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J Dent Res 84(5):407-413, 2005
© 2005 International and American Associations for Dental Research

REVIEWS
CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Bio-adhesive Surfaces to Promote Osteoblast Differentiation and Bone Formation

A.J. García*, and C.D. Reyes

Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, 2314 Petit Biotechnology Building, Atlanta, GA 30332-0363, USA;

* corresponding author, andres.garcia{at}me.gatech.edu


   ABSTRACT
TOP
 ABSTRACT
CELL ADHESION AND BONE...
 OSTEOGENIC CELL-BIOMATERIAL...
 BIO-ADHESIVE SURFACES
 CONCLUSIONS AND FUTURE PROSPECTS
 REFERENCES
 
Binding of integrin adhesion receptors to extracellular matrix components, such as fibronectin and type I collagen, activates signaling pathways directing osteoblast survival, cell-cycle progression, gene expression, and matrix mineralization. Biomimetic strategies exploit these adhesive interactions to engineer bio-inspired surfaces that promote osteoblast adhesion and differentiation, bone formation, and osseointegration. These emerging initiatives focus on directing integrin binding through presentation of bio-adhesive motifs derived from extracellular matrices. These biomolecular approaches provide promising strategies for the development of biologically active implants and grafting substrates for enhanced bone repair.

KEY WORDS: integrin • fibronectin • RGD • type I collagen • GFOGER • cell adhesion • biomaterial


   CELL ADHESION AND BONE FORMATION
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 ABSTRACT
 CELL ADHESION AND BONE...
OSTEOGENIC CELL-BIOMATERIAL...
 BIO-ADHESIVE SURFACES
 CONCLUSIONS AND FUTURE PROSPECTS
 REFERENCES
 
Cell adhesion to extracellular matrices is essential to the development, maintenance, and remodeling of osseous tissues (Damsky, 1999; De Arcangelis and Georges-Labouesse, 2000). Adhesive interactions with extracellular matrix components, including fibronectin and type I collagen, play critical roles in osteoblast survival, proliferation, differentiation, and matrix mineralization, as well as in bone formation (Weiss and Reddi, 1981; Franceschi et al., 1994; Gronowicz and DeRome, 1994; Moursi et al., 1996; Globus et al., 1998; Zimmerman et al., 2000). Furthermore, adhesive interactions are also important for osteoclast function and bone resorption (Fisher et al., 1993; McHugh et al., 2000).

Cell adhesion to extracellular matrix ligands is primarily mediated by integrins, a widely expressed family of transmembrane adhesion receptors (Hynes, 2002). Integrin heterodimers, consisting of non-covalently-associated {alpha} and ß subunits, bind to specific amino acid sequences, such as the arginine-glycine-aspartic acid (RGD) recognition motif present in many extracellular matrix proteins, including fibronectin, bone sialoprotein, and osteopontin (Ruoslahti and Pierschbacher, 1987). Integrin-mediated adhesion is a highly regulated process involving receptor-ligand interactions and subsequent adhesion strengthening and cell spreading. Upon ligand-binding, integrins rapidly associate with the actin cytoskeleton and cluster together to form focal adhesions, discrete complexes that contain structural and signaling molecules (Sastry and Burridge, 2000; Geiger et al., 2001) (Fig. 1Go). Focal adhesions are central elements in the adhesion process, functioning as structural links between the cytoskeleton and extracellular matrix to mediate stable adhesion and migration. Furthermore, in combination with growth-factor receptors, focal adhesions activate signaling pathways, such as MAPK and JNK, that regulate transcription factor activity and direct cell growth and differentiation (Giancotti and Ruoslahti, 1999). Many of these integrin-activated signaling cascades are required for mesenchymal cell commitment and osteoblast differentiation (Takeuchi et al., 1997; Tamura et al., 2001; Lai et al., 2001; Xiao et al., 2000, 2002; Jaiswal et al., 2000).



