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Biomaterials 26 (2005) 7525–7529

www.elsevier.com/locate/biomaterials

Leading Opinion

Get a grip: integrins in cell–biomaterial interactions$

Andres J. Garcıa�

Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology,

315 Ferst Drive, Atlanta, GA 30332-0363, USA

Received 17 March 2005; accepted 11 May 2005

Available online 5 July 2005

Abstract

Integrin adhesion receptors have emerged as central regulators of cell–biomaterial interactions. This opinion paper discusses how

integrins control cellular and host responses to biomaterials and new strategies to manipulate these adhesive interactions in order to

elicit specific cellular responses.

r 2005 Elsevier Ltd. All rights reserved.

Keywords: Integrins; Cell adhesion; Extracellular matrix; Signaling; Inflammation; Biomimetic materials; RGD

1. Introduction

A mechanistic understanding of cellular interactionswith synthetic surfaces, particularly in the context ofinflammatory and healing responses, has been a majorgoal of biomaterials science. While considerable pro-gress has been attained, an integrated molecular modelof dominant mechanisms remains incomplete. Integrinadhesion receptors have emerged as central regulators ofcell–biomaterial interactions. This understanding natu-rally leads to two fundamental questions: (1) How areintegrin activities integrated to regulate cellular re-sponses to biomaterials? (2) Can integrin interactionsbe manipulated to engineer cellular and host responses?

e front matter r 2005 Elsevier Ltd. All rights reserved.

omaterials.2005.05.029

te: Leading Opinions: This paper is one of a newly

s of scientific articles that provide evidence-based

ns on topical and important issues in biomaterials

ave some features of an invited editorial but are based

cts, and some features of a review paper, without

be comprehensive. These papers have been commis-

Editor-in-Chief and reviewed for factual, scientific

rees.

894 9384; fax: +1 404 385 1397.

ess: andres.garcia@me.gatech.edu.

2. Integrin family of adhesion receptors

Integrins constitute a widely expressed family oftransmembrane receptors involved in cell–extracellularmatrix (ECM) and cell–cell adhesion [1]. Integrinheterodimers, consisting of non-covalently associated aand b subunits, bind to specific amino acid sequencessuch as the arginine–glycine–aspartic acid (RGD)recognition motif present in many ECM proteins,including fibronectin and vitronectin. Integrins playcentral roles in development and the organization,maintenance, and repair of various tissues by providinganchorage and triggering signals that direct cell survival,migration, cell cycle progression, and expression ofdifferentiated phenotypes [2]. Abnormalities in integrinadhesive interactions are often associated with patholo-gical states, including blood clotting and wound healingdefects as well as malignant tumor formation [3].Moreover, integrins are important regulators of cellularand host responses to implanted devices, biologicalintegration of biomaterials and tissue-engineered con-structs, and the performance of cell arrays andbiotechnological cell culture supports [4–6].

Integrin-mediated adhesion is a highly regulated,complex process involving receptor-ligand binding aswell as post-ligation interactions with multiple binding

ARTICLE IN PRESSA.J. Garcıa / Biomaterials 26 (2005) 7525–75297526

partners. Upon ligand binding, integrins rapidly associ-ate with the actin cytoskeleton and cluster together toform focal adhesions, discrete supramolecular com-plexes that contain structural proteins, such as vinculin,talin, and a-actinin, and signaling molecules, includingFAK, Src, and paxillin [7]. These focal contacts arecentral elements in the adhesion process, functioning asstructural links between the cytoskeleton and ECM.Furthermore, in combination with growth factor recep-tors, these adhesive clusters activate signaling pathwaysthat regulate transcription factor activity and direct cellgrowth and differentiation [1,7].

3. Integrin-mediated responses to biomaterials

Because of their pivotal roles in cell adhesion,integrins participate in diverse host and cellularresponses to biomaterials. For instance, the plateletintegrin aIIb3 (GP IIb/IIIa) binds to several ligandsinvolved in platelet aggregation in hemostasis andthrombosis, such as fibrinogen, von Willebrand factor,and fibronectin [1,3]. This receptor also mediates initialevents in the blood activation cascade upon contact withsynthetic surfaces [8,9]. Similarly, leukocyte b2 integrins,in particular aMb2 (Mac-1), mediate monocyte andmacrophage adhesion to various ligands, includingfibrinogen, fibronectin, IgG, and complement fragmentiC3b, and this receptor plays a central role ininflammatory responses in vivo [10,11]. Moreover,binding of aMb2 integrin to fibrinogen P1 and P2domains exposed upon adsorption to biomaterialsurfaces controls initial recruitment and accumulationof inflammatory cells onto biomaterial surfaces [10,12].b1 integrins represent the dominant adhesion mechan-ism to extracellular matrix ligands, and consequentlybiomaterial surfaces, for numerous connective, muscu-lar, neural, and epithelial cell types. In additionto supporting adhesion, spreading, and migration,these receptors activate various intracellular signaling

Fig. 1. Mechanisms controlling ce

pathways controlling gene expression and proteinactivity that regulate higher order cellular functions [1].

