Biomedical Engineering Reference
In-Depth Information
Cohen 1959) has been the most frequently used model of a neuron-directed tro-
phic agent. Several other factors have also been shown to promote the survival of
axotomized neurons as well as to act on nonneuronal cells that are associated with
nerve regeneration. Other factors that comprise the so-called neurotrophin family
include brain-derived nerve growth factor (BDNGF), neurotrophin 4/5 (NT-4/5),
and neurotrophin 3 (NT-3). After axotomy, the synthesis of these neurotrophic fac-
tors, as well as of several cytokines and growth factors, is upregulated by both the
axotomized neurons and nonneuronal cells, especially SCs, both in the proximal
and distal nerve stumps. The list of factors produced by the two stumps resulting
from complete transection is long (Lundborg et al. 1982d; Longo et al. 1983a, b).
Included among these are factors that have been associated with the inflammatory
response in other organs: interleukins 1, 2, and 6 (IL-1, IL-2, IL-6), ciliary neuro-
trophic factor (CNTF), acidic fibroblast growth factor (aFGF), transforming growth
factor-β (TGFβ), platelet derived growth factor (PDGF), glial growth factor (GGF),
insulin-like growth factors (IGFs), interferon-g (IFN-g), and others (for review see
Fu and Gordon 1997). Both acidic fibroblast growth factor (aFGF, FGF-1) and basic
fibroblast growth factor (bFGF, FGF-2) have significantly upregulated proliferation
and migration in vitro of fibroblasts, endothelial cells, and SCs, as well as astrocytes
and oligodendrocytes (Burgess and Maciag 1989; Klagsbrun 1989). The synergistic
effect of NGF, BDNF and neurotrophin-3 (NT-3) for axonal guidance of embryonic
lumbar dorsal root ganglion cells has been studied (Cao and Shoichet 2003). There
has been an increase in interest in the controlled delivery of growth factors in nerve
regeneration studies (Pfister et al. 2007; Madduri and Gander 2012).
The tubulated gap spontaneously and completely fills with fluid within about
12 h after tubulation. The potential sources of chamber fluid have been described
as bleeding, leakage of endoneurial fluid, or leakage of outside fluid through the
narrow space between the inner walls of the tube edges and the outer sheath of the
inserted nerve stumps (Longo et al. 1983a, b). Both stumps contribute to the spon-
taneous presence of soluble regulators in the tubulated gap.
Investigators have augmented or supplemented the endogenous supply of in-
soluble regulators by adding regulators of their own choice (exogenous supply).
Methods of delivery have varied widely among investigators. As a result of such
wide range of conditions, very little information has become available that relates
the choice of delivery schedule to the efficacy of the regulator being delivered.
In several studies, exogenous addition of NGF was observed to have upregulated
various processes of regeneration across the tubulated gap compared with the un-
treated controls. These positive findings, in studies that spanned a 3-5-week period,
included an increase in the diameter of the regenerated nerve trunk by a factor
of two (Chen et al. 1989), a twofold (Rich et al. 1989) or a threefold increase in
myelinated axons in the regenerate (Derby et al. 1993), a significant increase in re-
generation of sensory neurons (DaSilva and Langone 1989), as well as a significant
increase in the rate of axonal regeneration in NGF-treated animals (Whitworth et al.
1996). However, there was evidence that the regenerative advantage conferred by
such early upregulation disappeared later; after 4 weeks, all regenerates had similar
numbers of myelinated axons (Derby et al. 1993).
