CN111526897A - 对生物组织局部暴露的方法、组织替代物施加器及多孔聚四氟乙烯的用途 - Google Patents
对生物组织局部暴露的方法、组织替代物施加器及多孔聚四氟乙烯的用途 Download PDFInfo
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- Materials For Medical Uses (AREA)
Abstract
本发明涉及医疗应用,可用于肿瘤学,也可用于神经外科、创伤学、神经病学、康复学。要求保护的发明的目的是创造一种对生物组织局部暴露的新方法和一种新的组织替代物施加器,它们可在不施加外部暴露(交变磁场、加热等)的情况下通过恢复的生物组织摧毁和替换肿瘤组织。使用多孔聚四氟乙烯作为细胞抑制材料也解决了该目的。在用于治疗或替代肿瘤组织的组织替代物施加器的生产中使用多孔聚四氟乙烯也实现了该目的。使用多孔聚四氟乙烯作为构成聚合物材料解决了对生物组织局部暴露的方法的目的,所述方法包括与待暴露的生物组织直接接触放置组织替代物聚合物施加器。
Description
本发明涉及医疗应用,可用于肿瘤学,也可用神经外科、创伤学、神经病学、康复学。
涉及肿瘤内注射纳米粒的治疗肿瘤疾病的方法是众所周知的。例如,应用脂质体,即表面可以进行化学改性以实现其对靶组织的亲和力的人工磷脂双层膜。因此,与带中性电荷的磁性脂质体相比,具有正表面电荷的脂质体对大鼠胶质瘤细胞的亲和力高10倍[Shinkai M.,Yanase M.,Honda H.,Wakabayashi T.,Yoshida J.,Kobayashi T.使用磁性阳离子脂质体针对癌症的细胞内高热:体外研究//Jpn.J.Cancer Res.1996.V.87.P.1179–1183]。使用皮下注射到肿瘤组织中的磁性阳离子脂质体的高热技术已被证明在具有各种类型肿瘤的动物中是有效的,例如小鼠的B-16黑色素瘤、大鼠的T-9胶质瘤、仓鼠的Os 515骨肉瘤、兔舌VX-7鳞癌[Yanase M.,Shinkai M.,Honda H.,Wakabayashi T.,Yoshida J.,Kobayashi,T.使用磁性阳离子脂质体通过细胞内高热的抗肿瘤免疫诱导//Jpn.J.CancerRes.1998.V.89.P.775–782;Matsuno H.,Tohnai I.,Mitsudo K.,Hayashi Y.,Ito M.,Shinkai M.,Kobayashi T.,Yoshida J.,Ueda M.使用磁性阳离子脂质体的间质高热抑制兔舌VX-7移植肿瘤的生长//Jpn.J.Hyperthermic Oncol.2001.V.17.P.141–149;SuzukiM.,Shinkai M.,Honda H.,Kobayashi T.磁性阳离子脂质体对恶性黑色素瘤高热的抗癌作用和免疫诱导//Melanoma Res.2003.V.13.P.129–135;Matsuoka F.,Shinkai M.,HondaH.,Kubo T.,Sugita T.,Kobayashi,T.使用磁性阳离子脂质体针对仓鼠骨肉瘤的高热//Res.Technol.2004,№2.P.3.]。为了实现肿瘤的完全消退,动物多次暴露于交变磁场是非常必要的:Ito等成功地检测了该方法对小鼠中15mm以上大小的小鼠乳腺癌的完全消退[Ito A.,Shinkai M.,Honda H.,Wakabayashi T.,Yoshida J.,Kobayashi,T.通过高热经由热休克蛋白表达增强MHC I类抗原呈递//Cancer Immmunol.Immunother.2001.V.50.P.515–522]。
