Applications of Micro- and Nano-technology to Study Cell Adhesion to Material Surfaces

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  • This article was downloaded by: [University of Waterloo]On: 27 October 2014, At: 06:41Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

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    Applications of Micro- and Nano-technology to Study Cell Adhesionto Material SurfacesFranz Bruckert a & Marianne Weidenhaupt ba Laboratoire des Matriaux et du Gnie Physique, UMRCNRS 5628, Grenoble Institute of Technology, Minatec,3 parvis Louis Nel, BP 257, 38016 Grenoble Cedex 1,France;, Email: Franz.Bruckert@grenoble-inp.frb Laboratoire des Matriaux et du Gnie Physique, UMRCNRS 5628, Grenoble Institute of Technology, Minatec,3 parvis Louis Nel, BP 257, 38016 Grenoble Cedex 1,FrancePublished online: 02 Apr 2012.

    To cite this article: Franz Bruckert & Marianne Weidenhaupt (2010) Applications of Micro-and Nano-technology to Study Cell Adhesion to Material Surfaces, Journal of AdhesionScience and Technology, 24:13-14, 2127-2140, DOI: 10.1163/016942410X507957

    To link to this article: http://dx.doi.org/10.1163/016942410X507957

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    http://www.tandfonline.com/page/terms-and-conditionshttp://www.tandfonline.com/page/terms-and-conditions

  • Journal of Adhesion Science and Technology 24 (2010) 21272140brill.nl/jast

    Applications of Micro- and Nano-technology to Study CellAdhesion to Material Surfaces

    Franz Bruckert and Marianne Weidenhaupt

    Laboratoire des Matriaux et du Gnie Physique, UMR CNRS 5628, Grenoble Institute ofTechnology, Minatec, 3 parvis Louis Nel, BP 257, 38016 Grenoble Cedex 1, France

    AbstractMicro- and nano-technologies provide new tools to study and control cell adhesion. These technologiesare well suited to reconstitute the cells natural environment and mimic its biochemical, morphologicaland mechanical peculiarities. Smart material surfaces and coatings, which allow controlling the bindingand release of specific macromolecules and/or cells, are being developed at a high pace. Moreover, theapplication of geometrical constraints at the micro- or nano-scale reveals some of the physico-chemicalprinciples underlying molecular and cellular organization.

    These technologies, combined with the growing knowledge in molecular biology and the spatial and tem-poral resolutions given by the various microscopy techniques, are going to boost our understanding of cellphysiology. The availability of well-defined multicellular assemblies opens new ways to test and analyzecells, either in a cluster, or in assemblies mimicking tissue organization. These techniques help bridging thegap between molecular biology and tissue or organism physiology.

    First, we list the main chemical and physical parameters in the cell micro-environment that influence itssurvival, proliferation, differentiation or migration. Then we review some examples where micro- and nano-technologies are used to control cell spreading and adhesion in different ways: (1) via the distance betweenadhesive molecules, (2) via the geometry of adhesive zones, (3) via surfaces with switchable adhesiveness,or (4) via three-dimensional coatings used as reservoir of active molecules. Koninklijke Brill NV, Leiden, 2010

    KeywordsLiving tissues, cell adhesion, cell differentiation, cell motility, mechanosensitivity, nanosciences, excitablesurfaces

    1. Cell Microenvironment: an Overview

    In the living tissues of pluricellular organisms, cells are attached to each other eitherdirectly by molecules embedded in the plasma membrane, or through the extracel-lular matrix, a mixture of polymers secreted by cells, onto which they adhere. Bloodvessels are a good example of such complex organized structures. They are made

    * To whom correspondence should be addressed. Tel.: (33) 4 56 52 93 21; e-mail:Franz.Bruckert@grenoble-inp.fr

