CN112040906A - 用于捕获毒素和释放剂的三维印刷的支架 - Google Patents
用于捕获毒素和释放剂的三维印刷的支架 Download PDFInfo
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- Materials For Medical Uses (AREA)
Abstract
一种吸收和释放化合物的化学吸收物，包括晶格的多孔支架、支架的经修饰的表面和在支架中容纳导丝的中央孔，其中所述修饰基于与特定化合物结合或释放特定化合物的能力来选择。
Description
政府支持
本发明根据由美国国立卫生研究院(National Institutes of Health)授予的合同/授权号CA194533和EB012331以及由能源部(Department of Energy)授予的合同/授权号DE-AC02-05CH11231和DE-AC02-05CH11232在政府支持下完成。政府在本发明中具有某些权利。
相关申请
本申请要求于2018年4月30日提交的美国临时专利申请62/664,508的优先权，该美国临时专利申请通过引用以其整体并入本文。
背景
用于治疗癌症、感染、血栓形成和其他疾病的药物通常是非常有毒的，并且因此在肿瘤或感染的位置处有效，但对正常组织有毒，导致显著的副作用。尽管努力开发越来越有针对性和个性化的治疗剂(therapeutics)，但全身的有毒副作用限制了特定药物的使用和用于治疗癌症、感染和血栓形成的许多药物的给药。限制在医学实践中对于特定类型的癌症常见的毒性的方法之一是将化疗剂(chemotherapy)直接输注到供应肿瘤的供血动脉中。这限制了有毒化学物质的全身暴露，并且将化疗剂引导到其中需要治疗的区域。
不幸地，超过50％-80％的注射的药物没有被截留在靶器官中，而是绕过肿瘤进入全身循环。这些有毒的化学物质然后进入身体，并且可以导致副作用，这些副作用可以包括不可逆的心力衰竭、疲劳、脱发、瘀伤和出血、感染、贫血、恶心和呕吐、食欲改变、消化中断、体重变化、认知能力影响、情绪变化等。
附图简述
图1A-图1C示出了吸收物(absorber)的实施方案的图、化疗药物的化学结构和肝癌的血管内治疗的示意图。
图2A-图2C示出了三维印刷的多孔圆柱体的实施方案、三维印刷的多孔圆柱体的光学显微照片以及在三维印刷机中使用的化学反应。
图3示出了可用于实施方案的嵌段共聚物的化学结构。
图4示出了体内实验的示意图。
图5A-图5B示出了在体内实验期间获取的吸收物的荧光透视检查图像。
图6A-图6D示出了用于放置吸收物的位置的示意图，对于每个吸收物在不同的采样位置中的化疗药物的浓度，以及来自对照吸收物和包覆的吸收物两者的血浆的照片。
图7A-图7B示出了在体内实验期间在添加粉碎的吸收物后的混合物的照片。
实施方案详述
工业通常使用吸收柱来从化学物质流中去除污染物。此处的实施方案包括多孔吸收物，用于捕获不被靶肿瘤吸收的过量化疗药物。此处的实施方案将吸收物引入到引流静脉中，并且然后吸收物去除大部分注射的化疗药物。吸收物还可以去除大量不同类型的药物，诸如抗微生物剂、血栓溶解剂、来自细菌感染的毒素、环境毒素、或细胞，这些药物可以使用三维的印刷的吸收物的不同特征，使用特定的化学、物理、生物及其任何组合来捕获或结合。此外，吸收物可以捕获/去除体内不希望的分子/材料，体内的自然***无法正确地起作用以去除这些分子/材料，并且导致慢性健康问题。例如，乳酸可以从患有急性乳酸酸中毒的患者的血液中去除。
