单独支架取栓术治疗犬急性栓塞性肠系膜缺血的可行性与安全性 机翻

Feasibility and safety of stand-alone stent retriever thrombectomy for acute embolic mesenteric ischemia in a canine model

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期刊Scientific Reports
发表日期2026-10-27
物种犬
DOIhttps://doi.org/10.1038/s41598-026-63911-3
PMIDOA:W7223829656

摘要

This pilot study aimed to evaluate the efficacy and safety of stent retriever thrombectomy for arterial embolic acute mesenteric ischemia (AEAMI) in a canine model. The AEAMI model was created in 10 beagles by transcatheter administration of autologous thrombus into the superior mesenteric artery (SMA). Follow-up angiography was performed 2 h after thrombus administration to assess the model stability. SMA recanalization was graded with the thrombectomy in visceral ischemia (TIVI) score, which ranges from 0 to 4. Clinical success was defined as a TIVI score of 3 or 4. Procedure-related complications and vessel injuries were recorded. The AEAMI model was successfully established in all canines and remained stable at 2-hour follow-up angiography. After a mean treatment time of 45.5 ± 19.0 min, the mean TIVI score significantly increased after stent retriever thrombectomy (0.5 ± 0.7 vs. 3.1 ± 1.0, p < .001). Clinical success was achieved in 8 (80%) canines. Mild vasospasm and new distal branch embolization occurred in 4 (40%) and 1 (10%) canines, respectively. No other procedure-related complications or histologically evident vessel injuries were observed. Stent retriever thrombectomy with the Solitaire FR device achieved rapid recanalization with few complications in this canine AEAMI model. With device optimization and further validation, this approach may represent a promising endovascular revascularization technique for AEAMI.

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OPEN Scientific Reports | (2026) 16:34520 1 | https://doi.org/10.1038/s41598-026-63911-3 犬模型中单独使用支架取栓器行血栓切除术治疗急性栓塞性肠系膜缺血的可行性与安全性 Yangyi Zhou 1,3,Shuqin Gan 2,3,Yuan Yuan 1,Boxiang Zhao 1,Maofeng Gong 1,Jie Kong 1,Haobo Su 1,Jianping Gu 1 & Yadong Shi 1 本初步研究旨在评估犬模型中支架取栓器血栓切除术治疗动脉栓塞性急性肠系膜缺血(AEAMI)的有效性和安全性。通过经导管向肠系膜上动脉(SMA)注入自体血栓,在10只比格犬中建立AEAMI模型。注入血栓后2小时行随访血管造影以评估模型稳定性。采用内脏缺血取栓(TIVI)评分对SMA再通进行分级,评分范围为0至4分。临床成功定义为TIVI评分为3分或4分。记录操作相关并发症和血管损伤。所有犬均成功建立AEAMI模型,且在2小时随访血管造影时保持稳定。平均治疗时间为45.5 ± 19.0分钟,支架取栓器血栓切除术后平均TIVI评分显著升高(0.5 ± 0.7 vs. 3.1 ± 1.0,p < .001)。8只(80%)犬获得临床成功。分别有4只(40%)和1只(10%)犬发生轻度血管痉挛和新发远端分支栓塞。未观察到其他操作相关并发症或组织学可见的血管损伤。在本犬AEAMI模型中,使用Solitaire FR装置的支架取栓器血栓切除术实现了快速再通且并发症少。经器械优化和进一步验证,该方法可能代表一种有前景的AEAMI血管内血运重建技术。关键词 急性肠系膜缺血,血管内血运重建,支架取栓器血栓切除术,动物模型 急性肠系膜缺血(AMI)由肠系膜血流突然减少引起,不足以满足肠道的代谢需求1。AMI不常见,占成人住院的0.038%2;估计年发病率为每10万居民6.2例新发病例3。尽管诊断和治疗取得进展,AMI仍是一项重大治疗挑战,短期死亡率接近50%2,3。动脉栓塞性AMI(AEAMI)是最危险的亚型之一2,约占AMI病例的一半1。及时恢复肠系膜灌注至关重要,现行指南支持将开放手术和血管内血运重建(EVR)作为特定患者的一线选择4,5。与开放血运重建相比,EVR似乎与较低的死亡率和发病率相关,并越来越多地被用作AMI的初始血运重建策略6,7。已有多种EVR技术用于治疗AMI的报道,包括局部溶栓、机械取栓和支架置入8,然而,尚无单一技术被证实更优9。经皮机械取栓因其微创且能快速清除血栓而具有吸引力,但现有证据仍然有限。此外,目前尚无专门用于AMI的机械取栓装置。支架取栓器血栓切除术已成为一种重要的血运重建技术 1 南京医科大学附属南京第一医院血管与介入放射科,中国南京长乐路68号,210006。2 南京医科大学附属南京第一医院神经内科,中国南京长乐路68号,210006。3 Yangyi Zhou和Shuqin Gan对本工作贡献相同。email: shiyadong0221@gmail.com www.nature.com/scientificreports

