SPECIAL ISSUE PAPER 1441

Focal adhesions in osteoneogenesis

M J P Biggs1* and M J Dalby2
1
Nanotechnology Center for Mechanics in Regenerative Medicine, Department of Applied Physics and Applied
Mathematics, Columbia University, New York, USA
2
Centre for Cell Engineering, Institute of Biomedical and Life Sciences, Joseph Black Building, University of Glasgow,
Glasgow, UK

The manuscript was received on 16 November 2009 and was accepted after revision for publication on 21 January 2010.

DOI: 10.1243/09544119JEIM775

Abstract: As materials technology and the field of tissue engineering advance, the role of
cellular adhesive mechanisms, in particular, interactions with implantable devices, becomes
more relevant in both research and clinical practice. A key tenet of medical device technology is
to use the exquisite ability of biological systems to respond to the material surface or chemical
stimuli in order to help to develop next-generation biomaterials. The focus of this review is on
recent studies and developments concerning focal adhesion formation in osteoneogenesis,
with an emphasis on the influence of synthetic constructs on integrin-mediated cellular
adhesion and function.

Keywords: focal adhesions, biomaterials, differentiation, cell signalling

1 INTRODUCTION biomedical applications and their lack of biofunc-

tionality reflect an increasing need for biomimetic
This review highlights the importance and develop- constructs but also indicate the challenges present
ment of the physiomechanical processes that reg- within the field, i.e. to control ultimately the inter-
ulate early cell–biomaterial interaction and the actions that occur at the cell–substratum interface.
influence of integrin-mediated cellular adhesion in A key tenet of medical device technology is to use
bone regeneration. As materials technology and the the exquisite ability of biological systems to respond
field of tissue engineering advance, the role of to the material surface or chemical stimuli in order
cellular adhesive mechanisms, in particular, inter- to help to develop next-generation biomaterials.
actions with implantable devices, becomes more Recently published in Science are the prerequisites
relevant in both research and clinical practice. for third-generation biomaterials; not only should
Biomaterials are never truly inert, being at best they support the healing site (as first-generation
biotolerable. The cell–substratum interface func- materials), but also they should be bioactive and
tions as more than a simple boundary of definition possibly biodegradable (as second-generation mat-
between the host and an implanted device; rather it erials) and they should influence cell behaviour in a
presents primary cues for cellular adhesion and defined manner at the molecular level [1].
subsequent induction and tissue neogenesis. Indeed, In order to investigate the reaction elicited by a
the function and cytocompatibility of a construct material in vivo an understanding is required of the
can be assessed in vitro by observing the viabi- roles played by the cytoskeleton, cellular mem-
lity and adhesion of cells at the substratum inter- branes, and the extracellular matrix (ECM) following
face. The range of materials currently in use with implantation of a foreign material. An increased
knowledge of the extracellular environment, topo-
*Corresponding author: Nanotechnology Center for Mechanics in graphical and chemical cues present at the cellular
Regenerative Medicine, Department of Applied Physics and level, and how cells react to these stimuli has
Applied Mathematics, Columbia University, 921 Schapiro resulted in the development of advanced orthopae-
CEPSR, 530 West 120th Street, MC 8903, New York 10027, USA. dic materials with an aim to regulate cell attachment
email: [email protected] and subsequent cellular function. The focus of this

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1442 M J P Biggs and M J Dalby