正在开发不同的方法,用于将颗粒(优选纳米级)引入肿瘤,随后通过外部施加磁场或电磁场来局部升高温度以实现对恶性组织的精确高温破坏[俄国专利No.2506971,公开日20/02/2014;美国专利No.6997863,公开日14/02/2006;美国专利No.8119165,公开日21/02/2012]。研究领域涉及悬浮在简单和流变复杂的流体中并被高强度和高梯度磁场激发的各种性质的磁性微粒系统(抗磁性和顺磁性颗粒,包括活细胞和铁颗粒)的细观力学和能量耗散(磁滞的微粒中能量吸收引起介电材料的体积电磁加热,尤其是恶性肿瘤局部铁磁性高热的实证)。在小鼠黑色素瘤模型中,在外部磁场的影响下,应用9nm Fe0.5Zn0.5Fe2O4纳米颗粒并不会伴随有效温度升高。[Heidari M,Sattarahmady N,Javadpour S,AzarpiraN,Heli H,Mehdizadeh A,Rajaei A,Zare T.磁流体高热对小鼠模型中植入的黑色素瘤的影响//Iran J Med Sci.2016Jul;41(4):314–321.PMCID:PMC4912650]。因此,抗肿瘤的效果取决于颗粒的大小和比表面积(分子数量随其大小降低而增加,同时表面积增加)[ChoiKH,Nam KC,Malkinski L,Choi EH,Jung JS,Park BJ.生物相容性多功能磁性亚微米颗粒在前列腺癌细胞中的尺寸依赖性光动力学抗癌活性//Molecules.2016Sep 6;21(9).pii:E1187.doi:10.3390/molecules21091187]。
纳米颗粒的生物相容性取决于大小、溶液中的ζ电位、疏水性。疏水颗粒在血液中的寿命非常短,因为它们通过肝脏和脾脏从体内迅速排出。示意性地,颗粒提取途径可如下所示:尺寸小于8nm的颗粒由肾脏排出;尺寸大于200nm的颗粒由由肝脏、脾脏排出;约30nm的颗粒由胆管排出,但在肺部积聚;在“增强的渗透和保留”(EPR-effect)的机理下,尺寸为30nm至200nm的颗粒被动地积聚在肿瘤部位。这是由于肿瘤中的血流增加和淋巴引流减少所致。在具有带正表面电荷的颗粒的情况下,阳离子颗粒在大多数情况下是有毒的,并且引起红细胞的溶血和聚集[(https://biomolecula.ru/articles/nevidimaia-granitsa-gde-stalkivaiutsia-nano-i-bio)]。
另外,由于肿瘤区域中活跃的血液流动,导致这些颗粒被血流迅速清除,因此这种治疗方法是相当无效的。然而,由于这些纳米颗粒保留在体内,因此从生物体中去除纳米颗粒通常是一个棘手的问题。
纳米材料被证明具有自组装和自组织特性。自组装过程中的调节过程受分子性质的各种相互作用力,即亲水-疏水相互作用、重力、范德华或库仑相互作用的竞争作用所调节。在有序的超分子结构或介质形成过程中,只有添加或“收集”所得复杂结构作为其整体部分的初始结构组分才能以基本不变的形式参与。与原始源系统相比,自组织可以用作在更高层次的组织级别上创建复杂“模板”、过程和结构的机制,这是因为低级别的组分之间存在大量的多变量交互,涉及局部交互定律,这与最终架构的行为的总体定律不同。纳米颗粒在生物体内的构象导致许多功能转移,其中毒性作用是主要因素。正是纳米颗粒的毒性限制了它们在诊断和治疗领域的广泛应用,附带地,这一不争的事实被周期性的抑制。
由于其特定的性质,纳米颗粒倾向于在排泄系统中(在血液和/或淋巴管中)集合并形成微米大小的聚集体。