Scientific Reports | (2026) 16:34520 2 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 用于大血管闭塞所致的急性缺血性卒中10,11。Muria等12于2017年首次描述了支架取栓器取栓联合抽吸治疗AEAMI,随后的报道进一步支持了该技术的可行性13,14。然而,支架取栓器取栓治疗AEAMI仍属于超说明书应用,尚未经过严格评估。支架取栓器取栓作为AEAMI独立技术的可行性和安全性也仍不明确。因此,本研究旨在犬AEAMI模型中评估使用Solitaire FR装置行独立支架取栓器取栓的有效性和安全性。研究结果可为AEAMI的潜在血管内治疗策略提供临床前证据。材料与方法 动物与准备 所有实验均按照《实验动物护理与使用指南》进行。研究医院的机构动物护理与使用委员会批准了所有实验程序(编号IACUC-2209011)。2022年11月至2023年6月期间,纳入10只体重15–20 kg的比格犬(常州贝乐实验动物养殖有限公司,许可证号:SCXK 2018-0007),以建立动物模型,评估使用Solitaire FR装置行支架取栓器取栓治疗AEAMI的可行性。所有犬在实验前禁食24 h,可自由饮水。手术前1天通过胃管给予聚乙二醇电解质(Beaufour Ipsen Industrie,法国)进行肠道准备。犬采用吸入异氟烷(深圳瑞沃德生命科学,中国)麻醉。以5%异氟烷加氧气、流量5 L/min经面罩吸入诱导麻醉。气管插管后,以2.5%-3%异氟烷加氧气、流量2–3 L/min维持麻醉。达到充分麻醉后,将犬仰卧位置于血管造影室。整个实验过程中监测生命体征参数,包括心率、血压、血氧饱和度、呼吸频率和体温。自体血栓制备、动物建模与支架取栓器取栓 手术区域常规消毒铺巾。经股动脉以8 Fr鞘管(Radifocus Introducer;Terumo Corporation,日本)建立通路。自体血栓制备方法:将8 mL股动脉血、64 mg牛血浆纤维蛋白原(Sigma-Aldrich,美国)和200单位冻干凝血酶(湖南一格制药有限公司,中国)在10 mL注射器中混合至少3分钟15。将混合物转移至直径5 mm的硅胶管中,室温孵育至少60 min。然后将形成的血栓切成约30 mm长的节段备用。犬AEAMI模型建立如下。经股动脉引入5 Fr多功能血管造影导管(Tempo;Cordis,美国),置于SMA开口处。通过血管造影导管注射碘克沙醇(Visipaque 320 mg/mL;GE HealthCare,美国)行SMA血管造影。测量SMA主干近端(S1)、中段(S2)和远端(S3)直径。术前血管造影后,经260 cm亲水导丝(Terumo Corporation,日本)将血管造影导管更换为8 Fr指引导管(Neuron MAX;Penumbra,美国)。在Y形止血阀(Access-9;Merit Medical,美国)辅助下,经指引导管注入制备好的血栓。注入后行血管造影评估血栓分布。若血栓分布不理想,以相同方式再次注入血栓。建模后2 h行随访血管造影评估稳定性,包括血栓迁移、血栓溶解和血管再通。支架取栓器取栓术前,经静脉给予普通肝素负荷剂量120–150 IU/kg进行全身肝素化,目标ACT为250–300 s。确认SMA主干闭塞后,经指引导管引入2.8 Fr微导管(Progreat;Terumo Corporation,日本),并推进至闭塞处附近。小心操作微导丝穿过闭塞段,将微导管推进至正常的SMA主干预远端。经微导管手推造影确认位置。随后跨闭塞段释放支架取栓器(Solitaire FR;Medtronic,美国)。支架取栓器尺寸主要根据术者经验和闭塞血管直径选择。释放后5 min行支架回收,以使支架充分展开。术后行血管造影,并根据需要追加支架取栓器取栓次数。取栓尝试不超过5次。组织学分析 手术后,所有犬在麻醉状态下经静脉注射致死剂量氯化钾安乐死,以进行组织学分析。安乐死后立即开腹探查,评估肠缺血的位置和严重程度。采集接受支架取栓器取栓的SMA节段组织标本进行分析。标本在10%福尔马林中固定至少24 h,石蜡包埋,切成5微米切片,行苏木精-伊红(H&E)或Masson三色染色。由一名对手术细节不知情的经验丰富的病理学家使用数字切片扫描仪(Pannoramic MIDI;3DHISTECH,匈牙利)检查同一蜡块的3张切片。定义 SMA主干分为三个节段,分别命名为S1、S2和S3。S1定义为SMA开口与胰十二指肠下动脉起始处之间的SMA近端节段。S2定义为胰十二指肠下动脉与回结肠动脉之间的SMA中段。S3定义为

Scientific Reports | (2026) 16:34520 3 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 作为回结肠动脉下游的远端SMA血管床16。闭塞血管的直径在邻近的正常近端SMA处测量14。手术时间定义为从支架取栓器血栓切除术前的诊断性血管造影至最终控制性血管造影的间隔时间。支架取栓器血栓切除术后血管再通采用TIVI评分评估,评分范围为0至4分17。TIVI 0表示栓塞性闭塞无再通;TIVI 1表示不完全或部分再通,无顺行远端血流;TIVI 2表示不完全或部分再通,伴轻微、不充分的顺行远端血流;TIVI 3表示完全再通,远端血流正常,仅在侧支中残留极少量血栓;TIVI 4表示完全再通,远端血流正常,侧支中无肉眼可见的残留血栓。TIVI评分在支架取栓器血栓切除术前的初始血管造影、支架取栓器血栓切除术后即刻以及最终控制性血管造影时进行评估。技术成功定义为支架成功跨越血栓部署并随后取出支架。临床成功定义为TIVI评分为3或4分。手术相关并发症包括血管痉挛、夹层、穿孔和新发远端栓塞。统计分析 所有统计分析均采用SPSS 24.0版(IBM,美国)进行。分类变量以n(%)表示,连续变量酌情以均值±标准差或中位数表示。采用配对t检验比较治疗前后的定量变量。图表采用GraphPad Prism 9.0版(GraphPad Software Inc.,美国)生成。p值<0.05被认为具有统计学意义。结果 动物 所有纳入的犬均为雌性,平均体重为17.1 ± 1.8 kg。术前SMA血管造影显示S1、S2和S3段SMA主干平均直径分别为5.0 ± 0.3 mm、4.5 ± 0.4 mm和3.0 ± 0.6 mm。在一只犬中观察到空肠动脉与肠系膜上静脉之间的动静脉瘘;其余犬未观察到SMA病变。手术过程中无动物死亡。AEAMI犬模型的结果 AEAMI模型在所有犬中均成功建立,自体血栓注射次数的中位数为1.5次。模型建立后即刻血管造影显示闭塞部位平均直径为3.5 ± 0.6 mm(范围2.7–4.7 mm)(表1)。SMA闭塞始于S1、S2和S3段者分别为0只(0%)、6只(60%)和4只(40%)。变量 所有犬(n = 10) 人口学特征 雌性10只(100%) 体重 - kg 17.1 ± 1.8 建模前血管造影结果 近端SMA(S1)直径 - mm 5.0 ± 0.3 中段SMA(S2)直径 - mm 4.5 ± 0.4 远端SMA(S3)直径 - mm 3.0 ± 0.6 血栓注射次数中位数 1.5 建模后血管造影结果 闭塞部位 近端SMA(S1)0 中段SMA(S2)6只(60%) 远端SMA(S3)4只(40%) 闭塞部位直径 - mm 3.5 ± 0.6 分支血管受累4只(40%) 远端栓塞2只(20%) 2小时随访血管造影 血栓溶解2只(20%) 血栓迁移0 血管再通1只(10%) 2小时随访时TIVI评分 0 6只(60%) 1 3只(30%) 2 1只(10%) 3 0 4 0 表1. 10只犬的建模相关信息。除非另有说明,数据以n(%)或均值±标准差表示。SMA肠系膜上动脉,TIVI内脏缺血取栓术。