review is on recent studies and developments network of dynamic contractile machinery facilitates
concerning focal adhesion formation in osteoneo- both cellular motility and the formation of protru-
genesis, with an emphasis on the influence of sions, termed lamellipodia structures, essential for
synthetic constructs on integrin-mediated differen- cellular spreading, polarization, and spreading in
tial cellular function. vitro [17–19]. Lamellipodia are associated with fine
hair-like protrusions termed filopodia (Fig. 1), which
contain a core of extended actin filament bundles
2 CELL–BIOMATERIAL INTERACTIONS and actively probe the external environment to
gather spatial, topographical, and chemical informa-
Cell–substrate interactions can be regarded as the tion from the ECM and/or material surface.
defining factors of the long-term performance and Initial cell tethering and filopodia exploration
biofunctionality of an orthopedic device in situ. It are followed by lamellipodia ruffling [20], periodic
can be reasoned that the integration of exogenous membrane activity, and cellular spreading. With
materials can be regulated by controlling the time, endogenous matrix is secreted by the cells,
associated interfacial reactions, in an attempt to and matrix assembly sites form on the ventral
minimize non-functional tissue generation or asep- plasma membrane. Once cells locate a specific
tic loosening. Materials that promote osteoblast- ECM protein motif, a signalling feedback pathway
specific adhesion may enhance functional differen- initiates integrin receptor clustering at the plasma
tiation [2], resulting in the neogenesis of mineralized membrane and focal-adhesion-associated protein
matrix, bony tissue formation, and deposition. recruitment [21]. It can be reasoned that this
Fibrous encapsulation is known to occur with both reduction in cellular migration, the formation of
metal [3] and polymeric [4] orthopaedic constructs, mature adhesion sites, and the onset of mineralized
usually with the presence of a fluid-filled void ECM synthesis are processes indicative of osteospe-
between the tissue and implant. This reduced cific differentiation and osteoneogenesis.
biocompatibility may have many causative origins; At present, the science of fracture fixation and
however, a frequent outcome is diminished device orthopaedic construct fabrication is being advanced
integration followed by destabilization alongside an by functional modification technologies, which aim
inhibition of tissue regeneration and repair as well as to regulate osteoblast adhesion and osteoneogenesis
an increase in the potential for infection [5]. both on the implanted device and at the peri-
Conversely, many functional biomaterials require implant site. Osteoconductive cement [22], topogra-
minimal protein and/or cellular interaction in vivo phical modification [17], and immobilization of
for optimal device function or to facilitate future bioactive molecules at the substrate surface [10]
device removal. For example a body of research have all been employed successfully to reduce giant
suggests that permanent device retention following
orthopaedic fixation is not ideal and may present
future implant site morbidity. Increased osteoblast
adhesion and bony tissue mineralization can, for
example, complicate the removal of plating systems,
increasing removal torque and predisposing screw
damage and bone refracture during the removal
procedure [6, 7]. It follows that selective adhesion of
specific cellular phenotypes is crucial to regulate
optimal tissue specific integration while preventing
inflammatory cell adhesion and scar tissue forma-
tion.
Adherent cells are complex self-sustaining units
[8] that require ECM anchorage in order to prolifer-
ate and undergo differential function [9]. Modern
implants make use of chemical and topographical
modification to regulate cellular adhesion [10, 11],
Fig. 1 Filopodia formation in endothelial cells on a
differentiation, and de novo tissue deposition [12– nanogroove substrate. Endothelial cells probe
14]. Following implantation, ECM proteins undergo the underlying grooved substratum with fine
rapid adsorption to a material surface in response to filopodial extensions (white arrows). These
surface free energy [15, 16]. In adherent cells a extend from the leading and trailing free edges.

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 Focal adhesions in osteoneogenesis 1443

