Abstract
Micro/nano-fabrication techniques, such as soft lithography and electrospinning, have been well-developed and widely applied in many research fields in the past decade. Due to the low costs and simple procedures, these techniques have become important and popular for biological studies. In this review, we focus on the studies integrating micro/nano-fabrication work to elucidate the molecular mechanism of signaling transduction in cell biology. We first describe different micro/nano-fabrication technologies, including techniques generating three-dimensional scaffolds for tissue engineering. We then introduce the application of these technologies in manipulating the physical or chemical micro/nano-environment to regulate the cellular behavior and response, such as cell life and death, differentiation, proliferation, and cell migration. Recent advancement in integrating the micro/nano-technologies and live cell imaging are also discussed. Finally, potential schemes in cell biology involving micro/nano-fabrication technologies are proposed to provide perspectives on the future research activities.
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Abraham LC, Dice JF, Finn PF, Mesires NT, Lee K, Kaplan DL (2007) Extracellular matrix remodeling methods to quantify cell matrix interactions. Biomaterials 28:151–161
Alyassin MA, Moon S, Keles HO, Manzur F, Lin RL, Haeggstrom E, Kuritzkes DR, Demirci U (2009) Rapid automated cell quantification on HIV microfluidic devices. Lab on a Chip 9:3364–3369
Bailly M, Yan L, Whitesides GM, Condeelis JS, Segall JE (1998) Regulation of protrusion shape and adhesion to the substratum during chemotactic responses of mammalian carcinoma cells. Exp Cell Res 241:285–299
Biggs MJP, Richards RG, Gadegaard N, McMurray RJ, Affrossman S, Wilkinson CDW, Oreffo ROC, Dalby MJ (2009) Interactions with nanoscale topography: adhesion quantification and signal transduction in cells of osteogenic and multipotent lineage. J Biomed Mater Res A 91A:195–208
Boland ED, Matthews JA, Pawlowski KJ, Simpson DG, Wnek GE, Bowlin GL (2004) Electrospinning collagen and elastin: preliminary vascular tissue engineering. Front Biosci 9:1422–1432
Broers AN, Molzen WW, Cuomo JJ, Wittels ND (1976) Electron-beam fabrication of 80 Ǻ metal structures. Appl Phys Lett 29:596–598
Buchko CJ, Chen LC, Shen Y, Martin DC (1999) Processing and microstructural characterization of porous biocompatible protein polymer thin films. Polymer 40:7397–7407
Carraro A, Hsu WM, Kulig KM, Cheung WS, Miller ML, Weinberg EJ, Swart EF, Kaazempur-Mofrad M, Borenstein JT, Vacanti JP, Neville C (2008) In vitro analysis of a hepatic device with intrinsic microvascular-based channels. Biomed Microdevices 10:795–805
Chan-Park MB, Yang C, Guo X, Chen LQ, Yoon SF, Chun JH (2008) Fabrication of 3-D curved microstructures by constrained gas expansion and photopolymerization. Langmuir 24:5492–5499
Chao SH, Carlson R, Meldrum DR (2007) Rapid fabrication of microchannels using microscale plasma activated templating (mu PLAT) generated water molds. Lab on a Chip 7:641–643
Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE (1997) Geometric control of cell life and death. Science 276:1425–1428
Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294:1708–1712
Dike LE, Chen CS, Mrksich M, Tien J, Whitesides GM, Ingber DE (1999) Geometric control of switching between growth, apoptosis, and differentiation during angiogenesis using micropatterned substrates. In Vitro Cell Dev Biol Anim 35:441–448
Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689
Even-Ram S, Yamada KM (2005) Cell migration in 3D matrix. Curr Opin Cell Biol 17:524–532
Fang X, Reneker DH (1997) DNA fibers by electrospinning. J Macromol Sci Phys B36:169–173
Giang UBT, Lee D, King MR, DeLouise LA (2007) Microfabrication of cavities in polydimethylsiloxane using DRIE silicon molds. Lab on a Chip 7:1660–1662
