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Cell-material interaction

Joachim Rychly / Barbara J. Nebe
Published Online: 2013-12-05 | DOI: https://doi.org/10.1515/bnm-2013-0019
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Abstract

The interaction of cells with material surfaces is of fundamental relevance and contributes to the clinical success of implants. Cells sense their physico-chemical environment resulting in focal adhesion reorganization, spatio-temporal localization and activation of integrin dependent signalling proteins as well as phenotypic changes, e.g., of the actin cytoskeleton. The technology of designing instructive biomaterials involves chemical modifications by grafting of chemical groups, adhesion ligands and growth factors. Physical modifications of the materials are created by structuring the surfaces stochastically and geometrically and by modifications of the material stiffness. Insights into the mechanism at the interface that are involved in the regulation of cells such as stem cells, osteoblasts and chondrocytes by materials will advance the development of innovative biomaterials in regenerative medicine.

Keywords: actin cytoskeleton; chemical characteristics; extracellular matrix proteins; integrins; plasma polymer; topography

Introduction

While in the past materials were widely used as medical implants to replace injured tissues without the provocation of harmful reactions, like toxicity, mutagenesis or inflammation, nowadays the challenge is to create bioactive materials to specifically control the surrounding tissue. In context with bioactive material surfaces, implant materials have now become a significant component in the field of regenerative medicine. The basis for generation of materials with a regenerative potential is the understanding of cellular mechanisms involved in the interaction of cells with the material surface. Cells are controlled by soluble factors, cell-cell interactions and by the cell adhesion to the extracellular matrix. The interaction of cells with the extracellular matrix plays a principal role in the regulation of the multiple biological responses of cells by characteristics of materials. Physical and chemical properties of the material determine qualitative and quantitative adsorption of proteins including proteins of the extracellular matrix, which in consequence influence the binding of cells mediated by adhesion receptors, like integrins. The dynamic interaction of cells with the extracellular matrix, facilitated by integrins and controlled by properties of a material surface, initiates a signal transduction that leads to biological responses of the cell, like proliferation, differentiation or release of cytokines. Based on our knowledge of the cellular ligands for cell adhesion and growth factors that act in concert with adhesion mediated mechanisms, modification of a material surface to specifically stimulate cellular responses include the immobilization of active biomolecules on the material surface [1]. Biomaterials for implantation into the human body comprise a wide range of materials, including inorganic artificial materials, such as metals or metals alloys and ceramics, polymers or natural materials, derived from plants up to higher organisms including human sources [2]. Because the clinical application of materials is aimed to regenerate an injured tissue, the defined control of stem cells regarding multiple differentiation pathways and release of bioactive factors induced by a material surface is of preferential interest. This article we organized into a passage describing cellular interactions with materials modified by physical modifications and a chapter about chemical modifications, although in many cases a chemical treatment of a material surface is combined with a physical modification.

Cell regulation by physical characteristics of a material

Topography

Modification of the topography of an implant surface is a common strategy to fabricate a structure on materials for bone implants. Different techniques have been used to roughen the surface of titanium, including blasting, etching, and oxidation. In vivo studies demonstrated an improved anchorage of the implant and a reduced healing time in bone defects [3–5]. These effects were observed in topographies in the micrometer level, whereas little is known about the effects in nanometer level [6]. Studies in vitro support these findings with a different behavior of cells in dependence on the scale of the topography. Cells are able to sense the micro- and nanoscale topography and react with bridging of grooves or conforming the surface structure [7–10]. An attractive approach to generate nanostructures on titanium is the formation of nanotubes [11, 12]. Such TiO2 nanotube arrays can be generated via electrochemical anodization which enables a precise control for nanotube morphology, diameter and length [13]. For example the lateral spacing of the nanotube system was varied by altering the tube diameter between 30 and 100 nm. On such topographies, cells alter not only the phenotype but also their internal architecture, e.g., the actin cytoskeleton, in a surface geometry-dependent manner [14, 15] (Figure 1).