cell recruitment, osteolysis, and fibrous capsule interactive domains in fibronectin and the fibrillar
formation. Of particular importance for the clinical collagens. Thus osteospecific adhesion at the im-
success of load-bearing orthopaedic constructs, plant surface is critically regulated by the composi-
however, is the adhesion of osteospecific cellular tion as well as orientation and spacing of the
populations, a process mediated by focal adhesion adsorped proteins [35]. Recent studies have
formation and reinforcement. exploited the specificity of the collagen GFOGER
sequence in an attempt to enhance the osteospecific
adhesive potential of orthopaedic materials while
3 THE INTEGRINS preventing inflammatory cell adhesion [36]. GFO-
GER-modified implants have been shown to en-
Osteoprogenitor cells, osteoblasts, and osteoblast- hance osseointegration significantly relative to sur-
derived osteocytic cells interact with the extracellu- faces modified with full-length type I collagen,
lar environment via single- or multiple-chain trans- highlighting the importance of presenting specific
membrane proteins termed integrins [23]. These biofunctional domains within the native ligand [37].
receptors are composed of non-covalently linked a The crystallization of a soluble integrin hetero-
and b subunits which bind specifically to motifs dimer has made clear that integrins exist in a
located on ECM molecules, i.e. the prototypic compact bent conformation [38]. Later research
integrin ligand fibronectin, which contains the has shown that this state represents an inactive
amino acid sequence RGD [24] and the GFOGER conformation [39]. Integrin ligation and strengthen-
motif present in collagen type I [25]. First cloned in ing are thought to involve the formation of specia-
1986 [26], integrin proteins are a fundamental lized catch bonds which appear to involve force-
initiator of cell and tissue organization and are assisted activation of the headpiece [40]. For a full
preserved throughout evolution, even in the most review of integrin structure, function, and their
primitive of metazoan organisms [27, 28]. Integrin- ligand-binding properties see reference [41]. Ligand
mediated adhesion is a highly regulated and com- binding in itself alters integrin conformation and
plex process involving receptor–ligand binding as affinity and, in the case of multivalent ligands,
integrin clustering. Upon activation, integrins ra-
well as post-ligation interactions with multiple
pidly associate with motif sequences via their
intracellular binding partners [29].
globular head domains and are reinforced intracel-
The function of the integrins in cell–matrix
lularly to form discrete supramolecular complexes at
adhesion can be divided into three mechanochem-
the lamellipodium leading edge that contain struc-
ical processes. First, ECM–integrin binding forces
tural adaptor proteins, such as vinculin, talin, and
must surpass a critical threshold in order to with-
paxillin [20, 42, 43]. These transient complexes are
stand the high forces [30, 31] required for adhesion
observed to have a substrate distance at closest
reinforcement, which lie in the nanonewton range.
approach of 10 nm [44] and, by reinforcement,
Second, integrins must mechanically couple the
undergo anisotropic growth in response to increased
ECM to the cytoskeleton, enabling extracellular
intracellular and/or extracellular tension to form
transmission of forces to the cell interior. Finally, anchoring focal adhesions.
these forces must be translated into biochemical
signals (mechanotransduction), promoting an inte-
grated cellular response. A recent study by Roca- 4 THE FOCAL ADHESION
Cusachs et al. [32] indicates the differential function
of integrin species in these processes. High matrix The regulation of focal adhesion formation in
forces were found to be primarily resisted by adherent cells is highly complex and involves both
clustered a5b1 integrins, while less stable avb3 the turnover of single contacts and the reinforce-
integrin binding was shown to initiate mechano- ment of the adhesion plaque by protein recruitment.
transduction, resulting in a reinforcement of inte- Focal adhesions emerge as diverse protein networks
grin–cytoskeleton interactions [32]; indeed these that provide structural integrity and dynamically link
integrins have been identified as key regulators of the ECM to the intracellular actin cytoskeleton
osteoblast proliferation [33] and differentiation [34]. (Fig. 2), directly facilitating cell migration and
Although the RGD and GFOGER binding integrins spreading through continuous regulation and dy-
rapidly associate with these motif sequences in vivo, namic reinforcement. Furthermore, in combination
their ability to recognize these sequences is depen- with transmembrane growth factor receptors, these
dent on the fibrillar status and accessibility of the adhesive clusters activate signalling pathways crucial

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1444 M J P Biggs and M J Dalby

motif density in affecting the size and strength of

focal adhesions [49]. This force threshold depends
on the precise biochemical nature of the adhesion.
However, there is an upper limit to the force; very
large stresses or a decrease in substrate rigidity
prevent adhesion elongation consistent with the
observation of the transformation of focal adhesions
into fibrillar adhesions [50].

