Over 18 million extremity injuries are recorded in the United States each year, resulting in a substantial number of peripheral nerve injuries that account for more than $150 billion in health care costs. Clinically, treatment consists of direct surgical repair, implantation of a nerve guidance conduit or the use of an autograft. However, less than 50% of individuals that undergo surgical repair regain useful function, and for many patients permanent or long-term disability is a frequent prognosis. Biomaterial scaffolds are promising for use in neural reconstruction, but to date, no neuroinductive biomaterials capable of acting directly on regenerative cells to stimulate nerve growth have been identified. The goal of this dissertation work was to develop and investigate the effectiveness of novel biomaterials for neural tissue engineering applications. This dissertation work has resulted in the development of two distinct scaffold-based guidance strategies for bridging peripheral nerve defects. The first strategy is based on a classic tissue engineering approach, and involves the use of modified acellular grafts interposed across a nerve gap. The second strategy introduces keratin made from human hair as a promising, neuroinductive biomaterial for use in neural regeneration. Keratin biomaterials were found to be highly biocompatible and able to promote Schwann cell adhesion, proliferation and migration. Implantation of a keratin hydrogel into a nerve guidance conduit resulted in a 150–300% improvement in motor function recovery in a small animal model at an early time point. Long-term functional and histological assessment confirmed improved neuromuscular regeneration in keratin-treated nerves. Furthermore, keratin was found to promote functional regeneration over a critical size defect in a large animal model. Investigations into the mechanism by which keratins act on regenerative cells suggest that activation of Schwann cells is integrin-mediated and dependent on the structural characteristics of human hair keratins. Thus, keratin biomaterials derived from human hair represent a neuroinductive scaffold-based conduit filler that may be used as an “off-the-shelf” product for treatment of peripheral nerve injuries. This dissertation work justifies the translation and clinical development of a keratin-based hydrogel filler as a complimentary product for use in existing nerve conduits, and suggests that keratin biomaterials may be capable of bridging peripheral nerve defects beyond current clinical limits.