Cells sense the underlying micro-ranged pyramidal topography and mimic the regular dimensions with their actin cytoskeleton. In contrast, stress fibers are pronounced on the planar titanium surface. Material: titanium covered silicon nitride pyramid arrays (5 µm in height), D. Kern, University of Tuebingen, (14); Cells: human MG-63 osteoblasts 24 h on pyramid structures, fixed (10 min 4% PFA, 10 min 0.1% TRITON-X100) and stained for actin (30 min phalloidin-TRITC, 1:7), confocal microscopy LSM410 (Carl Zeiss, bar=25 µm, zoom bar=5 µm); S. Staehlke, University Medical Center Rostock, Department of Cell Biology (DFG GRK welisa, 1505/1, KE 611/7-2, NE 560/7-2).
Figure 1

Cells sense the underlying micro-ranged pyramidal topography and mimic the regular dimensions with their actin cytoskeleton. In contrast, stress fibers are pronounced on the planar titanium surface.

Material: titanium covered silicon nitride pyramid arrays (5 µm in height), D. Kern, University of Tuebingen, (14); Cells: human MG-63 osteoblasts 24 h on pyramid structures, fixed (10 min 4% PFA, 10 min 0.1% TRITON-X100) and stained for actin (30 min phalloidin-TRITC, 1:7), confocal microscopy LSM410 (Carl Zeiss, bar=25 µm, zoom bar=5 µm); S. Staehlke, University Medical Center Rostock, Department of Cell Biology (DFG GRK welisa, 1505/1, KE 611/7-2, NE 560/7-2).

The response of cells due to changes in the topography of the surface is mediated by integrins. Changes in the organization of integrin containing cellular adhesions in dependence on the surface roughness were observed in correlation with the organization of fibronectin on the material surface [9]. For sensing of a micro-structured titanium surface by mesenchymal stem cells and osteoblasts to promote osteogenic differentiation, expression of α2β1 integrins in these cells is required [16]. Silencing of α2β1 integrins in an osteoblastic cell line which was co-cultured with mesenchymal stem cells reduced the osteogenic differentiation of mesenchymal stem cells on these structured surfaces. When human mesenchymal stem cells were cultured on polydimethylsiloxane with nanogratings of 250 nm lines, mesenchymal stem cells developed aligned stress fibers, smaller focal adhesions and a dense actin cytoskeleton. Expression of different integrin subunits were down regulated in these cells on nanogratings [17, 18]. There is convincing evidence that changes in structural organization and expression of adhesion related cellular components due to a structured material surface commit the direction of stem cell differentiation. Microstructured titanium surfaces favored mesenchymal stem cell differentiation towards the osteoblastic lineage [16]. On a surface with grooves, osteoblastic cells expressed a higher RNA level of osteopontin and osteocalcin than on a flat surface [19]. Experiments using defined sizes of pits demonstrated that activity of alkaline phosphatase as a marker for osteogenic differentiation was more stimulated on 11 nm islands compared with 85 nm islands [20]. On the titanium nanotubes, tube diameters of 70 and 100 nm enhanced the expression of different osteogenic markers in mesenchymal stem cells compared with cells on a flat titanium surface [21]. On nanogratings, also an up-regulation of neuronal markers, such as microtubule-associated protein 2, was observed in mesenchymal stem cells [22]. This effect of the nanostructure on the neuronal differentiation was stronger than biochemical cues which were added to induce neuronal differentiation. In addition to the scale of topographical patterns on a material surface, the organization of the topography appears to be a relevant feature. When nanoscale pits were generated with varying degrees of disorder in poly(methylmethacrylate), mesenchymal stem cells were able to sense the order of the nanoarray. On disordered pits, osteogenic differentiation measured by increased expression of osteopontin and osteocalcin was observed [23]. This was not found on pits which were perfectly ordered or randomly distributed. Osteogenic differentiation on disordered pits was obtained without addition of osteogenic differentiation supplements to the culture medium. The same authors provided also evidence that the order of pits determines the maintenance of mulitpotency in mesenchymal stem cells [24]. When reducing the disorder of the pits to a square lattice symmetry, the mesenchymal stem cells retained stem cell markers, like Stro-1 for a longer time compared with a disordered surface that stimulated the expression of osteogenic markers.