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  		Figure 1. Integrin-mediated cell adhesion to extracellular matrices involves integrin binding and clustering, focal adhesion assembly, and cytoskeletal interactions. Focal adhesions are supramolecular assemblies containing structural and signaling components regulating cell functions. Immunofluorescence staining for osteoblasts (DNA white) adhering to fibronectin showing actin cytoskeleton stress fibers (red) terminating in focal adhesions as shown by vinculin localization (green). Focal adhesions indicated by green arrowhead. Bar = 10 µm.

 
Osteoblasts and osteoprogenitor cells express multiple integrins—including {alpha}1ß1, {alpha}2ß1, {alpha}3ß1, {alpha}4ß1, {alpha}5ß1, {alpha}6ß1, {alpha}8ß1, and {alpha}vß3—that bind to numerous extracellular matrix components (Moursi et al., 1997; Gronthos et al., 2001). Integrin-mediated interactions with extracellular proteins are central to osteoblastic functions. For instance, using blocking antibodies in primary osteoblast cultures, Damsky and colleagues demonstrated that integrin interactions, in particular {alpha}5ß1, with fibronectin are essential for osteoblast survival, proliferation, osteoblast-specific gene expression, and matrix mineralization (Moursi et al., 1996, 1997; Globus et al., 1998). Integrin interactions with type I collagen are also important. Blocking adhesion with type I collagen-specific peptides or antibodies directed against the collagen-binding integrin {alpha}2ß1 interferes with the activity of the Runx2/Cbfa1 transcription factor, expression of osteoblast-specific genes, and matrix mineralization (Xiao et al., 1998; Jikko et al., 1999; Mizuno et al., 2000). These studies underscore the critical role of specific integrin-extracellular matrix interactions, particularly {alpha}5ß1-fibronectin and {alpha}2ß1-collagen type I, in osteoblast activities.


   OSTEOGENIC CELL-BIOMATERIAL INTERACTIONS
TOP
 ABSTRACT
 CELL ADHESION AND BONE...
 OSTEOGENIC CELL-BIOMATERIAL...
BIO-ADHESIVE SURFACES
 CONCLUSIONS AND FUTURE PROSPECTS
 REFERENCES
 
Because of the crucial role of extracellular matrix-mediated adhesion in osteoblast functions, cell adhesion considerations are central to many biotechnological and biomedical applications focusing on bone formation, including cell-culture supports, implant surfaces, and tissue-engineering scaffolds. Cell adhesion to synthetic supports and biomaterial surfaces involves dynamic interactions with extracellular ligands originating from several sources: (i) adsorption from protein-containing solutions, (ii) cell-mediated synthesis and deposition, and (iii) bio-adhesive motifs engineered on biomaterial surfaces (Fig. 2Go). Due to differences in surface properties (e.g., chemistry, roughness, energy), synthetic materials support osteoblastic activities to different extents (Puleo et al., 1991; Vrouwenvelder et al., 1993; Ishaug et al., 1994; El-Ghannam et al., 1997; Lincks et al., 1998; Ahmad et al., 1999; Zreiqat et al., 1999; Calvert et al., 2000; Mayr-Wohlfart et al., 2001; Schmidt et al., 2001; Yang et al., 2001; Stephansson et al., 2002; Keselowsky et al., 2004). Importantly, most synthetic materials do not support robust osteoblast activities, compared with natural matrices, and often result in poor cell differentiation and limited bone formation (Krause et al., 2000; Stephansson et al., 2002). These limited osteogenic activities arise primarily from inadequate bio-ligand presentation, biological activity, and density that result in suboptimal integrin-mediated cellular signaling.



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  		Figure 2. Mechanisms controlling cell adhesion to synthetic materials.

