Dual-drug releasing PEG-PLA hydrogels with tunable degradation for sustained local analgesia and anti-inflammatory therapy in a rat fracture/osteotomy model.

Abstract

Effective postoperative pain management remains a significant clinical challenge in orthopaedic surgery, necessitating alternatives to systemic opioid administration. This study investigated an in-situ polymerizable hydrogel system for the simultaneous local delivery of the analgesic bupivacaine and the nonsteroidal anti-inflammatory drug (NSAID) ketorolac in a rat model of tibia fracture/osteotomy and plate fixation. Two hydrogel formulations, slow-degrading (MAPLAPEG) and fast-degrading (MAPGAPEG), were synthesized and characterized. Functional recovery was assessed via static weight-bearing, gait analysis, and mechanical sensitivity (Von Frey tests). Local inflammation was evaluated by measuring serum alpha-2 macroglobulin (α2M) levels and local matrix metalloproteinase-9 (MMP-9) activity, along with histological and immunofluorescence analyses. Static weight-bearing analysis demonstrated a ∼80% improvement toward symmetric hind-limb loading in the MAPGAPEG treatment group compared with control at postoperative day 42 (p < 0.05). At POD 3, 2-4 toe spread demonstrated ∼80% normalization toward symmetric limb use in the MAPGAPEG treatment group compared with control. Minimal inflammation and no negative impact on bone healing were observed. This dual drug-loaded hydrogel system offers a promising strategy for postoperative pain management in orthopaedics, potentially reducing reliance on systemic opioids and enhancing patient recovery.