Stiffness

The tissues in the human body considerably vary in their mechanical properties and it is becoming more and more obvious that in vivo mechanics of the tissues control physiological processes. For example, embryonic development is dependent on mechanical forces, e.g., in the mouse embryo hemodynamic forces are required to induce vessel remodeling in the yolk sac [25]. Tissues are also able to modulate mechanical strength to match the forces encountered, e.g., bone density increases due to weight-bearing exercise [26]. In vitro it has been shown that cells when cultured on materials are able to sense mechanical characteristics of the material and respond with a function in dependence on the mechanics [27]. Differentiation of mammary epithelial cells increased on soft collagen gel, as opposed to rigid tissue culture plastics [28], experiments with endothelial cells demonstrated a lower branching of the cellular network on stiffer materials compared with soft substrate [29] and similarly, neurons are branching more on soft material than on a stiff substrate [30]. A role of the stiffness of a material for regenerative processes was convincingly demonstrated when mesenchymal stem cells were cultured on hydrogels with varying stiffnesses [31]. Substrate stiffness defined the differentiation lineage which correlated with the stiffness of the corresponding tissue. A soft matrix generated adipocytes, a mechanically intermediate material gave rise to muscle cells and the cells on a stiff hydrogel differentiated to osteoblasts. The influence of the mechanics on stem cell differentiation has also been shown on other materials, including hyaluronic acid gels, electrospun nanofibers, and polydimethylsiloxane [32–34]. Beside differentiation, mechanical properties of a substrate were also shown to control self-renewal of stem cells. Stem cells from skeletal muscle revealed increased proliferation with rising stiffness of the material [35]. Mesenchymal stem cells remained quiescent on a gel that mimicked the softness of bone marrow, while maintaining the multipotency [36].

However, recent experiments revealed that the mechanical property of the extracellular matrix (ECM) that covers the material surface is more important than the stiffness of the underlying material itself. ECM, adsorbed on the material surface, is produced by the adherent cells or can be generated by additional coating of the surface using defined matrix proteins. When polyacrylaminde-based hydrogels were coated with collagen, modified with different cross-linkers, the distances between tethering points of the collagen fibers to the hydrogel determined the stiffness of the collagen fibrils and directed stem cell differentiation [37]. On low concentration of a cross-linker, mesenchymal stem cell differentiated to adipocytes, because the cells could attract the soft ECM, whereas higher concentration of cross-linker generated more points of tethering with higher stiffness of collagen fibers which resulted in directed differentiation to osteoblasts.

Cells and mechanotransduction

To specifically stimulate the biological responses in cells by mechanical cues, including defined stiffnesses of a material, knowledge about intracellular mechanisms induced by mechanical forces are required. Transduction of forces by cells is bidirectional, cells exert forces and are able to sense mechanical forces applied to cells. Integrins are regarded as mechanotransducers that facilitate the mechanical coupling between outside the cell and the cytoskeleton [38]. The mechanical interaction of integrins with the cytoskeleton involves accumulation of a number of cytoskeletally associated proteins [39, 40]. Studies to directly apply mechanical forces to integrins on the apical surface of cells, provided insights into signaling mechanisms and biological responses of osteoblasts and mesenchymal stem cells [41–44]. These studies demonstrated a role of intracellular calcium in intracellular signaling which is required to activate and immobilize signaling proteins, like focal adhesion kinase to the actin cytoskeleton. Activation of Erk and Akt revealed that both the MAP kinase as well as the PI3K/Akt pathways are involved in mechanically induced integrin signaling. Active remodeling of the actin cytoskeleton plays a key role in response to forces [45, 46]. Modulating the actin cytoskeleton by depolymerizing and polymerizing drugs affected both, mechanically induced signal transduction as well as the direction of mesenchymal stem cell differentiation [47]. By modulation of the cytoskeleton using cytochalasin D and latrunculin A to inhibit actin filament formation, as well as jasplakinolide to stabilize actin polymerization, activation of Erk and Akt were differentially inhibited in dependence on the drug which was used to manipulate the actin cytoskeleton. Adipogenic differentiation of the cells could be enhanced, whereas osteogenic differentiation was impaired [47]. Effects on the biological response of mesenchymal stem cells provoked by mechanical integrin stress was also dependent on the type of the substrate for cell adhesion, which indicates the complex interaction of signaling pathways induced by different factors [44]. In addition to controlling differentiation and proliferation of cells by mechanical interaction with the substrate for adhesion, directed cell migration is facilitated by mechanical properties of the matrix. This so-called durotaxis enables cells to migrate from soft to rigid matrix. In mesenchymal stem cells a polarization of the cytoskeleton facilitated by myosin-II heavy chain is responsible for this mechanosensitive migration [48].

