Clinically available treatments are insufficient to achieve full functional recovery in large (>3cm) peripheral nerve injuries (PNI). The objectives in this thesis were 1) to study often overlooked elements of intrinsic PNI repair including release of inhibitory CSPGs and post-injury responses of inflammatory macrophages and dedifferentiated Schwann cells;​ 2) to create biomaterial scaffolds featuring topographical and adhesive cues to enhance neurite outgrowth;​ and 3) to test the ability of those cues to direct macrophages and Schwann cells towards a pro-regenerative phenotype. It is hypothesized that recapitulating the positive and negative cues of the PNI microenvironment can better improve regeneration. The effect of a characteristic CSPG, Chondroitin Sulfate A (CSA), was tested on neurite dynamics of dissociated chick embryo dorsal root ganglion (DRG) neurons using time lapse video microscopy. DRG growth was recorded on different adhesive substrates, including a novel, porcine-derived spinal cord matrix (SCM). The SCM significantly increased neurite extension, reduced neurite stalling, and mitigated CSA inhibition. Flow cytometry was used to measure changes in cell-substrate binding receptor expression in the neurons. Results showed a significant increase in Syndecan-3 receptor expression in neurons treated with CSA, suggesting a possible priming of the cells for regrowth. The CSA was successfully immobilized within electrospun hyaluronic acid (HA) nanofibers using a methacrylation reaction. Blended electrospinning was used to create scaffolds featuring the CSA and SCM cues. Results showed significantly increased neurite outgrowth on scaffolds with the SCM and low levels of CSA. Higher incorporation of CSA maintained its inhibitory properties. Next the CSA, SCM, and HA fiber cues were tested for their effects on macrophage and Schwann cell phenotype. It was hypothesized that one or more of the cues would accelerate the macrophages return to rest following classical activation (M1/pro-inflammatory) with lipopolysaccharide (LPS;​ 1μg/mL) and would accelerate the transformation of Schwann cells from an immature state following injury to a mature/pro-myelinating one. Cell phenotypes were functionally assessed using quantified reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, and sandwichELISA based antibody arrays to measure changes in mRNA expression, morphology, and cytokine release, respectively. Macrophages cultured with the SCM and HA fibers had significantly reduced M1 gene expression, released lower levels of M1 cytokines (IL-1a, RANTES and TFNa) and assumed an elongated morphology indicative of M2. These cues also induced changes in the Schwann cells including significantly reduced area, increased elongation, decreased expression of immature genes (GFAP) and increased expression of mature genes (Krox20 and Oct6). These results suggest that the SCM and HA nanofibers could trigger non-neuronal cells towards regenerative programs more quickly than traditional PNI interventions. Changes induced by biomaterials have distinct benefits over the use of immunomodulatory cytokines and would be a novel approach to direct repair. Our collective studies offer improved insight into the endogenous potential of the injured peripheral nerve and offer ways to incorporate intrinsic repair cues into a biomaterial system for treating large gaps.