Nerve transfer is an emerging treatment to restore upper limb function in people with tetraplegia. The objective of this study is to examine if a flexible collage sheet (FCS) can act as epineurial-like substitute to promote nerve repair in nerve transfer. A preclinical study using FCS was conducted in a rat model of sciatic nerve transection. A prospective case series study of nerve transfer was conducted in patients with C5-C8 tetraplegia who received nerve transfer to restore upper limb function. Motor function in the upper limb was assessed pre-treatment, and at 6-,12-, and 24-months post-treatment. Macroscopic assessment in preclinical model showed nerve healing by FCS without encapsulation or adhesions. Microscopic examination revealed that a new, vascularised epineurium-like layer was observed at the FCS treatment sites, with no evidence of inflammatory reaction or nerve compression. Treatment with FCS resulted in well-organised nerve fibres with dense neurofilaments distal to the coaptation site. Axon counts performed proximal and distal to the coaptation site showed that 97% of proximal axon count of myelinated axons regenerated across the coaptation site after treatment with CND. In the proof of concept clinical study 17 nerve transfers were performed in five patients. Nerve transfers included procedures to restore triceps function (N=4), wrist/finger/thumb extension (N=6) and finger flexion (N=7). Functional motor recovery (MRC ≥3) was achieved in 76% and 88% of transfers at 12 and 24 months, respectively. The preclinical study showed that FCS mimics epineurium and enable to repair nerve resembled to normal nerve tissue. Clinical study showed that patients received nerve transfer with FCS experienced consistent and early return of motor function in target muscles. These results provide proof of concept evidence that CND functions as an epineurial substitute and is promising for use in nerve transfer surgery