此处的实施方案还包括多孔材料，用于以患者的状况所需的恒定速率在靶位置处释放药物。此处的实施方案还包括在靶上游位置处释放药物并且在下游位置处捕获药物的***。应注意，虽然该设备被称为吸收物，但它也可以充当释放药物的递送***，诸如用于保健的治疗化合物和其他剂的纳米颗粒或微米颗粒。术语吸收物涵盖实施方案的释放和吸收方面两者。
虽然下文的讨论集中于化疗药物，但是吸收物从体内去除其他有害物质的应用不应限于此。如此处使用的术语“毒素”意指对人类身体有毒的任何物质，即使它用于***或其他疾病。该毒素对身体的其他部位有害。毒素的实例包括候选的化疗药物。
候选的化疗药物包括但不限于烷化剂：双官能烷化剂(环磷酰胺、氮芥、苯丁酸氮芥、美法仑)和单官能烷化剂(达卡巴嗪、亚硝基脲、替莫唑胺)(使用DNA链)；蒽环霉素类：多柔比星、柔红霉素、双柔比星(dipirubicin)、伊达比星、米托蒽醌和戊柔比星(使用离子交换官能团)；细胞骨架破坏剂：紫杉醇(pacilaxel)、多西他赛、白蛋白结合型紫杉醇(abraxane)和紫杉特尔(taxotere)(使用基于蛋白质(全蛋白质或蛋白质的亚单位)的捕获)；埃坡霉素；组蛋白脱乙酰酶抑制剂(HDAC)：伏立诺他和罗米地辛(使用基于蛋白质和/或DNA的捕获)；拓扑异构酶I的抑制剂：伊立替康和拓扑替康(使用基于蛋白质和/或DNA的捕获)；拓扑异构酶II的抑制剂：依托泊苷、替尼泊苷和他氟泊苷(tafluposide)(使用基于蛋白质和/或DNA的捕获)；核苷酸类似物：羟基脲、阿扎胞苷、卡培他滨、阿糖胞苷和去氧氟尿苷等(使用基于蛋白质和/或DNA的捕获)；肽抗生素：博来霉素和放线菌素；基于铂的剂：卡铂、顺铂和奥沙利铂(使用DNA链)；类视黄醇；长春花生物碱及衍生物：长春花碱、长春新碱、长春地辛和长春瑞滨(使用基于蛋白质和/或DNA的捕获)。
如此处使用的术语“血管”意指其中放置吸收物的任何血管。通常，这将是引流身体结构的静脉，诸如器官，但是也可以放置在其他血管中。此外，吸收物可以位于器官中，诸如位于器官的脂肪层中，或者可以被设计成在必要时部署在身体的任何位置处。
如此处所使用的，术语“晶格”是形成重复结构的晶胞(unit cell)的结构。在图2A中，底部图示出了立方体结构的柱状构造(columnar formation)36。在该实施方案中，这些立方体结构中的一种是晶格。可以具有多个柱的柱状结构在此处被称为支架。支架由一种结构组成，该结构将另一种功能材料支撑在表面上，以与靶分子诸如药物、DNA、蛋白质等具有化学和/或物理相互作用。在此处的实施方案中，支架接受涂层。支架还可以由功能性材料制成，或者可以在表面层上进行另外的表面修饰。如此处使用的术语“圆柱体”是3D印刷的支架的形状。支架由晶格34的网络组成。
通常，吸收物由圆柱体组成，该圆柱体在其内部具有支架或材料的晶格。吸收物/释放物的形状由患者的靶位置处的血管的形状决定。这可以通过诸如MRI的方法针对每个个体患者确定，并且根据患者的具体情况进行印刷。支架或晶格具有吸收毒素的涂层或其他表面修饰。因为圆柱体可以被印刷，因此该圆柱体可以具有可针对个体用户的血管定制的任何周长或长度。
支架或晶格表面可以使用不同的化学反应进行修饰，以引入可以捕获靶毒素/结合至靶毒素的官能团，所述化学反应诸如聚合、催化反应、表面包覆、蚀刻、表面修饰诸如多巴胺包覆、交联等。官能团可以是强阳离子交换基团或弱阳离子交换基团、强阴离子交换基团或弱阴离子交换基团、DNA链、生物配体、蛋白质、抗体、酶、纳米颗粒、微米颗粒、磁性颗粒等，取决于靶分子。磁性颗粒用于在NMR和/或MRI的情况下成像。这样的磁性颗粒在操作后的去除对于安全是重要的。
此外，吸收涂层或释放涂层可以由许多不同种类的聚合物形成。例如，一种可能性可以由嵌段共聚物组成，其中嵌段之一含有上文的活性官能团，而其他嵌段使聚合物粘附到支架。其他可能性包括包含官能单体和粘附单体的无规共聚物，以及包含官能单体和粘附单体的接枝共聚物。
