Biomedical Engineering Reference
In-Depth Information
Graft copolymers of collagen
and GAGs
synthesized. That this result was not confined to guinea
pigs was confirmed by grafting the same copolymer on
full-thickness skin wounds in other adult mammals, in-
cluding swine and, most importantly, human victims of
massive burns as well as humans who underwent re-
constructive surgery of the skin.
Although a large number of CG copolymers were
synthesized and studied as grafts, it was observed that
only one possessed the requisite activity to dramatically
modify the wound healing process in skin. In view of the
nature of its unique regenerative activity this biologically
active macromolecular network has been referred to as
dermis regeneration template (DRT). The structure of
DRT required specification at two scales: At the nano-
scale, the average molecular weight of the cross-linked
network that was required to induce regeneration of the
dermis was 12,500 5000; at the microscale, the aver-
age pore diameter was between 20 and 120 m m. Rela-
tively small deviations from these structural features led
to loss of activity.
The regeneration of dermis was followed by re-
generation of a quite different organ, the peripheral
nerve. This was accomplished using a distinctly different
ECM analog, termed nerve regeneration template
(NRT). Although the chemical composition of the two
templates was nearly identical, there were significant
differences in other structural features. NRT degrades
considerably more slowly than DRT (half-life of about
6 weeks for NRT compared to about 2 weeks for DRT)
and is also characterized by a much smaller average pore
diameter (about 5 m m compared to 20-120 m m for
DRT). DRT was also shown capable of inducing re-
generation of the conjunctiva, a specialized structure
underneath the eyelid that provides for tearing and other
functions that preserve normal vision. The mechanism of
induced organ regeneration by templates appears to
consist primarily of blocking of contraction of the injured
site followed by synthesis of new physiological tissue at
about the same rate that the tissue originally present is
degraded (synchronous isomorphous replacement).
These combined findings suggest that other ECM ana-
logs, still to be discovered, could induce regeneration of
organs such as a kidney or the pancreas.
The preceding discussion in this chapter has focused on
the individual macromolecular components of ECMs.
Naturally occurring ECMs are insoluble networks com-
prising several macromolecular components. Several
types of ECMs are known to play critical roles during
organ development. During the past several years certain
analogs of ECMs have been synthesized and have been
studied as implants. This section summarizes the evi-
dence for the unusual biological activity of a small
number of ECM analogs.
In the 1970s it was discovered that a highly porous
graft copolymer of type I collagen and chondroitin
6-sulfate was capable of modifying dramatically the ki-
netics and mechanism of healing of full-thickness skin
wounds in rodents. In the adult mammal, full-thickness
skin wounds represent anatomical sites that are de-
monstrably devoid of both epidermis and dermis, the two
main tissues that comprise skin, respectively. Such
wounds normally close by contraction of wound edges and
by synthesis of scar tissue. Previously, collagen and various
GAGs, each prepared in various forms such as powder and
films, had been used to cover such deep wounds without
observation of a significant modification in the outcome of
the wound healing process.
Surprisingly, grafting of these wounds with the porous
CG copolymer on guinea pig wounds blocked the onset
of wound contraction by several days and led to synthesis
of new connective tissue within about 3 weeks in the
space occupied by the copolymer. The copolymer un-
derwent substantial degradation during the 3-week
period, at the end of which it had degraded completely at
the wound site. Studies of the connective tissue syn-
thesized in place of the degraded copolymer eventually
showed that the new tissue was distinctly different from
scar and was very similar, though not identical, to phys-
iological dermis. In particular, new hair follicles and new
sweat glands had not been synthesized. This marked the
first instance where scar synthesis was blocked in a
full-thickness skin wound of an adult mammal and, in
its
place,
a
nearly
physiological
dermis
had
been
Bibliography
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Jr., Bondoc, C. C., and Jung, W. K.
(1981). Successful use of
a physiologically acceptable artificial
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Strichartz, G., and Spector, M. (1998).
Collagen-GAG substrate enhances the
quality of nerve regeneration through
collagen tubes up to level of autograft.
Exp. Neurol. 154: 315-329.
Chang, A. S., and Yannas, I. V. (1992).
Peripheral nerve regeneration. in
Neuroscience Year (Suppl. 2 to The
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collagen. in Fibrous Proteins: Scientific,
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pp.247-269.
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