Chinese Science Bulletin
© 2009
SCIENCE IN CHINA PRESS
Springer
Phenomenon of “contact guidance” on the surface
with nano-micro-groove-like pattern and cell physiological effects
ZHOU Feng 1,2, YUAN Lin 1,3, HUANG He 1,2 & CHEN Hong1,2†
1
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan 430070, China;
School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China;
3
Biomedical Materials Research Center, Wuhan University of Technology, Wuhan 430070, China
2
The topography of material surface has important influence on cell behavior and physiological functions. Groove-like pattern has drawn much attention among various patterns, due to the phenomenon
of “contact guidance” induced by this kind of topography. This review mainly focuses on “contact
guidance” formation as well as its influence on cell behavior and physiological effects. The possible
mechanisms of “contact guidance” formation were discussed. The research trend and the potential
applications were also suggested.
contact guidance, topography, cell, groove-like pattern
“Contact guidance” refers to the phenomenon that cells
to grow on nano-micro-groove-like patterns will adjust
their orientation and align along those patterns[1]. Early
in 1912, Harrison[2] noticed that the topography of spider
web can influence the direction of cell motion. This is
the first report that the topography of material could influence cell behavior. Subsequently, Weiss[1] confirmed
the phenomenon Harrison discovered, and defined it as
“contact guidance” in 1945. During 1970s, Rovensky et
al.[3] and Maroudas et al.[4] further substantiated “contact
guidance” in their own researches, respectively. With the
advancement of micro-fabrication technology, a series of
novel methods such as soft-lithography[5,6], electrical
spinning[7], laser beam etching[8,9], electron beam etching[10], hot embossing,[11] etc. have been utilized in fabricating groove-like patterns with different scales on a
variety of substrates. Meanwhile, the influence of the
patterns on cell’s behavior, such as physiological process
and function, has been intensively investigated by using
various cell types such as fibroblast[12], osteoblast[13],
epithelial[14], myoblast,[11] etc. With the further research
and the emerging of tissue engineering, it has been
found that “contact guidance” not only bears the poten-
tial application in construction of cell population with
defined orientation, such as in nerve, tendon repair and
regeneration, and the genesis of normal bone morphology, but also can be utilized in controlling the interactions between materials and cells or tissues, so as to induce specific cell response that can better serve the purpose of tissue engineering[15]. Therefore, “contact guidance” has drawn increasing attention in the application
of tissue engineering[16–20]. However, the factors involved in the occurrence of “contact guidance” and the
corresponding mechanisms have not been thoroughly
elucidated. Moreover, the cellular biological effects induced by the phenomenon have not been systematically
recognized. This review mainly focuses on the major
factors influencing the occurrence of “contact guidance”,
the corresponding mechanisms and the cellular physiological effects caused by the phenomenon, and the research trend is also suggested.
Received January 14, 2009; accepted April 16, 2009
doi: 10.1007/s11434-009-0366-1
†
Corresponding author (email: [email protected])
Supported by the National Natural Science Foundation of China (Grant Nos.
90606013 and 20634030) and Key Grant Project of Chinese Ministry of Education
(Grant No.107080)
Citation: Zhou F, Yuan L, Huang H, et al. Phenomenon of “contact guidance” on the surface with nano-micro-groove-like pattern and cell physiological effects. Chinese
Sci Bull, 2009, 54: 3200―3205, doi: 10.1007/s11434-009-0366-1
At present, a good understanding of the factors that
cause “contact guidance” has been recognized. More
and more evidence indicates that multiple factors, such
as the pattern scale (the width and depth of the ridge),
the mechanical and chemical properties of the material,
cell type and experimental conditions, are associated
with the occurrence of “contact guidance”.
