Development of novel tissue-engineered conduits for peripheral nerve repair

There are 300,000 peripheral nerve injuries per year in Europe (1/1,000 population) giving rise to substantial disability and often the development of chronic pain. Nerve regeneration is particularly poor where there is a gap in the injured nerve, preventing repair by anastomosis of the injured nerve stumps. In this situation, repair with a graft from the patient's own nerves (an autologous graft) is not ideal as it results in loss of function (and chronic pain) arising from the donor site, and may be followed by a disappointing outcome. The bioengineering challenge is to create an effective conduit to guide nerve regrowth that will promote functional outcomes better than those achieved by autologous nerve grafts. In Sheffield we have developed an interdisciplinary team with unique capability for implementing a critical path in medical device design, from biomaterials synthesis and fabrication, through neural cell testing, in-vivo evaluation and clinical trial.
A recent proof-of-concept study [1] demonstrates our ability to manufacture a nerve guidance conduit using a 3D printing process with micrometre resolution (microstereolithography). These nerve guidance conduits can support regeneration across short-gap injuries, equivalent to that achieved with a nerve graft. The overall aim of this project is to design, manufacture and evaluate a new class of biodegradable nerve conduits with the ability to promote peripheral nerve regeneration over long-gap injuries, as well as, or better than, an autologous nerve graft.
The specific objectives are to establish:
i) the optimal design (material and structure) of the microfibre conduit;
ii) whether optimally designed conduits can perform better than autologous nerve grafts;
iii) whether our optimally designed conduits populated with antifibrotic agents or support cells (in the form of Schwann or stem cells) perform better than empty conduits.
The project will use microstereolithography to construct customised biodegradable conduits made from polycaprolactone (an FDA-approved material) or poly-glycerol sebacate methacrylate (a novel formulation that has excellent mechanical properties for nerve repair, can be sutured and is photocurable). Comparisons will be made between nerve grafts, empty conduits and those with a range of different internal structures. We will also determine the effect of including antifibrotic agents. Our previous studies show that these agents can enhance nerve regeneration following nerve repair with end-to-end anastomosis [2-4]. In addition we will establish whether the addition of cells (Schwann cells or stem cells) can further facilitate nerve growth. Cells will be cultured using our established high efficiency techniques [5, 6]. Nerve regeneration will be assessed using methodologies that are well established in our laboratories. Genetically modified (thy-1-YFP-H) mice, with fluorescent axons, will be used to trace individual axons through the conduits and assess regeneration at the level of the individual axon [1, 4]. Further assessments will use a combination of methods including electrophysiological recordings of compound action potentials and functional assessment of outcome using walking track analysis [2, 3].