Spinal cord injury causes irreversible damage to the central nervous system and its treatment can be associated with costs in the millions of dollars over the individual’s lifetime. A major barrier for curative treatments is hindered regeneration by the induced scar that inhibits neuron axon crossing to reconnect neural circuits. Current treatments involve supporting and decompressing the spinal cord in combination with the use of anti-inflammatory agents. These treatments, along with physical therapy, improve functional outcomes, but do not cure spinal cord injury induced deficits. Prospective treatments to replace cells or inhibit the formation of the scar can improve functional outcomes in rodent models, but do not cure functional deficits indicating that insight into molecular level scar inhibitory properties and the mechanism of regenerative treatments is necessary. The glial scar is made up of reactive astrocytes that secrete neurite inhibitory molecules such as chondroitin sulfate proteoglycans, that surrounds a fibrotic scar composed of cystic cavities devoid of CNS cells. In this work, chronic spinal cord injury scar elasticity, cell composition and extracellular makeup were measured. Results uncover challenges to spinal cord injury regeneration including decreased elasticity and dysregulated extracellular matrix. The IFN-γ cued molecular mechanism of a potential regenerative system, neural stem cell seeded immobilized IFN-γ chitosan hydrogels, was evaluated. Neurogenic activity was assessed by measuring soluble and immobilized IFNγ mediated signaling and global metabolomic profiles. Immobilized IFN-γ did not sustain downstream signaling or dysregulate metabolism as re-dosed soluble IFN-γ. In vivo reaction to these constructs was marked by inflammation evaluated with cytokine panels and immunohistochemistry. Foreign body response was elicited with crosstalk between host tissue and scaffolds. Together, this work assesses spinal cord injury physical and molecular properties and mechanistic properties of a regeneration strategy in vitro and in vivo.