吸收物的表面可以被设计成捕获待与通常用于癌症化疗的药物混合物一起使用的多种药物。吸收物表面可以被印刷或修饰成具有不同材料的多个层，以促进药物捕获的能力和速率，以及捕获药物和靶分子的混合物。吸收物可以使用具有受控的机械性质的弹性材料来制备。表面修饰基于其与用于释放或捕获的特定靶分子结合的能力来选择。靶分子，无论是用于释放还是捕获，无论是药物还是纳米颗粒或微米颗粒，在此处都将被称为“化合物”。
具有不同设计和涂层的吸收物可以同时或快速连续地被部署，以影响多种毒素、药物或过程。
***可以并入吸收物和其他相关部件。吸收物可以并入导丝、导入护套和/或其他相关装置，诸如囊，用于在较少的血液损失的情况下更容易的操作。吸收物可以是可压缩的和可拉伸的，以填充感兴趣的血管并且用于更容易的操作。不同化学式和/或机械性质的吸收物可以被组装在期望的位置，以优化它们与靶分子的结合/释放能力，不干扰血流，和/或将血流操纵到期望的速率。包括装置形状和囊的装置设计特征还可以用于改变装置附近的血流，以改善药物结合或释放。
吸收物的尺寸、形状和机械性质可以被仔细地修改，以在体积流速、接触吸收物的血流停留时间、使血流在吸收物中循环等方面将血流操纵到期望的速率。吸收物的这样的尺寸、形状和机械性质可以由血管尺寸、位置和在期望的位置中的血液流速来确定。吸收物可以用作囊或支柱(stent)以构建血管或器官，其中结构被破坏或塌陷，诸如在动脉瘤中，和/或减慢血流。
关于通过使用3D印刷将护套和导丝与吸收物结合，护套、导丝和/或用于操作的其他必需部件可以通过具体的化学式来制备，以使这些部件作为吸收物很好地起作用。护套、导丝和/或其他部件的内部和外部可以被修饰，诸如通过表面修饰，以具有特殊的官能团以结合/释放用于药物捕获/药物释放目的的靶分子。由护套、导丝和其他部件组成的整个***，其可以包括导管、连接部件等，在此处可以被称为“吸收物/释放***”。多孔支架的某些设计可以通过更常规的聚合物加工方法诸如注射模制来制造。
下文的讨论集中于化疗，理解这仅仅是为了讨论的目的。癌症正在成为大多数西方国家的主要死亡原因(1)。尽管已经做出了巨大的努力来开发更有针对性和个性化的癌症治疗剂，但是在癌症化疗中的药物给药通常受到全身有毒副作用的限制。在对靶器官进行动脉内化疗输注期间(2,3)，未截留在靶器官中的过量药物穿过引流器官的静脉，并且然后循环到身体的其余部分，在远端位置中引起毒性。通常，超过50％-80％的注射的药物没有被截留在靶器官中，而是绕过肿瘤进入全身循环(4)。
在降低化疗的毒性的背景下，这些实施方案提出了新的生物医学装置的开发：一种在体内被释放之前捕获过量的化疗药物的吸收物(5-8)。该吸收物被暂时地部署在引流经历动脉内化疗输注的器官的静脉中，并且在输注完成后被去除。图1A示意性地描绘了这一点，示出了肝脏内肿瘤的治疗。药物10被注射在动脉12中，在这种情况下是肝动脉，如常规的动脉内化疗输注的情况。离开器官(在该实例中是肝脏)的血液通过引流静脉18(在该情况下是肝静脉)穿过吸收物16，吸收物16捕获过量的药物，导致无药物的血液20。在这项研究中使用的特定药物是多柔比星。
图1B示出了多柔比星的化学结构。在图1C中示出了所提出的用于多柔比星捕获的方法。微创图像引导的血管内外科手术程序用于使用肝动脉12将药物10递送至肿瘤14，并且将吸收物16放置在肝静脉14、肝静脉汇合处或肝上下腔静脉24中。在图1C中示出了用于完成该任务的标准导入护套(introducer sheath)诸如23和27，以及导丝诸如28。图1A-图1C中描述的方法可以用于使在体内不同位置处使用的化疗剂的毒性效果最小化。用于治疗除癌症以外的其他疾病的药物的毒性还可以通过所提出的方法来调节。类似地，来自细菌感染的毒素、环境毒素或细胞本身可以使用特定的化学特征、物理特征或生物特征来捕获(9-11)。
