Biomedical Engineering Reference
In-Depth Information
helical structure) which prevents platelet aggregation on the surface of collagen
fibers. Blocking platelet aggregation probably leads to inhibition of platelet
degranulation and concomitant relative depletion of TGF-
1 from the wound
environment (Sylvester
et al
., 1989). As mentioned above, TGF-
β
1 is a known
promoter of MFB differentiation. We conclude that DRT, partly at least, blocks
one of the normal differentiation process that leads to MFB, thereby depleting the
wound of MFB and reducing
N
in Equation 14.2.
Another mechanism that may account for the observed MFB depletion is based
on the finding that TGF-
β
1 binds avidly, though non-specifically, to the extensive
specific surface of DRT (Ellis
et al
., 1997). TGF-
β
1 binding to the scaffold surface
may contribute additionally to the relative unavailability of TGF-
β
2
in the wound fluid and, accordingly, may deplete cells from the cytokine that is
specifically required for MFB differentiation.
The second general mechanism for contraction blocking by DRT works by
reducing the in-plane vector component of the force per cell (see Equation 14.2),
thereby reducing the sum of forces generated by MFB. In the absence of DRT, the
wound contracts vigorously; under these conditions, myofibroblasts have been
observed to be densely packed with their axes lying primarily in the plane of the
wound. In the presence of DRT, however, contraction is arrested. Once having
migrated inside the DRT and become bound on the extensive surface of the highly
porous scaffold, the long axes of MFB have been observed to be oriented out of the
plane of the wound, where they are most effective in contracting the wound edges.
MFB have been observed to become almost randomly oriented and relatively
ineffective therefore, as a cooperative ensemble, for application of mechanical
forces in the plane of the wound. In such a nearly random assembly of force vectors
the sum of forces,
F
c
, must be near zero, leading to near cancellation of wound
contraction, as observed. In the context of this second mechanism, scaffolds block
MFB function but do not block MFB differentiation (Troxel, 1994; Yannas, 2001).
The structural determinants of scaffold activity have been largely identified
(Yannas, 2001). According to the second mechanism described above the contrac-
tion blocking activity of a scaffold clearly requires an ability to bind most of the
contractile cells in the wound. Accordingly, structural features that control cell-
scaffold binding play a major role. For example, fibroblast-DRT binding requires
participation of specific ligands, in particular those mediated by the
β
1 and TGF-
β
1 integrins
that have been shown (Racine-Samson
et al
., 1997) to control myofibroblast-
matrix binding during contraction. Such ligands are richly present on collagen
surfaces but not, for example, on synthetic polymers.
Ligand density is another critical feature of scaffold activity; a large concentra-
tion of ligands should lead to binding of large numbers of cells on the scaffold,
resulting in loss of their ability to scale up contraction forces and leading to blocked
contraction. At a very small pore size, cells are prevented from entering inside the
scaffold and binding to surface ligands; at very large pore size the specific surface
becomes very low (a result simply of decrease in pore size), corresponding to low
β
