Fisher John P. e.a. (ed.) Tissue Engineering
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[89] Meraw, S.J., Reeve, C.M., Lohse, C.M., and Sioussat, T.M. Treatment of peri-implant defects with
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10
Biomimetic Materials
Andrés J. García
Georgia Institute of Technology
10.1 Extracellular Matrices: Nature’s Engineered
Scaffolds .................................................. 10-1
10.2 Bioadhesive Materials.................................... 10-2
10.3 Materials Engineered to Interact with Growth Factors 10-3
10.4 Protease-Degradable Materials ......................... 10-3
10.5 Artificial Proteins as Building Elements for
Matrices .................................................. 10-4
10.6 Conclusions and Outlook ............................... 10-4
References ....................................................... 10-5
Over the last decade, considerable advances in the engineering of biomaterials that elicit specific cellular
responses have been attained by exploiting biomolecular recognition. These biomimetic engineering
approaches focus on integrating recognition and structural motifs from biological macromolecules with
synthetic and natural substrates to generate bio-inspired, biofunctional materials. These strategies repres-
ent a paradigm shift in biomaterials development from conventional approaches which deal with purely
synthetic or natural materials, and provide promising schemes for the development of novel bioactive
substrates for enhanced tissue replacement and regeneration. Because of the central roles that extracel-
lular matrices (ECMs) play in tissue morphogenesis, homeostasis, and repair, these natural scaffolds
provide several attractive characteristics worthy of “copying” or mimicking to convey functionality for
molecular control of cell function, tissue structure, and regeneration. Four ECM “themes” have been
targeted (i) motifs to promote cell adhesion, (ii) growth factor binding sites that control presentation and
delivery, (iii) protease-sensitive sequences for controlled degradation, and (iv) structural motifs to convey
mechanical properties.
10.1 Extracellular Matrices: Nature’s Engineered Scaffolds
ECMs comprise a complex, insoluble, three-dimensional mixture of secreted macromolecules, includ-
ing collagens and noncollagenous proteins, such as elastin and fibronectin, glycosaminoglycans, and
proteoglycans that are present between cells. In addition, provisional fibrin-based networks constitute
specialized matrices for wound healing and tissue repair. ECMs function to provide structure and order
in the extracellular space and regulate multiple functions associated with the establishment, maintenance,
and remodeling of differentiated tissues [1]. Matrix components, such as fibronectin and laminin, mediate
adhesive interactions that support anchorage, migration, and tissue organization and activate signaling
pathways directing cell survival, proliferation, and differentiation. ECM components also interact with
10-1
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10-2 Tissue Engineering
growth and differentiation factors, chemotropic agents, and other soluble factors that regulate cell cycle
progression and differentiation to control their availability and activity. By immobilizing and ordering
these ligands, ECMs control the spatial and temporal profiles of these signals and generate gradients
necessary for vectorial responses. Moreover, structural elements within ECMs, namely collagens, elastin,
and proteoglycans, contribute to the mechanical integrity, rigidity, and viscoelasticity of skin, cartilage,
vasculature, and other tissues. Finally, the composition and structure of ECMs are dynamically modulated
by the cells within them, reflecting the highly regulated and bidirectional communication between cells
and ECMs.
10.2 Bioadhesive Materials
Following the identification of adhesion motifs in ECM components, such as the arginine–glycine–aspartic
acid (RGD) tri-peptide for fibronectin [2] and tyrosine–isoleucine–glycine–serine–arginine (YIGSR) oli-
gopeptide for laminin [3], numerous groups have tethered short bioadhesive peptides onto synthetic or
natural substrates and three-dimensional scaffolds to produce biofunctional materials that bind adhesion
receptors and promote adhesion and migration in various cell types (as reviewed in References 4 to 6)
(Figure 10.1). Nonfouling supports, such as poly(ethylene glycol), poly(acrylamide), and alginate, are
often used to reduce nonspecific protein adsorption and background adhesion. The density of tethered
peptide is an important design parameter as cell adhesion, focal adhesion assembly, spreading and migra-
tion [7–10], neurite extension and neural differenitiation [11,12], smooth muscle cell activities [13], and
osteoblast and myoblast differentiation [14,15] exhibit peptide density-dependent effects. More import-
antly, tethering of bioadhesive ligands onto biomaterial surfaces and scaffolds enhances in vivo responses,
such as bone formation and integration [16–18], nerve regeneration [19,20], and corneal tissue repair [21].
