Biomedical Engineering Reference
In-Depth Information
loses a very large volume of fluid exudate from both stumps (Williams and Varon
1985). The process is arrested when a tissue capsule, associated with contraction
and neuroma formation, is spontaneously formed around each stump, stemming
the flow of exudate from the nerve stumps (Weiss 1944; Wall and Gutnick 1974;
Chamberlain et al. 1998b; Yannas 2001a). Significant restoration of the homeostatic
control occurs after closure of the defect by neuroma formation; however, there is
no restoration of physiological electrical excitability in axons inside the neuroma
(Wall and Gutnick 1974). Both in skin and peripheral nerves, defect closure partly
restores organ homeostasis, even though it does not necessarily restore physiologi-
cal function.
Far from being systems at static equilibrium, the freshly opened and the freshly
closed defect in a living organism are both time-dependent states. Immediately after
being opened, a defect immediately undergoes a host of changes (e.g., bleeding,
platelet degranulation, flow of exudate, and so on). Neither is the closed defect
in an anatomically static system. Early reports (Carrel and Hartmann 1916; Clark
1919), as well as more recent accounts, have described extensive tissue modifica-
tions that continue for a long time after closure, referred to as
wound remodeling
(Peacock and Van Winkle 1976; Mast 1992; Weber et al. 2012; Churko and Laird
2013). Such continuing activity partly reflects ongoing contraction of granulation
tissue underneath the epidermis, long after closure of the skin defect by epidermal
confluence had been completed. Severe defects in peripheral nerves also continue to
undergo structural and functional changes over at least 1 to 2 years after the defect
has closed (Le Beau et al. 1988; Archibald et al. 1991, 1995; Chamberlain et al.
1998b; Tan et al. 2011).
In addition to the remodeling processes in scar or in regeneration, another pro-
cess that is continuing after a defect has closed is the normal development of the
organism. The effect of development on the outcome of a healing process becomes
evident in two quite different ways. First, the outcome of wound healing is pro-
foundly affected qualitatively by the
developmental stage
of an organism at the
time of injury. This effect is reflected in the typically sharp difference between the
regenerative outcomes of early fetal and late fetal healing in an organ of a given spe-
cies. The important ontogenetic transition from early to late fetal mammalian heal-
ing (Colwell et al. 2005), as well as the wound healing transition in the developing
frog (Yannas et al. 1996), each become a major experimental variable in a study of
regeneration. Second, ongoing development of the organism during healing modi-
fies the outcome of the healing process quantitatively. For example, a change in the
area of a wound during healing generally reflects both the effect of contraction (area
decrease) as well as that of growth of the organism (area increase) (Yannas et al.
1989). In this case, raw data showing, e.g., a net decrease in area with time must be
corrected for growth before they can be used to describe the kinetics of contraction.
Remodeling and development alter, each in its own way, the raw data that de-
scribe the healing process. With the exception of the major developmental transi-
tion in healing behavior, from the early to the late fetal stages, discussed above,
