterning Three-dimensional (2008). 1909-1921. , 584-603. , 15 18) ouaino ertdpoen of proteins secreted of Modulation (1984). a.Phys. Nat. 13 378-386. , 20) nstoi ehnsnigby mechanosensing Anisotropic (2006). -,ato el 5-7. reply author 3-5, , 19) elmgain physically a migration: Cell (1996). 21) ansigtraction-mediated Harnessing (2010). 288 21) argl ope protein complex a Matrigel: (2010). Nature 9 C747-C756. , 20) hr onaiso Dpp of boundaries Sharp (2007). 5 455-463. , Proteomics 606-612. , .Cl Sci. Cell J. 103 20) hnigdrcin in directions Changing (2008). .Hsohm Cytochem. Histochem. J. 21) yai molecular Dynamic (2011). 475 rc al cd c.USA Sci. Acad. Natl. Proc. 20) arxcrosslinking Matrix (2009). 16095-16100. , 21) emti usfor cues Geometric (2010). 19) rtolcnand Proteoglycan (1991). Cell 316-323. , 23 .Cl Biol. Cell J. 19) leainof Alteration (1995). 139 1341-1345. , 10 a.Mater. Nat. 108 1886-1890. , 20) Directing (2009). rc al Acad. Natl. Proc. 891-906. , 595-607. , Biomaterials 98 (2009). (2001). 9 146- , 518- , Nat. Nat. 48 , ily .J,Shat,M . urde . itl .A,Gnbr,M . Borisy, H., M. Ginsberg, A., R. Firtel, K., Burridge, A., M. Schwartz, J., A. Ridley, enatKn,C . eb,M n amr .A. O. D. R. Hammer, Hynes, and M. Dembo, A., C. Reinhart-King, Chen, and M. C. Nelson, J., N. Sniadecki, A., R. Desai, J., C. Shen, S., Raghavan, aa . s,L,Cpt,R,Aaii,C,Hnisn .adSup .I. S. Stupp, and K. G. Henrikson, C., Ravichandran, Aparicio, R., and Capito, L., A. Hsu, A., D. Mata, Tirrell, C., Franck, A., S. Maskarinec, aaua,S,Pun . ce,T . rw,E . oce,Y n an .K. R. Jain, Ra and Y. Boucher, B., E. Brown, D., T. McKee, A., Pluen, S., Ramanujan, A. J. Hubbell, and P. M. Lutolf, P., G. Raeber, cet,R,Prn,D . esn .M,Barrj,K n hn .S. C. Chen, and K. Bhadriraju, M., C. Nelson, M., D. Pirone, R., McBeath, uk,S .adShrr A. Scherer, and R. S. Quake, ees . ri,J n de .J. D. Odde, and J. Craig, J., Meyers, rvnao .P,Eier,K . apel .M,Imn .R,Wie .G and G. J. White, R., D. Inman, M., J. Campbell, W., K. Eliceiri, P., P. Provenzano, A., Mayo, K., Rajendran, R., Krishnan, A., Lichtenstein, M., Prager-Khoutorsky, sk,T,Bmug .R n rmr .P. L. Cramer, and Chen, R. and L. J. B. Bamburg, Blakely, T., D., Mseka, J. Baranski, R., W. Legant, J., C. Shen, S., J. Miller, eesn .W,Rno-esn . olt,A .adBsel .J. M. Bissell, and R. A. Howlett, L., Rønnov-Jessen, W., O. Petersen, r,A . eme .P,Baka,B .adShat,M A. M. Schwartz, and R. B. Blackman, P., B. Helmke, W., A. Orr, Valentı Y., Bai, J. A., E. M. Calle, Bissell, T., and A. Yeh, A. E., D. L. Fletcher, Niklason, L., J. Inman, M., M. Vanduijn, M., C. Nelson, W. Mueller-Klieser, ahk .adKmr S. Kumar, and A. Pathak, ahn .S,Bkr .M,Nrra,N .adMuk .L. R. Mauck, and L. N. Nerurkar, M., B. Baker, S., A. Nathan, azk .J,Zhr . ono,K . ais .N,Rzneg .I,Gfn A., Gefen, I., G. Rozenberg, N., J. Lakins, R., K. Johnson, N., Zahir, J., M. Paszek, I. A. Shamseddine, and A. J. Makarem, R., A. R. Mahfouz, K., Z. Otrock, ar,G,Le .Y-. asn . oa,M n isl,M J. M. Bissell, and M. Koval, D., Farson, Y.-H., E. Lee, G., Parry, N. Ferrara, and A. G. Keller, E., J. Park, H. A. Reddi, and S. Vukicevic, M., V. Paralkar, ¨sa . asn,J .adHriz .R. A. back. Horwitz, to and front T. from J. Parsons, G., utr eel oefrmoi ntubulogenesis. in myosin for role a reveals culture S. C. rtoyial erdbedmis ytei C nlg o iseengineering. tissue for analogs ECM synthetic Biomaterials domains: degradable proteolytically ehnc fedteilcl spreading. cell endothelial of mechanics the Res. in Cell transport for implications gels: collagen in interstitium. tumor convection and Diffusion (2002). 