多柔比星是一种几十年来经常用于化疗的低成本、高效的剂(12)。基于线性剂量响应模型，增加多柔比星的剂量线性地增加了肿瘤细胞死亡(13-23)。这为较高剂量的多柔比星疗法提供了动力，但高剂量的多柔比星疗法的副作用包括不可逆的心力衰竭，这限制了高剂量方案的实施。一种已建立的且高效的剂如多柔比星是用于证明所提出的药物捕获方法的令人信服的第一个候选物。
为了使吸收物在肝输注化疗中使用多柔比星的实施方案中有效地工作，它必须在一小时或更短时间内选择性地结合靶药物。吸收物的结构必须被仔细地设计和制造，以便不严重地损害血流或导致血栓形成，尽管患者通常在限制血栓形成的介入放射学程序中被抗凝。必须使用定制的吸收物，因为个体患者具有不同尺寸的静脉。本发明人已经使用3D印刷来制造在本研究中使用的吸收物。吸收物的成功设计、制造和部署具有为帮助患者对抗癌症开辟一条新途径的潜力。
印刷图2A-图2C中所示的多孔圆柱体(24)。吸收物的直径为5mm，并且长度为30mm。圆柱体吸收物16的目标内部结构在图2A-图2B中示出。贯穿圆柱体的中央孔32使得能够将装置附接到微创手术所需的导丝。在一个实施方案中，中央孔具有0.89mm的直径，并且如果需要，可以改变中央孔的尺寸。它被具有800μm的特征尺寸的正方形晶格结构34包围，其中圆柱体充当用于晶格的支架。该尺寸被选择以防止血细胞的溶血；具有约9μm-20μm的直径的白细胞是血液的最大组分(25,26)。多孔圆柱体通过图2C中示出的聚(乙二醇)二丙烯酸酯(PEGDA)的光诱导的交联来印刷。
基于聚(乙二醇)的聚合物由于其生物相容性和抗污染性而被广泛地用于生物医学工程(27-33)。此外，基于PEG的聚合物的其他相关性质诸如机械强度和水膨胀可以通过控制聚合条件容易地调节(34-43)。3D印刷的多孔圆柱体的光学显微照片在图2B中示出。明显的是，印刷工艺如实地再现了图2A中所示的目标内部结构。多孔圆柱体用作吸收物16的支架。
多孔圆柱体的表面包覆有由Kraton Performance Polymers,Inc.(Houston,TX)提供的聚(叔丁基苯乙烯)-b-聚(乙烯-共-丙烯)-b-聚(苯乙烯-共-苯乙烯磺酸酯)-b-聚(乙烯-共-丙烯)-b-聚(叔丁基苯乙烯)(PtBS-PEP-PSS-PEP-PtBS)嵌段聚合物。嵌段共聚物的化学结构在图3中示出。嵌段共聚物以溶解在庚烷和环己烷(按质量计72:28)的混合物中的聚合物的10wt％溶液的形式提供(44-46)。将3D印刷的圆柱体装配到有机硅管中，并且将聚合物溶液泵送通过该圆柱体持续10min。然后将该圆柱体首先在50℃的空气中干燥持续1小时30分钟，随后在室温在真空下干燥持续24小时。这导致在印刷的圆柱体上的共聚物的涂层。为了使该涂层可视化，使用X射线显微断层摄影术对表面修饰的圆柱体成像(47,48)。涂层厚度是或多或少均匀的，在从30μm至50μm的范围内。
在一个实施方案中，对于聚合物涂层的选择由先前的研究提供，在先前的研究中示出了聚苯乙烯磺酸酯链显示出与多柔比星的高结合能力(5,7,8)。嵌段共聚物中的PtBS和PEP嵌段可能负责涂层和3D印刷的支架之间的粘附。此处描述的用于包覆圆柱体的方法在大量的试验和错误后得到。嵌段共聚物或溶剂的组成的小变化导致在支架上的不稳定的涂层。
在三种动物模型(猪)中用上文描述的包覆的3D印刷的吸收物进行体内实验。吸收物的直径(5mm)由导入护套的尺寸来确定，在一个实施方案中，护套由18French或6mm直径的护套组成，其可以容纳在猪的股总静脉和髂总静脉中。这些的直径与成人的肝静脉相似。
