Fisher John P. e.a. (ed.) Tissue Engineering

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5-8 Tissue Engineering

50 100 150 200

250

0.0

0.2

0.4

0.6

0.8

1.0

Fraction adherent

Wall shear stress,t

(dyn/cm

)

␶50

FIGURE 5.3 Probability distribution for cell adhesion. NIH 3T3 ﬁbroblasts were detached from glass using a radial-

ﬂow chamber. Squares correspond to the fraction of cells that resisted detachment as a function of the applied shear

stress. The curve is a best ﬁt of the integral of a normal distribution function to the data. The characteristic measure

of cell adhesion, τ

, is 129 dyn/cm

for this test.

∆P

FIGURE 5.4 Micropipet aspiration. As suction, P, is applied the cell is drawn into the pipet and membrane tension,

, is exerted at the point of cell/material contact. (Adapted from Evans, E., Berk, D., and Leung, A., Biophys. J. 59,

838, 1991. With permission.)

receptor/ligand contact [89]

≈ PR

/2[1 −R

] (5.1)

The tension disrupts adhesive contacts in a manner that may be modeled as either a peeling process [91] or

the failure of discrete cross-bridges [92], and can be used to predict receptor/ligand dissociation kinetics

under mechanical strains [93].

5.4.2 Centrifugation

The centrifugation approach exploits the difference in density between cells, ρ

= 1.07 [62], and culture

medium, ρ

= 1.00, to exert a supergravitational body force,

f = (ρ

−ρ

a (5.2)

on the cell. Here V

and a are the volume of the cell and the acceleration generated by the centrifuge,

respectively. Distractive vectors both tangential [94] and normal [95,96] to the adhesive substrate have

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Cell Adhesion 5-9

been used experimentally, although computational modeling predicts that tangential forces can be 20 to

56 times more disruptive to cell adhesion [97].

The experimental approach of Chu et al. [95] involves seeding cells onto substrates within 96 well plates,

placing the plates into the 96 well-plate buckets of a table top centrifuge, and then applying accelerations of

a = 50, 100, 200, or 300 g. Images are then collected to calculate the percent of cells that remain attached

as a function of applied force, f . In contrast, the approach of Thoumine et al. [94] involves seeding cells

onto plastic slides that are then ﬁt into centrifuge tubes and placed in a swinging bucket centrifuge. Cells

are then exposed to accelerations of 9,000 to 70,000 g for 5 to 60 min. Thoumine et al. also showed that

the distractive force can be increased further by allowing the cells to phagocytose 1.5 µm gelatin-coated

glass beads. As with Chu et al., images are analyzed to determine the percent of adherent cells as a function

of time and distractive force.

5.4.3 Laminar Flow Chambers

Laminar ﬂow devices are commonly used to characterize cell adhesion, and include rotating disc, parallel-

plate (and variants), and radial-ﬂow devices. These devices all employ tangential ﬂuid ﬂow to exert

hydrodynamic drag and torque on adherent cells [98]. Among the different devices, the parallel-plate ﬂow

chamber (Figure 5.5a) is described most extensively, and has been used primarily to characterize cell and

tissue phenomena under a well-deﬁned hydrodynamic shear stress, τ .Here,τ can be predicted from ﬂuid

mechanics,

τ =

6µQ

(5.3)

(b)

(c)

Inlet

Outlet

(a)

Inlet

Outlet

Cell-coated substrate

h(x)

Cell-coated substrate

Axis of

symmetry

Outlet

Inlet Inlet

Cell-coated substrate

FIGURE 5.5 Various laminar ﬂow chambers geometries. (a) Parallel-plate ﬂow chamber uses linear laminar ﬂow

through a rectangular conduit with constant width, b, and height, h,whereb  h. (b) Variable height laminar ﬂow

chamber uses ﬂow through a tapered conduit, h(x), of constant width to produce a ﬂow proﬁle that depends on

position, x. (c) Radial-ﬂow chamber uses cylindrical geometry to produce a ﬂow proﬁle that depends on position, r.

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5-10 Tissue Engineering

where Q is volumetric ﬂow rate, h and w are the height and width of the ﬂow path, respectively, and µ is

the ﬂuid viscosity [99]. The advantage of this device is that it permits nondestructive in situ visualization

of cell attachment [100], detachment [101], and rolling processes [102]. However, because a single shear

stress is generated across the cell-seeded substrate, multiple substrates must be tested at different shear

stresses in order to construct shear-dependent patterns of cell adhesion [100,101].

Minor modiﬁcations have been made to the parallel-plate ﬂow chamber geometry in order to produce

a spatially dependent range of shear stresses across a single substrate. For example, a variable gap height

device has been constructed in which h is a linear function of the distance from the inlet, x (Figure 5.5b)

[103]. In another device the width of the ﬂow path varies inversely with distance from the inlet, w ∝ 1/x,

to produce a Hele–Shaw ﬂow pattern and a hydrodynamic shear stress that increases linearly with distance,

τ ∝ x [104,105].