5 THE FIBRILLAR ADHESION

Focal complexes originate as dot-like structures

0.5 mm in length, which are regulated by the guano-
sine triphosphatase (GTPase) Rac and precede larger
Fig. 2 A simplified overview of the molecular composi- focal adhesions that are regulated by the small G-
tion of the focal adhesion. Focal adhesions are protein Rho [51]. Mature focal adhesions are typically
dynamic supramolecular structures that function dash shaped, are 1–5 mm in length (Fig. 3(A)), contain
as anchoring complexes as well as mechanome- vinculin, paxillin, and talin signalling complexes, and
diated modulators of cellular function. These mediate integrin function to regulate cellular beha-
complexes effectively couple the ECM to the viours such as cell migration [52]. Fibrillar-type
cytoskeletal filamentous actin (F-actin) through adhesions specifically contain a5 and b1 integrins
the dynamic interactions that exist between the
component proteins, and in particular talin and
and tensin [51] and play a major role in fibronectin
vinculin. Focal adhesion kinase (FAK) acts as a organization [53].
modulator of protein recruitment to the focal When intracellular force per unit length exceeds a
adhesion as well as an important initiator of critical threshold at the integrin–substrate interface, the
downstream signalling pathways. displacement of the anchoring integrins is sufficient to
induce a stick–slip motion where the adhesion complex
to cell survival, cell growth, and differentiation, as moves rather than deforms. In this scenario, changes in
will be discussed below. the protein density around the adhesion plaque are
Ward and Hammer [45] developed a model of negligible and no further adsorption of proteins to the
adhesion strengthening which predicts large in- focal adhesion occurs [50]. This progressive recruit-
creases in the adhesion strength following increased ment of integrins in the absence of focal adhesion
receptor clustering and adhesion size, marked by an proteins results in the formation of tension-insensitive
elongation of the adhesion plaque. This process is fibrillar adhesions, structures intimately associated
believed to be due to an increase in tension at the with extracellular fibronectin (Fig. 3(B)). The assembly
adhesion site as the focal adhesion size has been of a fibronectin matrix, a structure essential for cell
shown to be proportional to the force applied to it by migration during embryogenesis and wound healing, is
the cell [46], indicating that adhesion sites act as dependent on integrin clustering and fibrillar adhesion
mechanosensors [8] that form additional contact formation [54, 55]. While these adhesions are involved
points with the underlying substratum in response in fibronectin organization, fibrillar adhesions are
to internal tension. relatively weak contacts, which are morphologically
This force must exceed a critical value for adhe- fibrillar by co-alignment with actin stress fibres.
sion reinforcement but, when growth occurs, it However, fibrillar adhesions have been shown to play
occurs preferentially in an anisotropic manner in an important role in osteoblast assembly of the ECM
the direction of the force [31]. When a cell adheres to [56] and may be fundamental in the deposition of an
a surface, it exerts traction forces to balance the ECM architecture favourable to osteoblast and osteo-
internal forces generated by cytoskeletal tension progenitor adhesion.
[47]. These forces have been measured, and most
cells appear to generate traction forces in the range
of tens to hundreds of nanonewtons [30, 48]. This 6 BONE REPAIR AND OSTEOGENESIS
fixes a minimal value for the force that enables the
growth of the focal adhesion by anisotropic elonga- Osteogenesis is an active process tightly regulated
tion and indicates the role of substrate stiffness and to ultimately generate a normal vascularized bone

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 Focal adhesions in osteoneogenesis 1445

Fig. 3 Focal adhesions are distinct from fibrillar adhesions. Focal adhesion elongation is either
associated with (A) mature adhesion formation (vinculin label) or (B) fibrillar adhesion
formation (tensin label). These structures are morphologically and biochemically distinct
and play individual roles in cellular adhesion and tissue formation respectively.

structure. Bone formation depends on the coopera-

tion of several factors, as follows:

(a) the genesis of specific cell types such as

progenitor cells and osteoblasts;
(b) a mineralized ECM scaffold;
(c) soluble bioactive molecules (cytokines, growth
factors, hormones, ions, and vitamins);
(d) mechanical stimuli.

