mikos: “9026_c025” — 2007/4/9 — 15:52 — page6—#6
25-6 Tissue Engineering
The three groups of polymeric biomaterials commonly used in tissue engineering applications include
(1) naturally derived polymers, that is, alginates, chitosan, hyaluronic acid; (2) biologically derived
materials such as the decellularized tissues, that is, collagens, small intestinal submucosa, urinary bladder
matrix, and amniotic membranes; and (3) synthetic polymers, that is, poly(lactic acid), poly(glycolic
acid), and poly(lactic-co-glycolic acid), poly(hydroxybutyrate-valerate). Some of the recent developments
in biomaterials for tissue engineering applications include self-assembly nanofibers [Huang et al., 2000;
Hartgerink et al., 2002], and elastic protein-based polymer systems [Urry et al., 1991; McMillan and
Conticello, 2000].
Many materials have been evaluated for esophagus repair and reconstruction. These include collagens
[Natsume et al., 1993], poly(glycolic acid) [Shinhar et al., 1998, Miki et al., 1999], urinary bladder matrix
[Badylak, et al. 2000]; elastin biomaterials obtained from porcine aorta [Kajitani et al., 2001], and Allo-
derm®[Isch et al., 2001]. All the above materials showed promise, especially the collagen and acellular
matrices, but the problem of stenosis remained. The acellular matrices appear to show better cell–matrix
interactions than synthetic ones. This may be due to the fact that these acellular matrices, being the
ECM materials, contain a complex mixture of structural and functional proteins, glycoproteins, and pro-
teoglycans arranged in a unique, tissue-specific three-dimensional ultrastructure [Badylak, 2002]. How-
ever, cell adhesion to degradable synthetic polymers can be improved by modifying the surfaces with RGD
peptide for cell surface adhesion receptors [Glass et al., 1994; Cook et al., 1997; Schmedlen et al., 2002].
Our research group is currently evaluating the interactions between the esophageal epithelial and
smooth muscle cells on various materials including chitosan, various blends of biodegradable poly-
mers with chitosan, collagens; and decellularized porcine matrices such as urinary bladder matrix, small
intestinal submucosa, and esophagus.
25.4.3 Scaffold Design
With the exception of the acellular matrices, all other scaffolds using synthetic polymers or pure collagen
must be fabricated. As such, important structural features of the scaffold design must be considered.
The ideal scaffold should direct the biological process of tissue formation and regeneration. One of
the principal objectives in tissue engineering is to mimic the ECM in terms of their surface chemistry,
mechanical properties and structure. In addition to the choice of biomaterials, to provide suitable surfaces
for cell attachment and recognition, the physical structure of the scaffold plays an equally important
role. The effects of pore size, morphology, microgeometry, and scaffold thickness are known to influence
cellular adhesion, tissue organization, angiogenesis, and matrix deposition [Wake et al., 1994; Brauker
et al., 1995; Zeltinger et al., 2001; Ward et al., 2002; Rosengren and Bjursten, 2003].
Pore size and total porosity, for example, are also known to influence fibrovascular tissue invasion and
extent of fibrosis [Mikos et al., 1993]. In the case of the esophagus, fibrosis reaction must be minimized in
order to maintain its mechanical performance. Conceptually, the scaffold for esophageal tissue should
have a range of pore sizes. On the outer surface of the scaffold, the pore size should be large (ranging
from 50 to 200 µm) to facilitate cell seeding, and transport of nutrients and waste. There should also
be smaller pores (ranging from 35 to 70 µm) necessary to promote angiogenesis [Marshall et al., 2004].
The luminal surface, in order to mimic the basal membrane in the esophagus, should be dense (in the
range of several microns in size). This barrier layer is to facilitate diffusion of signaling molecules and
nutrients but prevents cell migration across the surface. An example of such a scaffold structure with
varying pore sizes is shown in Figure 25.3a,b [Chian, 2003].
Another important aspect of the esophageal scaffold is the need for pores with specific orientation. The
muscularis mucosa of the esophagus consists of a single layer of longitudinally oriented smooth muscle
fibers, whereas the muscularis externa has an inner circular and outer longitudinal muscle layers. It is
therefore advantageous to have channels in the scaffold that can provide directional guidance for these
muscular tissues. Examples of such scaffolds with porous channels are shown in Figures 25.4a,b [Chian,
2003]. Our research effort is currently underway to study if these channels in the scaffold are effective in
guiding these smooth muscle cells in culture.