2883. migration. cell mediated proteolytically for J. system model novel a hydrogels: irptenn fbociesl-sebiggels. self-assembling bioactive of Micropatterning dimensions. three in 106 forces traction cellular Quantifying materials. oa invasion. local J. P. Keely, D. mechanosensing. A. Biol. adhesion Cell focal Bershadsky, by and controlled process B. matrix-rigidity-dependent Geiger, Z., Kam, macromers. S. C. shape. and size cell via commitment. pathways lineage cell stem regulate RhoA and Cell Dev. tension, cytoskeletal shape, Cell 21) nbigtosfregneigclaeostsusitgaigbioreactors, integrating modeling. tissues biomechanical 3335-3339. collagenous and engineering imaging, for intravital tools Enabling (2010). in morphogenesis branching mammary of cultures. sites organotypic determines geometry Tissue (2006). trigger to body cell the in bundles actin-filament oriented polarization. fibroblast of formation control neato ihbsmn ebaesre orpdydsigihgot and growth cells. distinguish epithelial breast rapidly human USA to malignant Sci. and Acad. serves Natl. normal of membrane pattern basement differentiation with Interaction stiffness. matrix beyond moving oorpi ouaino tmcl ula hp nnnfbosscaffolds. nanofibrous on shape nuclear cell stem Biomater. of modulation topographic applications. clinical to enatKn,C . agle,S . eb,M,Betgr .e al. et D. Boettiger, phenotype. M., malignant Dembo, the S., and S. homeostasis Margulies, Tensional A., C. Reinhart-King, 499. mechanotransduction. of Mechanisms usrt euaetentr n itiuino lcsmngyaspoue by produced cells. glycosaminoglycans epithelial of mammary distribution mouse and of cultures nature differentiated the regulate substrata extracellular subepithelial VEGF. matrix-bound the extracellular 1326. into of for bioactivity deposition and implications differential matrix matrix: isoforms: membrane (VEGF) basement factor of IV collagen to binds development. 1 type beta molecular important most the of review angiogenesis: mechanisms. of biology the Understanding nn .adVhr,A. Vaheri, and K. ¨nen, 89 22108-22113. , 1374-1388. , 21) eopigdfuinlfo iesoa oto fsgaigi 3D in signaling of control dimensional from diffusional Decoupling (2010). 21) iatv yrgl aefo tpgot eie PEG-peptide derived step-growth from made hydrogels Bioactive (2010). 316 6 Science 13 7 483-495. , 18) nern:afml fcl ufc receptors. surface cell of family a Integrins: (1987). eosrcigtetiddmnin3023 dimension third the Deconstructing 57-66. , Biomaterials 20) olgnrognzto ttetmrsrmlitraefacilitates interface tumor-stromal the at reorganization Collagen (2006). 1457-1465. , 22 2713-2722. , lo el o.Dis. Mol. Cells Blood e.Biol. Dev. M Med. BMC 3045-3051. , 19) he-iesoa elclue:fo oeua mechanisms molecular from cultures: cell Three-dimensional (1997). 290 ipy.J. Biophys. Science Science 89 1536-1540. , m .Physiol. J. Am. .Cl Sci. Cell J. 9064-9068. , 143 31 4 21) ipyia euaino uo elinvasion: cell tumor of regulation Biophysical (2011). 21) ciaino irbat ncne stroma. cancer in fibroblasts of Activation (2010). 3736-3743. , 302 38. , 303-308. , 314 83 1704-1709. , 20) rmmco onnfbiainwt soft with nanofabrication to micro- From (2000). nerBo (Camb) Biol Integr 1650-1660. , 298-300. , ur Biol. Curr. 120 39 e.Cell Dev. 273 212-220. , 4332-4344. , ipy.J. Biophys. 20) oeta o oto fsignaling of control for Potential (2006). 20) elmgain nertn signals integrating migration: Cell (2003). C1109-C1123. , 19) h aclredteilgrowth endothelial vascular The (1993). 16 20) oeual nierdPEG engineered Molecularly (2005). 20) D/oii aiyproteins family ADF/cofilin (2007). 