与所要求保护的方法和所要求保护的组织替代物施加器最接近的现有技术对比文献是俄罗斯专利No.2497489,公开日10/11/2013,其中对生物组织局部暴露的方法包括以下步骤:与带暴露的生物组织直接接触放置组织替代物施加器,其由添加了200至1000μm大小的导电铁磁性颗粒的聚合物材料制成。接下来,通过施加交变的HF磁场来进行组织替代物施加器和邻近生物组织的感应加热,以产生过热效应,从而破坏肿瘤组织。
这些技术解决方案的缺点包括:首先,在加热和破坏肿瘤细胞时,肿瘤诱导剂可能会扩散到邻近组织中。
此外,肿瘤组织的崩解导致有毒物质的浓度增加,这些物质很难从体内清除。为了最大程度地减少有毒物质的暴露,操作人员考虑到淋巴和循环系统在细胞水平和排泄器官水平(肾脏和肝脏)上的排泄能力,尝试最大程度地减少暴露区域,从而计算出要破坏的组织的体积。如果可能的话,例如通过洗涤去除被破坏的组织。
该方法的另一个缺点在于实施该方法所需设备的复杂性。
要求保护的发明的目的是创造一种对生物组织局部暴露的新方法和一种新的组织替代物施加器,它们可在不施加外部暴露(交变磁场、加热等)的情况下通过恢复的生物组织摧毁和替换肿瘤组织。
使用多孔聚四氟乙烯作为构成聚合物材料解决了对生物组织局部暴露的方法的目的,所述方法包括与待暴露的生物组织直接接触放置组织替代聚合物施加器。
在此方法的框架内,可以对肿瘤生物组织和周围的生物组织都采用暴露。
采用多孔聚四氟乙烯作为构成材料解决了用于与肿瘤组织直接接触放置的组织替代聚合物施加器的目的。
在研究抑制纳米颗粒从肿瘤中逸出的资源时,作者选择多孔聚四氟乙烯(“PTFE”)作为导电铁磁性纳米颗粒的构成聚合物载体,期望肿瘤组织在PTFE孔中发芽,并将这些颗粒保持在附近,从而防止其被血流携带出去。然而,在这些研究过程中,也检测到多孔聚四氟乙烯的细胞抑制特性。
因此,使用多孔聚四氟乙烯作为细胞抑制材料解决了该目的。
在用于治疗或替代肿瘤组织的组织替代物施加器的生产中使用多孔聚四氟乙烯也实现了该目的。
在以下非限制性附图中详细说明了本发明。
图1显示了要求保护的组织替代物施加器的示意图。
图2和图3显示了多孔PTFE对肿瘤细胞培养(此情况中为胶质瘤)的作用的体外研究结果。
图4和图5显示了多孔PTFE对健康细胞培养(此情况中为成纤维细胞)的作用的体外研究结果。
图6至图8显示了研究后30天的雄性Wistar大鼠大脑皮层感觉运动切片图像:a)胶质瘤细胞异种移植后30天的雄性Wistar大鼠大脑皮层感觉运动切片图像;b)与异种移植的胶质瘤细胞直接接触的多孔PTFE移植后30天的雄性Wistar大鼠大脑皮层感觉运动切片图像;c)多孔PTFE移植后30天的雄性Wistar大鼠大脑皮层感觉运动切片图像。
图9和图10显示了研究后4个月的雄性Wistar大鼠大脑皮层感觉运动切片图像:a)与异种移植的胶质瘤细胞直接接触的多孔PTFE移植后4个月的雄性Wistar大鼠大脑皮层感觉运动切片图像;b)多孔PTFE移植后4个月的雄性Wistar大鼠大脑皮层感觉运动切片图像。
可例如通过白俄罗斯专利No.10325(公开日28/02/2008)中描述的方法制造要求保护的组织替代物施加器1(见图1)。组织替代多孔PTFE施加器通过以下方式制成:将原材料颗粒与多孔(porophore)颗粒(氯化钠)混合,压缩所得混合物,从所得多孔预成型物中洗掉氯化钠残留物,然后进行烧结过程。在这种情况下,通过使用粉碎形状的多孔颗粒获得复杂的孔结构。闭孔的尺寸取决于微细的多孔颗粒的尺寸,而开孔的尺寸则由较大份额的多孔颗粒的尺寸决定。
为了测试所要求保护的方法、组织替代物施加器的可行性和有效性以及PTFE性能,进行了动物实验,如以下实施例所示。
实施例1
为了测定多孔PTFE对肿瘤细胞和健康细胞的细胞毒性,进行了两个系列的体外研究。
第一系列:
将肿瘤细胞引入培养基(本研究中为C6胶质瘤),一部分培养基完整地留作参照,另一部分则放置了多孔PTFE组织替代物施加器。
在48小时的追踪后,拍摄了下列照片:
-完整C6胶质瘤细胞分布(图2a,70±3%汇集)和放置多孔PTFE组织替代物施加器后的C6胶质瘤细胞分布(图2b,20±4%汇集);
-台盼蓝染色的完整C6胶质瘤细胞单层(图3a,完整C6胶质瘤细胞存活率-90±3%)和具有多孔PTFE组织替代物施加器的C6胶质瘤细胞单层(图3b,具有多孔PTFE组织替代物施加器的C6胶质瘤细胞存活率-55±3%)。
因此,在这一系列的研究中,发现多孔PTFE对C6胶质瘤细胞培养展现出体外细胞毒性。
第二系列:
将健康细胞引入培养基(本研究中为成纤维细胞),一部分培养基完整地留作参照,另一部分则放置了多孔PTFE组织替代物施加器。
在48小时的追踪后,拍摄了下列照片:
-完整成纤维细胞分布(图4a,53±3%汇集)和放置多孔PTFE组织替代物施加器后的成纤维细胞分布(图4b,35±4%汇集);
-台盼蓝染色的完整成纤维细胞单层(图5a,完整成纤维细胞存活率-99±3%)和具有多孔PTFE组织替代物施加器的成纤维细胞单层(图5b,具有多孔PTFE组织替代物施加器的成纤维细胞存活率-98±3%)。
因此,在这一系列的研究中,据报道多孔PTFE对健康细胞,特别是成纤维细胞没有展现出体外细胞毒性。
实施例2
体内研究集中于Wistar大鼠的大脑皮层测试,将大鼠分为3个组:第1组为在感觉运动皮层中植入了C6胶质瘤异种移植物1个月(30天)的大鼠;第2组为在感觉运动皮层中植入了C6胶质瘤异种移植物和多孔PTFE组织替代物施加器1个月(30天)的大鼠;第3组为仅在感觉运动皮层中植入了多孔PTFE组织替代物施加器1个月(30天)的大鼠。
该研究应用了组织学(苏木精和曙红染色)、神经组织学(Nissl染色)和组织化学研究方法(乙酰胆碱酯酶(AChE)活性检测)。
用苏木精、曙红和甲苯胺蓝对Wistar大鼠脑组织的冷冻切片进行染色,然后进行光学显微镜检查。
图6a显示了C6胶质瘤异种移植后30天的Wistar大鼠脑组织的冷冻切片。
C6胶质瘤由小的未分化细胞和致密的多态核组成。神经胶质组织代表内部的血管。苏木精和曙红染色;放大率x200。
在30天的追踪中,对实验性C6胶质瘤大鼠脑横切片的组织学分析显示了存在大量具有中度细胞多态的肿瘤细胞。细胞呈细长的纺锤形形式,大的深色不规则形状的高色核,薄而略带颜色的细胞质层和短突起。空泡化有多个丝裂点和病灶。存在多个有丝分裂和空泡灶。在细胞团簇内检测到不同大小的血管以及新形成的小毛细血管。
图6b显示了放置C6胶质瘤异种移植物和多孔PTFE组织替代物施加器后30天的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器在肿瘤组织内。胶质细胞周围有轻微的反应性肿胀,并且分化较差的肿瘤细胞积聚。组织替代物施加器包封在神经胶质荚膜中。苏木精和曙红染色;放大率x200。
植入后30天具有实验性C6胶质瘤和组织替代物施加器的大鼠脑横切片的组织学分析显示了在合成材料周围形成了胶质真皮(gliomesodermal)荚膜,并在相邻区域形成了透明区域(其可以被视为肿瘤病灶崩解),其周围是分化较差的细胞簇“假细胞层(pseudopalisade)”。
图6c显示了多孔PTFE组织替代物施加器植入后30天的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器植入脑灰质中。苏木精和曙红染色;放大率x200。
组织替代物施加器的植入区域显示出柔嫩的疤痕的形成,该瘢痕由松散的胶质真皮组织(其纤维发芽进入材料孔中)和围绕组织替代物施加器的胶质荚膜组成。在植入材料表面的一些区域中,由于在邻近的大脑皮层中形成清晰的病灶(其可被认为是反应性水肿的区域),因此荚膜壁较薄。在此处也检测到成纤维细胞和胶质细胞簇。