 

   BIO-ADHESIVE SURFACES
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 ABSTRACT
 CELL ADHESION AND BONE...
 OSTEOGENIC CELL-BIOMATERIAL...
 BIO-ADHESIVE SURFACES
CONCLUSIONS AND FUTURE PROSPECTS
 REFERENCES
 
Over the last decade, biomimetic approaches have sought to convey biofunctionality to synthetic materials by presenting bio-adhesive motifs derived from extracellular matrix components, such as RGD for fibronectin (Shakesheff et al., 1998; Hubbell, 1999, 2003). These biomolecular strategies mostly focus on immobilizing short peptides onto synthetic or natural materials to produce biofunctional surfaces that bind adhesion receptors and promote cell adhesion (Fig. 3Go). Non-fouling/non-adhesive supports, such as poly(ethylene glycol) (PEG) or alginate, are often used to reduce background effects arising from non-specific protein adsorption. Tethering of RGD peptides onto biomaterial supports and tissue-engineering scaffolds results in enhanced osteogenic cell adhesion, proliferation, and differentiation, as evidenced by higher alkaline phosphatase and osteocalcin expression and matrix mineralization (Dee et al., 1996; Bearinger et al., 1998; Rezania and Healy, 1999; Alsberg et al., 2001; Sofia et al., 2001; Itoh et al., 2002; Barber et al., 2003; Behravesh and Mikos, 2003; Hu et al., 2003; Huang et al., 2003; Zreiqat et al., 2003; Shin et al., 2004). Moreover, RGD-functionalized materials exhibit enhanced bone formation in vivo. Implant surfaces presenting RGD display higher levels of implant-associated bone area and thickness when compared with unmodified controls (Ferris et al., 1999; Kantlehner et al., 2000). Similarly, RGD immobilization improves early bone ingrowth and matrix mineralization in implanted tissue-engineered constructs (Alsberg et al., 2001; Eid et al., 2001; Lutolf et al., 2003). The density of tethered peptide is an important design parameter, since higher RGD densities promote osteoblast proliferation, bone-specific gene expression, and mineralization (Rezania and Healy, 2000). In addition, there is evidence that RGD-mediated enhancements in osteogenic function depend on the presentation of RGD within a non-fouling background to prevent non-specific protein adsorption. Simple presentation of RGD on titanium surfaces does not improve bone-implant contact (Schliephake et al., 2002), presumably due to non-specific adsorption of plasma proteins and interactions with inflammatory components that drown the engineered RGD signals. Interestingly, RGD presentation does not necessarily lead to enhancements in osteoblast differentiation. Boyan and colleagues recently reported reduced alkaline phosphatase and osteocalcin expression, as well as lower secreted levels of TGF-ß1 and PGE2, for cells cultured on surfaces coated with RGD-functionalized PLL-g-PEG compared with control PLL-g-PEG (Tosatti et al., 2004). These investigators attributed the limited osteogenic differentiation on RGD-functionalized surfaces, compared with control substrates, to differences in cellular morphology/shape. These results underscore the complexity associated with cellular interactions with these engineered biomaterials, and the need for rigorous analyses of cell adhesion and signaling on bio-adhesive supports.



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  		Figure 3. Bio-inspired bio-adhesive surfaces. (A) General strategy focusing on immobilizing short adhesive peptides onto various supports. (B) RGD immobilization onto non-fouling/non-adhesive support (top) results in robust osteoblast adhesion, while non-functionalized surface (bottom) resists cell adhesion.