In the adult, the osteoblast is derived from a bone

marrow stromal fibroblastic stem cell termed the
mesenchymal stem cell (MSC), a non-haematopoie-
tic multi-potent stem-like cell vital for the osteogenic
process and capable of differentiating into both
osteoblastic and non-osteoblastic lineages (Fig. 4).
The adult stem cell, first described in the haemato- Fig. 4 The osteodifferentiation pathway of MSCs.
poietic system following an investigation sparked by MSCs undergo differential functions following
the detonation of atomic devices in Nagasaki and cellular adhesion and in response to external
Hiroshima has been isolated from virtually every stimuli, i.e. mechanical loading, substrate to-
tissue of the body [57]. Of greater interest, however, pography. and secreted growth factors.
is the apparent phenomenon that these adult cells
arising from different sources have the inherent
potential to trans-differentiate spontaneously into defined as maintaining a supply of undifferentiated
other tissue progenitor cells [58]. progenitor cells (self-renewal) in spite of continual
Following the implantation of exogenous materi- differentiation. Owing to difficulties in MSC isolation
als, inflammation factors and cytokines attract and maintenance as well as the ethical issues
regenerative cells, which expand and differentiate associated with cell harvesting, recent studies have
in order to build up a bone highly similar to that begun to focus on the molecular circuitry of
before injury. Bone-marrow-derived MSCs as skele- pluripotency and self-renewal. Genomic reprogram-
tal stem cells, in conjunction with endothelial ming, i.e. the process of resetting the epigenetic
progenitors, are at the origin of such reparation modifications that are characteristic of the adult
mechanisms. Stem cells form uncommitted popula- cell nucleus to modifications that approximate the
tions, capable of self-renewal and differentiation characteristics of the embryonic cell, indicate that
into multiple cell lineages, and with the capacity for somatic cells might be reprogrammed back to the
maintained proliferation. Thus a stem cell can be pluripotent state [59]; it is envisaged that such

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1446 M J P Biggs and M J Dalby

