Tissue engineering - Biomedical Engineering Desk Reference - page 620

sciences that use living cells or attract endogenous cells to
aid tissue formation or regeneration, and thereby pro-
duce therapeutic or diagnostic benefit. In the most fre-
quent paradigm, cells are seeded on a scaffold composed
of synthetic polymer or natural material (collagen or
chemically treated tissue), a tissue is matured in vitro,
and the construct is implanted in the appropriate ana-
tomic location as a prosthesis ( Langer and Vacanti, 1993 ;
Fuchs et al. , 2001 ; Griffith and Naughton, 2002 ; Rabkin
and Schoen, 2002 ; Vacanti and Langer, 1999 ). A typical
scaffold is a bioresorbable polymer in a porous configu-
ration in the desired geometry for the engineered tissue,
often modified to be adhesive for cells, in some cases
selective for a specific circulating cell population.
The first phase is the in vitro formation of a tissue
construct by placing the chosen cells and scaffold in
a metabolically and mechanically supportive environ-
ment with growth media (in a bioreactor ), in which the
cells proliferate and elaborate extracellular matrix. In the
second phase, the construct is implanted in the appro-
priate anatomic location, where remodeling in vivo is
intended to recapitulate the normal functional architec-
ture of an organ or tissue. The key processes occurring
during the in vitro and in vivo phases of tissue formation
and maturation are (1) cell proliferation, sorting, and
differentiation, (2) extracellular matrix production
and organization, (3) degradation of the scaffold, and
(4) remodeling and potentially growth of the tissue. The
general paradigm of tissue engineering is illustrated in
Fig. 7.1.1-2 . Biological and engineering challenges in
tissue engineering are focused on the three principal
components that comprise the ''cell-scaffold-bioreactor
system''; control of the various parameters in device
fabrication ( Table 7.1.1-1 ) may have major impact on the
ultimate result. Exciting new possibilities are opened by
advances in stem cell technology ( Blau et al. , 2001 ;
Bianco and Robey, 2001) and the recent evidence that
some multipotential cells possibly capable of tissue re-
generation are released by the bone marrow and circu-
lating systemically (Hirschi et al. , 2002) while others
may be resident in organs such as heart and the central
nervous system formally not considered capable of re-
generation ( Hirschi and Goddell, 2002 ; Grounds et al. ,
2002 ; Nadal-Ginard et al. , 2003 ; Johansson, 2003 ; Orlic
et al. , 2003 ).
Tissue-engineered configurations for skin replacement
have achieved clinical use. Further examples of previous
and ongoing clinical tissue engineering approaches include
cartilage regeneration using autologous chondrocyte
transplantation (Brittberg et al. , 1994) and a replacement
thumb with bone composed of autologous periosteal cells
and natural coral (hydroxyapatite) ( Vacanti et al. , 2001 ).
A key challenge in tissue engineering is to understand
quantitatively how cells respond to molecular signals
and integrate multiple inputs to generate a given response,

Third Generation (~2000>)
Goal: Regenerate functional tissue
Biointeractive, integrative, resorbable; stimulate
specific cell response at molecular level
(e.g., proliferation, differentiation, ECM production
and organization)

Second Generation (1980s>)
Goal: Bioactivity
Resorbable biomaterials; controlled reaction
with physiological environment (e.g., bone
bonding, drug release)

First Generation (1950s>)
Goal: Bioinertness
Minimal interaction/reaction

Fig. 7.1.1-1 Evolution of biomaterials science and technology.
(From Rabkin, E., and Schoen, F. J. 2002. Cardiovascular tissue
engineering. Cardiovasc. Pathol. 11: 305.)

The second generation of biomaterials also included
the development of resorbable biomaterials with variable
rates of degradation matched to the requirements of
a desired application. Thus, the discrete interface be-
tween the implant site and the host tissue could be
eliminated in the long term, because the foreign material
would ultimately be degraded by the host and replaced
by tissues. A biodegradable suture composed of poly-
(glycolic acid) (PGA) has been in clinical use since 1974.
Many groups continue to search for biodegradable poly-
mers with the combination of strength, flexibility, and
a chemical composition conducive to tissue development
(Hubbell, 1999; Griffith, 2000 ; Langer, 1999 ).
With engineered surfaces and bulk architectures tai-
lored to specific applications, ''third generation'' bio-
materials are intended to stimulate highly precise
reactions with proteins and cells at the molecular level.
Such materials provide the scientific foundation for mo-
lecular design of scaffolds that could be seeded with cells
in vitro for subsequent implantation or specifically attract
endogenous functional cells in vivo. A key concept is that
a scaffold can contain specific chemical and structural
information that controls tissue formation, in a manner
analogous to cell-cell communication and patterning
during embryological development. The transition from
second- to third-generation biomaterials is exemplified by
advances in controlled delivery of drugs or other bi-
ologically active molecules. Nanotechnology and the de-
velopment of microelectromechanical systems (MEMSs)
have opened new possibilities for fine control of cell be-
havior through manipulation of surface chemistry and the
mechanical environment (Chen et al., 1997; Bhatia et al.,
1999;

Huang and Ingber, 2000 ; Chiu et al., 2000,

2003).
Tissue engineering is a broad term describing a set of
tools at the interface of the biomedical and engineering