引入器护套的直径被最小化，以使手术期间的血液损失最小化。吸收物的长度(30mm)被选择成与髂总静脉的长度相匹配。髂总静脉42被选择以便于解释实验数据和证明概念验证。此外，髂总静脉的直径为约10mm，类似于人类肝静脉与下腔静脉汇合处附近的直径，吸收物将被放置在髂总静脉中，用于在肝动脉内化疗输注期间捕获从肝排出的过量药物，如参见图1C所示。为了使吸收物周围的血流最小化，使用导入护套将两个圆柱体48和50一个接一个地带到期望的位置，并且如图4中所示平行布置。
在猪模型中测试吸收物，该猪模型在10min内在髂总静脉42中经历50mg的多柔比星的化学输注，对应于临床上用于肝细胞癌的动脉内治疗的化疗的典型剂量。在三个不同位置处使用采血导管监测多柔比星浓度随时间的变化。在图4中示意性地描绘了两个位置，装置前采样导管44和装置后采样导管46。装置前导管位于注射导管40和吸收物之间。装置后导管位于吸收物之后。第三个导管(此处未示出)位于颈内静脉处，从髂总静脉很好地去除，使得从该位置采集的任何血液样品都将反映全身药物浓度，因为多柔比星将必须穿过下腔静脉、心脏、肺血管***、全身动脉、毛细血管和全身静脉以到达该采样点。此处的讨论将其称为外周位置。
在图5A-图5B中示出了在体内实验之一期间获得的髂总静脉中吸收物的X射线荧光透视检查图像。在图5A中清楚地看到用于递送吸收物的导入护套和导丝。护套经由股总静脉引入。吸收物位于金属紧固件之间，金属紧固件在图5A中也是可见的。图5B的较高放大率图像示出了平行排列的两个吸收物48和50。
两个单独的体内实验的结果在图6A-图6D中示出。图6A示出了在对照实验期间在上文描述的三个位置处作为时间的函数的所测量的多柔比星浓度，其中未包覆的吸收物被放置在髂总静脉中。在以线60位置示出的装置前处和以线62位置示出的装置后处测量的多柔比星浓度在定性上是相似的，指示注射的多柔比星的大部分穿过吸收物。在这两种情况下，多柔比星浓度在前3min期间迅速增加，在约5min保持恒定，并且然后在约30min内下降至零。当多柔比星被注射到动物模型中时，在以线64示出的外周位置处测量的多柔比星浓度仅略微增加。图6B示出了在对照实验期间从三个采样导管获得的离心样品的血浆的图像。由于多柔比星具有特征性的橙色，因此多柔比星的浓度越高，样品中的橙色越暗，这在描绘中转化为更暗的灰色阴影。样品中的颜色暗度与图6A中所示的多柔比星浓度概况在定性上一致。在对照实验中，在从装置前导管和装置后导管获得的图像之间几乎没有定性差异。
图6C示出了当部署包覆的吸收物时，作为时间的函数的测量的多柔比星浓度。这些结果与图6A中的结果显著不同。图6C示出了线62处和线64的外周位置处的装置后多柔比星浓度显著地低于在线60处的装置前位置处测量的浓度。两个数据集下的积分区域使得能够定量药物捕获功效。
在该实验中，69％的多柔比星被包覆的3D印刷的吸收物捕获。在该实验期间，在图6D中示出的来自从三个采样导管获得的离心样品的血浆的图像证实了多柔比星的去除。在体内实验后，将吸收物粉碎并浸没在氯化钾和乙醇的含水混合物中，在一个实施方案中为20％w/v(50-54)，以从吸收物中扩散出多柔比星。当研究用于体内实验的未包覆的吸收物时，获得无色溶液，如图7A中所示。相反，当研究用于体内实验的包覆的吸收物时，获得橙色溶液，在此处转化为灰色阴影，如图7B中所示。
实验表明多柔比星不可逆地结合至吸收物；发明人试图通过将上文描述的氯化钾和乙醇的含水混合物泵送通过过滤器持续一个月来释放多柔比星。混合物的分析示出了可忽略不计的多柔比星浓度(小于0.001mg/ml)。在此程序后获得的图7B中示出的图像表明，吸收的多柔比星在扩散通过涂层后强烈地结合至支架。在完成体内实验后，使用X射线显微断层摄影术对吸收物进行再分析。所获得的显微断层摄影术图像与图3B中所示的图像相似，指示涂层在药物捕获过程期间是稳定的。此外，在操作期间没有观察到与血凝块和其他生物相容性问题有关的问题。
