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

Tissue Engineering 821

which is isolated from rat tail or bovine skin by mild acid development of synthetic biocompatible polymers, which
treatment. The acid solution of collagen can be induced theoretically have an unparalleled range of physical and
to form a gel upon restoring a physiological pH of 7.4, chemical properties. In practice, however, most tissue en-
which causes the polymerization of collagen molecules gineering development has been limited to using a rela-
into a large network of fibrils. The extent of cross-linking tively small number of man-made materials, in part due to
in this collagen is very low in comparison with that of a reluctance to expend time and money to secure regula-
the native tissue, and as a result reconstituted collagen tory approval for clinical use of untested biomaterials. The
gels undergo rapid proteolytic degradation in vivo.To most extensively used materials in medicine are titanium
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remediate this problem, chemical cross-linking is induced and inert plastics such as Teflon for orthopedic applica-
by either glutaraldehyde or dehydrothermal (vacuum tions and artificial vascular graft prostheses, respectively.
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and ∼100 C) treatment. For example, the skin substitute Typical problems encountered with artificial orthopedic
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Integra is made of a mixture of solubilized collagen and materials include failure of the graft–host tissue interface
glycosaminoglycans whose extent of cross-linking has in the case of bone substitutes, which may be due to an
been optimized to withstand the specific environment of adverse reaction to the artificial material, and progressive
dermal wounds such as nonhealing ulcers and deep burns. wear-and-tear in artificial joints, which do not have the
Materials used in tissue engineering must be able to ability to regenerate and repair, unlike natural joint sur-
withstand physical forces to which they are subjected. faces. Artificial vascular grafts tend to activate the blood
These forces naturally occur in load-bearing tissues such clotting cascade and may also cause thickening of the vas-
as bone and cartilage, as well as in other applications such cular tissue near the point of attachments to the host’s
as blood vessels, which must have burst pressures exceed- vascular tree. These responses do not pose a major prob-
ing arterial levels. Physical forces can also be generated lem for the function of large-diameter grafts (e.g., thoracic
by the cells making up the bioartificial tissue, as cells have aorta), but have prevented their use as smaller vessels such
been shown to exert tractional forces on their points of at- ascoronarybypasssegments,forwhichthedemandisvery
tachment. Known examples of the effect of cell tractional high. Finally, all artificial materials implanted in vivo are
forces include the contraction of collagen gels by fibrob- highly susceptible to colonization by bacteria which can
lasts and the formation of “ripples” by cells placed on thin form biofilms highly resistant to antibiotics. Furthermore,
flexible silicone sheets. Specific mechanical properties are recent studies suggest that the function of immune cells
required in certain applications, especially in the case of may also be compromised on certain artificial surfaces,
artificialvasculargrafts,whichmustexhibitthesamecom- which reduces the ability of the host to clear infections.
pliance as that of normal blood vessels. The mismatch in To overcome the problems due to foreign-body re-
compliance that often occurs between the host’s vessel and actions caused by artificial materials, there is currently
the graft is believed to be be an important factor leading heightened interest in the use of biocompatible polymers
to artificial vascular graft failure in vivo. which naturally degrade in vivo. One of the best known
Systems using cells that do not secrete a structurally and most commonly used synthetic biodegradable poly-
dense extracellular matrix must rely on the synthetic ma- mers in tissue engineering are the poly(lactic-co-glycolic)
trix provided to retain their structural integrity. The matrix acid copolymers, which have been used in the form of
must be able to withstand both the weight of the cul- biodegradable sutures for several decades. In 1988, Robert
tured cells as well as tensile forces generated by cells S. Langer (Massachusetts Institute of Technology) and
growing on the substrate. The use of relatively fluid sub- Joseph P. Vacanti (Children’s Hospital, Boston) pioneered
strates induces different cellular morphologies than does their use in tissue engineering. Currently used as part of
the use of rigid surfaces. Because fluid substrates can- skin substitutes commercialized by Advanced Tissue Sci-
not oppose cell-generated forces, cell–cell adhesive forces ences, they are now the most widely investigated artifi-
predominate over cell–substrate adhesive forces, which cial biodegradable polymers in tissue engineering, with
leadstocellaggregationasseenwithhepatocytesplatedon applications including cartilage, bone, and various ep-
heat-denatured collagen as opposed to type I collagen. In ithelia (intestine, bladder, liver). This material hydrolyzes
high-density, three-dimensional cultures, cell-generated completely within weeks, months, or years, depending on
forces may become significant as seen with fibroblasts that the exact composition (in general, increased hydropho-
can dramatically reduce the volume of collagen lattices. bicity correlates with a decreased degradation rate) and
Naturally derived matrices provide good substrates for thickness. Cells migrating in from surrounding tissues
cell adhesion because cells express the adhesion recep- after implantation in vivo, or cells directly seeded into
tors which specifically recognize and bind to extracellular the polymer, secrete their own extracellular matrix which
matrix molecules which make up these matrices. Nev- gradually replaces the polymer scaffold as the latter slowly
ertheless, there have been considerable advances in the dissolves away. It is important that the degradation rate of