Development of a multifunctional, injectable biomaterial using hyaluronan as a bioactive nanocarrier

Hyaluronic acid-based biomaterials provide diverse functionality due to the inclusion of bioactive domains within the glycosaminoglycan molecule. This attribute is promising for regenerative strategies to treat central nervous system (CNS) injury, which is a complex system that requires combinatorial approaches to address different mechanisms. Here, TGFβ small molecule inhibitor, sb431542, and repulsive guidance molecule A (RGMa) antagonist peptide are conjugated to a hyaluronan-based nanocarrier to simultaneously address multiple aspects of the injury microenvironment. The modified hyaluronan is paired with a thermo-responsive hydrogel, pluronic f-127, to create an injectable delivery system. Synthesis, validation, and characterization of the injectable platform demonstrates mechanical properties on par with previous scaffolds used in the CNS, physiologically relevant release rates of cargo, and the ability to modulate cellular function in a three-dimensional in-vitro model. Proof of concept studies in a cervical-level hemisection spinal cord injury (SCI) animal model indicate increased infiltration of both host axons and astrocytes within the lesion following delivery of the hydrogel. Additionally, tracing of rubrospinal and reticularmotor tracts across the site of injury suggests improvements in connectivity at 8 weeks post-injury. Overall, this study establishes the utility of combining different biochemical moieties to build heterofunctional nanocarriers and restore connectivity in the CNS.