将Wistar大鼠脑组织冷冻切片暴露于Nissl染色,然后进行研究以鉴定神经组织的成分,放大率x100。
图7a显示了在C6胶质瘤异种移植后30天的Wistar大鼠脑组织的冷冻切片。
C6胶质瘤在脑灰质中
图7b显示了在C6胶质瘤异种移植和多孔PTFE组织替代物施加器植入后30天的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器在肿瘤内。围绕组织替代物施加器的胶质有中度反应性肿胀;小多态肿瘤细胞积聚。
图7c显示了在多孔PTFE组织替代物施加器植入后30天的Wistar大鼠脑组织的冷冻切片。
PTFE合成材料在脑灰质内。组织替代物施加器区域内的胶质细胞活化。组织替代物施加器周围存在中度胶质反应性肿胀。
图8a显示了在C6胶质瘤异种移植后30天的Wistar大鼠脑组织的冷冻切片。
AChE阳性神经纤维在肿瘤内;放大率x400。
C6胶质瘤由具有致密多态核的小的未分化细胞代表。神经胶质组织代表内部的血管。这提供了肿瘤过程活化的证据。形成环状聚集物的胆碱能神经纤维沿随着脉管系统。
图8b显示了在C6胶质瘤异种移植和多孔PTFE组织替代物施加器植入后30天的Wistar大鼠脑组织的冷冻切片。
AChE阳性神经纤维在肿瘤内的PTFE植入区域中;放大率x200。多孔PTFE组织替代物施加器倾向于发展出胶质瘤细胞的中度反应性水肿;据报道,一簇小的多态未分化肿瘤细胞形成了特殊的荚膜。
检测到胆碱能神经纤维被沿随着肿瘤内部的脉管系统。
图8c显示了在多孔PTFE组织替代物施加器植入后30天的Wistar大鼠脑组织的冷冻切片。
AChE阳性神经纤维在脑灰质内的PTFE植入区域中;放大率x400。
在多孔PTFE组织替代物施加器放置后一个月,在植入区域未观察到坏死,但反应性水肿持续存在。据报道,小胶质细胞以及中枢神经系统的巨噬细胞(从远端的脑区域迁移到组织替代物施加器)活化。
施加器周围的灰质区域代表神经纤维网络,该神经纤维沿随着血管并渗透到组织替代物施加器的孔中。
结论:在具有实验性C6胶质瘤的大鼠大脑皮层植入多孔PTFE组织替代物施加器1个月(30天)后,可在组织替代物施加器周围的邻近区域检测到肿瘤病灶崩解。在病灶附近,观察到分化较差的肿瘤细胞的积聚,然后形成“假细胞层”。所获得的数据可证明植入大脑皮层的PTFE材料有利于周围肿瘤组织的崩解。
实施例3
在感觉运动皮层中植入多孔PTFE组织替代物施加器或C6胶质瘤和多孔PTFE组织替代物施加器后,在4个月的追踪中进行Wistar大鼠脑组织的组织学分析。
体内研究集中于Wistar大鼠的大脑皮层测试,将大鼠分为2个组:第1组为在感觉运动皮层中植入了C6胶质瘤异种移植物和多孔PTFE组织替代物施加器4个月的大鼠;第2组为仅在感觉运动皮层中植入了多孔PTFE组织替代物施加器4个月的大鼠。
该研究应用了组织学(苏木精和曙红染色)、神经组织学(Nissl染色)和组织化学研究方法(乙酰胆碱酯酶(AChE)活性检测)。
用苏木精、曙红和甲苯胺蓝对Wistar大鼠脑组织的冷冻切片进行染色,然后进行光学显微镜检查。用于组织结构测定的苏木精-曙红染色包括使用作为主要染色剂的苏木精(其将嗜碱性细胞结构染为亮蓝色)和酒精性曙红Y溶液(其将嗜酸性细胞结构染为粉红色)。通常,嗜碱性结构是包含核酸(DNA和RNA)的结构:细胞核,核糖体和细胞质的富含RNA的部分。嗜酸性结构包含细胞内和细胞外蛋白质,例如路易体。细胞质是嗜酸性介质。红细胞总是染成鲜红色。
图9a显示了在C6胶质瘤异种移植和多孔PTFE组织替代物施加器植入后4个月的Wistar大鼠脑组织的冷冻切片。
肿瘤组织的大病灶崩解。用苏木精和曙红染色;放大率x100。