体内药物捕获实验被重复四次。其他三个实验的结果与图6A-图6D中报道的结果相似。多柔比星的捕获功效在从57％至69％的范围内。结果在补充材料中示出。
此处的实施方案包括设计的、构建的和部署的多孔吸收物，用于在化疗药物释放在体内之前在体内捕获化疗药物，以减少全身性有毒副作用。孔隙率通过圆柱体内晶格结构的3D印刷获得。聚苯乙烯磺酸酯涂层在吸收物上的应用对于药物捕获是必需的。最初的设计使得能够捕获69％的施用的药物而没有明显的不良副作用。
已经开发了许多用于使用该平台的方法以改善药物捕获的功效。最简单地说，可以增加吸收物装置的数目，增加药物结合的总表面积。晶格尺寸可以减小以增强药物捕获。通过改变涂层的化学组成和厚度，或者通过改变晶格结构诸如从立方体到六边形，或者通过制造在前面具有较大孔的不均匀晶格，可以获得性能的另外的改善。晶格可以是不同的几何形状，它们可以是立方体状或六边形的、准周期性结构如准晶，或者在前面和后面具有不同几何形状的非周期性结构。晶格的几何形状可以径向地或轴向地连续变化，在一些位置处具有较宽的支柱，并且在其他位置处具有较窄的支柱。
在未来的临床试验中，人们可以使用定制的3D印刷的弹性吸收物，其具有最佳地适合患者的静脉的特定于患者的形状因素，如可以通过手术前计算机断层扫描(CT)或磁共振成像(MRI)数据集创建的。
实施例1
用于本研究的圆柱形多孔吸收物由位于Redwood City,CA,USA的3D印刷公司Carbon,Inc.制备。预聚物溶液通过将1wt％的引发剂(即0.8wt％的2,4,6-三甲基苯甲酰基-二苯基氧化膦(TPO,Sigma Aldrich,USA)和0.2wt％的2-异丙基噻吨酮(ITX,Esstech,Inc.,USA))和0.23wt％的炭黑颜料添加到聚(乙二醇)二丙烯酸酯(PEGDA,MW＝250g/mol,Sigma Aldrich,USA.)中来制备(参见图2C)。该溶液通过使用连续液体界面生产(CLIP)方法进行光聚合；关于CLIP的更多信息可以在其他地方找到(24,55-57)。将通过该工艺获得的圆柱体在2-丙醇中洗涤，以从聚合物网络中洗涤掉未固化的树脂。在洗涤后允许圆柱体空气干燥，并且使用Dymax ECE 5000UV固化室(Torrington,CT,USA)在30秒时间间隔内进行UV后固化，其中中间旋转固化持续总共2min。使用Keyence VHX-5000显微镜(Itasca,IL,USA)对吸收物进行成像测量。
3D印刷的多孔圆柱体的表面通过包覆磺化的苯乙烯五嵌段共聚物的薄层来修饰。磺化的苯乙烯五嵌段共聚物(PtBS-PEP-PSS-PEP-PtBS)经由阴离子聚合和随后的聚合后磺化工艺来合成，并且详细的程序已经在其他地方描述(58,59)。中间聚苯乙烯(PS)嵌段的磺化水平(mol％)被控制到期望的离子交换容量(IEC)。在本研究中，使用IEC＝2.0meq/g(干聚合物)的磺化的五嵌段共聚物(磺化水平＝52mol％)。未磺化的五嵌段共聚物的数均分子量为约78,000g/mol(嵌段质量分数为PtBS:PEP:PSS＝0.33:0.27:0.40)，并且中间PSS嵌段的体积分数为0.434(44,45)。
