Biomedical Engineering Reference
In-Depth Information
et al. 2001a; Harley et al. 2008), it appears necessary to apply forces from as many
as 10
8
-10
9
cells during wound contraction to close a skin wound in the rodent.
The required macroscopic force appears to be generated by assemblies of myofi-
broblasts, organized to apply cooperative forces and provide for a “mechanically
coherent” wound (Yannas 1998).
Assemblies of contractile cells are known to be held together by stress fibers in
neighboring myofibroblasts that are joined together at the sites of cadherin-type in-
tercellular adherens junctions (AJs) (Hinz et al. 2004). AJs are dense plaques found
under the plasma membrane of fibroblasts in granulation tissue of wounds as well
as in scar-like tissues (Welch et al. 1990). Maturation processes take place in AJs
during healing; for example, it has been shown that fibroblasts change cadherin
expression from N-cadherin in early wounds to OB-cadherin in wounds undergoing
contraction (Hinz et al. 2004). Intercellular mechanical coupling of stress fibers via
AJs improves contraction of collagen gels by myofibroblasts. There is evidence that
local contractile events are mechanically coordinated by AJs, via synchronization
of periodic intracellular Ca2+ oscillations between physically contacting myofibro-
blasts (Follonnier et al. 2008, 2010; Goodbout et al. 2013). It appears very likely
that these coordinated associations among myofibroblasts are responsible for gen-
eration of macroscopic contraction forces across a closing wound.
Orientation of long axes of contractile cells is a distinctive feature of such as-
semblies. Axial orientation appears to be mechanically required for generation of
a directed macroscopic contractile force. This feature was demonstrated in vitro,
with fibroblasts incubated inside a collagen scaffold, applying forces to the struts
of the matrix along their long axis, causing them to buckle (Freyman et al. 2001b;
Harley et al. 2008). In the guinea pig skin wound, the long axes of myofibroblasts
have been shown, based on transmission electron microscopic observation, to be
highly oriented in the plane of the epidermis (Murphy et al. 1990). In an earlier
study, myofibroblasts showed cytoplasmic microfilaments that were aligned along
the direction of their long axes; in this study, contractile cells were aligned parallel
to the plane of the epidermis and the applied macroscopic forces appeared to be
consistent with the observed reduction in wound area in the plane of the epidermis
(Baur et al. 1984). The orientation of long axes of myofibroblasts inside a contract-
ing skin wound in the guinea pig (Fig.
8.5
) is consistent with these observations.
The simplest mechanical field that corresponds to such an array of cells is the plane
stress field.
Contractile forces in skin wounds are applied not only in the plane of the epi-
dermis but also out of plane. Observations of deformation of subdermal tissues in a
closed skin wound in the guinea pig support the existence of mechanical forces that
act immediately below the scar (Fig.
8.6
; see area at bottom right labeled deformed
subdermal tissue). This cross-sectional view of an initially dermis-free defect in
the guinea pig skin shows the final stage of defect closure. In this micrograph,
closely apposed dermal edges are separated by a small mass of scar. The micrograph
obtained with polarized light shows highly deformed birefringent fibrous tissues,
almost certainly stretched collagen fibers, connecting the proximal adipose layer
at the base of the wound with distal scar mass (Troxel 1994). The photographic
