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CHAPTER 10
Cell Behavior Toward Nanostructured
Surfaces
SANGAMESH G. KUMBAR, MICHELLE D. KOFRON, LAKSHMI S. NAIR, and
CATO T. LAURENCIN
10.1 INTRODUCTION
A basic understanding and knowledge of cellbiomaterial surface interaction
is of immense interest in tissue engineering and other related biomedical
applications. Studies have shown that cells respond to the surface topography
and their performances vary with topographic features [1]. Such studies on
cellbiomaterial surface interactions could better predict the cell behavior
under in vivo conditions. Based on these interactions, many biological
processes such as embryogenesis, angiogenesis, or tumor metastasis can also
be elucidated. This knowledge will be useful in designing various structures
with different surface topographies that can elicit the desired cellular behavior
when implanted in the body. Further, these cellular interactions with surface
topographies are also of prime importance in other related fields such as the
production of pharmaceuticals, toxicology screening, and design of various
prosthetic devices [2–4].
Basement membranes are unique extracellular matrices that support cell
adhesion and provide an environment for the cells to interact with the
surroundings. The extracellular matrix (ECM) is composed of specific proteins,
several functional groups, and growth factor reservoirs along with many tropic
agents that are responsible for cellular function. Several cellular activities such
as adhesion, proliferation, migration, differentiation, and cell shape are
influenced by the ECM in which they reside [5–9]. The ECM is principally
composed of hierarchical ly arranged collagen, laminin, other fibrils, and
proteoglycans in a complex topography in the nanometer range. Cells
BiomedicalNanostructures, Edited byKennethE.Gonsalves, CraigR. Halberstadt,CatoT.Laurencin,
and Lakshmi S. Nair
Copyright # 2008 John Wiley & Sons, Inc.
261
experience nanotopography and interact with nanofeatures in vivo as evident
from Fig. 10.1c. The basement membrane is an integrated component of the
ECM and measures approximately 200 nm in thickne ss. The basement
membrane separates various tissues such as epithelia, endothelia, muscle
fibers, and the nervous system from connective tissue compartments. The
basement membrane is characterized by a co mplex surface topography
consisting of intertwining fibers, ridges, and pores in the nanometer scale as
is evident from Fig. 10.1ac. The corneal membrane of rhesus macaque is
presented in Fig. 10.1a [10,11]. The topographical feature measured was
178 57 nm for the basement membrane height, the interpore dist ance was
127 54 nm, and fiber and pore diameters were 52 28 nm and 82 49 nm,
respectively [10,11]. These measured topographic feature values are similar to
FIGURE 10.1 Scanning electron micrographs (SEM) of the basement membrane
present (a) corneal of the rhesus macaque. The surface topography of the membrane is
a mixture of ridges, pores, and fibers in the nanometer scale. SEM micrographs of the
basement membrane from mice (b) and the dermis (c) present the dense collagen
meshwork consisting of fibers and pore structures in nanometer scale. SEM (c)
presents an attached fibroblast (asterisk) to the collagen meshwork (dermis). This
explains the actual nanotopographic features experienced by micrometer dimension
cells in vivo. (Reprinted with permission from (a) Reference [11], and (b and c), and
Reference [12].)
262
BIOMEDICAL NANOSTRUCTURES
the reported human basement membrane values [12, 13] SEM micrographs (b)
and (c) represent the dense collagen nanofiber bundles present in the basement
membrane and dermis of mouse skin. The collagen network appears less
compact in the dermis (Fig. 10.1c), and a fibroblast attached to collagen
nanofibrils can be seen. This explains the actual nanotopographic features
experienced by micrometer dimension cells in vivo. This complex three-
dimensional surface topography of the ECM provides not only the chemical
stimulus but also biophysical cues for the cells attached to it. The ECM
components and its topographic features are well characterized; however, the
mechanisms that can predict the ECMcell inter actions are not well
understood. The cellECM interaction based on integrin receptors that are
associated with the cell membrane to specific sequences such as (RGD)
arginineglycineaspartic acid part of the ECM is well characterized [14–17].
Cells produce ECM proteins to inter act with the surfaces or the substrate on
which they are growing. These ECM proteins act as transducers for
extracellular signals, namely physical and chemical, through the cytosol
membrane using focal contacts [18–20]. The cellECMsubstrate interaction
is shared among cell networks through intercellular communi cation. The
cellsubstrate interactions are critical for the integration and amplification of
extracellular signals [21, 22]. Change in substrate surface properties, namely
chemical composition, surface energy, surface roughness, and surface
topography, can significantly affect cellsubstrate interfacial characteristics
and potentially influence cellular behavior and function [23]. These factors are
more important when developing novel materials and surfaces for tissue
engineering applications as well as prosthetic devices . Cells produce complex
chemical and topographical cues in natural tissue and these cues will differ with
the synthetic surfaces normally used for in vitro culture. Cells may encounter
different surface topographie s and that might vary from macro- to nano-size
dimension, for example, macrotopographies experienced in bone or ligament
shape, microtopographies with the shapes of other cells, and nanotopographies
with protein folding and collagen banding [24].
