A Novel Gelatin Hydrogel‐Based Drug‐Delivery System Promotes Antimicrobial Efficacy in a Pyogenic Spondylodiscitis Rat Model

ABSTRACT Background Spondylodiscitis/spondylitis is an intractable disease requiring long‐term intravenous antibiotics administration. However, drug delivery is greatly restricted because of the avascular nature in the intervertebral disc, which not only delays recovery but increases antimicrobial resistance and osteomyelitis. The purpose of this study is to elucidate the efficacy of gelatin hydrogel microsphere incorporating cefazolin (GM‐CEZ) using a rat spondylodiscitis model. Methods First, GM‐CEZ was characterized by in vitro degradability, sustainability, and antimicrobial effects. Second, its efficacy in vivo was evaluated using a rat spondylodiscitis model of bioluminescent methicillin‐susceptible Staphylococcus aureus . Antimicrobial effects were monitored using an in vivo imaging system and blood tests. Residual bone volume was evaluated using micro‐computed tomography. Immunohistology for angiogenesis‐related CD31 and smooth muscle actin was also performed. Third, in vivo safety was evaluated using a rat intervertebral disc injection model with blood tests for systemic safety and TUNEL staining for local safety. Results In vitro, CEZ was gradually released with GM degradation and antimicrobial effects increased proportionally to the degradation. In vivo, single topical injection of GM‐CEZ (1 mg GM, 250 μg/kg CEZ, 100 μL collagen) significantly reduced the amount of bacteria with fewer white blood cells 7 days after treatment and bone destruction 28 days after treatment, compared to local administration of CEZ (250 μg/kg) and systemic administration of CEZ (25 mg/kg/day for 28 days) (all, p < 0.05). Immunopositivity was significantly higher in rats with local GM‐CEZ administration than those with local CEZ and systemic CEZ administration (all, p < 0.05), indicating greater tissue reformation. In vivo safety experiments demonstrated no significant myelotoxicity, nephrotoxicity, and local cytotoxicity of GM‐CEZ. Conclusions The local administration of GM‐CEZ using a fraction of the systemic CEZ dose achieved enhanced antimicrobial effects without systemic and local toxicity, suggesting its potential as a promising treatment strategy for pyogenic spondylodiscitis.