Intra-articular injection of triamcinolone acetonide releasing biomaterial microspheres inhibits pain and inflammation in an acute arthritis model

Inflammation of the synovium and joint capsule is a main driver of pain in an osteoarthritic (OA) joint. Triamcinolone acetonide (TAA) is a classical corticosteroid that reduces synovitis and alleviates pain, albeit transiently. Biomaterial-based local TAA release may prolong the suppression of pain without the need for multiple injections. Polylactic-co-glycolic acid (PLGA) formulations of TAA prolong OA pain relief to a limited extent. A novel polyesteramide (PEA) microsphere platform allows for extended release in the OA joint for over 3 months. To evaluate their effect on pain and inflammation, TAA-loaded microspheres were intra-articularly delivered to the knee joint in a rat model of acute arthritis induced by intra-articular injection of streptococcal cell wall peptidoglycan-polysaccharide (PGPS) and subsequent flare-ups by intravenous PGPS injections. PEA-loaded microspheres were benchmarked with TAA-loaded PLGA microspheres and bolus TAA injection. TAA treatments were injected intra-articularly before the first induced flare-up. TAA-loaded PEA and PLGA microspheres reduced joint swelling and signs of pain-like behavior over the entire study period, as assessed by weight bearing and referred mechanical hypersensitivity, whereas bolus suspension was effective for a shorter time period. TAA-loaded PEA microspheres reduced lameness to a greater extent than TAA-loaded PLGA microspheres. In conclusion, a single intra-articular injection of TAA-loaded PEA microspheres reduced joint swelling and induced longer pain relief compared to bolus injection. Hence relief of inflammation and pain by PEA-based delivery of TAA may prove to be effective and durable.

滑膜与关节囊炎症是骨关节炎（OA）关节疼痛的主要致病因素。曲安奈德（TAA）作为经典糖皮质激素，可暂时缓解滑膜炎并减轻疼痛，但效果具有一过性。基于生物材料的局部TAA递送策略，可避免多次注射，延长疼痛抑制时长。聚乳酸-羟基乙酸共聚物（PLGA）搭载的TAA制剂仅能有限延长OA疼痛缓解周期。一种新型聚酯酰胺（PEA）微球平台，可在OA关节内实现长达3个月以上的长效药物释放。为评估该制剂对疼痛与炎症的调控效果，本研究将负载TAA的微球关节腔内注射至大鼠急性关节炎模型：该模型通过关节腔内注射链球菌细胞壁肽聚糖-多糖（PGPS）构建，并经静脉注射PGPS引发后续病情发作。实验以负载TAA的PLGA微球与单次大剂量TAA混悬液注射作为对照，且所有TAA治疗均需在首次诱导病情发作前完成关节腔内注射。经负重能力与牵涉性机械痛敏评估，负载TAA的PEA与PLGA微球可在整个研究周期内减轻关节肿胀与痛样行为症状，而单次大剂量混悬液的镇痛抗炎效果持续时长更短。此外，负载TAA的PEA微球在缓解跛行方面的效果优于负载TAA的PLGA微球。综上，单次关节腔内注射负载TAA的PEA微球，相较于单次大剂量注射，可减轻关节肿胀并实现更持久的疼痛缓解。因此，基于PEA递送平台的TAA抗炎镇痛策略，有望成为有效且持久的临床治疗方案。