Hydrogel-mediated local delivery of dexamethasone reduces neuroinflammation after traumatic brain injury

Abstract

Excessive and prolonged neuroinflammation leads to neuronal cell death and limits functional recovery after traumatic brain injury (TBI). Dexamethasone (DX) is a steroidal anti-inflammatory agent that is known to attenuate early expression of pro-inflammatory cytokines associated with activated microglia/macrophages. In this study, we investigated the effect of dexamethasone-conjugated hyaluronic acid (HA-DXM) incorporated in a hydrolytically degradable, photo-cross-linkable poly (ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) hydrogel on the inflammatory response, apoptosis, and functional recovery in a controlled cortical impact (CCI) rat TBI model. In vitro, DX release from PEG-bis-AA/HA-DXM hydrogel was slow in phosphate-buffered saline without enzymes, but significantly increased in the presence of hyauronidase/esterase enzymes. TBI was generated by a CCI device armed with a 3 mm tip (3.5 m s−1, depth: 2 mm) and treated immediately with PEG-bis-AA/HA-DXM hydrogel. PEG-bis-AA/HA hydrogel without DX was used for comparison and untreated TBI group was used as a control. Significant reductions in cavity size, inflammatory response, and apoptosis were observed in animals treated with PEG-bis-AA/HA-DXM compared to those receiving PEG-bis-AA/HA and untreated. Animals receiving the PEG-bis-AA/HA-DXM hydrogel also exhibited higher neuronal cell survival and improved motor functional recovery compared to the other two groups.