Biomedical Engineering Reference
In-Depth Information
to inability of tubular epithelial cells to bridge large enough gaps in the membrane
(Oliver 1953; Vracko 1974). The data from these studies of cell necrosis have been
interpreted to suggest that failure to preserve the basement membrane surfaces of
tubules or glomeruli prevents repopulation by cells and eventual recovery of kidney
function (Vracko 1974). Clinically relevant injuries to the kidney are usually much
harder to describe than are injuries with experimental animal models. For example,
investigators have emphasized efforts to understand the pathophysiology of sepsis-
induced acute kidney injury (Lameire et al. 2005; Bellomo et al. 2012). Extensive
microvascular alterations, including vasoconstriction, capillary leak syndrome with
tissue edema, leukocytes, and platelet adhesion with endothelial dysfunction and/
or microthrombosis have been identified (Bouglé and Duranteau 2011). Although
there is clear evidence of an inflammatory response neither the extent nor the pre-
cise location of any irreversibility involved is clear in this clinical injury.
These examples mostly show that tissue identity matters in the response of an
organ to injury. The evidence from several organs has shown that an injury of the
epithelial and endothelial cell layers that cover the surfaces of an organ appears
to be always reversible; injuries that reach much deeper, typically involving the
stroma, appear to be irreversible. A more precise identification of the limiting tissue
depth that is consistent with reversible injury in skin and peripheral nerves will be
discussed in the next chapter.
Nevertheless, the response of
bone
to fracture appears to be an instance where
the scale of injury rather than the nature of injured tissue plays an important role in
the outcome of the healing process. The site of a bone fracture or osteotomy that
had been anatomically reduced and mechanically stabilized has been described as
a very fine line corresponding to a defect of order 0.1 mm (Shapiro 1988). Under
the highly controlled experimental conditions of this study, lamellar bone formed
across the interfragmentary space in a direction parallel to the long axis of the bone
(contact healing). Larger defects, up to 0.5 mm, also healed by formation of lamel-
lar bone; however, the new bone tissue was deposited perpendicularly to the long
axis of the bone and originated from marrow and periosteal cells (gap healing; Sha-
piro 1988). Defects that significantly exceed the 0.5-mm size typically heal by for-
mation of nonmineralized connective tissue (soft callus); this tissue later becomes
mineralized, forming hard callus (union; Ham 1965; Hay 1966). Larger gaps or
smaller gaps that have not been mechanically stabilized may not heal by formation
of osseous tissue (formation of nonunion). In the adult rat, a clear gap larger than
about 2 mm is not bridged with new mineralized tissue (nonunion; McMinn 1969).
The problem of nonunion continues to be studied intensively (Al-Jabri et al. 2014).
A
critically-sized defect
is of sufficiently large size to prevent healing by re-
connection. Nonunion of a long bone is a well-known example. Data supporting
the existence of a critically-sized defect in other organs have been reported; for
example, following an increase in bone defect size in the skull of the rat from 4 to
8 mm there was significantly less bridging by bone formation than with smaller
defects (Schmitz and Hollinger 1986; Schmitz et al. 1990). The minimum gap that
can be bridged is not a constant for a given species but appears to vary with age
and with the precise anatomical nature of the lesion. Generally, when bone loss is