An alternative device, the radial-ﬂow chamber uses axisymmetric ﬂow between parallel surfaces to

generate a spatially dependent range of hydrodynamic shear stresses [65,106] (Figure 5.5c). Here, the

magnitude of the shear stress is predicted by the equation

τ =



3µQ

πh

−

3ρQ

70π



(5.4)

where r is radial distance from the axis of symmetry, and ρ is ﬂuid density. The ﬁrst term of this equation

is the creeping ﬂow solution (analogous to Equation 5.3) and the second term is a ﬁrst-order correction

to account for inertial effects at high Reynolds numbers or low radial positions. It is interesting to note

that the contribution of the second term depends on the direction of ﬂow (i.e., the sign of Q) [106].

5.4.4 Rotating Disc

The rotating disc differs from laminar ﬂow chambers in that a motor is used to put the cell-seeded

substrate in motion, rather than a pressure gradient to put the ﬂuid in motion [47,107,108] (Figure 5.6).

An advantage of this device is that generates a shear stress, τ , that varies linearly with radial position, r,

by the equation [107]

τ = 0.800r



ρµω

(5.5)

Here, ρ, µ, and ω are ﬂuid density, ﬂuid viscosity, and angular velocity, respectively. However, a dis-

advantage is that cell adhesion cannot be examined in situ. Instead, the cell-seeded substrate must be

removed from the apparatus in order to collect images of adherent cells.

Cell-coated

substrate

Baffles

Shaft to motor

Axis of

symmetry

FIGURE 5.6 Rotating disc apparatus. The rapid rotation of the cell-seeded substrate generates a hydrodynamic shear

that is proportional to radial position, r. (Adapted from García, A.J., Huber, F., and Boettiger, D., J. Biol. Chem. 273,

10988, 1998. With permission.)

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Cell Adhesion 5-11

5.4.5 Interpretation of Adhesion Data

Proper interpretation of adhesion data remains a technical challenge because quantitative measures are

sensitivetocell history. As spherical, nonadherent cellsare brought into contact with biomaterial interfaces,

receptor-mediated contact initiates, followed by the clustering of receptors, cell spreading, and reorgan-

ization of the actin cytoskeleton. This dynamic process involves changes in the number and organization

of adhesive contacts, cell shape, and the viscoelastic properties of the cell body — all of which inﬂuence

the measured strength of adhesion. For example, quantitative measurements have demonstrated a linear

dependence of the strength of cell adhesion on the density of adhesive ligands in the absence of cooperat-

ive binding [47] that is consistent with kinetic theory [109], but the strength of adhesion is increased by

receptor activation [107] and modulated by receptor clustering [62]. In addition, cell adhesion has been

shown to increase with the duration of cell/surface incubation [101], but it is difﬁcult to deconvolve the

individual effects of cell/surface contact area, focal adhesion organization, and ﬁlamentous actin content.

Further, detachment assays that use hydrodynamic shear are sensitive to the hydrodynamic proﬁle of the

cell [110] and its deformability [111]. Consequently cells that are more spread or deform rapidly at the

onset of shearing ﬂow are more likely to resist detachment [48].

5.5 Effect of Biomaterial on Physiological Behavior

Establishment of adhesive cellular contacts with a biomaterial surface is critical for anchorage-dependent

cell functions, such as spreading, proliferation, and migration. Studies of cell spreading indicate system-

atic increases in the rate and the extent of spreading with increasing density of adhesive ligands [112]

or peptides [113]. In addition, microtubule and ﬁlamentous actin content increase during the initial

spreading process [112]. Cell shape is also affected by the extent of cell spreading. For example, the aspect

ratio of ﬁbroblastic cells — which typically exhibit a spindle-shaped morphology — is maximal at an

intermediate projected cell area [113]. Cell viability and proliferation also depend on projected cell area.

Using microcontact printing to restrict the extent of cell spreading, Chen et al. [114] showed that when

cells are able to adhere but not spread, apoptosis (programmed cell death) is signiﬁcant. However, as the

area for cell spreading is increased apoptosis declines and cell proliferation occurs.

Migration is another adhesion-dependent phenomenon, and requires polarized cells to executecoordin-

ated steps that include pseudopodal extension, ﬁrm adhesion, contraction, and uropodal release [115].

Because both the pseudopodal attachment and uropodal release are adhesive processes, the capacity of

the substratum to mediate cell adhesion directly affects the speed of cell migration. Manipulation of the

strength of cell adhesion by changing the density, and type of ECM proteins has been shown to affect

migration, with maximal speed occurring at an intermediate substratum adhesiveness [46]. In addition,

migration rate can be modulated by depositing adhesive moieties as clusters [116] or by introducing

topographical features [117].

5.6 Summary

In mammalian tissues and organs cell/cell and cell/ECM interactions are mediated through several families

of adhesion receptors, which include integrins, cadherins, and members of the immunoglobulin super-

family. Biological studies have revealed that these adhesive contacts mechanically link the cell cytoskeleton

to extracellular structures, initiate intercellular signaling cascades, and regulate cell viability, prolifera-

tion, organization of tissue structures, and cell function. Existing biomaterials — intended to replace

tissue function or to serve as temporary scaffolds for engineered tissues — are capable of supporting

cell adhesion, viability, and proliferation through a combination of nonspeciﬁc and integrin-mediated

interactions. The current challenge is to develop bioactive materials that can act through different types

of cell receptors to regulate cell and tissue behavior.

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5-12 Tissue Engineering

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