1685-1693. , 21) irbatplrzto sa is polarization Fibroblast (2011). 10 19) rnfriggot factor growth Transforming (1991). rc al cd c.USA Sci. Acad. Natl. Proc. otMatter Soft 11-20. , 89 3 acrCell Cancer 267-278. , 676-689. , n .adHmhe,J D. J. Humphrey, and A. ´n, rc al cd c.USA Sci. Acad. Natl. Proc. 20) h yaisand dynamics The (2005). .Cl Sci. Cell J. x.Cl Res. Cell Exp. o.Bo.Cell Biol. Mol. 5 1228-1236. , 18) Collagenous (1985). Cell 21) Mechano- (2011). 8 241-254. , 48 549-554. , 123 156 Biophys. 4 2877- , (2009). (2009). (2004). (1992). (2005). (2006). (2007). 1317- , 487- , Proc. Acta Exp. 107 Nat. , Journal of Cell Science oke,E,Dos,I,Ot,S,Saglae,A,Segl,M,Kluaa,B C., B. Kallukalam, M., Stengele, A., Stangelmayer, S., Otto, I., Drosse, E., Volkmer, ldvk,I,Flmn . ulvn . rda,R,IhiMcal,R,Sse J. Sasse, R., Ishai-Michaeli, R., Fridman, R., Sullivan, J., Folkman, I., Vlodavsky, po,M . icrs,C . ulk .adSto,L A. L. Setton, and F. Guilak, L., C. Gilchrist, L., M. Upton, hms .H,Clir .H,Ser .S n el,K E. K. Healy, and S. C. Sfeir, H., J. Collier, H., C. Thomas, The The exia .I,Arm,G . etc,P . upy .J n ely .F. P. The Nealey, S. and J. C. C. Chen, Murphy, J., and P. K. Bertics, A., Bhadriraju, G. Abrams, S., I., D. A. Teixeira, Gray, M., D. Pirone, J., M., Tien, P. L., Kraan, I., J. der van D. Tan, D., Versleyen, Wang, J., G. N., Osch, van G. P., Buma, Stephanopoulos, L., J. P., Susante, van G. Lopez, A., Kumar, R., Singhvi, aat,K,Ni,P . ei,R . ee .M,Ds . ry .W n Groves, and W. J. Gray, D., Das, M., R. Neve, S., R. Petit, M., P. Nair, V. K., Salaita, D. Schaffer, and K. Saha, 3024 ytm o iseegneigo bone. of engineering tissue for M. systems Schieker, and W. Mutschler, ytei n eoiinit uedteiletaellrmatrix. extracellular subendothelial USA into Sci. deposition and synthesis M. Klagsbrun, and arsaetsu tant irsaecl ein ntedfre meniscus. deformed the in regions cell J. microscale to strain tissue macroscale xrsinadpoensnhssb ouaino ula shape. nuclear of modulation USA by Sci. synthesis protein and expression orientation. spindle mitotic of study theoretical and Experimental 19771-19776. nenlognzto n retto fpolarity. of orientation and organization internal M. Bornens, functions. substrates. nanostructured and micro- Sci. well-defined Cell on guidance contact Epithelial force. mechanical isolate to USA approach Sci. an Acad. microneedles: of Natl. bed Proc. a on lying Cells (2003). N. G. Homminga, gels. carrier and collagen B. and W. alginate Berg, der van E. D. Ingber, Science and M. G. Whitesides, esn yEphA2. by sensing T. J. patterning. r,M,Jime M., ´ry, r,M,Rcn,V,Pe,M,Pe M., Piel, V., Racine, M., ´ry, r,M. ´ry, 95 2116-2124. , 21) etito frcpo oeetatr ellrrsos:pyia force physical response: cellular alters movement receptor of Restriction (2010). 264 116 84 99 21) irptenn sato odcpe elmrhgnssand morphogenesis cell decipher to tool a as Micropatterning (2010). ora fCl cec 2 (13) 125 Science Cell of Journal .Cl Sci. Cell J. Development 696-698. , 2292-2296. , 1972-1977. , 1881-1892. , nzDlaoi . aie . onn,M n Ju and M. Bornens, V., Racine, A., ´nez-Dalmaroni, 20) nstoyo elahsv irevrnetgvrscell governs microenvironment adhesive cell of Anisotropy (2006). Science 18) nohla eldrvdbscfbols rwhfactor: growth fibroblast basic cell-derived Endothelial (1987). 123 133 4201-4213. , 100 327 889-900. , 20) inldnmc nSnchdeo tissue hedgehog Sonic in dynamics Signal (2006). 1484-1489. , pn . iirv . hn . iaia .B and J.