Biomedical Engineering Reference
In-Depth Information
conditions during fabrication of scaffolds while keeping other processing variables
fixed. The value of such a library derives from the tight internal control of structural
properties of its members, a characteristic which allows to pinpoint with accuracy
whether changes in the reference variable (e.g., pore size, degradation half-life)
affect the outcome or not (contraction inhibition, regenerative activity). Further-
more, discovery of a maximal value in a given outcome along a series identifies the
structural property that maximizes that outcome and serves to define the scaffold
structure that possesses optimal activity.
In order to confirm the specificity of structural features that defines DRT, we
provide below a brief list of collagen scaffolds that, even though very similar in
structure to DRT, were shown incapable of blocking contraction or inducing re-
generation. The requirement for porosity in a scaffold was confirmed in an ear-
ly study by comparing a highly porous implant with pore size 50 ± 20 µm and a
scaffold that had been prepared identically except that, following all preparation
steps, the porous structure was virtually eliminated by simple evaporative drying
at atmospheric pressure, a process that yielded a nonporous collagen film. When
implanted subcutaneously, the nonporous film became surrounded with scar rather
than a small mass of dermis (Yannas 1981). A later study made use of a library
of collagen scaffolds with variable pore size and otherwise identical structure and
showed that specific scaffolds with pore size of 5 ± 2.5, 450 ± 100, or 850 ± 200 µm
failed to block contraction and lacked regenerative activity (Yannas et al. 1989). In a
related study (Troxel 1994), a scaffold with a pore size of 400 µm was compared by
microscopy with a DRT-like scaffold having a pore size of 40 µm. This comparison
showed fibroblasts clustered very tightly inside the large pores of the first scaffold
while fibroblasts in the second scaffold were present instead as isolated cells inside
individual pores (Fig.
9.2
). In a later study with a different collagen library having
members that differed in degradation rate (Soller et al. 2012), the baseline uncross-
linked control (uncrosslinked; half-life < 1.5 week) and the inactive scaffold (highly
crosslinked; half life > 100 weeks) did not inhibit contraction nor did they show any
significant regenerative activity. These examples indicate the high degree of struc-
tural specificity of the DRT scaffold.
Optimal values of structural parameters of DRT are required for maximum
blocking of wound contraction. A mechanistic analysis for each optimal level is
presented below.
The average pore size is required to have a lower limit of approximately 20 µm,
as shown in measurements of contraction delay (Fig.
9.3
; Yannas et al. 1989), in
order to allow cells to migrate inside the scaffold and bind on the surface. Cells have
not been generally observed to migrate in any significant number inside scaffolds
with much smaller pores. Once inside the scaffold, cell binding occurs via integrins
for specific ligands on the collagen surface, as described above. At the other end of
the pore diameter range, a sufficient number of cells must be bound on the scaffold
surface in order to participate in sufficient contraction blocking, as explained above.
This requires a large enough specific surface,
σ
(measured in mm
2
scaffold surface
per mm
3
scaffold volume; Yannas 1997). The specific surface of porous materi-
als is known to decrease monotonously with increasing pore diameter. Estimated
