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Encyclopedia of Physical Science and Technology EN016J-783 August 1, 2001 10:58

Tissue Engineering 837

FIGURE 17 Deformation of cell aggregate during compression.
FIGURE 16 Possible configurations of cells on a flat substrate.
In the absence of any adhesion, cells remain in single cell sus-
pension (bottom left quadrant). Increasing substrate-cell adhesion
they will reach a predictable configuration that minimizes
causes cells to stick to the surface. Increasing cell–cell adhesion
the surface free energy. In the case where each cell has
from that point causes the cells to attach to each other and form
monolayers. Increasing cell–cell adhesion further promotes ag- uniform stickiness on its entire surface, the possible con-
gregation of the cells on the substrate. figurations are illustrated in Fig. 18.
This theory has been tested and verified extensively us-
trophic factors (for the most part unknown) secreted by ing aggregates of embryonic cells. Furthermore, by chang-
“feeder” cells. Greater use of different cell types used in ing the level of expression of surface adhesion molecules
co-culture will enable engineered cell systems to closely via hormonal induction or genetic engineering, it was pos-
mimic in vivo organization, with potential benefits includ- sible to alter the organization of such cell aggregates in
ing increased cell function and viability and greater range a predictable fashion. It is important to note, however,
of functions expressed by the bioartificial tissue. The orga- that although the theory was derived for a closed system
nization of multicellular three-dimensional structures may at equilibrium, all of the cultured cell systems examined
not be obvious. Provided that the adherence of homotypic were in fact open systems because the cells were dissi-
and heterotypic interactions is known, a thermodynamic pating energy provided by the culture medium. Thus, care
analysis similar to that used to describe the morphology should be taken when using this approach to analyze more
of a pure cell culture on a surface can be used to predict complex cases. In addition, further refinement to the ap-
how cells will organize in these systems. The process of plication of the equations will be required in cases where
cell–cell sorting in multicellular systems may be altered cell adhesiveness is not uniformly distributed. This situa-
by changing the composition of the medium or altering tion is common to most epithelial cells, which exhibit poor
the expression of proteins mediating cell–cell adhesion to negligible cell–cell adhesiveness on the apical surface,
via genetic engineering. and as a result tend to form tubular cell structures.
Predicting the organization of simple multicellular sys-
tems containing more than one cell type is possible if
E. Summary
the relative cohesiveness of each cell type with respect
to each other is known. The cohesiveness of a tissue is Tissue engineering is the construction of bioartificial tis-
exactly the same as a tissue surface tension analogous sues in vitro as well as the in vivo alteration of cell
to a liquid surface tension. The tissue surface tension growth and function via implantation of suitable cells iso-
σ has been measured in homogenous three-dimensional lated from donor tissue and biocompatible scaffold mate-
cellular aggregates by measuring the compression force rials. Biomaterials for tissue engineering must have con-
required to deform an aggregate into a flattened droplet trolled surface chemistry, porosity, and biodegradability
shape (Fig. 17). in order to promote optimal cell adhesion, migration, and
The force exerted by the cell aggregate on the compres- deposition of endogenous extracellular matrix materials
sion plate is given by the Laplace equation: by the cells. Strategies to switch cells between growth
and differentiation, which tend to be mutually exclusive,

F eq 1 1
= σ + (25) are used in order to provide a large cell mass that can
π R 2 R 1 R 2
3 perform specific differentiated functions required for the
where F eq is the force measured after sufficient time has tissue construct. Combinations of cells and materials have
been allowed for the aggregate, which behaves as a visco- the ability to reorganize themselves based on the strength
elastic liquid, to relax. of adhesion between cells and substrate and among the
When tissues A and B are combined, they will reorga- various cell types present in the tissue construct. Finally,
nize depending on the relative values of σ. At equilibrium, tissue constructs must be intimately integrated into the