Scientific Reports | (2026) 16:34520 4 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 分别见于这些犬。侧支受累和远端栓塞分别见于4只(40%)和2只(20%)犬。即刻血管造影显示,7只犬的TIVI评分为0,3只犬的TIVI评分为1。模型建立后2小时的随访血管造影证实了模型的稳定性。3只(30%)犬观察到部分近端血栓溶解(TIVI 1),1只犬观察到部分再通但顺向远端血流不足(TIVI 2)。其余所有闭塞均保持稳定,未见明显的血栓溶解或迁移。支架取栓器血栓切除术的疗效与安全性结果 支架取栓器血栓切除术的平均治疗时间为45.5 ± 19.0分钟,所有犬均实现了技术成功。8只(80%)犬实现了临床成功,中位取栓尝试次数为1次。代表性犬的成功AEAMI建模及随后的支架取栓器血栓切除术见图1A–H。分别有7只(70%)和3只(30%)犬使用了6 mm × 30 mm和4 mm × 20 mm的支架取栓器(表2)。支架取栓器血栓切除术后平均TIVI评分显著升高(0.5 ± 0.7 vs. 3.1 ± 1.0,p < .001)(图2A、B)。支架取栓器与闭塞直径比的中位数为1.6 ± 0.3。再通失败犬的平均支架取栓器与闭塞直径比为1.28,再通成功犬为1.64。关于安全性结果,任何犬均未发生血管夹层或穿孔。4只(40%)犬在支架取栓器血栓切除术后观察到轻度血管痉挛,所有痉挛均在未额外用药的情况下缓解。1只(10%)犬在支架取栓器血栓切除术后发生新的远端栓塞。组织学上未见明显内膜损伤,代表性大体和组织学肠道表现见图3A、B。关于术后肠道宏观表现。在8只再通成功的犬中,小肠黏膜呈正常粉红色,肠道蠕动规律,无浆膜出血或发黑。偶见轻度多灶性肠管扩张(图1H)。在其余2只再通失败的犬中,低灌注区域可见局灶性肠段苍白,伴有肠管扩张和肠道蠕动减弱。任何犬均未发现肠道出血或坏疽。讨论 尽管近几十年来治疗取得了进展,AMI仍然是一个治疗挑战8。在最近发表的前瞻性多中心AMESI研究中,动脉闭塞性AMI的30天死亡率仍接近50%2。早期诊断和及时血运重建对于成功管理至关重要。欧洲心脏病学会的指南指出,除非仅存在远端血管闭塞,否则所有动脉闭塞性AMI病例均应尝试血运重建18。尽管指南建议开放手术和血管内治疗均可作为AEAMI的一线血运重建选择4,18,但EVR创伤小,可能更适合老年或体弱患者。多项研究表明,与开放血运重建相比,AMI的一线EVR可能与更低的死亡率、更好的成本效益、更少的肠切除、更少的短肠综合征以及更短的住院时间相关7,19,20。因此,EVR越来越多地被用作AMI的一线治疗6,19。尽管已报道了多种用于AMI的EVR技术8,但大多数研究受限于回顾性设计和小样本量。局部溶栓是一种简单有效的EVR技术。在一项纳入34例患者的回顾性研究中,88%的患者实现了成功溶栓,6例患者出现了自限性出血21。然而,局部溶栓通常需要24–48小时的输注时间,这可能延迟完全血运重建21。此外,高出血风险和坏死肠管是溶栓的禁忌证。机械取栓可以提供快速血运重建,可能是AMI更有前景的EVR技术8,9。手动经导管抽吸是最简单的机械取栓技术,可尝试用于无腹膜炎的患者4。尽管报道的成功率为73.3%至100%22,但通常需要辅助局部溶栓23,24。另一个重要问题是,该操作过程中可能丢失多达300 mL血液24。与手动抽吸相比,机械抽吸理论上可提供更持续的负压,从而改善再通。然而,一项纳入31例AMI患者的回顾性研究发现,机械抽吸并不优于手动抽吸25。其他报道的用于AMI的机械取栓装置包括AngioJet和Straub Rotarex血栓切除系统。Ballehaninna等26报道了一例使用AngioJet血栓切除联合EKOS导管辅助局部溶栓成功治疗的AMI病例。既往研究表明,Rotarex血栓切除与高技术成功率27和令人满意的再通率相关17,27。然而,已有报道称存在操作相关并发症,包括血管穿孔和导管尖端断裂17,27。AngioJet和Rotarex装置在抽吸前先碎裂血栓,这可能增加远端栓塞的风险17。尽管SMA支架置入期间的栓塞保护装置可行且有用28,但其在SMA机械取栓中的作用尚未被评估9。与药物治疗相比,使用Solitaire FR装置的支架取栓器血栓切除术已被证明可改善急性前循环卒中的再通和结局11。鉴于急性缺血性卒中与AEAMI在概念上的相似性,支架取栓器血栓切除术也可能促进AEAMI的快速血运重建。Miura等人于2017年描述了首例使用Solitaire FR装置成功进行支架取栓器血栓切除术治疗AEAMI的病例12。作者认为,Solitaire FR支架结合了临时支架置入(可立即恢复血流)和支架取栓器血栓切除术(可从闭塞血管中清除血栓)的优点12。Shi等人随后证明了支架取栓器血栓切除术联合抽吸治疗AEAMI的可行性13,14。这种联合技术还显示出比单独抽吸更高的完全血栓清除率14。然而,