technology will be instrumental in revolutionizing 8 FOCAL ADHESION KINASE

the field of regenerative medicine.
With reference to focal-adhesion-mediated mechan-
otransduction, integrin-dependent signalling path-
7 OSTEOSPECIFIC DIFFERENTIATION ways are mediated by non-receptor tyrosine kinases
THROUGH FOCAL ADHESIONS [64, 66]; most notable of these is FAK, a molecule
constitutively associated with the b-integrin subunit
The major event that triggers osteogenesis is the [67]. FAK plays central roles in adhesive interactions
transition of MSCs into bone-forming differentiated by functioning as a scaffold for focal adhesion
osteoblast cells and is controlled by sequential components [68] as well as an important initiator of
activation of diverse transcription factors that reg- multiple signalling cascades via its many binding
ulate the expression of specific genes. In addition to partners including Src [69], Cas [70], and paxillin [71].
their adhesive functions, integrins mediate bidirec- Upon integrin ligation, FAK is activated to bind to
tional signalling between the ECM and the cell Src which then phosphorylates FAK on multiple
interior and are crucial in cell survival and differ- residues [72]; moreover, FAK activation is highly
entiation [60–62]. Although integrin molecules pro- regulated by integrin ligation to specific ECM motifs
vide a platform for intracellular signalling, they do not [29]. This phosphorylation increases FAK activity
have intrinsic enzymatic activities in their cytoplas- and can influence cellular transcriptional events
mic domains [63]. Therefore, downstream signalling through FAK phosphorylation of downstream signal-
is mediated by non-receptor tyrosine kinases [64]. It ling molecules rich in the SH2 domain [68]. In
is becoming increasingly clear that cellular interac- osteoblasts, FAK directly influences the survival
tion with the cell–substrate interface and the induc- signalling pathway and is responsible for negating
tion of focal adhesion formation play central roles in mitochondria-dependent apoptosis (programmed
the process of osteospecific differentiation and sub- cell death), resulting in the inactivation of caspase
sequent osteoneogenesis. However, little is known 9 and the inhibition of cellular anoikis (apoptosis
regarding the influence of osteospecific biomaterials resulting from insufficient adhesion) [60].
on integrin-mediated adhesion and the activation of Further to the role of FAK in adhesion-mediated
osteospecific signalling pathways [65]. The process of cellular survival, recent studies indicated the role of
integrin-mediated mechanotransduction relies on FAK in promoting osteoblast focal adhesion forma-
the ability of proteins of the focal adhesion to change tion on orthopaedic constructs [73, 74] and suggest
the chemical activity state when physically distorted, that its expression is up-regulated during osteospe-
converting mechanical energy into biochemical cific differentiation [75], acting to phosphorylate
energy by modulating the kinetics of intracellular downstream signalling targets that regulate the
protein–protein or protein–ligand interactions within synthesis of osteospecific proteins. Of these func-
the cell. The ability of proteins to translate the tional cascades, the best studied is FAK activation of
mechanical forces observed at the site of focal the ERK 1 and 2 pathways, important mediators of
adhesion to nuclear activity facilitates the process of osteodifferentiation in mesenchymal progenitor
focal-adhesion-mediated cellular function. cells [76, 77].
The exact signalling mechanisms linking integrin
clustering with the commitment of MSC to the
osteogenic lineage are essentially unknown. However, 9 FOCAL ADHESION KINASE-MEDIATED ERK 1
several studies suggest that the FAK R extracellular- AND 2 SIGNALLING
signal-regulated kinase (ERK) R Runx2 signalling
pathway constitutes an important element of the It is well known that the mitogen-activated protein
transduction machinery controlling this process. The kinases (MAPKs) play important roles in cellular
way in which this process may be regulated in vivo by response to environmental stimuli. There are at least
osteoinductive biomaterials is currently of much three distinctly regulated groups of MAPKs: ERK 1
interest and represents a major challenge in the field and 2; c-jun N-terminal kinases 1, 2, and 3; and p38
of orthopaedic device design. In the following, this MAPKs.
pathway is described within the context of osteoneo- Preliminary studies indicate that the 44 kDa and
genesis following material implantation, a process 42 kDa ERK proteins participate in early osteodiffer-
that translates the dynamics of focal adhesion entiation [76, 78–81], proceeding to phosphorylate
initiation and reinforcement to the regulation of a multitude of downstream target substrates [82].
differential processes in adherent progenitor cells. It has also been shown that an increase in the

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 Focal adhesions in osteoneogenesis 1447

distribution and reinforcement of focal adhesions in Runx2 is a Runt-related transcription factor, char-
both osteoblasts [83] and MSCs [84] results in the acterized as a heterodimeric protein with a deoxy-
activation of ERK 1 and 2 by the Grb2–Sos–Ras ribonucleic-acid (DNA)-binding a subunit and a
pathway (Fig. 5). Further to this, MSCs cultured on non-DNA binding b subunit. Examination of differ-
bioactive materials such as hydroxyapatite have ent truncations of the Runx2 protein showed that the
been shown to up-regulate osteospecific genes and C-terminal proline–serine–threonine region of
osteoinductive proteins through the activation of Runx2 is required for both ERK 1 and 2 responsive-
ERK 1 and 2 [85]. ness and ERK 1 and 2 phosphorylation [88]. Runx2
As might be expected, activation of ERK by expression is highly restricted to bone, and its
progenitor cell adhesion to an orthopaedic construct activity during early embryonic development acts
and the onset of integrin clustering result in the as a master regulator in the commitment of these
increased activity of osteospecific transcription cells to the osteoblastic lineage [77]; indeed homo-
factors, i.e. the mediators of osteospecific differen- zygous deletion of Runx2 in mice results in the
tiation and early function [86]. complete absence of osteoblasts and bone formation
[89, 90], while the extent of mineralization in
trabecular bone is higher in transgenic mice that
10 FOCAL ADHESION REGULATION OF RUNX2 have been modified to over express RUNX2 [94].
MEDIATED TRANSCRIPTION Further to this, Runx2 is shown to regulate several
osteoblast-specific genes including alkaline phos-
The central regulation of bone differentiation and phatase, osteopontin, osteocalcin, and matrix me-
formation in osteoprogenitor cells is controlled by talloproteinase 13 [90–93], which are vital mediators
the transcriptional activity of Runx2, a factor subject of bone homeostasis.
to a number of post-transcriptional controls includ- In a biomaterials setting, MSCs have been shown
ing selective proteolysis and phosphorylation [87]. to undergo osteospecific differentiation and func-