Integrins mediate cellular interactions with biomater-ial surfaces by interacting with adhesive extracellularligands that can be (i) adsorbed from solution (e.g.,protein adsorption from blood, plasma, or serum); (ii)engineered at the interface (for example, bioadhesivemotifs such as RGD); and/or (iii) deposited by cells(e.g., fibronectin and collagen deposition) (Fig. 1). Theseinteractions are often highly dynamic in nature. Forinstance, the dominant adhesive ligand present on asurface may change over time due to exchange withother proteins in solution (i.e., Vroman effect) [4].Additionally, cells may initially adhere to syntheticsurfaces via proteins adsorbed from solution, such asvitronectin, but they can rapidly degrade/reorganize thislayer of adsorbed proteins and deposit their own ECM.Furthermore, the integrin expression and activity profileon a particular cell can change over time. Most cellsexhibit multiple integrins for the same ligand and thebinding activity of these receptors can be rapidlyregulated via changes in integrin conformation. More-over, the integrin expression profile does not necessarilycorrelate with integrin function on a particular sub-strate. Finally, multiple integrins may be involved in aparticular cellular response. For example, initial mono-cyte adhesion to biomaterials is mediated primarily byb2 integrin, while both b1 and b2 integrins are involvedin macrophage adhesion and fusion into foreign bodygiant cells [13]. These complex interactions oftenconfound analyses of integrin binding on biomaterialsand can lead to erroneous conclusions. For example,attributing cellular outcomes, especially long-termresponses, to ECM proteins precoated onto biomaterialsurfaces neglects potential contributions from proteinsadsorbed from the cell culture media and ECMcomponents deposited by cells. Therefore, the use ofblocking antibodies against specific integrin subunitsand adhesive ligands or protein knockdown via RNAinterference to perturb integrin function is highly

ll adhesion to biomaterials.

ARTICLE IN PRESSA.J. Garcıa / Biomaterials 26 (2005) 7525–7529 7527

recommended to rigorously analyze adhesive interac-tions to biomaterials.

4. Integrins as targets for biomaterial manipulations

Integrins represent promising targets for manipulat-ing cellular and host responses to biomaterials. Directinhibition of integrin function by soluble or immobilizedagents can reduce thrombosis and inflammatory re-sponses associated with implanted biomaterials [14,15](Fig. 2A). Alternatively, controlled integrin binding atthe biomaterial interface, in terms of specific integrinreceptors, bound numbers and distribution, may acti-vate specific signaling pathways and adhesive activitiesthat elicit desired cellular and host responses (Fig. 2B).There is mounting evidence in the biomaterials literaturethat this biomolecular strategy can be exploited toengineer cellular activities. Current biomimetic strate-gies focusing on presenting short bioadhesive oligopep-tides, including RGD, on a non-fouling support totarget integrin receptors have demonstrated in vitrocontrol of cell adhesion and differentiation, and more

Fig. 2. Strategies for modulating integrin function in cell–biomaterial inter

binding (e.g., blocking antibody), anti-inflammatory agents that down-regul

integrin expression or ECM ligand production. (B) Strategies directing integ

RGD), ligands mimicking secondary and tertiary structure to convey integ

activation of specific integrins.

importantly, enhancements in in vivo responses, includ-ing bone formation and integration [16–19], nerveregeneration [20,21], and corneal tissue repair [22].Nonetheless, these biomimetic strategies are limited by(i) low activity of the oligopeptides compared to thenative ligand due to the absence of complementary ormodulatory domains, (ii) limited specificity for particu-lar integrin receptors, and (iii) inability to bind certainreceptors due to conformational differences comparedto the native ligand. It is expected that ‘‘secondgeneration’’ bioadhesive motifs with enhanced activityand specificity will result in materials with improvedbiofunctionality [23,35]. For example, surfaces present-ing a triple helical peptide mimicking the secondary andtertiary structure of type I collagen support binding ofthe a2b1 integrin and promote osteoblastic differentia-tion and mineralization to similar levels as collagen[23,24].

The ability to convey integrin binding specificity mayprovide a powerful strategy to elicit specific cellularresponses to biomaterials (Fig. 2B). Different adhesiveligands on biomaterial surfaces differentially influencemacrophage adhesion and function as well as neural

actions. (A) Inhibitory approaches include direct blocking of integrin

ated integrin function, and RNA interference methods to knock down

rin binding, such as oligopeptides containing bioadhesive motifs (e.g.,

rin binding specificity, and ligand presentation to direct binding and

ARTICLE IN PRESSA.J. Garcıa / Biomaterials 26 (2005) 7525–75297528

stem cell migration and differentiation, presumably viadifferences in receptor binding [25–28]. Furthermore,different integrins that bind to the same ligand, either tothe same or separate sites, can trigger diverse signalingpathways regulating distinct cellular programs [29–31].More importantly, biomaterial surface properties, viaalterations in adsorbed protein structure, can regulateintegrin binding specificity, thereby modulating signal-ing and expression of differentiated phenotypes [32–34].These results suggest that by engineering integrinspecificity into biomimetic materials and/or developingsynthetic surfaces to control the functional presentationof adsorbed bioactive moieties, it may be possible toprecisely control cell–material biomolecular interactionsto activate specific signaling programs and elicit desiredcellular responses. This strategy represents a shift fromcurrent schemes seeking to prevent protein adsorptionand inflammation to approaches focusing on controllingcellular interactions to direct healing responses.

5. Future prospects

Given the critical importance of integrins in cellularand host responses to biomaterials, it is expected thatsteady progress will continue in the understanding andmanipulation of these adhesive interactions. In parti-cular, significant research progress must be attained inmore physiologically relevant models, such as organo-typic culture and in vivo models, to better understandthe roles of integrins in responses to biomaterials.Furthermore, biomolecular engineering strategies needto evolve beyond the ‘‘static density of linear RGD’’ tofully realize the potential of these biomimetic ap-proaches, especially in terms of developing interactiveinterfaces presenting spatiotemporal gradients of multi-ple adhesive signals. Finally, it may be possible tomanipulate inflammatory and healing responses bydelivering agents that modulate integrin function and/or engineering interfaces that control the presentationand biological activity of adsorbed biological moieties.

Acknowledgements

A.J.G. gratefully acknowledges support from theNational Science Foundation, National Institutes ofHealth, Arthritis Foundation, Whitaker Foundation,and the Georgia Tech/Emory NSF ERC on EngineeringLiving Tissues.

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