Scientific Reports | (2026) 16:34520 5 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 由于血管直径较小,抽吸可能不适用于远端SMA主干(S3)的栓塞,且单独使用支架取栓器行血栓切除术治疗AEAMI的有效性尚未评估。Solitaire FR装置推荐的目标血管直径为2.0–5.5 mm,提示该装置可用于S3闭塞12。在本研究中,支架取栓器血栓切除术在直径为2.7至4.8 mm的目标血管中实施,4只犬有S3段受累。单独支架取栓器血栓切除术与高临床成功率和短手术时间相关,支持了图1. 犬模型中AEAMI模型建立及随后支架取栓器血栓切除术的过程。(A) 术前行SMA血管造影。(B) 通过置于SMA近端的8 Fr导引导管行经导管血栓注射。(C) 即刻血管造影显示S2和S3 SMA主干栓塞性闭塞(白色箭头),累及数条侧支(黑色箭头)。(D) 栓塞后2小时随访血管造影显示SMA主干持续闭塞(TIVI 1)。未见明显血栓溶解、迁移或再通。(E) 将支架取栓器(Solitaire FR;6 × 30 mm)部署跨过栓塞段,经导引导管手动血管造影时远端SMA(箭头)显影。闭塞部位目标血管直径为2.86 mm。(F) 一次血栓切除后实现SMA成功血运重建(TIVI 4),无远端侧支栓塞。可见小残留充盈缺损(箭头)。(G) 取出的血栓和支架取栓器。(H) 术后尸检显示肠道颜色正常和多灶性肠管扩张(黑色箭头),可能归因于短暂性麻痹性肠梗阻或缺血再灌注损伤。肠系膜瘀点和斑状出血纯属尸检操作继发,未见肠坏死。AEAMI = 动脉栓塞性急性肠系膜缺血;SMA = 肠系膜上动脉。

Scientific Reports | (2026) 16:34520 6 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 该技术的有效性。值得注意的是,半数犬仅经过1次血栓切除即获得临床成功。再通未成功犬的平均支架取栓器与闭塞血管直径比低于再通成功犬(1.28 vs. 1.64),提示较大的比值可能提供更大的向外径向力并促进血栓融入支架。未观察到重大并发症或内膜损伤,支持了支架取栓器血栓切除术在该模型中的安全性。1只犬在支架取栓器血栓切除术后发生新的远端分支栓塞。尽管由于肠系膜侧支网络29,远端闭塞很少加重肠道灌注,但在技术可行时可考虑同步手动抽吸以减少远端分支栓塞15。这项初步研究有几项重要局限性。首先,本研究仅提供了小样本动物的假设生成性临床前证据。其次,人类与犬之间SMA直径的差异不可忽视。由于支架取栓器与闭塞血管直径比可能影响再通成功,人类可能需要更大的支架规格以覆盖整个SMA主干。第三,大多数栓塞性AMI患者患有心房颤动30,本研究中创建的自体血栓可能无法完全模拟心房颤动所致机化栓子。尽管有这些局限性,本研究是首个对单独支架取栓器血栓切除术治疗AEAMI的体内评估。总之,使用Solitaire FR装置的支架取栓器血栓切除术在该犬模型中治疗AEAMI可行且安全,并与快速再通和较少并发症相关。通过适当的装置改良和进一步验证,支架取栓器血栓切除术可能成为AEAMI有前景的血运重建技术。图1.(续)

Scientific Reports | (2026) 16:34520 7 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 图1.(续)

Scientific Reports | (2026) 16:34520 8 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 图1.(续)

Scientific Reports | (2026) 16:34520 9 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 图2. (A) 动脉栓塞性急性肠系膜缺血支架取栓器血栓切除术前后TIVI评分的散点图,(B) 术后与术前TIVI评分的平均差值。TIVI 内脏缺血中的血栓切除术。

变量 所有犬(n = 10) 血栓切除术通过次数中位数1.0 支架取栓器尺寸 6 mm × 30 mm7(70%) 4 mm × 20 mm3(30%) 支架取栓器与闭塞血管直径比中位数1.6 治疗时间 - 分钟45.5 ± 19.0 安全性结局 血管夹层0 血管痉挛4(40%) 血管穿孔0 新发远端分支栓塞1(10%) 完成血管造影时的TIVI评分 00 11(10%) 21(10%) 34(50%) 44(50%) 有效性结局 技术成功10(100%) 临床成功8(80%) 表2. 10只接受支架取栓器血栓切除术的AEAMI犬的手术相关结局。除非另有说明,数据以n(%)或均值 ± 标准差表示。AEAMI 动脉栓塞性急性肠系膜缺血,TIVI 内脏缺血血栓切除术。

Scientific Reports | (2026) 16:34520 10 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 图3. 接受支架取栓器血栓切除术的血管组织学表现。如H&E(x200)(A)和Masson三色染色(x200)(B)所示,一只接受3次血栓切除术通过的代表性犬未观察到明显的血管损伤。H&E = 苏木精-伊红。

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Scientific Reports | (2026) 16:34520 12 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports 解读数据;Y.Z.、S.G.和B.Z.撰写了初稿;Y.S.、H.S.和J.G.修订了论文;Y.S.对最终内容负主要责任。所有作者阅读并批准了最终稿件。声明 利益冲突 作者声明无利益冲突。伦理批准 南京第一医院机构动物护理与使用委员会批准了本研究的所有实验程序(编号:IACUC-2209011)。补充信息 通讯及材料索取请致Y.S.。转载与许可信息见www.nature.com/reprints。出版者注 Springer Nature对已发表地图中的管辖权主张及机构隶属关系保持中立。开放获取 本文依据Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License许可授权,允许任何非商业性使用、共享、分发和以任何媒介或格式复制,前提是您须适当注明原作者及来源、提供Creative Commons许可链接,并说明是否对许可材料进行了修改。根据本许可,您无权共享源自本文或其部分的改编材料。本文中的图片或其他第三方材料均包含在本文的Creative Commons许可中,除非在材料致谢行中另有说明。如果材料未包含在本文的Creative Commons许可中,且您的预期使用未获法定法规许可或超出许可范围,您需要直接向版权持有人获取许可。要查看本许可副本,请访问http://creativecommons.org/licenses/by-nc-nd/4.0/。© 作者 2026

