Title : Fibrin/agarose-based strategies and natural matrices for peripheral nerve repair
Peripheral nerve (PN) are essential organs that communicate the central nervous system to distal target organs at the motor, sensory and autonomic level. PN can be affected by different pathological conditions and their continuity is frequently affected by a wide range of traumatic injuries or cancer removal. These injuries can occur at any anatomic location with severe consequences for these patients worldwide. Nowadays, incomplete or complete PN defects are managed by well-known surgical procedures. Short nerve gaps are repaired directly with acceptable success. However, in the case of critical PN defects, the re-establishment of the nerve trunk continuity can be achieved with the use of grafts material, being the nerve autograft the current gold standard technique to treat these patients. Nerve autograft promotes an acceptable regeneration and functional recovery in the repair of nerves gaps with a maximum length of 5 cm being inefficient in the treatment of defects beyond this distance. In this context, our aim during the last few years was to develop novel nerve substitutes for peripheral nerve repair. On the one hand, we designed and characterized novel strategies based on the use of fibrin-agarose hydrogels (FAH) containing or not adipose-derived mesenchymal stem cells (ADMSCs). On the other hand, we developed new decellularized nerve allografts. These strategies were characterized ex vivo and then used to repair a gap of 1 cm in the sciatic nerve of Wistar rats.
First, we evaluated the use of acelular and cellular FAH as intraluminal fillers of collagen conduits. From the clinical and functional point of view, filled conduits were significantly superior to the use of hollow collagen conduits used as control. In addition, superior sensory, motor and neurophysiological profile was achieved with the use of FAH containing ADMSCs. Histology revealed an active nerve tissue regeneration characterized by the presence of abundant Schwann cells, regenerating axons and tissue organization with the use of cellular FAH.
Secondly and based on the positive results obtained with FAH and ADMSCs, we developed a novel nanostructured FAH bioartificial nerve substitutes (NFABNS). Ex vivo studies confirmed that, with subjecting FAH containing ADMSCs to plastic compression technique, it is possible to generate biomimetic constructs in a controlled manner with acceptable biomechanical properties and preserving the cell viability and functionality. The in vivo analysis of the NFABNS revealed acceptable degree of nerve tissue regeneration, sensory and motor function recovery and neurophysiological profile. Overall results were comparable, and in some cases superior than autograft technique used as control.
Finally, concerning our acellular nerve grafts, ex vivo studies confirmed an efficient decellularization and acceptable preservation of the structure and chemical composition of the ECM. The in vivo evaluation revealed that all acellular grafts were able to promote an efficient peripheral nerve regeneration, being these results closely comparable to the autograft technique, which still remains as the gold standard technique for the treatment of sever nerve defects.
In conclusion, our studies confirmed that engineered substitutes are promising alternatives for peripheral nerve repair. Furthermore, clear differences can be obtained in function of the molecular composition of the scaffolds used, the 3D configuration and the presence or not of viable and active cells. However, more research is still needed to generate more efficient alternative for peripheral nerve repair.