Gillette BM, Jensen JA, Tang BX, Yang GJ, Bazargan-Lari A, Zhong M, Sia SK (2008) In situ collagen assembly for integrating microfabricated three-dimensional cell-seeded matrices. Nat Mater 7:636–640
Gomez N, Chen SC, Schmidt CE (2007) Polarization of hippocampal neurons with competitive surface stimuli: contact guidance cues are preferred over chemical ligands. J R Soc Interface 4:223–233
Hartman O, Zhang C, Adams EL, Farach-Carson MC, Petrelli NJ, Chase BD, Rabolt JF (2009) Microfabricated electrospun collagen membranes for 3-D cancer models and drug screening applications. Biomacromolecules 10:2019–2032
Hodgson L, Chan EWL, Hahn KM, Yousaf MN (2007) Combining surface chemistry with a FRET-based biosensor to study the dynamics of RhoA GTPase activation in cells on patterned substrates. J Am Chem Soc 129:9264–9265
Hoff JD, Cheng LJ, Meyhofer E, Guo LJ, Hunt AJ (2004) Nanoscale protein patterning by imprint lithography. Nano Lett 4:853–857
Hoover DK, Chan EWL, Yousaf MN (2008) Asymmetric peptide nanoarray surfaces for studies of single cell polarization. J Am Chem Soc 130:3280–3281
Hsiong SX, Boontheekul T, Huebsch N, Mooney DJ (2009) Cyclic arginine-glycine-aspartate peptides enhance three-dimensional stem cell osteogenic differentiation. Tissue Eng A 15:263–272
Hu SH, Eberhard L, Chen JX, Love JC, Butler JP, Fredberg JJ, Whitesides GM, Wang N (2004) Mechanical anisotropy of adherent cells probed by a three-dimensional magnetic twisting device. Am J Physiol Cell Physiol 287:C1184–C1191
Hwang YS, Chung BG, Ortmann D, Hattori N, Moeller HC, Khademhosseini A (2009) Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11. Proc Natl Acad Sci USA 106:16978–16983
Hyun JH, Ma HW, Zhang ZP, Beebe TP, Chilkoti A (2003) Universal route to cell micropatterning using an amphiphilic comb polymer. Adv Mater 15:576–579
Jeon NL, Baskaran H, Dertinger SKW, Whitesides GM, Van de Water L, Toner M (2002) Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat Biotechnol 20:826–830
Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120–126
Kim TJ, Seong JH, Ouyang MX, Sun J, Lu SY, Hong JP, Wang N, Wang YX (2009) Substrate rigidity regulates Ca2+ oscillation via RhoA pathway in stem cells. J Cell Physiol 218:285–293
Kim TJ, Xu J, Dong R, Lu SY, Nuzzo R, Wang YX (2009) Visualizing the effect of microenvironment on the spatiotemporal RhoA and Src activities in living cells by FRET. Small 5:1453–1459
Kong HJ, Boontheekul T, Mooney DJ (2006) Quantifying the relation between adhesion ligand-receptor bond formation and cell phenotype. Proc Natl Acad Sci USA 103:18534–18539
Kwon IK, Kidoaki S, Matsuda T (2005) Electrospun nano- to microfiber fabrics made of biodegradable copolyesters: structural characteristics, mechanical properties and cell adhesion potential. Biomaterials 26:3929–3939
Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369
Lee KB, Park SJ, Mirkin CA (2002) Protein nanoarrays generated by dip-pen nanolithography. Abstr Pap Am Chem Soc 223:506-PHYS
Liu GY, Xu S, Qian YL (2000) Nanofabrication of self-assembled monolayers using scanning probe lithography. Acc Chem Res 33:457–466
Ma HW, Hyun J, Zhang ZP, Beebe TP, Chilkoti A (2005) Fabrication of biofunctionalized quasi-three-dimensional microstructures of a nonfouling comb polymer using soft lithography. Adv Funct Mater 15:529–540
Martinez E, Engel E, Planell JA, Samitier J (2009) Effects of artificial micro- and nano-structured surfaces on cell behaviour. Ann Anat Anatomischer Anzeiger 191:126–135
Matthews JA, Wnek GE, Simpson DG, Bowlin GL (2002) Electrospinning of collagen nanofibers. Biomacromolecules 3:232–238
McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6:483–495
Min BM, Lee G, Kim SH, Nam YS, Lee TS, Park WH (2004) Electrospinning of silk fibroin nanofibers and its effect on the adhesion and spreading of normal human keratinocytes and fibroblasts in vitro. Biomaterials 25:1289–1297