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OPEN Scientific Reports | (2026) 16:34520 1 | https://doi.org/10.1038/s41598-026-63911-3 Feasibility and safety of stand-alone stent retriever thrombectomy for acute embolic mesenteric ischemia in a canine model Yangyi Zhou 1,3 , Shuqin Gan 2,3 , Yuan Yuan 1 , Boxiang Zhao 1 , Maofeng Gong 1 , Jie Kong 1 , Haobo Su 1 , Jianping Gu 1 & Yadong Shi 1 This pilot study aimed to evaluate the efficacy and safety of stent retriever thrombectomy for arterial embolic acute mesenteric ischemia (AEAMI) in a canine model. The AEAMI model was created in 10 beagles by transcatheter administration of autologous thrombus into the superior mesenteric artery (SMA). Follow-up angiography was performed 2 h after thrombus administration to assess the model stability. SMA recanalization was graded with the thrombectomy in visceral ischemia (TIVI) score, which ranges from 0 to 4. Clinical success was defined as a TIVI score of 3 or 4. Procedure-related complications and vessel injuries were recorded. The AEAMI model was successfully established in all canines and remained stable at 2-hour follow-up angiography. After a mean treatment time of 45.5 ± 19.0 min, the mean TIVI score significantly increased after stent retriever thrombectomy (0.5 ± 0.7 vs. 3.1 ± 1.0, p < .001). Clinical success was achieved in 8 (80%) canines. Mild vasospasm and new distal branch embolization occurred in 4 (40%) and 1 (10%) canines, respectively. No other procedure-related complications or histologically evident vessel injuries were observed. Stent retriever thrombectomy with the Solitaire FR device achieved rapid recanalization with few complications in this canine AEAMI model. With device optimization and further validation, this approach may represent a promising endovascular revascularization technique for AEAMI. Keywords Acute mesenteric ischemia, Endovascular revascularization, Stent retriever thrombectomy, Animal model Acute mesenteric ischemia (AMI) results from an abrupt reduction in mesenteric blood flow that is insufficient to meet the metabolic demands of the bowel 1 . AMI is uncommon, accounting for 0.038% of adult admissions 2 ; with an estimated annual incidence of 6.2 new cases per 100,000 inhabitants 3 . Despite advances in diagnosis and treatment, AMI remains a major therapeutic challenge, with short-term mortality approaching 50% 2,3 . Arterial embolic AMI (AEAMI) is among the most dangerous subtypes 2 and accounts for approximately half of AMI cases 1 . Prompt restoration of mesenteric perfusion is essential, and current guidelines support both open and endovascular revascularization (EVR) as first-line options in selected patients 4,5 . Compared with open revascularization, EVR appears to be associated with lower mortality and morbidity and has been increasingly adopted as an initial revascularization strategy for AMI 6,7 . Several EVR techniques, including local thrombolysis, mechanical thrombectomy, and stenting, have been reported for the treatment of AMI 8 , however, no single technique has been proven superior 9 . Percutaneous mechanical thrombectomy is attractive because it is minimally invasive and can rapidly remove thrombus, but the available evidence remains limited. In addition, no dedicated mechanical thrombectomy device for AMI is currently available. Stent retriever thrombectomy has become an important revascularization technique 1 Department of Vascular and Interventional Radiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing 210006, China. 2 Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing 210006, China. 3 Yangyi Zhou and Shuqin Gan contributed equally to this work. email: shiyadong0221@gmail.com www.nature.com/scientificreports