Charest et al.[11] found that after pre-adsorbing a layer
of fibronectin on the polycarbonate substrate, which
consisted of microgrooves with a depth of 5.1 m and
different “ridge” widths, the degree of “contact guidance” primary myoblasts exhibited was inversely proportional to the width of “ridge”. Their findings were
consistent with other similar researches[21]. Additionally,
when the “ridge” width was 10 m, the primary myoblasts exhibited the maximal degree of “contact guidance”, indicating that 10 m was the optimal scale of the
width of “ridge” to induce “contact guidance” of primary myoblasts in their research[22]. Other similar reports also showed that an “optimal scale” of microgroove existed in the induction of “contact guidance” to
a specific type of cell. On the other hand, Teixeira et
al.[14] investigated the influence of groove depth on the
occurrence of “contact guidance”. They found that all
groove-like patterns with “ridge” widths varying from
70nm to 1900nm can induce “contact guidance” among
human corneal epithelial cells. In addition, no significant
difference was detected in the occurrence of “contact
guidance” when the microgrooves were identical in
depth but different in “ridge” widths. However, with the
same “ridge” width, the deeper the groove, the more
pronounced “contact guidance occurred”. And the results were in accordance with other researches; i.e.,
when the “ridge” width is fixed, the groove depth was
the predominant factor in determining the occurrence of
“contact guidance”[12,14,15,23]. Apart from the factors such
as depth and width, researchers further investigated the
threshold scale that can cause “contact guidance”.
Loesberg et al.[12] fabricated microgrooves with different
scales on polystyrene substrate via soft-lithography.
They found that no “contact guidance” occurred during
the initial 4 h, if the depth of micro-groove was smaller
than 75 nm or the “ridge” width was narrower than 100
nm, whereas “contact guidance” occurred if the culture
time was prolonged to 24 h. But the threshold scale
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they reported was different from other researchers` results[22,24]. For example, Rajnicek et al.[22]reported that
bovine corneal epithelial cells and xenopus neurites exhibited significant “contact guidance” on quartz substrates with nano- grooves as shallow as 14 nm. And this
was the shallowest pattern that can induce “contact
guidance” reported till now.
Moreover, research also showed that the occurrence
of “contact guidance” and the occurrence degree were
cell-type-dependent[11,22,23]. According to Fraser et al.[23],
the occurrence of “contact guidance” was cell-type-dependent to a certain extent, e. g., the “threshold” scale
that led to “contact guidance” varied from cell to cell,
meanwhile, the occurrence degree of “contact guidance”
was also different on a specific groove-like patterns for
different cell types. To explain the above discrepancies,
some reports attribute it to the natural differences in cell
biological characteristics. Due to the natural differences
of niches where the cells grow in vivo, the basement of
corneal epithelial cells is normally on the order of
nanometer, while the basement that lens epithelial cells
adhere to is at micron scale in vivo. These inherent biological differences probably account for the distinct
“sensitivity” of the cells to a specific pattern in the similar size, thus resulting in the discrepancies when
“threshold” scale that induces “contact guidance” is investigated[25,26]. In addition, cell culture conditions, for
example, the existence or absence of serum[12,14], the
length of cell culture time[12], etc. can also influence the
occurrence of “contact guidance”. With respect to cell
culture time, no further investigation has been reported. It
has been reported that increasing the culture time is beneficial for the occurrence of “contact guidance”[12,27,28].
However, its mechanism is still not clear.
As discussed above, the scale of groove-like pattern,
especially the depth, has a crucial effect on the occurrence of “contact guidance”. However, compared with
“ridge” width, the reason why the depth of groove plays
a predominant role in the occurrence of “contact guidance” is vague. Additionally, the above researches also
indicate that both “threshold” scale and “optimum” scale
exist in the occurrence of “contact guidance”. Though
discrepancies exist among conclusions in “threshold”
and “optimum” scales, we should consider the potential
influence of the mechanical and chemical properties of
different substrates on the research results. It is reported
that the mechanical properties of substrates such as the
elasticity, and chemical composition will directly influ-
POLYMER PHYSICS
1 The major factors to influence the occurrence of “contact guidance”
ence the behavior and physiological functions of cells on
the substrates[29–32]. All these results enlighten us that
when investigating the influence of groove-like pattern
on cells, we should never ignore those non-pattern factors such as the physical and chemical characteristics,
while considering the geometric scale of the pattern.