-B. Sibarita, Y., Chen, A., Dimitrov, A., ´pin, 1380-1385. , 20) yoi nsai n yai Dculture 3D dynamic and static in Hypoxia (2008). caOto.Scand. Orthop. Acta 19) niern elsaeadfunction. and shape cell Engineering (1994). iseEg atA Part Eng. Tissue 19) utr fcodoye in chondrocytes of Culture (1995). rc al cd c.USA Sci. Acad. Natl. Proc. 66 549-556. , 20) niern gene Engineering (2002). 14 1331-1340. , Nature 20) rnfrof Transfer (2008). lce,F. ¨licher, rc al Acad. Natl. Proc. rc al Acad. Natl. Proc. 447 493-496. , Biophys. (2003). (2007). 103 J. , o e ak . as,V,vndrMr,H n Mu and H. Mark, der von V., Gauss, K., Mark, der von hn,S. Zhang, od,A,Wn,G n ee,F. Beier, and G. Wang, A., Woods, aa,M . rpn,L . imnk,A . akla,D,Gn,H,Kamm, H., Gong, D., Mackellar, L., A. Sieminski, M., L. Trapani, H., M. Zaman, u . lxne,C .adBee .J. D. Beebe, and M. C. Alexander, J. Patricia. H., Keely, Yu, and L. Kwong, K., Modzelewska, A., M. Wozniak, F. Beier, and I., A. E. Woods, Deryugina, H., U. Andrian, von K., Engelke, B. H., Leung, Hinz, I., and Mazo, K., J.-J. Wolf, Meister, B., D. Rifkin, P.-J., E. D. Ingber, Wipff, and X. Jiang, S., Takayama, E., Ostuni, M., G. Whitesides, Lelie M., V. Weaver, ee,G . jre .A n eioe .W. D. DeSimone, and A. M. Bjerke, F., G. Weber, C. Damsky, P., Briand, A., C. Larabell, F., Wang, W., O. Petersen, M., V. Weaver, ewe elsaeadtp fclae yteie scodoye oetheir lose chondrocytes as synthesised collagen of culture. type in and phenotype cartilage shape cell between a.Biotechnol. Nat. uo el n3 arcsi oendb arxsifesaogwt cell-matrix with along stiffness matrix by governed P. is proteolysis. Matsudaira, matrices and and 3D adhesion A. in D. cells Lauffenburger, tumor A., Wells, D., R. utr:prmtr novdi oul atrsignaling. factor soluble in involved parameters culture: chondrogenesis. during 11634. organization actin and expression manner. context-dependent Bro Y., A. Strongin, 1311-1323. TGF- latent activates contraction deinrglto fcl behavior. cell of regulation adhesion pericellular of blocking after proteolysis. transition mesenchymal-amoeboid migration: cell tumor biochemistry. and biology in and lithography normal networks. in adhesive form to apoptosis forces to resistance epithelium. confers mammary malignant architecture J. M. three-dimensional Bissell, and Z. Werb, F., antibodies. blocking integrin by vivo in and Biol. culture three-dimensional in J. cells M. Bissell, and 137 20) arcto fnvlboaeil hog oeua self-assembly. molecular through biomaterials novel of Fabrication (2003). 231-245. , .Cl Biol. Cell J. 21 ve . ais .N,Crnk .A,Jns .C,Giancotti, C., J. Jones, A., M. Chrenek, N., J. Lakins, S., `vre, 1171-1178. , 19) eeso ftemlgatpeoyeo ua breast human of phenotype malignant the of Reversion (1997). ce,E-.adFid,P. Friedl, and E.-B. ¨cker, 20) hARC inln euae hnrgnssi a in chondrogenesis regulates signaling RhoA/ROCK (2006). 160 rc al cd c.USA Sci. Acad. Natl. Proc. .Bo.Chem. Biol. J. 267-277. , Nature (2002). b acrCell Cancer rmteetaellrmatrix. extracellular the from 1 .Cl Sci. Cell J. 20) hARC inln euae Sox9 regulates signaling RhoA/ROCK (2005). B o.Cl Res. Cell Mol. BBA 267 b nerndpnetfraino polarized of formation integrin-dependent 4 nu e.Boe.Eng. Biomed. Rev. Annu. 531-532. , 281 2 13134-13140. , 124 20) nesadn microchannel Understanding (2007). 205-216. , 20) opnainmcaimin mechanism Compensation (2003). 21) nern n ahrn join cadherins and Integrins (2011). 1183-1193. , 103 le,P. ¨ller, a Chip Lab , .Bo.Chem. Biol. J. 10889-10894. , 1692 20) Myofibroblast (2007). 20) irto of Migration (2006). 103-119. , 17) Relationship (1977). .Cl Biol. Cell J. 7 3 726-730. , 335-373. , 20) Focal (2004). 280 20) Soft (2001). 11626- , .Cell J. 179 ,