Na S, Collin O, Chowdhury F, Tay B, Ouyang M, Wang Y, Wang N (2008) Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc Natl Acad Sci USA 105:6626–6631
Neeley WL, Redenti S, Klassen H, Tao S, Desai T, Young MJ, Langer R (2008) A microfabricated scaffold for retinal progenitor cell grafting. Biomaterials 29:418–426
O’Neill C, Jordan P, Ireland G (1986) Evidence for two distinct mechanisms of anchorage stimulation in freshly explanted and 3T3 Swiss mouse fibroblasts. Cell 44:489–496
Ohgo K, Zhao CH, Kobayashi M, Asakura T (2003) Preparation of non-woven nanofibers of Bombyx mori silk, Samia cynthia ricini silk and recombinant hybrid silk with electrospinning method. Polymer 44:841–846
Ouyang MX, Sun J, Chien S, Wang YX (2008) Determination of hierarchical relationship of Src and Rac at subcellular locations with FRET biosensors. Proc Natl Acad Sci USA 105:14353–14358
Park J, Toner M, Yarmush ML, Tilles AW (2006) Microchannel bioreactors for bioartificial liver support. Microfluid Nanofluid 2:525–535
Park JY, Hwang CM, Lee SH (2009) Ice-lithographic fabrication of concave microwells and a microfluidic network. Biomed Microdevices 11:129–133
Petrie RJ, Doyle AD, Yamada KM (2009) Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10:538–549
Pham QP, Sharma U, Mikos AG (2006) Electrospinning of polymeric nanofibers for tissue engineering applications: a review. Tissue Eng 12:1197–1211
Piner RD, Zhu J, Xu F, Hong SH, Mirkin CA (1999) “Dip-pen” nanolithography. Science 283:661–663
Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709
Rogers JA, Nuzzo RG (2005) Recent progress in soft lithography. Mater Today 8:50–56
Ruiz SA, Chen CS (2008) Emergence of patterned stem cell differentiation within multicellular structures. Stem Cells 26:2921–2927
Saadi W, Rhee SW, Lin F, Vahidi B, Chung BG, Jeon NL (2007) Generation of stable concentration gradients in 2D and 3D environments using a microfluidic ladder chamber. Biomed Microdevices 9:627–635
Seong J, Lu S, Ouyang M, Huang H, Zhang J, Frame MC, Wang Y (2009) Visualization of Src activity at different compartments of the plasma membrane by FRET imaging. Chem Biol 16:48–57
Shiu YT, Li S, Yuan S, Wang Y, Nguyen P, Chien S (2003) Shear stress-induced c-fos activation is mediated by Rho in a calcium-dependent manner. Biochem Biophys Res Commun 303:548–555
Subbiah T, Bhat GS, Tock RW, Pararneswaran S, Ramkumar SS (2005) Electrospinning of nanofibers. J Appl Polym Sci 96:557–569
Takayama S, Ostuni E, LeDuc P, Naruse K, Ingber DE, Whitesides GM (2001) Laminar flows: subcellular positioning of small molecules. Nature 411:1016
Wang YX, Wang N (2009) FRET and mechanobiology. Integr Biol 1:565–573
Webb A, Clark P, Skepper J, Compston A, Wood A (1995) Guidance of oligodendrocytes and their progenitors by substratum topography. J Cell Sci 108:2747–2760
Wood A (1988) Contact guidance on microfabricated substrata: the response of teleost fin mesenchyme cells to repeating topographical patterns. J Cell Sci 90:667–681
Yasin S, Hasko DG, Ahmed H (2001) Fabrication of <5 nm width lines in poly(methylmethacrylate) resist using a water:isopropyl alcohol developer and ultrasonically-assisted development. Appl Phys Lett 78:2760–2762
Yi Y, Kang JH, Park JK (2005) Moldless electroplating for cylindrical microchannel fabrication. Electrochem Commun 7:913–917
Yu J, Xiao J, Ren XJ, Lao KQ, Xie XS (2006) Probing gene expression in live cells, one protein molecule at a time. Science 311:1600–1603
Zhou D, Bruckbauer A, Ying LM, Abell C, Klenerman D (2003) Building three-dimensional surface biological assemblies on the nanometer scale. Nano Lett 3:1517–1520
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Qian, T., Wang, Y. Micro/nano-fabrication technologies for cell biology. Med Biol Eng Comput 48, 1023–1032 (2010). https://doi.org/10.1007/s11517-010-0632-z
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DOI: https://doi.org/10.1007/s11517-010-0632-z