Finally, we should also consider the difference in cell
type, culture conditions and observation time, so as to
draw more comprehensive and systematic conclusions
that can guide the potential applications in tissue engineering for the control of cell behavior in the future.
2 The mechanism of “contact guidance”
Further studying the mechanism of “contact guidance” is
important for illustrating this phenomenon. For a long
time, intensive researches on the mechanisms of “contact guidance” have been conducted. Several possible
mechanisms and major factors involved were proposed,
such as the selective distribution of proteins on the patterned surface, the formation of focal adhesion and
alignment, the aggravation and alignment of specific
cytoskeleton and the function of pseudopodia.
2.1 The selective adsorption of proteins
Braber et al.[33] and Recum et al.[34] revealed the mechanism of “contact guidance” in terms of protein adsorption. They discovered that nonuniform deposition of the
extracellular matrix (ECM) protein on anisotropic patterned surface was one possible reason for the occurrence of “contact guidance”. They thought that due to
the different surface energy on anisotropic patterned
surface regions, ECM protein is selectively adsorbed
along the grooves. When contacting such surface, cells
may recognize the proteins regionally distributed on the
surfaces of the patterns and then adhere to the protein,
resulting in the alignment of cell on the groove-like pattern.
It is generally acknowledged that the protein adsorption on the surface is the initial event after the implantation of biomaterials. The structure and composition of
the protein layer determine the type and degree of consequent physiological reaction[35]. Protein adsorption is a
complex process influenced by multiple factors such as
the properties of protein, the surface properties of materials and the microenvironment of the process[36]. More
and more researches have proved that the topography of
the surface can influence the distribution, conformation,
activity and adsorption of protein significantly[36–39].
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Thus, the selective adsorption of protein can cause
“contact guidance”.
2.2 The formation of focal adhesion
Focal adhesion is a kind of trans-membrane complex
mainly composed of integrins, and the major functions
of focal adhesion are mediation of conjunction between
actin filaments and ECM, transduction of mechanical
force and signals[40]. It is reported that the focal adhesion
and its alignment are involved in the occurrence of
“contact guidance”. Braber et al.[33,41], Meyle et al.[42]
and Matsuzaka et al.[43] reported on closely arranged
microgroove patterns, and focal adhesions were almost
exclusively located on the top of the “ridges” and
aligned along with them, due to the restriction imposed
by steric hindrance. The changes of the alignment of
focal adhesion will cause the assembly of microfilaments along the groove, resulting in the directional
alignment of cells, namely, “contact guidance”.
2.3 The aggravation and alignment of cytoskeleton
Cytoskeletons refer to the dynamic structure system that
maintains cell shape and enables cellular motion, and
they primarily consist of microfilaments, intermediate
filaments and microtubules. Gerecht et al.[44] found that
the addition of actin disrupting agents attenuated the
“contact guidance”, if human embryo stem cells were
cultured on poly(dimethylsiloxane) substrate with submicron scale grooves. Based on the findings, they
deemed that the actin played a crucial role in the occurrence of “contact guidance”. However, some other findings showed that the cell can still align along the microgrooves even if actin and microfilament were both inhibited by their respective disrupting agents[45–47]. Based
on the above findings, they thought the activity of both
the proteins was not the prerequisite for the occurrence
of “contact guidance”.
At present, no agreed conclusion has been reached on
whether the activity of actin and microfilament is essential for the occurrence of “contact guidance”.
2.4 The function of pseudopodia
Pseudopodia, which are primarily composed of actin, are
temporary dynamic projections of eukaryotic cell membrane. Pseudopodia play an important role in sensing the
stimulus of surroundings and guiding the locomotion of
cells[48]. Evans et al.[49] investigated the behavior of
pseudopodia, and they reported that the occurrence of
“contact guidance” was due to the steric hindrance caused
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3 The physiological effects induced by
“contact guidance”
With the further research of “contact guidance”, researchers not only studied the influence of “contact
guidance” on cell behavior, but also investigated the
effects on cell physiological functions in the meantime.
They discovered that the groove pattern can not only
influence the macroscopic behavior such as the cell
alignment, but also has profound influence on the cell
physiological behavior and function.