Fig. 5 Integrin-mediated regulation of the ERK 1 and 2 signalling pathway. Extracellular forces
and cellular adhesion are translated into differential cellular function through the
regulatory effects of ERK 1 and 2 on the nuclear machinery of cellular transcription. FAK
recruitment and subsequent activation at the focal adhesion site result in Runx2
modulation of cellular transcription mediated primarily by Grb2-Sos-Ras activation of the
ERK 1 and 2 pathway.

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1448 M J P Biggs and M J Dalby

tional tissue formation when cultured on topogra- mechanotransductive and other developmental path-
phies that increase focal adhesion frequency and ways that regulates transcriptional events.
reinforcement [95, 96]. Further to this, Runx2 It can be hypothesized that third-generation
expression has been directly correlated with focal biomaterials may be modified to present osteocon-
adhesion reinforcement [77, 97] and increased in ductive elements with a view to controlling the
mesenchymal populations cultured on a variety of cellular processes [105] specific to bone regenera-
next-generation materials including nanostructures tion. The next stage in the evolution of orthopaedic
[98], three-dimensional fibrous scaffolds [99], bio- biomaterials may rely on a highly specific regime of
functionalized titanium [100] and polymers [101], topographical modification coupled with bioactive
and hydroxyapatite–tricalcium phosphate scaffolds eluting properties with the aim of regulating cellular
[102]. adhesion and differentiation through specific os-
teoinductive pathways. Specifically, manipulation of
MAPK signalling could offer interesting opportu-
11 CONCLUSIONS nities for enhanced bone repair and device integra-
tion. However, the participation of this pathway in
It is predicted that the percentage of persons over 50 numerous biological processes, notably inflamma-
years of age affected by bone diseases will double by tion, may restrict the therapeutic use of modified
2020 [103]. Clearly this represents a need for materials, which should strongly depend on the
permanent, temporary, or biodegradable orthopae- indication or stage of bone repair.
dic devices that are designed to substitute or guide
bone repair. Orthopaedic biomaterials should be
designed with optimal physical and chemical prop- ACKNOWLEDGEMENTS
erties to promote tissue regeneration as well as
bioactivity to induce specific cellular responses at This work was funded by the AO Research Fund,
the molecular level and to modulate cellular func- Switzerland (Grant 04-D81), and The National
tion. It is known that enhanced osteoneogenesis can Institute Of Health, Nanomedicine Roadmap Initia-
be induced by surface chemical or topographical tive (Grant PN2EY016586). M. J. D. is supported by
functionalization; however, the ideal materials for the Biotechnology and Biological Sciences Research
the induction of osteoadhesion and osteoneogenesis Council. The authors acknowledge and thank the
are still under investigation. following people: Professor Adam Curtis, Dr Mathis
It has previously been observed that focal adhe- Riehle, Professor Geoff Richards, Professor Chris
sion maturation rather than frequency is important Wilkinson, and Professor Shalom Wind for their
in osteospecific differentiation [84, 104] and that, interesting discussions and support.
with focal adhesion reinforcement, increased FAK is
activated to initiate downstream signalling cascades. F Authors 2010
Conversely, when integrin-mediated adhesion is
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