Cell regulation by chemical characteristics of a material

Beside physical properties, the adhesive interactions of cells with a material surface are controlled by chemical characteristics of the surface. Depending on the application of implants regarding tissue and function, a variety of materials from metals to synthetic polymers and natural biological materials are used which differ in chemistry. The chemical characteristics of the material surface determine adsorption, composition and conformation of the extracellular matrix, which is secreted by the cells and serve as substrate for integrin mediated cell adhesion [49]. However, prior to matrix secretion, cells are able to adhere to material surfaces without binding domain for adhesion receptors. When cells are seeded to a surface, an immediate adsorption of proteins, salts and sugars from the medium occur. However, within the first minutes after cell seeding a secretion and adsorption of extracellular matrix proteins can be excluded. Recent findings indicated that this first cellular attachment is mediated by the negatively charged, pericellular matrix substance glycosaminoglycan hyaluronan [50]. This mechanism of a first initial interaction with a material surface, like titanium, was demonstrated in epithelial cells, chondrocytes and osteoblasts [51–53]. The role of surface charges to mediate cell adhesion on a pure material surface was confirmed by generation of a positively charged plasma polymer nanolayer on titanium that boosted the first contact of an osteoblast [54]. Grafting of chemical groups onto a material surface to provide charged molecules enabling additional protein binding is a suitable approach to tune the interaction of cells with materials.

To graft positively charged amino groups on a material surface, allylamine plasma can be used which forms a thin layer, resistant to hydrolysis. Such a layer stimulated the mobility of vinculin containing focal adhesion contacts [55]. Other techniques, like self assembled monolayers of alkanethiols, silanisation, radiation grafting are also applied to generate chemical groups onto a material surface, including amino, methyl, hydroxyl, ether, carbonyl, carboxyl and carbonate [56–58]. In addition, thiol (-SH) functional head groups has been successfully generated on artificial surfaces [59]. The thiol groups can be obtained by irradiating phenylsulfonic acid monolayers. Specific alterations of the chemistry were found to guide differentiation and proliferation of mesenchymal stem cells [60, 61]. –NH2 and –SH modified surfaces stimulated osteogenic differentiation, whereas –OH and –COOH modified surfaces promoted chondrogenesis. Under specific culture conditions, –NH2 surfaces enhanced the formation of adipogenic cells [61]. Generation of –CH3 groups maintained the phenotype of mesenchymal stem cells [60]. The impact of a defined surface chemistry for the biological response of stem cells was demonstrated by a screening of 576 polymers, generated by a combination of 25 different monomers. In these experiments, only some polymers stimulated the differentiation of pluripotent stem cells to epithelial cells [62]. The effects observed can be explained by a modified interaction of extracellular matrix proteins with the polymer surface. Polymers are not only capable to adsorb different amounts of fibronectin, but also induce different activities of this matrix protein [63]. While some monomers induce the adsorption of fibronectin in its inactive state, which inhibits cell adhesion, other monomers enable the adsorption of active fibronectin, which facilitates cell adhesion. These different states of activities depend on the conformation of the matrix protein.

When implants are used for bone healing, a calcium phosphate coating is a common approach to generate materials with a regenerative potential. The most successful technique to coat metallic implants with calcium phosphate has been the plasma-spray technique. Other techniques include sol-gel deposition, electrospray deposition, electrolyte deposition to deposit a layer of at least 50 µm thickness [64]. These coatings are described to induce an increased bone-to-implant contact and are regarded as osteoinductive [65]. In vitro, several studies have shown that a calcium phosphate coated implant surface promotes osteogenic differentiation of mesenchymal stem cells, which implies a stimulating effect of calcium phosphate for the formation of new bone [66–68].

Grafting of chemical groups can be combined with creating a defined topography of the surface to regulate cellular components. Fabrication of 5 µm high pillars on a titanium surface was coated with an allylamine plasma polymer layer to generate a high density of positively charged amino groups [69]. On this surface, osteoblastic cells completely merged the pillar structure with strong adhesion both to the pillars and to the bottom of the titanium surface (Figure 2). Topographical structures in combination with chemical grafting can manipulate the morphology of cells, the adhesive interaction with the substrate, including organization of focal contacts to control the biological responses of cells. Interestingly, cells lost their ability to align their actin fibers parallel to the grooves of the machined titanium if the surface was well-directed plasma-chemically modified [69] indicating that a specific surface chemistry is dominant vs. the topography.