 
Although results with surfaces presenting RGD peptides indicate that this biomolecular strategy enhances osteoblast adhesion and differentiation as well as bone formation, three critical factors limit the potential of this approach for bone repair. First, the biological activity of short adhesive peptides is significantly lower than that of the complete protein (Pierschbacher et al., 1983). This loss in activity results from conformation-dependent effects and the absence of crucial modulatory domains present in the native molecule (Aota et al., 1994; Akiyama et al., 1995). For example, osteoblast growth and differentiation—as evidenced by Runx2/Cbfa1, type I expression, and alkaline phosphatase expression and mineralization—are enhanced on RGD-functionalized poly(lactic acid) films compared with unmodified controls; however, osteoblastic markers are 50-fold higher on fibronectin-coated substrates compared with RGD-presenting polymers (Yang et al., 2001). Second, RGD peptides exhibit limited specificity among integrins, and, in some cases, RGD, although required, is not sufficient for efficient binding of particular integrin receptors. For instance, binding of {alpha}5ß1 requires both the PHSRN sequence in the 9th type III repeat and RGD motif in the 10th type III repeat of fibronectin (Aota et al., 1994). Each domain independently contributes little to binding, but in combination, they synergistically bind to {alpha}5ß1 to provide stable adhesion (Redick et al., 2000; García et al., 2002). This is a critical consideration, given the essential role that {alpha}5ß1 plays on osteoblast activities. Third, osteogenic cells require signals from non-RGD-binding integrins, notably {alpha}2ß1, for robust differentiation. These considerations motivate the engineering of ‘second generation’ surfaces that present more complex ligand formulations to overcome the limitations associated with short RGD peptides (Fig. 4Go).



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  		Figure 4. Biomolecular engineering strategies for bio-adhesive surfaces. First-generation substrates concentrate on tethering RGD to direct integrin binding and cell adhesion. Second-generation strategies focus on enhancing biological activity, integrin specificity, and binding non-RGD integrins.

 
One strategy to provide biofunctionality beyond RGD relies on tethering mixtures of short peptides targeting integrin and non-integrin receptors to improve osteoblast adhesion and differentiation. Dee et al.(1998) reported selective heparan-sulfate-mediated adhesion of osteoblasts compared with fibroblasts and endothelial cells on surfaces grafted with KRSR. Rezania and Healy (1999) demonstrated enhanced osteoblast adhesion and mineralization on surfaces functionalized with mixtures of RGD and FHRRIKA (consensus heparin-binding motif), compared with substrates presenting RGD or FHRRIKA peptides alone. Additional studies focusing on various peptide ratios and densities, as well as nano-scale clustering, should provide important insights into optimizing these mixed-peptide substrates. In fact, recent analyses demonstrate that substrate compliance and ligand-clustering and patterning, as well as combinations of bioligands and microstructured substrata, modulate cell adhesion, spreading, and migration (Maheshwari et al., 2000; Ranucci and Moghe, 2001; Gallant et al., 2002; Brock et al., 2003; Wong et al., 2003).

Synthetic approaches have been pursued to convey receptor specificity among RGD-binding integrins. Inclusion of flanking residues and constraining the conformation of the RGD motif to a loop via cyclization improve ligand specificity for integrins, including {alpha}5ß1 (Scarborough et al., 1993; Koivunen et al., 1994; Humphries et al., 2000). Nevertheless, these short peptides are limited in their ability to support robust {alpha}5ß1 binding when compared with native fibronectin (Akiyama et al., 1995; García et al., 2002). In efforts to include the essential PHSRN synergy site outside the RGD binding motif in fibronectin, mixtures of RGD and PHSRN peptides, either independently or within the same backbone, have been tethered onto non-fouling supports (Dillow et al., 2001; Kao et al., 2001). Although these bio-adhesive supports promote integrin binding and cell adhesion, their activity has not been directly compared with that of native fibronectin. However, due to the exquisite sensitivity of {alpha}5ß1 binding to small perturbations in the orientation and conformation of these domains (Grant et al., 1997; García et al., 1999), reconstitution of the proper binding structure using short peptides remains a challenging task. As an alternative to these synthetic routes, Cutler and García (2003) functionalized non-adhesive supports with a recombinant fragment of fibronectin spanning the 7th to 10th type III repeats, which include the PHSRN and RGD binding sites in the correct spatial orientation and conformation. These biomimetic surfaces supported {alpha}5ß1-mediated osteoblast adhesion and focal adhesion assembly at levels comparable with those of plasma fibronectin. In addition to providing increased specificity over RGD peptides, the use of recombinant fibronectin fragments offers several advantages over the entire molecule, including reduced antigenicity, elimination of domains that may elicit undesirable reactions, and enhanced cost-efficiency. Recombinant fragments also provide flexibility in the engineering of specific characteristics on the fragment via site-directed mutagenesis, to enhance protein immobilization, orientation, and activity. Further studies focusing on osteoblastic differentiation and mineralization are needed to establish the potential of these bio-adhesive surfaces for directing cell functions.

