Tissue engineering - Biomedical Engineering Desk Reference - page 648

appropriate scaffold. One essential criterion is bio-
compatibility, i.e., the polymer scaffold should not invoke
an adverse inflammatory or immune response once
implanted ( Babensee et al. , 1998 ). Some important fac-
tors that determine its biocompatibility, such as the
chemistry, structure, and morphology, can be affected by
polymer synthesis, scaffold processing, and sterilization.
Toxic residual chemicals involved in these processes (e.g.,
monomers, stabilizers, initiators, cross-linking agents,
emulsifiers, organic solvents) may be leached out from the
scaffold with detrimental effects to the engineered and
surrounding tissue.
The primary role of a scaffold is to provide a temporary
substrate to which transplanted cells can adhere. Most
organ cell types are anchorage-dependent and require the
presence of a suitable substrate in order to survive and
retain their ability to proliferate, migrate, and differenti-
ate. Cell morphology correlates with cellular activities and
function; strong cell adhesion and spreading often favor
proliferation while a rounded cell shape is required for
cell-specific function. For example, it has been demon-
strated that the use of substrates with patterned surface
morphologies or varied extracellular matrix (ECM) sur-
face coatings can modulate cell shape and function ( Chen
et al. , 1998; Mooney et al. , 1992; Singhvi et al. , 1994 ).
For epithelial cells, cell polarity is essential for their
function. Polarity refers to the distinctive arrangement,
composition, and function of cell-surface and intracellular
domains. This typically corresponds to a heterogeneous
extracellular environment. For example, retinal pigment
epithelium (RPE) cells have three major surface domains:
the apical surface is covered with numerous microvilli;
the lateral surface is joined with neighboring cells by
junctional complexes; and the basal surface is convoluted
into basal infoldings and connected to the basal lamina.
The polymer scaffold for RPE transplantation should
therefore provide proper surface chemistry and surface
microstructure for optimal cell-substrate interaction and,
along with appropriate culture conditions, be able to
induce proper cell polarity ( Lu et al. , 1998 ).
Besides cell morphology, the function of many organs
is dependent on the 3D spatial relationship of cells with
their ECM. The shape of a skeletal tissue is also critical
to its function. Gene expression in cells is regulated
differently by 2D versus 3D culture substrates. For in-
stance, the differentiated phenotype of human epiphy-
seal chondrocytes is lost on 2D culture substrates but
reexpressed when cultured in 3D agarose gels ( Aulthouse
et al. , 1989 ). A polymer scaffold should be easily and
reproducibly processed into a desired shape that can be
maintained after implantation so that it defines the ul-
timate shape of the regenerated tissue. A suitable scaf-
fold should therefore act as a template to direct cell
growth

Porosity, pore size, and pore structure are important
factors to be considered with respect to nutrient supply
to transplanted and regenerated cells. To regenerate
highly vascularized organs such as the liver, porous scaf-
folds with large void volume and large surface-area-to-
volume ratio are desirable for maximal cell seeding,
attachment, growth, ECM production, and vasculariza-
tion. Small-diameter pores are preferable to yield high
surface area per volume provided the pore size is greater
than the diameter of a cell in suspension (typically
10 m m). However, topological constraints may require
larger pores for cell growth. Previous experiments have
demonstrated optimal pore sizes of 20 m m for fibroblast
ingrowth, 20-125 m m for adult mammalian skin re-
generation, and 200-400 m m for bone ingrowth ( Boyan
et al. , 1996; Whang et al. , 1995 ). The rate of tissue in-
vasion into porous scaffold also depends on the pore size
and polymer crystallinity ( Mikos et al. , 1993c; Park and
Cima, 1996; Wake et al. , 1994 ). Compared to isolated
pore structure, an interconnected pore network enhances
the diffusion rates to and from the center of the scaffold
and facilitates vascularization, thus improving oxygen and
nutrient supply and waste removal. The vascularization
of an implant is a prerequisite for regeneration of most
3D tissues except for cartilage, which is avascular.
Mechanical properties of the polymer scaffold should
be similar to the tissue or organ intended for regenera-
tion. For load-bearing tissues such as bone, the scaffold
should be strong enough to withstand physiological
stresses to avoid collapse of the developing tissue. Also,
transfer of load to the scaffold (stress shielding) after
implantation may result in lack of sufficient mechanical
stimulation to the ingrowing tissue. For the regeneration
of soft tissues such as skin, the scaffolds are required
to be pliable or elastic. The stiffness of the scaffold may
affect the mechanical tension generated within the cell
cytoskeleton, which is critical for the control of cell
shape and function ( Chicurel et al. , 1998 ). A more rigid
surface may facilitate the assembly of stress fibers
and enhance cell spreading and dividing. Scaffold com-
pliance may also affect cell-cell contacts and aggregation
( Moghe, 1996 ).
Understanding and controlling the degradation pro-
cess of a scaffold and the effects of its degradation
products on the body is crucial for long-term success of a
tissue-engineered cell-polymer construct. The local drop
in pH due to the release of acidic degradation products
from some implants may cause tissue necrosis or in-
flammation. Polymer particles formed after long-term
implantation of a scaffold or due to micromotion at the
implantation site may elicit an inflammatory response.
Microparticles of polymers have been shown to suppress
initial rat-marrow stromal osteoblast proliferation in
culture ( Wake et al. , 1998 ). The mechanism by which
the scaffold degrades should also be considered. For

and ECM formation and facilitate the de-

velopment of a 3D structure.