Scientific Reports | (2026) 16:34520 2 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports for acute ischemic stroke caused by large-vessel occlusion 10,11 . Stent retriever thrombectomy combined with aspiration for AEAMI was first described by Muria et al. 12 in 2017, and subsequent reports further supported the feasibility of this technique 13,14 . Nevertheless, stent retriever thrombectomy for AEAMI remains an off-label application and has not been critically evaluated. The feasibility and safety of stent retriever thrombectomy as a stand-alone technique for AEAMI also remain unclear. Therefore, this study aimed to evaluate the efficacy and safety of stand-alone stent retriever thrombectomy with the Solitaire FR device in a canine AEAMI model. The findings may provide preclinical evidence for a potential endovascular strategy for AEAMI. Materials and methods Animals and preparation All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals. The Institutional Animal Care and Use Committee of the study hospital approved all experimental procedures (No. IACUC-2209011). Between November 2022 and June 2023, 10 beagles (Changzhou Beile Experimental Animal Breeding Co., Ltd., license number: SCXK 2018-0007) weighing 15–20  kg were included to establish an animal model for evaluating the feasibility of stent retriever thrombectomy with the Solitaire FR device for AEAMI. All canines were fasted for 24  h before the experiments, with free access to water. Bowel preparation with polyethylene glycol electrolytes (Beaufour Ipsen Industrie, France) was administered through a gastric tube 1 day before the procedures. Canines were anesthetized with inhaled isoflurane (Shenzhen RWD Life Science, China). Anesthesia was induced with 5% isoflurane in oxygen at 5 L/min by mask inhalation. After tracheal intubation, anesthesia was maintained with 2.5%-3% isoflurane in oxygen at 2–3  L/min. Once adequate anesthesia was achieved, canines were positioned supine in the angiography suite. Vital parameters, including heart rate, blood pressure, oxygen saturation, respiratory rate, and body temperature, were monitored throughout the experiments. Autologous thrombus preparation, animal modeling, and stent retriever thrombectomy The procedural area was routinely disinfected and draped. Femoral arterial access was obtained with an 8 Fr sheath (Radifocus Introducer; Terumo Corporation, Japan). Autologous thrombus was prepared by mixing 8 mL of femoral arterial blood, 64  mg of bovine plasma fibrinogen (Sigma-Aldrich, USA), and 200 units of lyophilized thrombin (Hunan Yige Pharmaceutical Co., Ltd., China) in a 10 mL syringe for at least 3 minutes 15 . The mixture was transferred to a 5 mm diameter silicone tube and incubated at room temperature for at least 60 min. The formed thrombus was then cut into approximately 30 mm length segments for administration. The canine AEAMI model was created as follows. A 5 Fr multipurpose angiographic catheter (Tempo; Cordis, USA) was introduced through the femoral artery and positioned at the ostium of the SMA. SMA angiography was performed by injecting iodixanol (Visipaque 320 mg/mL; GE HealthCare, USA) through the angiographic catheter. The proximal (S1), middle (S2), and distal (S3) SMA trunk diameters were measured. After preprocedural angiography, the angiographic catheter was exchanged for an 8 Fr guiding catheter (Neuron MAX; Penumbra, USA) over a 260  cm hydrophilic guidewire (Terumo Corporation, Japan). The prepared thrombus was administered through the guiding catheter with the assistance of a Y-shaped hemostasis valve (Access-9; Merit Medical, USA). Post-administration angiography was performed to evaluate thrombus distribution. If the thrombus distribution was unsatisfactory, a second thrombus injection was performed in the same manner. Follow-up angiography was performed 2 h after model creation to assess stability, including thrombus migration, thrombus dissolution, and vessel recanalization. Before the stent retriever thrombectomy procedure, systemic heparinization was achieved using intravenous administration of unfractionated heparin at a loading dose of 120–150 IU/kg with a target ACT of 250–300 s. After SMA trunk occlusion was confirmed, a 2.8 Fr microcatheter (Progreat; Terumo Corporation, Japan) was introduced through the guiding catheter and advanced close to the occlusion. A microguidewire was carefully manipulated across the occluded segment, and the microcatheter was advanced into the normal distal SMA trunk. Manual angiography through the microcatheter was performed to confirm the position. A stent retriever (Solitaire FR; Medtronic, USA) was then deployed across the occluded segment. Stent retriever size was selected primarily according to operator experience and the diameter of the occluded vessel. Stent retrieval was performed 5 min after deployment to allow sufficient expansion. Postprocedural angiography was performed, and additional stent retriever thrombectomy passes were performed as needed. No more than 5 thrombectomy passes were attempted. Histological analysis After the procedures, all canines were euthanized under anesthesia with an intravenous lethal dose of potassium chloride for histological analysis. The abdomen was explored immediately after euthanasia to assess the location and severity of bowel ischemia. Tissue specimens from the SMA segment that underwent stent retriever thrombectomy were collected for analysis. The specimens were fixed in 10% formalin for at least 24 h, embedded in paraffin, cut into 5-micrometer sections, and stained with hematoxylin and eosin (H&E) or Masson trichrome. Three slices from the same section were examined with a digital slide scanner (Pannoramic MIDI; 3DHISTECH, Hungary) by an experienced pathologist who was blinded to the procedural details. Definitions The SMA trunk was divided into three segments, designated S1, S2, and S3. S1 was defined as the proximal SMA segment between the ostium and the origin of the inferior pancreaticoduodenal artery. S2 was defined as the middle SMA segment between the inferior pancreaticoduodenal artery and the ileocolic artery. S3 was defined

Scientific Reports | (2026) 16:34520 3 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports as the distal SMA vascular bed downstream from the ileocolic artery 16 . The diameter of the occluded vessel was measured in the adjacent normal proximal SMA 14 . Procedure time was defined as the interval from diagnostic angiography before stent retriever thrombectomy to final control angiography. Vessel recanalization after stent retriever thrombectomy was assessed with the TIVI score, which ranges from 0 to 4 17 . TIVI 0 indicates no recanalization of the embolic occlusion; TIVI 1 indicates incomplete or partial recanalization without antegrade distal flow; TIVI 2 indicates incomplete or partial recanalization with minor, insufficient antegrade distal flow; TIVI 3 indicates complete recanalization with normal distal flow and only minimal residual thrombus in side branches; and TIVI 4 indicates complete recanalization with normal distal flow and no visually discernible residual thrombus in side branches. TIVI score was assessed on the initial angiogram before stent retriever thrombectomy, immediately after stent retriever thrombectomy, and at final control angiography. Technical success was defined as successful stent deployment across the thrombus followed by stent retrieval. Clinical success was defined as a TIVI score of 3 or 4. Procedure-related complications included vasospasm, dissection, perforation, and new distal embolization. Statistical analysis All statistical analyses were performed with SPSS version 24.0 (IBM, USA). Categorical variables are presented as n (%), and continuous variables are presented as mean ± standard deviation or median, as appropriate. Paired t tests were used to compare quantitative variables before and after treatment. Plots were generated with GraphPad Prism version 9.0 (GraphPad Software Inc., USA). A p value < 0.05 was considered statistically significant. Results Animals All included canines were female, and the mean body weight was 17.1 ± 1.8 kg. Pre-procedure SMA angiography showed the mean S1, S2, and S3 SMA trunk diameters were 5.0 ± 0.3  mm, 4.5 ± 0.4  mm, and 3.0 ± 0.6  mm, respectively. An arteriovenous fistula between the jejunum artery and the superior mesenteric vein was observed in one canine; no SMA disease was observed in the remaining canines. No animal died during the procedures. Outcomes of the AEAMI canine model The AEAMI model was successfully created in all canines with a median of 1.5 autologous thrombus injections. Immediate angiography after model creation showed a mean occlusion site diameter of 3.5 ± 0.6  mm (range, 2.7–4.7 mm) (Table 1). SMA occlusion beginning in S1, S2, and S3 was found in 0 (0%), 6 (60%), and 4 (40%) VariablesAll canines (n = 10) Demographics Female10 (100%) Body weight - kg17.1 ± 1.8 Pre-modeling angiography results Proximal SMA (S1) diameter - mm5.0 ± 0.3 Middle SMA (S2) diameter - mm4.5 ± 0.4 Distal SMA (S3) diameter - mm3.0 ± 0.6 Median number of thrombus injections1.5 Post-modeling angiography results Occlusion site Proximal SMA (S1)0 Middle SMA (S2)6 (60%) Distal SMA (S3)4 (40%) Occlusion site diameter - mm3.5 ± 0.6 Branch vessel involvement4 (40%) Distal embolization2 (20%) Follow-up angiography at 2 h Thrombus dissolution2 (20%) Thrombus migration0 Vessel recanalization1 (10%) TIVI score at 2-hour follow-up 06 (60%) 13 (30%) 21 (10%) 30 40 Ta b l e 1. Modeling related information of 10 canines. Data are presented as n (%) or mean ± standard deviation unless otherwise stated. SMA superior mesenteric artery, TIVI thrombectomy in visceral ischemia.

