Application of Chitosan-Based Biomaterials in Tissue Engineering - Chitosan Based Hydrogels: Functions and Applications - page 444

standard for nerve reconstruction, is associated with some major disadvantages. The nerve
graft cannot be harvested from amputated extremities in the same operation and it can
result in new nerve injures. One the other hand, although allograft can overcome these
major drawbacks, as soon as cellular components are transferred, immunosuppression
becomes mandatory [177].
Tissue-engineered conduits have been developed as a promising option for nerve regen-
eration, due to their mechanical support and chemical stimulation for axonal elongation.
The conduit allows for neurotropic and neurotrophic communication between the nerve
stumps and provides physical guidance to regenerating axons. The topographical cues
induce cabling of cells within the conduit [178]. Chitosan has been studied as a candidate
conduit material for nerve regeneration due to its natural features. It can support the adhe-
sion, migration, and proliferation of nerve cells (e.g., Schwann cells, cerebral cortex cells,
and PC12). Some polymers are added into the chitosan network to modulate the nervous
cell behaviors.
Besides, a chitosan-based biomaterial, in order to be an ideal nerve conduit, should have
the following characteristics. (a) It must have enough internal surface area for the nerve
fibers and Schwann cells to cohere. It must allow diffusion transport of nutrients while
preventing external cells from entering the conduit. The optimal porosity of the nerve
conduit is 70-98% [179]. (b) The chitosan-based biomaterial must have appropriate matrix
stiffness. A soft biomaterial with low Young's modulus, which can better mimic the
mechanical properties of soft nerve tissue, is a more favorable scaffold for nerve regenera-
tion. But chitosan is considerably more rigid and brittle than nerve tissues. Nerve conduits
made from chitosan may compress the regenerating nerve cells and may rupture in vivo
before wounds are completely healed. Therefore, chitosan must be modified to improve its
mechanical properties before it can be used in nerve repair. Some flexible molecules are
introduced into the chitosan network to improve the proliferation and differentiation
capacity of nerve cells. For example, the P12 cells cultured on the composite film with
60 wt% gelatin differentiated more rapidly and extended longer neurites than on the pure
chitosan film [180]. (c) The chitosan-based biomaterial must have sufficient mechanical
stability during nerve regeneration. It is demonstrated that the chitosan mesh tubes with a
DD of 93% have sufficient mechanical properties to preserve tube space, provide a better
scaffold for cell migration and attachment, and facilitate humoral permeation to enhance
nerve regeneration. (d) The chitosan-based biomaterial must become revascularized fast
enough to overcome nutrient transport limitations into the graft. (e) It must have appropri-
ate degradation rate to maintain a stable support structure for the entire regeneration pro-
cess, but should not remain in the body much longer than needed to prevent later
compression of the nerve. (f) It must have an appropriate degree of inflammatory response
after implanted in vivo . The potency of the chitosan-based conduits for promoting nerve
regeneration will eventually depend on its interaction with the relevant tissues. Some
degree of inflammatory response may therefore play a positive role; however, a high num-
ber of inflammatory cells blocked the way for the sprouting axons, and nerve regeneration
was delayed. Pure chitosan conduits showed high infiltration of inflammatory cells such
as macrophages during the first 2 weeks, which will limit the application of chitosan con-
duits in nerve regeneration. Thus, some proteins or polymers should be incorporated into
the chitosan network to decrease the inflammatory response [181,182].
Typical materials for nerve guide coatings are adhesion proteins, such as laminin,
fibronectin, or poly(l-lysine), which have been found to be specific for nerve regeneration,
thus allowing more rapid recovery of nerve functionality. Chitosan modified by blending
with proteins or poly(l-lysine) had significantly improved nerve cell affinity as indicated