应用Agent-Based-Model研究围术期单剂量地塞米松对手术切口愈合的影响及机制

Perioperative single dose of dexamethasone has been found to have many advantages, such as anti-inflammation, analgesic and postoperative nausea and vomiting prevention. However, its effect on wound healing is not clear. In our previous clinical study, single small dose of dexamethasone caused the amount of cytokines change from time to time. To elucidate whether these changes have impact on wound healing, we will set up an agent-based model of wound healing on the basis of our animal experiments in which a comprehensive view of inflammation changes under different doses of dexamethasone will be explored. In the model, agents will be cells (platelet, inflammative cells, epithelial cell, fibroblasts etc.), cytokines (proinflammatory cytokines, anti-inflammatory cytokines and growth factors) and proteins (gelatin). Dexamethasone will be the control factor for the model. The model will simulate the whole dynamic process of wound healing under different doses of dexamethasone. The model will be validated and calibrated by the clinical patient’s data through Pattern-Oriented analysis. Eventually, individual patient’s data will be used for model calibration to predict the outcome of the wound healing. This project will find the safe dose range of dexamethasone in perioperative use. More importantly the model will be used to predict the wound-healing outcome for individual patient, in the personalized and precision medicine fashion.

围术期单次小剂量地塞米松被发现有抗炎、镇痛和预防术后恶心呕吐等多种优势。然而，单剂量地塞米松对术后伤口愈合有何影响，众说纷纭。我们在前期预实验中发现地塞米松会使术后伤口引流液中的细胞因子产生时间－数量的改变。为探索这些改变对伤口愈合的利弊，我们拟用基于介质建模（Agent-Based-Model）技术建立地塞米松下炎症反应-伤口愈合模型。模型中的介质（agents) 将包括细胞（血小板、炎症细胞、上皮细胞等），细胞因子（促炎因子、抗炎因子和生长因子）和胶原蛋白等。各种介质的运动规则和相互关系将根据动物实验的结果而制定。模型将体现不同剂量地塞米松作用下各种介质之间相互关系和伤口愈合的动态变化。采用面向模式分析法用临床试验的数据对模型进行验证和校准。本课题将阐述单剂量地塞米松影响术后炎症反应及伤口愈合的相关机制，明确地塞米松的安全剂量范围，预测患者的伤口愈合情况，实现个体化精准医疗。

围术期使用小剂量地塞米松被报道具有抗炎、预防术后恶心呕吐的发生，加速围术期康复等诸多优势，但其对于围术期伤口愈合的影响尚不明确。我们建立了一个有效的地塞米松对内毒素介导的巨噬细胞炎症反应影响的ABM 模型,并使用细胞模型进行了校准与验证。在动物实验中，我们发现单剂量地塞米松（1mg/kg，i.p.）促进脂多糖诱导的脓毒症小鼠的伤口愈合，但延迟正常小鼠的伤口愈合。揭示了在正常和脓毒症小鼠中，地塞米松的安全剂量范围,在正常小鼠中，地塞米松的安全范围为0~0.6333mg/kg,在脓毒症小鼠中，地塞米松的安全剂量范围为0.1210~2.031mg/kg。在临床试验中，我们探究了围术期小剂量单次地塞米松对传统术式甲状腺肿瘤切除术后伤口愈合的影响。在术后一周和一月使用SBSES（石溪瘢痕评估量表）、MSS（曼彻斯特伤疤量表）和 POSAS（患者和观察者疤痕评估量表）对患者切口进行评估，结果显示围术期小剂量单次地塞米松可以显著改善甲状腺手术患者术后一周的切口愈合情况，但对术后一个月的伤口愈合情况未见明显改善。本课题为明确地塞米松的安全剂量范围，预测患者的伤口愈合情况，实现个体化精准医疗提供了理论依据。