Impact of plasma chemistry vs. topography on cell attachment. Note that cells seem to merge with the geometrical pillar structure while ignoring the pillar height of 5 µm if chemically modified with plasma polymerized allylamine (left). Cell adhesion on controls is exclusively concentrated on the pillar top (right). Material: cubic SU-8, 5x5x5 µm in dimension, D. Kern, University of Tuebingen, (10); Plasma: microwave-excited, pulsed, low pressure gas-discharge plasma, K.-D. Weltmann, INP Greifswald, (54); Cells: human MG-63 osteoblasts, SEM DSM 960A (bar=20 µm); EMZ of the University Medical Center Rostock and H. Rebl, Department of Cell Biology (BMBF 13N11183, Campus PlasmaMed).
Figure 2

Impact of plasma chemistry vs. topography on cell attachment. Note that cells seem to merge with the geometrical pillar structure while ignoring the pillar height of 5 µm if chemically modified with plasma polymerized allylamine (left). Cell adhesion on controls is exclusively concentrated on the pillar top (right).

Material: cubic SU-8, 5x5x5 µm in dimension, D. Kern, University of Tuebingen, (10); Plasma: microwave-excited, pulsed, low pressure gas-discharge plasma, K.-D. Weltmann, INP Greifswald, (54); Cells: human MG-63 osteoblasts, SEM DSM 960A (bar=20 µm); EMZ of the University Medical Center Rostock and H. Rebl, Department of Cell Biology (BMBF 13N11183, Campus PlasmaMed).

A next step to further specifically modify the surface of implants is to graft cell adhesion ligands. In the tissue, cell behaviour is regulated by specific adhesion to extracellular matrix proteins, like collagens, fibronectin, laminin, vitronectin. The presence and organisation of individual proteins depend on the type of tissue. Coating of implant materials with full-length extracellular matrix proteins has shown to stimulate cell adhesion, proliferation, or differentiation [1, 70]. Matrix proteins can be adsorbed to nearly all biomaterial surfaces, including metals, ceramics, and organic polymers. For bone implants, titanium was coated with collagen or collagen in combination with apatite, which promoted osteoblast activities [71, 72]. However, the use of full-length matrix proteins to coat material surfaces revealed several limitations. The adsorption process can cause protein to undergo conformational changes and denaturation, which can lead to a foreign body response when implanted into the body. In addition, isolation and purification of native proteins at larger scale for tissue engineering approaches is expensive [70]. Therefore, the generation of integrin receptor ligands on material surfaces is focused on peptide domains of the matrix proteins.

Outlook

Gaining insights into the complexity of cellular reactions at the biomaterial interface is a huge task for the contemporary research, because: “The whole is truly greater than the sum of its parts” [73]. It is important to recognize changes of the single molecular components of cell adhesion and of the linear signalling pathways of cells at the material interface, but this does not necessarily lead to insights in the whole cell reaction. Superordinate structures are presumably co-decisive for the fate of cells and ultimately for tissue. Knowledge about their biocomplexity would be of clinical relevance, for instance for the development of optimal designs for biomaterials or in the area of tissue engineering.

In future, system biology could answer questions regarding the superordinate regulation mechanisms of cells [74, 75]. This field of research, which combines concepts derived from biology, informatics and systems science, is increasingly dedicated to the mathematical modeling of intracellular signal mechanisms and their interactions. This allows for conclusions to be drawn about the mechanisms of action of the individual components in the cell [76]. The vision is a complete simulation of the cell in silico [77, 78].

The authors are thankful for the financial support of the (i) German Research Foundation DFG SFB TRR-37-1, DFG projects NE 560/7-2, BE 2362/2-2, KE 611/7-2, and DFG graduate school welisa (1505/1), (ii) German Ministry of Education and Research (BMBF, grant no, 13N9779, 13N11188) for the multi-disciplinary research cooperation “Campus PlasmaMed”.

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About the article

Corresponding author: Joachim Rychly, Department of Cell Biology, University Medical Center Rostock, Schillingallee 69, D-18057 Rostock, Phone: +49 381 494 5730, Fax: +49 381 494 7764, E-mail:

Received: 2013-08-26

Accepted: 2013-10-31

Published Online: 2013-12-05

Published in Print: 2013-12-01

Citation Information: BioNanoMaterials, Volume 14, Issue 3-4, Pages 153–160, ISSN (Online) 2193-066X, ISSN (Print) 2193-0651, DOI: https://doi.org/10.1515/bnm-2013-0019.

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