These results indicate that functionalization of biomaterials with short adhesive oligopeptides
significantly enhances cellular activities. In addition to conveying biospecificity while avoiding
unwanted interactions with other regions of the native ligand, short bioadhesive peptides allow
facile incorporation into synthetic backbones and enhanced stability of the tethered motif. These
strategies, however, are limited by (i) low activity of oligopeptides compared to native ligand
due to the absence of modulatory domains, (ii) limited specificity for adhesion receptors and cell
types, and (iii) inability to bind certain receptors due to conformational differences compared to
the native ligand. Conformationally constrained (e.g., cyclic) RGD [22], oligopeptides mixtures
[23,24], and recombinant protein fragments spanning the binding domains of native ligands [25]
GRGDS
GRGDS
GRGDS
(a)
PHSRN
G
R
G
D
PHSRN
RGD
GFOGER
Cyclic
RGD
Peptide
mixtures
Recombinant
proteins
Triple-helical
peptides
(b)
GRGDS
FIGURE 10.1 Biomimetic materials supporting cell adhesion. (a) Basic strategy focusing on RGD tethering to
promote binding of cell adhesion receptors. (b) Biomolecular approaches to improve ligand activity and specificity.
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Biomimetic Materials 10-3
growth
factor
heparin
hep
hep
hep
scaffold
heparin-binding
motif
hep
hep
direct
immobilization
tethering via
immobilized heparin
immobilization via heparin bridge
to heparin-binding motifs
FIGURE 10.2 Biomimetic strategies for controlled growth factor interactions.
have been explored to improve ligand activity. Similarly, substrates presenting RGD in combina-
tion with other peptides, such as heparan sulfate-binding lyrine–arginine–serine–arginine (KRSR)
[26] and Phenylalanine–histidine–arginine–arginine–isoleucine–lysine–alanine (FHRRIKA) [27], display
improved cell adhesion and selectivity over materials modified with RGD alone. Finally, self-assembling
peptides reconstituting the triple helical structure of type I collagen have been used to target collagen integ-
rin receptors and promote enhanced osteoblastic differentiation and mineralization on biomaterial sup-
ports [28,29]. The improved activity and selectivity of these “second generation” biomolecular materials
are expected to reconstitute additional features of natural ECMs and promote enhanced cellular activities.
10.3 Materials Engineered to Interact with Growth Factors
Natural ECMs interact with soluble growth and differentiation factors to control their activity by
regulating their presentation, delivery kinetics, and stability [1]. Three general strategies have been
pursued to convey growth factor activity to synthetic materials (Figure 10.2). Covalent immobil-
ization of growth factors onto biomaterial supports, either via conventional peptide chemistry or
enzymatic cross-linking, results in enhanced signaling activity [30,31]. Furthermore, enzyme-regulated
release of tethered growth factors by incorporating protease-sensitive sequences in the tether has
been applied to modulate release kinetics [32,33] and shown to improve blood vessel growth [34].
Mimicking the natural affinity of ECM glycosaminoglycans for heparin-binding growth factors, hep-
arin has been covalently immobilized onto scaffolds to control the presentation and release kinetics
of heparin-binding growth factors, such as basic fibroblast growth factor [35,36] and transforming
growth factor-β [37]. Similarly, engineering of basic heparin-binding motifs, such as phenylalanine–
alanine–lysine–leucine–alanine–alanine–arginine–lysine–tyrosine–arginine–lysine–alanine (FAKLAAR-
LYRKA) and tyrosine–lysine–lysine–isoleucine–lysine–lysine–leucine (YKKIIKKL), into scaffolds and
sequestering of heparin-binding growth factors via a heparin bridge results in enhanced delivery kinetics
and nerve regeneration [38,39].
10.4 Protease-Degradable Materials
Cell-mediated local degradation of ECMs is critical to tissue development, maintenance, and remodeling
[40]. To mimic this behavior, proteolytically sensitive substrate motifs specific for natural ECM enzymes,
including matrix metalloproteinases and plasmin, have been incorporated into biomaterial scaffolds [41]
(Figure 10.3). Consistent with migration behaviors in collagen and fibrin ECMs [40], cell migration
and neurite extension through engineered networks require protease activity specific for the incorporated
proteasesubstrate motifs [42,43]. Structure–functionanalyses of cell invasion into synthetic hydrogelshave
shown that the extent of invasion depends on protease substrate activity, adhesion ligand concentration,
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10-4 Tissue Engineering
protease
VPR
GGLGPAGG
FIGURE 10.3 Enzyme-sensitive materials incorporating protease substrate motifs.
and network cross-linking density [44]. Furthermore, poly(ethylene glycol)-based hydrogels containing
RGD oligopeptides and substrates for matrix metalloproteinases engineered to deliver BMP-2 to bone
defects exhibit enhanced healing compared to standard treatments [44]. Bone regeneration in this model
is dependent on the proteolytic sensitivity of the matrices and their architecture.