Relatively little work has concentrated on engineering bio-adhesive surfaces targeting non-RGD binding receptors, principally due to the lack of identification of binding sequences, as well as the complexity associated with these binding interactions. Nevertheless, as discussed previously for the {alpha}2ß1 integrin-collagen type I interaction, signals triggered by non-RGD binding integrins are essential for osteoblast differentiation. Stayton et al. demonstrated {alpha}2ß1-mediated adhesion and FAK phosphorylation for osteoblasts plated on hydroxyapatite surfaces functionalized with a peptide containing the hydroxyapatite-binding domain of statherin and the putative collagen-binding motif DGEA (Gilbert et al., 2003). However, analyses with purified integrin receptors indicate that this short peptide does not bind to integrin {alpha}2ß1 (Knight et al., 1998). These conflicting results may be explained by differences in the density or presentation of the ligand. Based on recent work identifying the hexapeptide GFOGER from residues 502–507 of the {alpha}1(I) chain of type I collagen as a major binding locus for the {alpha}2ß1 integrin (Emsley et al., 2000; Knight et al., 2000), Reyes and García (2003) engineered bioadhesive surfaces that specifically target {alpha}2ß1 integrin using a stable triple-helical, collagen-mimetic peptide. In addition to the GFOGER adhesion motif, this peptide incorporates GPP triplets, on either side of the GFOGER recognition site, that provide cooperative clusters promoting the formation of a right-handed triple-helical structure equivalent to the native conformation of type I collagen. This triple-helical conformation is essential for integrin recognition and {alpha}2ß1-mediated cell adhesion (Knight et al., 2000). This GFOGER peptide specifically targets the {alpha}2ß1 integrin receptor, and its cell adhesion activity is comparable with that of type I collagen (Reyes and García, 2003). Furthermore, GFOGER-functionalized surfaces supported FAK activation, expression of osteoblast-specific genes, and matrix mineralization at levels equivalent to those of type I collagen matrices, but significantly higher than conventional cell-culture supports (Reyes and García, 2004). These promising results warrant further analyses to evaluate these collagen-mimetic bio-adhesive surfaces as surface-modification strategies for osseous implants and tissue-engineering scaffolds.


   CONCLUSIONS AND FUTURE PROSPECTS
TOP
 ABSTRACT
 CELL ADHESION AND BONE...
 OSTEOGENIC CELL-BIOMATERIAL...
 BIO-ADHESIVE SURFACES
 CONCLUSIONS AND FUTURE PROSPECTS
REFERENCES
 
Biomimetic surfaces incorporating bio-adhesive motifs from extracellular matrices have emerged as promising surface-modification strategies for biomaterials, implant surfaces, and tissue-engineering scaffolds. While considerable progress has been achieved with short peptides such as RGD, that bind integrin receptors and promote cell adhesion and bone formation, engineered bio-adhesive substrates should incorporate additional characteristics present in extracellular matrices. These include multiple binding motifs that support binding to various integrin and non-integrin receptors, gradients in ligand density, nanoscale clustering, dynamic interfacial properties, and growth factor interaction sites (see review by Hubbell, 2003). The development of these bio-inspired surfaces mimicking extracellular matrices relies heavily on the integration of advances in biochemistry, cell biology, synthetic chemistry, and materials science and engineering.


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge funding from NSF (BES-0093226), the NSF-sponsored Georgia Tech/Emory Center for the Engineering of Living Tissues (EEC-9731643), and the Arthritis and Whitaker Foundations.

Received April 1, 2004; Accepted September 8, 2004


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