Continuum Modelling of In Vitro Tissue Engineering: A Review - Computational Modeling in Tissue Engineering - page 222

engineering involves implanting (e.g.) degradable scaffolds or gels loaded with
cells directly into the body. In each case, degradation of these artificial supporting
structures and their replacement by extracellular materials—such as collagen and
proteoglycans (Freed et al. 1994 ; Hutmacher 2000 )—leads to eventual tissue
repair. In vivo tissue engineering uses the human body as a natural bioreactor, the
perceived advantage being that the human body offers the correct physical and
biochemical cues to enable creation of functional, viable tissue. However, the
mechanisms by which these cues are employed by the cells are not well under-
stood; a thorough review of in vivo tissue engineering considerations is given by
Zdrahala and Zdrahala ( 1999 ). In what follows, we concentrate on in vitro tissue
engineering, where tissue growth occurs under closely monitored and controlled
environmental and operating conditions.
1.1.1 Cell Populations
The tissue engineering concepts outlined above are conceptually straightforward;
however, in practice many barriers remain to be overcome. Fundamental problems
include stimulating sufficient cellular proliferation to colonise the scaffold and
preventing dedifferentiation of the seeded cell population. An approach mitigating
the former problem involves using tissue precursor cells or multipotent stem cells,
which have high proliferative capacity and can be induced to differentiate to a
number of different cell types (Risbud and Sittinger 2002 ). The literature regarding
the use of stem cells in tissue engineering and, for instance, the methods by which
they can be induced to differentiate along different cell lines is extensive; a good
introduction is given by Salgado et al. ( 2004 ) and references therein. We choose not
to review this literature here, preferring to focus on continuum modelling of bio-
chemical (and biophysical) aspects of tissue growth; implicit in the mathematical
models that we analyse are the assumptions that, on the timescale of interest, the cell
population has sufficient proliferative capacity to colonise the scaffold.
The mechanical forces that cells experience affect their differentiation, prolif-
eration, orientation, gene activity and a host of other activities; indeed, as we
indicate below, culturing cells in an in vivo-like mechanical environment can
maintain differentiated function of the seeded cells. The stimuli are integrated into
the cellular response via a process known as mechanotransduction. The mechan-
ical environment of the tissue comprises both internally generated and externally
applied forces. Internally generated forces may include active forces generated by
cells during movement and adhesion, or residual stresses brought about by tissue
growth and remodelling; the presence of such stresses has been observed in a
variety of soft tissues (examples include arterial and venous tissue, myocardium
and the trachea) and, in many cases, is crucial to their correct function. For
example, residual stresses act to minimise the peak stress across the depth of the
arterial wall (Chuong and Fung 1986 ) and are involved in wall remodelling (Fung
1991 ). Externally applied loads that act in vivo include macroscale forces due to
movement and muscle contraction, and shear stress induced by fluid flow. Such