A Review of Methods for Establishing and Evaluating Animal Models of Stroke

doi:10.12300/j.issn.1674-5817.2025.037

Abstract

Abstract:

Stroke is one of the leading causes of disability and mortality worldwide. Research into its mechanisms and the development of therapeutic strategies heavily rely on animal models that accurately replicate the pathological features of human disease. An ideal animal model for stroke should not only reproduce the neurological deficits and pathological changes observed in clinical patients but also demonstrate good reproducibility and translational value. This review focuses on the preparation and evaluation methods of ischemic stroke animal models. Firstly, it elaborates on the selection criteria, advantages, and disadvantages of experimental animals, including rodents (rats, mice) and non-rodents (non-human primates, miniature pigs, rabbits, zebrafish). Secondly, it provides a detailed overview of the modeling principles, key procedures, and application scopes for ischemic stroke models and hemorrhagic stroke models. Furthermore, the review summarizes advances in the applications of emerging technologies,including gene editing [e.g., clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing], multimodal imaging (e.g., two-photon microscopy, photoacoustic imaging), artificial intelligence, optogenetics, 3D bioprinting, organoid models, and multi-omics in model optimization, precise assessment, and mechanistic investigation. Finally, based on a systematic analysis of relevant domestic and international literature from 2019 to 2024, this review discusses model selection strategies based on research objectives, a multidimensional evaluation system encompassing behavioral, imaging, and molecular pathological assessments, and envisions future directions involving technological integration to achieve model precision and individualization. This article aims to provide a comprehensive methodological reference to help researchers select appropriate animal models of stroke according to specific scientific questions.

Key words: Stroke, Animal model, Ischemic stroke, Hemorrhagic stroke, Modeling methods, Model optimization

CLC Number:

R-332

YANG Yunrong,WU Wenyu,TAN Yue,et al. A Review of Methods for Establishing and Evaluating Animal Models of Stroke[J]. Laboratory Animal and Comparative Medicine, 2026, 46(1): 94-106. DOI: 10.12300/j.issn.1674-5817.2025.037.

Figures/Tables 4

References 76

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物种 Species	优点 Advantages	主要品种/品系 Main breeds/strains	主要局限 Main limitations	典型应用场景 Typical application scenarios	常用建模方法 Common modeling methods
大鼠 Rat	手术稳定性高，行为学丰富，适用于药效评价	SD、Wistar、Long-Evans等	基因工具有限	神经保护剂验证、康复训练机制研究	线栓法、光化学法、三氯化铁法、胶原酶法、血管穿刺法、血栓法、双侧颈总动脉结扎
小鼠 Mouse	遗传操作便捷，成本低，适合高通量筛选	C57BL/6（常用）、SV129、BALB/c等，以及各类基因修饰品系	梗死体积变异大、血管脆弱	基因-表型关联、免疫机制研究	线栓法、光化学法、三氯化铁法
非人灵长类 Non-human primate	脑结构/功能高度类人，影像兼容性强	食蟹猴、普通猕猴、狨猴等	实验成本极高、实验动物福利伦理复杂	高级认知障碍研究、临床前终效验证	线栓法及其他定制化手术方案
小型猪 Miniature pig	脑体积大，手术操作方便	哥廷根小型猪、尤卡坦小型猪、巴马香猪、五指山小型猪等	侧支循环异常、康复过程不典型	外科技术开发、急性期介入治疗评价	线栓法、球囊闭塞法、微导管栓塞法
兔 Rabbit	血管介入友好，血栓模型稳定	新西兰大白兔、日本大耳白兔等	缺乏相应的神经行为评价体系	取栓/溶栓器械测试、血栓病理研究	三氯化铁敷贴法、血栓栓塞法
斑马鱼 Zebrafish	活体血管可视化，基因筛选高效	AB系、TU系、TL系等野生型及各类转基因荧光品系	缺乏高级脑结构和认知功能	血管完整性机制、高通量药物初筛	光化学血栓法

物种 Species	优点 Advantages	主要品种/品系 Main breeds/strains	主要局限 Main limitations	典型应用场景 Typical application scenarios	常用建模方法 Common modeling methods
大鼠 Rat	手术稳定性高，行为学丰富，适用于药效评价	SD、Wistar、Long-Evans等	基因工具有限	神经保护剂验证、康复训练机制研究	线栓法、光化学法、三氯化铁法、胶原酶法、血管穿刺法、血栓法、双侧颈总动脉结扎
小鼠 Mouse	遗传操作便捷，成本低，适合高通量筛选	C57BL/6（常用）、SV129、BALB/c等，以及各类基因修饰品系	梗死体积变异大、血管脆弱	基因-表型关联、免疫机制研究	线栓法、光化学法、三氯化铁法
非人灵长类 Non-human primate	脑结构/功能高度类人，影像兼容性强	食蟹猴、普通猕猴、狨猴等	实验成本极高、实验动物福利伦理复杂	高级认知障碍研究、临床前终效验证	线栓法及其他定制化手术方案
小型猪 Miniature pig	脑体积大，手术操作方便	哥廷根小型猪、尤卡坦小型猪、巴马香猪、五指山小型猪等	侧支循环异常、康复过程不典型	外科技术开发、急性期介入治疗评价	线栓法、球囊闭塞法、微导管栓塞法
兔 Rabbit	血管介入友好，血栓模型稳定	新西兰大白兔、日本大耳白兔等	缺乏相应的神经行为评价体系	取栓/溶栓器械测试、血栓病理研究	三氯化铁敷贴法、血栓栓塞法
斑马鱼 Zebrafish	活体血管可视化，基因筛选高效	AB系、TU系、TL系等野生型及各类转基因荧光品系	缺乏高级脑结构和认知功能	血管完整性机制、高通量药物初筛	光化学血栓法