Scientific Reports | (2026) 16:34520 4 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports of the canines, respectively. Side branch involvement and distal embolization were observed in 4 (40%) and 2 (20%) canines, respectively. Immediate angiography showed a TIVI score of 0 in 7 canines and a TIVI score of 1 in 3 canines. Follow-up angiography 2  h after model creation confirmed model stability. Partial proximal thrombus dissolution was observed in 3 (30%) canines (TIVI 1), and partial recanalization with insufficient antegrade distal flow was observed in one canine (TIVI 2). All other occlusions remained stable with no notable thrombus dissolution or migration. Efficacy and safety outcomes of stent retriever thrombectomy The mean treatment time for stent retriever thrombectomy was 45.5 ± 19.0  min, and technical success was achieved in all canines. Clinical success was achieved in 8 (80%) canines with a median of one thrombectomy attempt. Successful AEAMI modeling and subsequent stent retriever thrombectomy in a representative canine are shown in Fig. 1A–H. Stent retriever sizes of 6 mm × 30 mm and 4 mm × 20 mm were used in 7 (70%) and 3 (30%) of the canines, respectively (Table 2). The mean TIVI score increased significantly after stent retriever thrombectomy (0.5 ± 0.7 vs. 3.1 ± 1.0, p < .001) (Fig. 2A, B). The median stent retriever-to-occlusion diameter ratio was 1.6 ± 0.3. The mean stent retriever-to-occlusion diameter ratio was 1.28 in canines with unsuccessful recanalization and 1.64 in those with successful recanalization. Regarding safety outcomes, no vessel dissection or perforation occurred in any canine. Mild vasospasm after stent retriever thrombectomy was observed in 4 (40%) canines, and all spasms resolved without additional medication. New distal embolization after stent retriever thrombectomy occurred in 1 (10%) canine. No obvious intimal injury was identified histologically, and representative gross and histological intestinal findings are shown in Fig. 3A, B. Regarding post-procedure macroscopic intestinal findings. In the 8 canines with successful recanalization, the small intestine exhibited normal pink mucosal color, regular intestinal peristalsis, and no serosal hemorrhage or black discoloration. Mild multifocal intestinal distension was sporadically observed (Fig. 1H). In the remaining 2 canines with failed recanalization, focal pale bowel segments were visible in the hypoperfusion territory, accompanied by distension and weakening of intestinal peristalsis. No intestinal hemorrhage or gangrene was identified in any canines. Discussion AMI remains a therapeutic challenge despite advances in treatment during recent decades 8 . In the recently published prospective multicenter AMESI study, 30-day mortality for arterial occlusive AMI remained close to 50% 2 . Early diagnosis and prompt revascularization are essential for successful management. Guidelines from the European Society of Cardiology state that revascularization should be attempted in all cases of arterial occlusive AMI unless only distal vessel occlusion is present 18 . Although guidelines suggest that both open and endovascular therapy may be considered first-line revascularization options for AEAMI 4,18 , EVR is minimally invasive and may be preferable for elderly or frail patients. Several studies have suggested that first-line EVR for AMI may be associated with lower mortality, improved cost-effectiveness, reduced bowel resection, less shortbowel syndrome, and shorter hospital stay compared with open revascularization 7,19,20 . Accordingly, EVR has been increasingly used as a first-line treatment for AMI 6,19 . Although multiple EVR techniques have been reported for AMI 8 , most studies have been limited by retrospective design and small sample size. Local thrombolysis is a simple and effective EVR technique. In a retrospective study of 34 patients, successful thrombolysis was achieved in 88% of patients, and 6 patients experienced self-limited bleeding 21 . However, local thrombolysis usually requires an infusion time of 24– 48  h, which may delay complete revascularization 21 . In addition, high bleeding risk and necrotic bowel are contraindications to thrombolysis. Mechanical thrombectomy can provide rapid revascularization and may be a more promising EVR technique for AMI 8,9 . Manual transcatheter aspiration is the simplest mechanical thrombectomy technique and may be attempted in patients without peritonitis 4 . Although reported success rates range from 73.3% to 100% 22 , adjunctive local thrombolysis is often required 23,24 . Another important concern is that as much as 300 mL of blood may be lost during this procedure 24 . Compared with manual aspiration, mechanical aspiration may theoretically provide more sustained negative pressure and thereby improve recanalization. However, a retrospective study of 31 patients with AMI found no benefit of mechanical aspiration over manual aspiration 25 . Other reported mechanical thrombectomy devices for AMI include the AngioJet and Straub Rotarex thrombectomy systems. Ballehaninna et al. 26 reported a case of AMI successfully treated with AngioJet thrombectomy and adjunctive local thrombolysis using an EKOS catheter. Previous studies suggested that Rotarex thrombectomy is associated with high technical success 27 and satisfactory recanalization rates 17,27 . However, procedure-related complications, including vessel perforation and catheter tip fracture, have been reported 17,27 . AngioJet and Rotarex devices fragment thrombus before aspiration, which may increase the risk of distal embolization 17 . Although embolic protection devices during SMA stenting are feasible and useful 28 , their role during mechanical thrombectomy in the SMA has not been evaluated 9 . Stent retriever thrombectomy with the Solitaire FR device has been shown to improve recanalization and outcomes in acute anterior circulation stroke compared with medical therapy 11 . Given the conceptual similarity between acute ischemic stroke and AEAMI, stent retriever thrombectomy may also facilitate rapid revascularization in AEAMI. The first reported case of successful stent retriever thrombectomy with a Solitaire FR device for AEAMI was described by Miura et al. in 2017 12 . The authors suggested that the Solitaire FR stent combines the advantages of temporary stent deployment, which enables immediate flow restoration, and stent retriever thrombectomy, which removes thrombus from the occluded vessel 12 . Shi et al. subsequently demonstrated the feasibility of stent retriever thrombectomy combined with aspiration for AEAMI 13,14 . This combined technique also showed a higher complete thrombus clearance rate than aspiration alone 14 . However,

