Concept of the project

Post-traumatic peripheral nerve repair is one of the major challenges in restorative medicine and microsurgery. Primary causes of damage are traumatic accidents, tumour resection, iatrogenic side effects of surgery or repetitive compression (tunnel syndromes). At present, peripheral nerve injuries are cause of medical consultation in more than 1,000,000 patients per year in the United States and Europe, with more than 100,000 cases undergoing surgery [1]. Severe nerve injury has a devastating impact on patients' quality of life. Typical symptoms are sensory and motor function defects that could result in complete paralysis of an affected limb or development of intractable neuropathic pain. Despite the progress in understanding the pathophysiology of peripheral nervous system injury and regeneration, as well as advancements in microsurgical techniques, peripheral nerve injuries are still a major challenge for reconstructive surgeons.

The surgical treatment for the complete severing of a nerve with small gap length (≤5mm) and no loss of tissue is direct suturing of opposite nerve stumps. In this particular case, nerve co-aptation with fascicle alignment and tension-free suturing is feasible because peripheral nerves are phenotypically driven to regenerate spontaneously following injury. However when direct suturing is not possible because would cause tissue tension affecting nerve regeneration or where there is a discontinuity (> 1 cm) between both distal and proximal stumps, tissue engineering approaches are required. During nerve regeneration, axons grow randomly forming a nerve fibre mass called bands of Büngner. Unless surgically intervened, these regenerative sprouts will result in complete axonal degeneration affecting motor control and sensory perception. Nerve autografting is still the gold standard technique for nerve gap repair. Autografts are primarily taken from purely sensory nerves, since this allows the obtention of longer grafts with lower donor-site morbidity than from motor or mix nerves, as the primary complication is often temporary localized numbness rather than a motor deficit. The most commonly donor source is the sural nerve, which allows for the harvest of up to 50 mm of nerve graft (up to 30 mm nerve gaps), with quite well-tolerated adverse effects ranging from sensory deficit around the lateral foot (9,1 - 41% of patients), to neuroma formation and unbearable pain (6,1 - 8,1% of cases) . Autograft has several disadvantages such as limited sources of donor nerve, the need for a second surgery to obtain the donor nerve, loss of nerve function in transplantation, and a lack of correspondence between the repaired nerve and the graft for the cross sectional area. According to these drawbacks, the success rate in patients treated with sural nerves is limited to 50%.

Thanks to progress in the field of tissue engineering, it appears increasingly possible to use artificial conduits for reconstruction of nerve gaps. Implantable nerve guidance conduits (INGCs) offer a promising alternative to conventional treatments, supporting and guiding the axons during their growth, while avoiding scar tissue infiltration in the gap. Fundamental requirements for effective nerve tissue regeneration demands a tubular scaffold that should be biocompatible, have sufficient mechanical stability during nerve regeneration, be flexible (with mechanical properties close to that of nerve tissues to prevent compression of the regenerating nerve), be porous to ensure supply of nutrients, and degrade in a proper time (after nerve regeneration) into nontoxic products to prevent long-term irritation.

In this scenario, NEURIMP project aim to produce a novel biomimetic nerve prostheses paying special attention to device structure, biomaterials and their combination with high troughput manufacturing methods which play a vital role in the industrialization process. In a first stage, NEURIMP will study those biomaterials previously tested in pre-clinical in vitro and in vivo experiments and clinical trials, having shown a positive outcome for nerve tissue regeneration due to axon growth facilitation, myelinating cell proliferation, reactive gliosis inhibition, anti-inflammatory activity and revascularization. These materials will be evaluated in terms of manufacturability, analysing their ability to be processed into predefined microstructures to address the challenges described above. In a second stage, new formulation of biomaterials based on the prior study, and combination of different materials (copolymers and bleds) will be developed to overcome the limitations observed in the first stage. The main objective here is, exploring which of the most promising biomaterials (natural and synthetic) or combinations thereof are compatible with the recently established technologies, potentially scalable to generate valid microstructures containing nerve devices. The final goal is to scale up the biomaterial production and manufacturing technologies in order to generate a next generation of peripheral nerve devices that will overcome the limitations of state of the art INGCs in terms of regenerative capacity, biodegradability, physical properties and manufacturability.