图9b显示了在多孔PTFE组织替代物施加器植入后4个月的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器植入创伤后的实验性大鼠大脑皮层(4个月)。用再生的神经组织(PTFE-深棕色)代替脑缺损区域。用苏木精和曙红染色;放大率x100。
采用Nissl法对Wistar大鼠脑组织的冷冻切片进行染色,然后进行研究以鉴定神经组织的成分;放大率x100。
图10a显示了在C6胶质瘤异种移植和多孔PTFE组织替代物施加器植入后4个月的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器植入实验性大鼠的脑肿瘤组织中(4个月)。小胶质细胞在肿瘤崩解区中。Nissl染色;放大率x100。
图10b显示了在多孔PTFE组织替代物施加器植入后4个月的Wistar大鼠脑组织的冷冻切片。
多孔PTFE组织替代物施加器植入创伤后的实验性大鼠大脑皮层(4个月)。小胶质细胞簇迁移到损伤区。Nissl染色;放大率x100。
结论:
在植入实验性大鼠肿瘤大脑皮层组织4个月后,多孔PTFE组织替代物施加器有利于形成多个小的液化坏死灶和肿瘤组织的大规模中心病灶的崩解,从而减少肿瘤。
在多孔PTFE组织替代物施加器植入实验性大鼠大脑皮层损伤区4个月后,观察到再生神经组织替代了缺损,并伴有组织替代物施加器内的胆碱能神经纤维的血管化和发芽。
在4个月的追踪后,具有实验胶质瘤且在肿瘤组织中植入了多孔PTFE组织替代物施加器的大鼠脑切片的组织学分析显示出大量小的肿瘤液化坏死灶以及施加器区域中的肿瘤组织的大规模中心病灶的消退。在肿瘤残留区域,报告了细胞结构的多态性,大量多核巨细胞具有渐进性坏死的迹象。显示出肿瘤区域具有完全损坏的实质和部分保留的间质。
在多孔PTFE组织替代物施加器的植入区域,肿瘤组织显示出一条细的沿着新形成血管的胆碱能神经纤维。
大脑皮层创伤后4个月并植入了多孔PTFE组织替代物施加器的实验性大鼠脑切片的组织学分析展现了病灶区修复过程的发展。大脑皮层持续水肿的背景下,注意到星形胶质细胞在多孔PTFE区域中增殖,其在此于组织替代物施加器纤维内积聚。在那里还检测到小胶质细胞簇,其迁移到损伤区域并转化为巨噬细胞。在与多孔PTFE组织替代物施加器相邻的大脑皮层再生区域,观察到血管化过程。脑缺损区域完全被再生的神经组织所替代。
细的胆碱能神经纤维出现在组织替代物施加器内的大脑再生区域,其沿随着合成PTFE材料孔之间的血管。
最终结论
在植入实验性大鼠肿瘤大脑皮层组织4个月后,多孔PTFE组织替代物施加器有利于形成多个小的液化坏死灶和肿瘤组织的大规模中心病灶的崩解,从而减少肿瘤。
在多孔PTFE组织替代物施加器植入实验性大鼠大脑皮层损伤区4个月后,观察到再生神经组织替代了缺损,并伴有组织替代物施加器内的胆碱能神经纤维的血管化和发芽。
根据所得到的结果,可以得出这样的结论:研发的制造PTFE型材料的技术可以创建组织替代物施加器,其有望用于可能的生物医学应用的进一步研究。
Claims (6)
1.对生物组织局部暴露的方法,所述方法包括与待暴露的生物组织直接接触放置组织替代物聚合物施加器,其特征在于使用多孔聚四氟乙烯作为构成聚合物材料。
2.如权利要求1所述的方法,其特征在于肿瘤组织用于待暴露的生物组织。
3.如权利要求1所述的方法,其特征在于暴露肿瘤周围的生物组织。
4.与肿瘤组织直接接触放置的组织替代物聚合物施加器,其特征在于所述施加器由PTFE制成。
5.多孔聚四氟乙烯作为细胞抑制材料的应用。
6.多孔聚四氟乙烯在生产用于治疗或替代肿瘤组织的组织替代物施加器中的用途。
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