特征 Features	颈外动脉入路 External carotid artery approach	颈总动脉入路 Common carotid artery approach
操作步骤 Procedures	需永久结扎颈外动脉远心端	无需结扎颈外动脉，操作更简便
插入路径 Insertion path	经颈外动脉切口转向颈内动脉	经颈总动脉直接进入颈内动脉
优点 Advantages	插入角度自然，通向颈内动脉的路径直接，成功率较高	保留颈外动脉完整性，对手术创伤更小
缺点 Disadvantages	永久结扎颈外动脉，终止其供血区域血流	易误伤血管内膜或误入颈总动脉近心端
适用场景 Applicable scenarios	无需保留颈外动脉血供的研究	需要保留颈外动脉血流的实验设计

特征 Features	颈外动脉入路 External carotid artery approach	颈总动脉入路 Common carotid artery approach
操作步骤 Procedures	需永久结扎颈外动脉远心端	无需结扎颈外动脉，操作更简便
插入路径 Insertion path	经颈外动脉切口转向颈内动脉	经颈总动脉直接进入颈内动脉
优点 Advantages	插入角度自然，通向颈内动脉的路径直接，成功率较高	保留颈外动脉完整性，对手术创伤更小
缺点 Disadvantages	永久结扎颈外动脉，终止其供血区域血流	易误伤血管内膜或误入颈总动脉近心端
适用场景 Applicable scenarios	无需保留颈外动脉血供的研究	需要保留颈外动脉血流的实验设计

模型方法 Modeling approaches	主要品种/品系 Main breeds/strains	造模原理 Modeling Principles	开颅 Cranio-tomy	优势 Advantages	局限性 Limitations	应用场景 Scope of application
线栓法 Intraluminal filament occlusion model	C57BL/6小鼠、SD雄性大鼠等	插入尼龙线阻断大脑中动脉血流	否	高度可复制性，模拟再灌注损伤	体重要求严格，脑卒中梗死体积难以控制	缺血性脑卒中的再灌注损伤机制、神经保护策略及康复治疗效果
光化学栓塞法 Photothrombotic model	C57BL/6小鼠、SD大鼠等	静脉注射光敏染料，用特定波长进行激活	是	高存活率、定点精准损伤	参数敏感，易自发恢复	缺血性脑卒中的病理机制、药物筛选及治疗方案评估
血栓法 Thromboembolic model	SD大鼠等	直接注射血栓物质	否	高精度，真实性强	技术要求较高，个体差异大	血栓形成机制、抗凝药物疗效及血栓溶解疗法
三氯化铁敷贴法 Topical FeCl₃-induced model	C57BL/6小鼠、SD大鼠等	三氯化铁诱导血管壁化学损伤，形成原位血栓	是	病理生理相关性高，血栓形成过程接近临床	手术创伤大，难以实现再灌注	抗血小板/抗凝药物评价、血栓形成机制研究
双侧颈总动脉结扎法 Bilateral common carotid artery ligation model	SD大鼠等	结扎双侧颈总动脉	否	简单易行，成本低廉	无法完全模拟人类复杂性	血管损伤后的修复机制及新型血管支架材料的生物相容性
自体血注射法 Autologous blood injection model	C57BL/6小鼠、SD大鼠等	立体定位注射自体动脉血形成血肿	是	出血量精确可控、形态一致性好	需立体定位与显微操作，技术要求高	血肿清除策略、颅内压变化、神经炎症及神经保护治疗研究
胶原酶诱导法 Collagenase-induced model	SD大鼠等	胶原酶可降解血管壁中的胶原纤维，破坏血管壁的完整性	是	操作简便，出血量稳定	与自然出血存在差异	出血性脑卒中的发病机制、止血药物及神经保护剂的效果
血管穿刺法 Vessel puncture-induced intracerebral hemorrhage model	SD大鼠等	直接刺入目标血管	是	接近人类病理特征	技术要求高，手术风险大	出血性脑卒中的发病机制、止血药物及神经保护剂的效果