    Koninklijke Brill NV, Leiden, 2010 DOI:10.1163/016942410X507957

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  • 2128 F. Bruckert, M. WeidenhauptJournal of Adhesion Science and Technology 24 (2010) 21272140

    of three layers. First, in contact with the blood flow, a monolayer of endothelialcells provides an impermeable barrier to most molecules and cells, but allows thetransport of specific molecules (e.g., glucose) by transcytosis and the transmigra-tion of specific cells (e.g., monocytes) between the lumen and the vessel wall. In thisvery thin layer (a few m), cells are attached to each other by adherens junctions.Second, layers of smooth muscle cells, organized around the endothelial cell mono-layer, control the vessel diameter in response to mechanical stimuli (blood pressure,blood flow shear stress). These are relayed by chemical mediators secreted by theendothelial layer. For example vasodilation and vasoconstriction are regulated bynitric oxide and angiotensin, respectively. Depending on the vessel size, the smoothmuscle cell layer thickness varies from 50 m to several mm. Third, an externallayer made of elastic fibers and fibroblast cells ensures mechanical stiffness. Inlarge vessels, this layer may be a few millimeters thick and also contains nutritivevessels and nerves that stimulate smooth muscle cells. A specific 80 nm thick ex-tracellular matrix layer, called the basal membrane, separates the endothelial cellsfrom smooth muscle cells [1]. Another specific extracellular matrix layer separatesthe smooth muscle cell layer from the external layer. This example shows that in liv-ing tissues, several differentiated cell types co-exist in oriented structures organizedat different scales, from about 10 nm to several mm.

    Despite its apparent stability, the structure of living tissues is dynamic. Cellscontinuously synthesize and degrade the extracellular matrix [2], divide themselvesand die in response to precise molecular clues [3]. These mechanisms allow liv-ing tissue growth, physiological adaptation and repair. Cell signalling may occurdirectly, by cellcell contact, by secretion of growth factors, differentiation fac-tors, chemo-attractants (molecules that influence cell proliferation, differentiationstate, or directed movement), or indirectly by the secretion of extracellular matrixand guidance molecules. Many proteins constituting the extracellular matrix indeedcontain molecular motives analogous to growth factors or differentiation factors(e.g., fibulins [4]). Therefore, a specific interaction between cells and the extracellu-lar matrix is necessary for cell survival, differentiation or proliferation. In addition,hydrated, charged polymers contained in the extracellular matrix bind many growthand differentiation factors with various specificities by hydrogen bonds and elec-trostatic interactions. These immobilized molecules may come in contact with cellexplorative structures such as filopodia, where they can stimulate, in an orientedmanner, intracellular signalling pathways. Conversely, cells produce enzymes thatdegrade specific molecules in the extracellular matrix (e.g., matrix metallopro-teinase [5]). The mixture of macromolecules and cells composing living tissuesreact therefore together in an interdependent manner. Taking again blood vessels asan example, cells may proliferate axially or radially, which either extends or widensthe vessel [6].

    In living tissues, stem cells play a special role. Contrary to differentiated cellswhich undergo a limited number of symmetrical divisions, they may proliferate

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  • F. Bruckert, M. Weidenhaupt 2129Journal of Adhesion Science and Technology 24 (2010) 21272140

    without limit, in specific conditions. They generate differentiated cells by asym-metric division: one daughter cell keeping stem cell properties while the otherdifferentiates. Stem cells maintain the steady-state number of differentiated cellsand are, therefore, essential for tissue development, renewal and repair. A well-known example of stem cells are blood stem cells, which are localized in the bonemarrow, generating erythrocytes, lymphocytes, monocytes and platelets in responseto specific growth and differentiation factors. For blood vessels, stem cells reside inthe wall around the endothelial cell layer (pericytes). During angiogenesis, endothe-lial cells are also able to degrade the basement membrane and together reorganizeinto new vessels. Recent progress has shown that stem cells exist in most tissues,and their stimulation could be a target for future regenerative medicine [7]. An al-ternative challenge is to integrate them in biomaterials to reconstitute tissues, ortissue components.