Surface topography and biochemical cu es have been shown previously to
alter cell behaviors such as adhesion, orientation, cell activation, and migration
significantly [25–32]. Furthermore, these topographical cues are shown to
influence various modes of cell adhesion and consequently changes in cell
shape, growth, apoptosis and regulation of certain gene expressions [28, 29, 33–
35]. For instance, aligned fibroblasts on groove microtopography produced
higher quantities of the adhesive protein fibronectin than the nonaligned cells
on control plane surfaces [35, 36, 38].
Nanotopographical features of the ECM can significantly affect cellular
behavior and were the inspiration for the favored nanoscale dimensions used in
the design of new generation tissue engineering scaffolds and biomedical
implants. Several evidences documented in the literature clearly showed the
influence of nanotopography on cellular behavior that accounts for changes in
morphology [25, 30], adhesion [26], motility [34], proliferation [36], endo cytotic
activity [37], and gene regulation [35] of various cell types, namely fibroblasts
CELL BEHAVIOR TOWARD NANO STRUCTURED SURFACES 263
[36, 38], osteoblasts [39], osteoclasts [40], endothelial [41], smooth muscle [42],
epithelial [43, 44], and epitenon cells [45]. A detailed understanding of
nanotopographical surface interaction with precursor cells and their differ-
entiation is essential. In addition to fundamental understanding of
cellnanotopographic surface interactions, the nanotopographies may have
potential applications in various biomedical fields.
10.2 NANOTOPOGRAPHIC SURFACES: FABRICATION TECHNIQUES
Presently, the experiments perfor med on conventional tissue culture polystyr-
ene (TCPS) flat surfaces give an idea of cellsubstrate interaction; however,
they do not simulate the complex ECM topography and dimensions. Earlier
studies have shown the effect of micro- and nanoscaled surface topographies
on cellular functions including morphology, adhesion, motility, proliferation,
and gene regulation [25–35]. Thus, various topographic features namely pores,
ridges, grooves, fibers, nodes, and combinations of these features were created
using a wide range of fabrication techniques [1, 46–54].
Advances in nanotechnology have enabled the fabrication of various
structures in nanodimensions, and such structures vary from thin films to
genetic constructs that are used for building biological molecules. All the
nanofabrication techniques have been focused on two approaches, namely the
top-down and bottom-up. The top-down approach includes lithographic
techniques (e.g., soft, photo, colloidal, and electron beam lithography),
electrospinning, polymer demixing, phase separation, evaporation techniques,
and chemical etching. The bottom-up includes assembly process (supramole-
cular, assembly, monolayer, directed self-assembly), nanoparticle formation,
and probe lithography to name a few. The resulting nanostructures may result
in an ordered surface nanotopography or a ran dom topography that will affect
cellular functions, and thus cells behave according to the surface topography to
which they are exposed. Nanofabrication techniques such as photolithography
and electron beam lithography provide ordered nanotopographic surfaces.
Recently, electrospinning has emerged as a promising technique to create
nanofibers, and these nanofibers, can also be aligned to produce ordered
nanotopographies [54]. Other techniques such as polymer demixing, phase
separation, colloidal lithography, and self-assembly result in random surface
topographies. Random topographies are created spontaneously during the
process of fabrication or processing itself. These structures are randomly
organized, arranged without any control on the geometry and reproducibility.
However, creating these nanotopographic features is simple, inexpensive, and
spontaneous. On the contrary, fabrication of ordered nanotopographic
features requires complex and expensive equipments and sound technical
knowledge. Table 10.1 summarizes various popularly studied nanotopography
fabrication techniques, advantages, shortcomings, and observed changes in
cellular behavior. We will discuss some of the most commonly used
264 BIOMEDICAL NANOSTRUCTURES
TABLE 10.1 Summary of Nanotopographic Surfaces Created Using Different Fabrication Techniques and Observed Cellular Behavior
Technique
Topographic
features Merits Shortcomings Cell type used
Observed
change in
cellular
behaviors References
Ordered nanotopographic surfaces
1 Electron
beam
lithography
Square groove,
ridges, and
nanopillars
Dimensions
14 nm to
several microns
With the aid of
computer can
create precise
geometries and
patterns without
any mask
Expensive
equipment, more
time, lower
resolution, hard
to pattern large
surface area
Gingival
fibroblasts,
embryonic
Xenopus spinal
cord neurons,
rat hippocampal
neurons, corneal
epithelial cells,
keratocytes
Strong
alignment,
migration,
and
orientation
[52, 55–62]
2 (a) Photolithography
(near-UV)
coupled with
(b) etching
(a) Square- and
V-shaped
grooves,
ridges, round
nodes.
Dimensions
range between
30 nm to several
microns and
most frequently
dimensions with
few microns are
created
(b) Depends
on the nature and
time of etching
agent used
(a) Create precise
geometries and
patterns
(b) Fast,
simple, and
inexpensive
(a) Expensive and
complicated
instrumentation
and nanodimensions
at the higher side
(b) Difficult to
fabricate specific
geometric features
Rat dermal
fibroblasts,
P388D1
macrophages,
peritoneal
macrophages,
BHK, MDCK
cells, chick
embryo cerebral
neuron, Uromyces
appendiculatus
fungus, murine
macrophages, rat
astrocytes
Improved
orientation,
faster
spreading,
migration
into the
structures
and strong
alignment
[63–69]
265