Yim et al.[52] found that “contact guidance” can significantly promote the differentiation of mesenchymal
stem cells on PDMS substrates consisting of microgrooves, and the promotion was indicated by the Tuj1,
MAP2, and GFAP genes, which are linked to the expression of tubulin. In addition, they also found the
promotion was directly proportional to the occurrence
degree of “contact guidance”. Gomez et al.[53]also reported that “contact guidance” can effectively induce the
polarization and axon formation of embryonic hippocampal neurons. On the other hand, Chaubey et al.[54]
compared the influence of microgrooves made of different substrates on multipotent mouse bone marrow
stromal cells (D1 cells). According to their research, the
D1 cells cultured on PLLA substrates displayed an intermediate rate of lipid production through out the experiment, whereas at the early stage of the experiment,
the lipid production of the D1 cells cultured on PS substrates was higher than that of the cells cultured on
PLLA substrate, but the trend was reversed at the late
stage. Apart from the factor of chemical properties of
materials, the influence of mechanical properties such as
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the rigidity, elastic modulus on cell behavior and function has also drawn widespread attention recently.
Tzvetkova-Chevolleau et al.[55] fabricated microgrooves
on PDMS substrates with three different elastic modulus:
“soft” (500 kPa), “hard” (750 kPa), and “very hard”
(2000 kPa). In addition, they investigated the effects of
the three different substrates on the behavior and function of 3T3 cells and SaI/N cells, such as the motility
and polorisation kinetics. They found the time that 3T3
cells need for the ready-state polorisation decreased with
the reduction of elastic modulus of the substrates, while,
the motility of SaI/N cancer cells was significantly
higher on “very hard” (2000 kPa) substrates than on
“soft” (500 kPa) ones.
In conclusion, groove pattern can influence cell’s
physiological function and process profoundly, and the
influence is related to the occurrence and the extent of
“contact guidance”. Besides the geometrical factors, the
material chemical and mechanical properties also have
important effects on cell behavior and function. This
reveals that in addition to cell type and material properties, the behavior and function of seed cells used in tissue engineering can be influenced and regulated by optimizing the topographical structures and chemical
properties of the scaffold.
4 Outlook
In the past, researchers were generally more concerned
about the influence of groove patterns differing in material properties and geometrical scales on the occurrence
and mechanism of “contact guidance”. Currently, with
the deepened research and the improvements made in
fabricating patterns, the researches have begun to embody the following features: first, the combination of
patterns and non-pattern factors. This mainly includes
two sub-areas: a) the combination of pattern and bioactive molecules[54] and b). the combination of patterns and
extra forces[22]. Cell physiological response might be
controlled more effectively by the systematic combination of pattern and other factors. Second, the application
of intelligent materials. For example, in the field of Cell
Sheet Engineering, researchers can achieve the non-invasive detachment of cell sheet by decorating a layer of
thermo-sensitive material on the groove pattern[56]. Third,
the influence of groove pattern on cells in vivo. It is well
known that it is an extremely complicated environment
in vivo, and the implant materials always endure the
Zhou F et al. Chinese Science Bulletin | September 2009 | vol. 54 | no. 18
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POLYMER PHYSICS
by the “ridges” horizontally perpendicular to groove
pattern filopodia and lamellipodium confronted. Teixeira
et al.[14] and Dalby et al.[50] also reported that filopodia
and lamellipodium can “sense” the stimulus of the steric
hindrance horizontally perpendicular to groove-like pattern. Therefore, pseudopodia can only exert contracting
force parallel with the groove, resulting in the cell
alignment along the groove-like pattern.
Based on the above research, it is widely accepted
that the co-effect of one factor or multiple factors contribute to the mechanism of “contact guidance”.
Andersson et al.[28] and Hamilton et al.[51] also substantiated that multiple factors were involved in the mechanism of “contact guidance” as we discussed above.
chronical influences of dynamic stress, and chemical
and biological factors. To the best of our knowledge, the
researches primarily focused on cellular level in vitro at
present, and the similar studies in vivo were overlooked.
Whereas it is more important and meaningful in the de1
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