    Thanks to the progress made in molecular and cellular biology, the use of mu-tants, the visualization of fluorescently labelled molecular structures and numer-ous molecular identification techniques (transcriptomics and proteomics), a goodknowledge of genes involved in cell differentiation and tissue biogenesis is nowa-days available. For instance, in blood vessels, VE-cadherin and the type 2 VEGFreceptor are specific for endothelial cells, caldesmon and -actin for smooth mus-cle cells, and collagen I for fibroblasts. Similarly, signalling pathways triggeredby growth or differentiation factors, chemoattractants and adhesion molecules havebeen thoroughly studied. Generally speaking, the binding of extracellular moleculesto membrane-bound receptors triggers some conformational changes that allow thecooperative assembly of intracellular molecules at the plasma membrane, resultingin ion flow regulation, protein phosphorylation and second messenger biosynthesis(outside-in signalling). These transient molecular modifications assure the relay ofthe signal within the cell and they may amplify it. They have a direct, short-termeffect on macromolecules already present in the cell (primary response, ms to min)or an indirect, long-term effect by acting on transcription factors that translocateto the nucleus and control protein biosynthesis (delayed response, 20 min to days).Cells are also able to change the number and conformation of adhesion molecules(e.g., integrins) by membrane trafficking and protein phosphorylation (inside-outsignalling). In living tissues, many of these signals prevent programmed cell death(apoptosis) and control symmetrical or asymmetrical cell division (see below). It istherefore essential to understand and to be able to reconstitute the proper molecularenvironment of cells to ensure their survival, differentiation state and physiologi-cal function. Micro- and nano-technologies are well suited to conceive appropriateenvironments for different cell types in a very reproducible manner.

    Although significant progress has been made in the identification of relevantgenes and macromolecules involved in cell physiology, an integrated picture of thecell molecular mechanisms is still lacking. Even for relatively simple cell struc-tures mediating attachment to the extracellular matrix such as focal adhesions, the

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  • 2130 F. Bruckert, M. WeidenhauptJournal of Adhesion Science and Technology 24 (2010) 21272140

    hierarchical assembly and disassembly of these multi-molecular structures and thecross-talk between different signalling pathways are largely unknown [8]. More-over, focal adhesions, stable adhesion structures often observed in cells anchored inthe extracellular matrix, and podosomes, i.e., dynamic adhesion structures involvedin cell migration through tissues, share the same set of structural proteins: integrins,talin, paxillin, vinculin, actin, etc., but are controlled by different phosphorylationsignals (FAK versus Src, [9]). The assembly of adherens junctions is modulatedsimilarly. Cadherins connect cells together, and their assembly is stabilized by theirconnection to the actin cytoskeleton via catenins. All these various cell structuresconsist of the same basic elements that ensure plasma membrane binding to the out-side (e.g., integrins, cadherins), plasma membrane binding to the actin cytoskeleton(talin, paxillin), localized actin polymerization catalysis (ERM proteins) and me-chanical force application and mechanosensitivity (myosins).

    Many studies have shown that mechanical forces can trigger biochemical sig-nalling at cellcell or cellextracellular matrix contacts. The effect of blood flowon endothelial cell morphology is one of the earliest documented examples [10]. Inadherens junctions, an increase of -catenin tyrosine phosphorylation in responseto fluid shear stress regulates the linkage between VE-cadherin and the actin cy-toskeleton and is involved in their redistribution [11]. The molecular mechanismsof mechanotransduction are unknown. It is possible that specific proteins such asthose forming ion channels are sensitive to mechanical stimuli [12, 13] or thatlocal mechanical forces control the association and dissociation rates within co-operative molecular assemblies [14]. Recently, Whitehead et al. [15] reported thatheterozygous expression of a mutant form of APC (Adenomatous Polyposis Coli)protein renders colon tissue especially sensitive to mechanical stimuli. Compres-sion of the colon tissue increases the expression of c-myc and twist-1 transcriptionfactors by activating the Wnt/-catenin pathway. Translocation of -catenin fromadherens junctions to the nucleus in response to...

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