Rapid Gelling Chitosan/Polylysine Hydrogel with Enhanced Bulk Cohesive and Interfacial Adhesive Force: Mimicking Features of Epineurial Matrix for Peripheral Nerve Anastomosis

Prompt and strong reconnection of severed peripheral nerves is crucial to nerve regeneration. The development of biocompatible nerve adhesives that are stronger than commonly used fibrin glue would be extremely beneficial to this field. We designed an in situ forming nerve adhesive hydrogel composed of chitosan and ε-polylysine (PL), which mimics the polysaccharides/protein structure of natural epineurium matrices, thus, enhancing the compatibility with nerves. Michael-type addition between the maleimide and thiol group was employed as a cross-linking reaction to eliminate foreign damage to nerves and to ensure a fast hydrogel formation speed (curing speed). Gelation occurred within 10 s, quick enough to promptly seal the transected nerve. Catechol groups conjugated onto PL molecules were demonstrated to reinforce both the bulk cohesive force of the hydrogel and the interfacial adhesive force between the hydrogel and epineurium. The storage modulus of the hydrogel was elevated to more than 2400 Pa. A superior nerve adhesion property that can tolerate 0.185 N of force (8× higher than fibrin glue) was obtained. After 8 weeks, the morphology of the repaired nerve fiber coapted by our hydrogel was very close to the morphology of normal nerve, and the axon cross ratio of the regenerated nerves coapted using hydrogel (57%) was much higher than employing the suture technique (35%). Thus, the in situ rapid gelling system offers a promising approach to the repair of severed peripheral nerves.