Sustained neurotrophin-3 delivery from hyaluronic acid hydrogels for neural tissue regeneration

The goal of this work was to design a polymer-based platform capable of localized, long-term delivery of biologically active neurotropic factors using an affinity-based approach. Here, we synthesized hyaluronic acid-methylfuran (HA-mF) hydrogels that provide sustained, affinity-based release of neurotrophin-3 (NT-3), a growth factor that promotes axon growth for 28 days. A Diels-Alder crosslinking reaction between HA-mF and polyethylene glycol (PEG)-dimaleimide occurs within 15 min under physiological conditions, resulting in hydrogels that can be polymerized in the presence of cells and growth factors. We also tuned the hydrogel's storage modulus to match that of native rat spinal cord tissue, providing a platform not only for localized drug delivery but also a suitable vehicle for cellular transplantation. The NT-3 released from the HAmF hydrogels remains bioactive for at least 14 days, promoting axonal growth from primary sensory neurons as well as stem cell-derived V2a interneurons and motoneurons in vitro. The hydrogels also supported cell growth allowing for 3-dimensional axonal extensions within the scaffold matrix. Here we confirm the protective role of HA-mF on matrix-bound NT-3 activity and show that these hydrogels are an excellent platform for growth factor delivery for neural applications.