Scientific Reports | (2026) 16:34520 5 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports aspiration may not be feasible for embolization in the distal SMA trunk (S3) because of the small vessel diameter, and the usefulness of stand-alone stent retriever thrombectomy for AEAMI has not been evaluated. The recommended target-vessel diameter for the Solitaire FR device is 2.0–5.5 mm, suggesting that the device could be used for S3 occlusion 12 . In the present study, stent retriever thrombectomy was performed in target vessels ranging from 2.7 to 4.8  mm in diameter, and 4 canines had S3-segment involvement. Stent retriever thrombectomy alone was associated with a high clinical success rate and short procedure time, supporting the Fig. 1. Process of AEAMI model creation and subsequent stent retriever thrombectomy in a canine model. (A) Preprocedural SMA angiography was performed. (B) Transcatheter thrombus injection was performed through an 8 Fr guiding catheter positioned in the proximal SMA. (C) Immediate angiography showed embolic occlusion in the S2 and S3 SMA trunk (white arrowhead) with involvement of several side branches (black arrowheads). (D) Post-embolization follow-up angiography at 2 h showed persistent SMA trunk occlusion (TIVI 1). No obvious thrombus dissolution, migration, or recanalization was noted. (E) The stent retriever (Solitaire FR; 6 × 30 mm) was deployed across the embolic segment, and the distal SMA (arrowhead) was visualized during manual angiography through the guiding catheter. The target vessel diameter at the occlusion site was 2.86 mm. (F) Successful SMA revascularization (TIVI 4) was achieved after one thrombectomy pass, without distal side-branch embolization. A small residual filling defect was noted (arrowhead). (G) Retrieved thrombus and stent retriever. (H) Postprocedural autopsy showed normal intestinal color and multifocal intestinal distension (black arrows), which may be attributed to transient paralytic ileus or ischemia-reperfusion injury. The petechial and macular hemorrhages in the mesentery are purely secondary to autopsy manipulation, and no intestinal necrosis was noted. AEAMI = arterial embolic acute mesenteric ischemia; SMA = superior mesenteric artery.

Scientific Reports | (2026) 16:34520 6 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports efficacy of this technique. Notably, half of the canines achieved clinical success after only 1 thrombectomy pass. The mean stent retriever-to-occlusion diameter ratio was lower in canines with unsuccessful recanalization than in those with successful recanalization (1.28 vs. 1.64), suggesting that a larger ratio may provide greater outward radial force and facilitate thrombus integration into the stent. No major complications or intimal injury were observed, supporting the safety of stent retriever thrombectomy in this model. New distal branch embolization after stent retriever thrombectomy occurred in 1 canine. Although distal occlusion rarely worsens intestinal perfusion because of the mesenteric collateral network 29 , synchronous manual aspiration may be considered when technically feasible to reduce distal branch embolization 15 . This preliminary study has several important limitations. First, this study only provided hypothesis-generating preclinical evidence with a small number of animals. Second, differences in SMA diameter between humans and canines are nonnegligible. Because the stent retriever-to-occlusion vessel diameter ratio may influence recanalization success, a larger stent profile may be required in humans to cover the entire SMA trunk. Third, most patients with embolic AMI have atrial fibrillation 30 , and the autologous thrombus created in this study may not fully mimic organized emboli resulting from atrial fibrillation. Despite these limitations, this study is the first in vivo evaluation of stand-alone stent retriever thrombectomy for AEAMI. In conclusion, stent retriever thrombectomy with the Solitaire FR device was feasible and safe for AEAMI in this canine model and was associated with rapid recanalization and few complications. With appropriate device modifications and further validation, stent retriever thrombectomy may become a promising revascularization technique for AEAMI. Fig. 1. (continued)

Scientific Reports | (2026) 16:34520 7 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports Fig. 1. (continued)

Scientific Reports | (2026) 16:34520 8 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports Fig. 1. (continued)

Scientific Reports | (2026) 16:34520 9 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports Fig. 2. (A) Scatter plot of TIVI scores before and after stent retriever thrombectomy for arterial embolic acute mesenteric ischemia, and (B) mean difference between postprocedure and preprocedure TIVI scores. TIVI thrombectomy in visceral ischemia.

VariablesAll canines (n = 10) Median number of thrombectomy passes1.0 Stent retriever size 6 mm × 30 mm7 (70%) 4 mm × 20 mm3 (30%) Median stent retriever-to-occlusion diameter ratio1.6 Treatment time - min45.5 ± 19.0 Safety outcomes Vessel dissection0 Vessel spasm4 (40%) Vessel perforation0 New distal branch embolization1 (10%) TIVI scores at completion angiography 00 11 (10%) 21 (10%) 34 (50%) 44 (50%) Efficacy outcomes Technical success10 (100%) Clinical success8 (80%) Ta b l e 2. Procedure-related outcomes in 10 canines with AEAMI underwent stent retriever thrombectomy. Data are presented as n (%) or mean ± standard deviation unless otherwise stated. AEAMI arterial embolic acute mesenteric ischemia, TIVI thrombectomy in visceral ischemia.

Scientific Reports | (2026) 16:34520 10 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports Fig. 3. Histological findings of the vessel that underwent stent retriever thrombectomy. No obvious vessel injury was observed in a representative canine that underwent 3 thrombectomy passes, as shown by H&E (x200) (A) and Masson trichrome (x200) (B) staining. H&E = hematoxylin and eosin.

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Author contributions Y.S., H.S., and J.G. designed the study; Y.S., M.G., J.K., and Y.Y. did the experiments; Y.Z. and S.G. collected and

Scientific Reports | (2026) 16:34520 12 | https://doi.org/10.1038/s41598-026-63911-3 www.nature.com/scientificreports interpreted data; Y.Z., S.G., and B.Z. wrote the initial paper; Y.S., H.S., and J.G. revised the paper; Y.S. had primary responsibility for final content. All authors read and approved the final manuscript. Declarations Competing interests The authors declare no competing interests. Ethical approval The Institutional Animal Care and Use Committee of Nanjing First Hospital approved all experimental procedures in this study (No. IACUC-2209011). Additional information Correspondence and requests for materials should be addressed to Y.S. Reprints and permissions information is available at www.nature.com/reprints. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit h t t p : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / . © The Author(s) 2026

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