10.5 Artificial Proteins as Building Elements for Matrices
Artificial analogues of ECM proteins incorporating structural motifs to reconstitute secondary structures
(e.g., coiled coil, α-helix) and convey controlled mechanical properties have been engineered via both
synthetic routes and recombinant DNA technology [45]. These artificial proteins provide opportunities to
generate novel hybrid macromolecules with additional or new functionalities and enhanced cost-efficiency,
while overcoming limitations associated with natural ECMs, such as a restricted range in mechanical prop-
erties, processability, batch-to-batch variability, and the potential of pathogen transmission. For example,
artificial proteins consisting of terminal leucine zipper domains flanking a central polyelectrolyte segment
produce coiled-coil domains that render the material into a reversible, self-assembling hydrogel [46].
Polymers containing the glycine–valine–glycine–valine–proline (GVGVP) repeat from elastin have been
designed to mimic the mechanical behavior of elastin [47]. These materials can be formulated as fibers and
networks to create artificial ECMs [48,49]. Moreover, combination of elastin and fibronectin motifs has
resulted in novel materials with biological and mechanical properties similar to those from natural ECMs
[50]. Engineering of biofunctionalized and synthetic glycosaminoglycan polymers represents another
promising avenue to artificial ECMs [51–53].
10.6 Conclusions and Outlook
Biomimetic materials incorporating bioactive motifs from natural ECMs have emerged as promising,
novel biofunctional materials for tissue maintenance, repair, and regeneration. Although considerable
progress has been attained in mimicking particular characteristics of ECMs, next-generation, bio-inspired
materials must incorporate multiple characteristics from biological matrices to recapitulate the robust
activities associated with these natural scaffolds. Furthermore, advances in materials engineering should
provide routes for integrating multiple ligands, ligand gradients, nanoscale clustering, and dynamic,
environment-responsive interfacial, and bulk properties. Finally, these biomimetic materials must be
designed to support the activities of multiple cell types to successfully mimic desired tissue behavior and
function.
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Biomimetic Materials 10-5
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11
Nanocomposite
Scaffolds for Tissue
Engineering
Amit S. Mistry
Xinfeng Shi
Antonios G. Mikos
Rice University
11.1 Introduction.............................................. 11-1
11.2 Nanocomposite Materials ............................... 11-2
Nanomaterials Overview • Functionalized Alumoxane
Nanocomposites • Polymer-Layered Silicate
Nanocomposites • Hydroxyapatite Nanocomposites •
Other Ceramic Nanocomposites • Carbon Nanotube
Nanocomposites
11.3 Conclusions .............................................. 11-8
Acknowledgments............................................... 11-8
References ....................................................... 11-8
11.1 Introduction
In recent years, a great deal of attention has been directed toward nanotechnology and the potential
benefits that this growing field may bring to a wide variety of engineering applications. One of the
many applications of nanotechnology toward the biomedical sciences is the advancement of biomaterials
designed for tissue engineering, especially those intended for biological tissues with complex properties.
Nanoscience will be particularly useful in tissue engineering since the interactions between cells and
biomaterials occur in the nanoscale and the components of biological tissues are nanomaterials themselves.
Bone tissue, for example, is a nanocomposite composed of rigid hydroxyapatite (HA) nanocrystals
(60%) precipitated onto collagen fibers (30%) (Figure 11.1) [1]. Hydroxyapatite, which occurs as small
plates that are tens of nanometers in length and width and 2–3 nm in depth, impart compressive strength
to bone. Collagen fibrils (1.5–3.5 nm in diameter) form triple helices and bundle into fibers (50–70 nm
diameter) responsible for the unique tensile properties of composite bone tissue [2]. The unique and
complex mechanical properties of bone tissue arise from the interaction of these two components in the
nanoscale [3].
Similarly, nanomaterials possessing superior properties compared to conventional materials are cap-
able of imparting some of their properties onto macroscopic materials to form nanocomposites. In this
manner, biomaterials may gain enhanced properties for medical applications with the addition of nanoma-
terials. Biodegradable polymers, for example, are generally too weak for load-bearing tissue applications.
However, the incorporation of nanofillers into the polymer matrix can greatly improve the polymer’s
11-1