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

840 Tissue Engineering

relevant compounds. The surface onto which cells are testine use cellular aggregates isolated from intestinal
grown is often shaped according to the final application. tissue which are seeded onto polymer meshes shaped in a
For example, bioartificial vascular grafts have been pro- tubularformandanastomosedtothesmallbowelinanimal
ducedbyseedingendothelialcellsontotheluminalsurface models. The aggregates develop and form villus structures
of small-diameter (6 mm or less) synthetic vascular grafts. lined with a columnar epithelium reminiscent of the in
In cases where the ability to control transport is not vivo counterpart, and in some areas a subjacent connective
an important aspect of the function of the bioengineered tissue containing smooth muscle cells develops. Anas-
tissues, a simple way to maintain certain epithelial cells tomosis to the existing bowel and bowel resection in the
is via seeding in a three-dimensional matrix in a man- host receiving the implants have significantly improved
ner similar to that used for connective tissue construction. morphogenesis and differentiation of the implant.
For example, hepatocytes can be maintained in porous or
mesh-type matrices made of a variety of materials includ-
C. Endocrine Tissues
ing polylactic–glycolic copolymer, alginate, etc., wherein
they have a tendency to aggregate. Such aggregates (some- Major efforts in this area focus on the development of
times called organoids) are known to contain cells that a bioartificial pancreas. Unlike other engineered tissues,
have maintained their phenotypic stability. However, for the bioartificial pancreas does not need to physically inte-
this process to be beneficial, the aggregate size must be grate with the host’s tissues, as its primary function is to
controlled to prevent the formation of large aggregates release insulin in a controlled manner as a function of the
with anoxic cores. patient’s glucose levels. Furthermore, the typical patients
needing insulin therapy do not have any functional islet
tissue available; therefore, allogeneic or xenogeneic islet
3. Epithelial and Connective Tissue Composites
sources must be used. For these reasons, the bulk of stud-
The long-term survival of endothelial and epithelial cells ies on bioartificial pancreases use islets encapsulated in
seeded onto artificial polymers is often problematic due membrane-based devices protecting the islets from the re-
to inflammatory responses and the poor retention of the cipient’s immune system. The first devices (dating back
seeded cells under in vivo conditions. Relevant to the case to the 1970s) mostly consisted of hollow-fiber bioreactors
of vascular grafts, it is noteworthy that cultured endothe- in which islets were placed on the shell side of the biore-
lial cells rapidly become senescent and die in vitro when actor, and the patient’s blood flowed through the fibers.
growth factors are removed from the culture medium. Although these systems worked well over short periods
Thus, long-term retention of the cultured endothelium of- of time, chronically implanted devices tended to activate
ten requires the continual presence of such factors in the blood clotting and eventually become clogged. More re-
implant. A solution to this problem, which also provides cently, more simple avenues have been explored, such as
a more intrinsically biocompatible approach to vascular encapsulating islets in spherical or flat membranes placed
graft production, is to seed cells on an in vivo-like stromal in the host’s tissues.
layer releasing the necessary trophic factors. Similarly, In theory, allogeneic implants will not trigger immune
keratinocytes require either growth factors or a mesenchy- responses as long as the pore size of the capsule is small
mal “feeder layer” of cells in order to survive and grow. enoughtopreventimmunecellsfromthehostfromaccess-
Some epithelial tissues have by the nature of the ing the antigens expressed on the implanted cells. How-
functions performed an extremely complex topology and ever, antigens shed from the cell surface may trigger a
organization, which makes it difficult to reproduce humoral immune response leading to the formation of an-
faithfully in vitro. For example, the intestine has on one tibodies. The proteins involved in this type of immune
side a layer of epithelial cells which selectively transport rejection include immunoglobins such as IgG and IgM,
metabolites into the interstitial tissue space, where a and complement molecules, the largest of which is C1q
large number of microscopic lymphatic and blood vessels (mol wt = 410 kD, diameter = 30 nm) which is required
absorb the transported metabolites. The epithelial layer is for classical pathway complement-mediated cell damage.
organized in the form of villi or invaginations to increase Binding of immunoglobins to cells in the implant without
the surface area of exchange. Although it may be at the presence of the complement system would not neces-
some point possible to reproduce these structures “from sarily lead to cell damage; therefore, some investigators
scratch,” it turns out that some of these features can be have claimed that a membrane with an effective pore size
generated by the cells themselves if placed in the correct of less than 30 nm may suffice to protect the encapsulated
environment, in which case they display an amazing cells. Smaller membrane pore sizes (<50 kD) have been
ability to reorganize themselves into functional tissues. typically used, however. This strategy has shown promise
Recent efforts in the development of bioengineered neoin- in animal models, with function remaining after several