New hemostatic agents in the combat setting.

Various biomaterials have been proposed to build up scaffolds for promoting neural repair. Among them, chitosan, a derivative of chitin, has been raising more and more interest among basic and clinical scientists. A number of studies with neuronal and glial cell cultures have shown that this biomaterial has biomimetic properties, which make it a good candidate for developing innovative devices for neural repair. Yet, in vivo experimental studies have shown that chitosan can be successfully used to create scaffolds that promote regeneration both in the central and in the peripheral nervous system. In this review, the relevant literature on the use of chitosan in the nervous tissue, either alone or in combination with other components, is overviewed. Altogether, the promising in vitro and in vivo experimental results make it possible to foresee that time for clinical trials with chitosan-based nerve regeneration-promoting devices is approaching quickly.

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The use of chitosan-based scaffolds to enhance regeneration in the nervous system.

Developments in tissue engineering yield biomaterials with different supporting strategies to promote nerve regeneration. One promising material is the naturally occurring chitin derivate chitosan. Chitosan has become increasingly important in various tissue engineering approaches for peripheral nerve reconstruction, as it has demonstrated its potential to interact with regeneration associated cells and the neural microenvironment, leading to improved axonal regeneration and less neuroma formation. Moreover, the physiological properties of its polysaccharide structure provide safe biodegradation behavior in the absence of negative side effects or toxic metabolites. Beneficial interactions with Schwann cells (SC), inducing differentiation of mesenchymal stromal cells to SC-like cells or creating supportive conditions during axonal recovery are only a small part of the effects of chitosan. As a result, an extensive body of literature addresses a variety of experimental strategies for the different types of nerve lesions. The different concepts include chitosan nanofibers, hydrogels, hollow nerve tubes, nerve conduits with an inner chitosan layer as well as hybrid architectures containing collagen or polyglycolic acid nerve conduits. Furthermore, various cell seeding concepts have been introduced in the preclinical setting. First translational concepts with hollow tubes following nerve surgery already transferred the promising experimental approach into clinical practice. However, conclusive analyses of the available data and the proposed impact on the recovery process following nerve surgery are currently lacking. This review aims to give an overview on the physiologic properties of chitosan, to evaluate its effect on peripheral nerve regeneration and discuss the future translation into clinical practice.

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Relevance and Recent Developments of Chitosan in Peripheral Nerve Surgery

Non-surgical approaches have been developed to enhance nerve recovery, which are complementary to surgery, and are an adjunct to the reinnervation process. A search of PubMed, Medline, CINAHL, DH data and Embase databases was performed using the keywords ‘peripheral nerve injury’ and ‘treatment’. Most of the conservative therapies are focused to control neuropathic pain after nerve tissue damage. Only physical therapy modalities have been studied in humans and their effectiveness is not proved. Many modalities have been experimented with to promote nerve healing and restore function in animal models and in vitro studies. Despite this, none have been actually translated into clinical practice. The hypotheses proved in animals and in vitro should be translated to human clinical practice.

Non-surgical therapies for peripheral nerve injury

Recently, numerous guide chambers for the treatment of injured nerves made up of different biomaterials have been designed, capable of hosting living cells or carrying neurotrophic or neuroactive substances to be directly released to the injured tissue. In this study, chitosan prostheses containing neurosteroids (progesterone and pregnenolone) were used for bridging a 10-mm gap in the rabbit facial nerve. Gas chromatography was used to quantify neurosteroid content in the prostheses prior to and after subcutaneous implantation at different periods of up to 60 days. The regeneration of the nerve fibers were evaluated at 15 and 45 days after axotomy by means of ultrastructural morphometric analysis. Different nerve fibers regenerative patterns were seen depending the groups studied and the analyzed stages. At 15 days after axotomy, the newly regenerating tissue revealed Schwann cells holding nonmyelinated nerve fiber bundles in an incipient and organized regenerative pattern. At 45 days, the regenerating tissue showed myelinated nerve fibers of different sizes, shapes, and myelin sheath thickness. Although the regeneration of the nerve fibers under neurosteroid treatment showed statistically significant differences in comparison with vehicle regenerated tissue, progesterone-loaded chitosan prostheses produced the best guided nerve regeneration response. These findings indicate that chitosan prostheses allowed regeneration of nerve fibers in their lumen, and when containing neurosteroids produced a faster guided nerve regeneration acting as a long-lasting release delivery vehicle.

Ultrastructural analysis of guided nerve regeneration using progesterone- and pregnenolone-loaded chitosan prostheses.

Objective: To seek new method for the treatment of peripheral nerve injury. Methods: In rat model with sciatic nerve defect, chitosan collagen film was sutured into conduit to bridge 5 mm , 10 mm nerve defects. Rats that underwent end to end anastomosis were taken as controls. General observation, electrophysiological study, histological study and image analysis were performed at 4, 8, 12 weeks postoperatively. Results: In 5 mm nerve defects, the quality of nerve regeneration was similar to that of the control group. For 10 mm nerve defect, nerve regeneration was inferior to that of the control group. Chitosan collagen film obviously degraded at 12 weeks postoperatively. Conclusions: Chitosan collagen film conduit can be used to bridge peripheral nerve defect.

Xin Wei

Papers

Bridging peripheral nerve defect with chitosan-collagen film.