Wu Meng-Huang, Shih Ming-Hung, Hsu Wei-Bin, Dubey Navneet Kumar, Lee Wen-Fu, Lin Tsai-Yu, Hsieh Meng-Yow, Chen Chin-Fu, Peng Kuo-Ti, Huang Tsung-Jen, Shi Chung-Sheng, Guo Ren-Shyang, Cai Chang-Jhih, Chung Chiu-Yen, Wong Chung-Hang
Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Orthopedics, Taipei Medical University Hospital, Taipei, Taiwan.
PLoS One. 2017 Oct 23;12(10):e0186784. doi: 10.1371/journal.pone.0186784. eCollection 2017.
This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.
本研究评估了酮咯酸缓释热敏性可生物降解水凝胶在大鼠后爪足底切口疼痛模型中的持续镇痛效果。基于最佳的溶胶-凝胶相变和体外药物释放曲线，合成了一种嵌入酮咯酸的2,2'-双(2-恶唑啉)(BOX)连接的甲氧基聚(乙二醇)和聚(丙交酯-共-乙交酯)(mPEG-PLGA)二嵌段共聚物(BOX共聚物)作为酮咯酸水凝胶。使用已建立的大鼠后爪足底切口疼痛模型评估酮咯酸水凝胶对术后疼痛(POP)的影响，并与酮咯酸溶液进行比较。分别通过麻醉计和失能装置，采用行为测试评估疼痛和感觉阈值以及疼痛评分。通过酶联免疫吸附测定法(ELISA)测量切口伤口周围促炎细胞因子水平(TNF-α、IL-6、VEGF和IL-1β)。使用苏木精和伊红以及Masson三色染色评估组织组织学。10mg/mL(25wt%)的酮咯酸水凝胶在26.4°C表现出溶胶-凝胶转变，在体外具有10天的持续药物释放曲线。与酮咯酸溶液组相比，在应用的前18小时内，酮咯酸水凝胶组组织液中酮咯酸的浓度更高。酮咯酸水凝胶提高了疼痛和感觉阈值，增加了负重能力，并显著降低了TNF-α、IL-6和IL-1β的水平，同时提高了组织液中VEGF的水平。组织学分析显示，用酮咯酸水凝胶处理的伤口周围有更大程度的上皮化和胶原蛋白沉积。总之，我们的研究表明，酮咯酸水凝胶是治疗术后疼痛的理想化合物，还能促进切口伤口愈合。