未包覆的吸收物和包覆的吸收物在劳伦斯伯克利国家实验室(LawrenceBerkeley National Laboratory)的高级光源的光束线8.3.2.处使用同步加速器硬X射线显微断层摄影术来成像。具有在从12keV-25keV范围内的能量的X射线由同步加速器产生，并且照射样品。透射穿过样品的X射线阴影使用闪烁体转换成可见光。该图像通过光学显微镜放大，并且被转换成数字图像文件。当样品以几分之一度旋转经过180°时，收集了总共1,313～2016幅图像[31]。这些投影图像使用程序Xi-Cam(60)被重建为横截面切片图像，并且随后被堆叠以产生397个圆柱体的3D重建图像。
在三个猪模型(40kg-45kg)中体内测试了3D印刷的吸收物。吸收物沿着聚四氟乙烯(PTFE)包覆的镍钛诺导丝(
Terumo Interventional Systems,Somerset,NJ,USA)排列，用于通过弯曲的血管平稳且快速地移动；导丝穿过吸收物的中间孔，并且吸收物的每一端上的两个金属紧固件用于将吸收物保持在适当的位置。
体内实验根据美国加州大学旧金山分校(University of California,SanFrancisco)(UCSF)的机构动物护理和使用委员会(Institutional Animal Care and UseCommitte)(IACUC)的协议进行。在用异氟烷全身麻醉下，监测每只动物的血压、脉搏血氧、心率和心电图。放置到股总静脉中的18French(直径＝6mm)的引入护套用于将吸收物递送到髂总静脉中。将采样和注射导管在荧光透视检查引导下放置在相对于吸收物的感兴趣的位置。装置前采样导管经由护套引入到左侧髂总静脉。装置后采样导管通过颈内静脉引入，并且被放置在腔静脉的分叉附近的髂总静脉中。在一系列体内实验中，导管和吸收物之间的距离被仔细地调整到一致。在实验开始之前，使用碘化的造影剂注射(iohexol,Omnipaque-300,GE Healthcare,USA)证明了静脉***的开放性。
为了模拟动脉内化疗给药，将50mg的多柔比星(2mg/ml，多柔比星419盐酸盐注射液，美国药典，Pfizer,New York,NY,USA)经由输注泵以2.5ml/min的恒定速率在10min内注射到髂总静脉中。在浪费1.5ml的血液以计算导管内的体积后，从装置前、装置后和外周采样位置收集不同时间的2ml的血液等分试样。
使用荧光光谱法来确定血液等分试样中的多柔比星浓度。荧光测量使用FlexStation 3多模式微板读数器(Molecular Devices,San Jose,CA)在480nm激光的激发下以550nm的已知发射波长进行(5,7,8,50-53,61)。使用校准曲线从在550nm处测量的荧光来计算多柔比星浓度，该校准曲线将荧光发射与多柔比星浓度相关联。
实施例2
将实施例1的包覆的吸收物和未包覆的吸收物用于另外的体内实验，通过在动物的肝静脉和下腔静脉(IVC)中部署多个包覆的吸收物，在四只猪上进行该体内实验，如图1C中所描绘的。猪经历10分钟的动脉内输注多柔比星(200mg)到肝总动脉中，以模拟临床TACE(经动脉化疗栓塞)程序。在安乐死后，分析器官组织中的多柔比星浓度。在体内实验期间，没有观察到血液动力学、血栓形成或免疫并发症。
测量肝脏、心脏和肾脏中的多柔比星浓度，以评估主要器官中多柔比星积累的减少。对三只猪进行对照实验，其中没有部署吸收物，但是这些猪经历如上文所描述的相同的多柔比星(200mg)的动脉内输注。为了更容易的比较，对照实验的器官中的多柔比星浓度被用于使体内实验的器官中的多柔比星浓度归一化，在体内实验中部署了包覆的吸收物。
在图8中示出了器官组织分析的结果。对于肝脏，在对照实验中和在体内实验中积累的多柔比星的量是相似的，如所预期的。然而，通过在肝静脉和/或IVC中部署包覆的吸收物，观察到在心脏(在7个包覆的吸收物的情况下减少40％，并且在11个包覆的吸收物的情况下减少65％)和肾脏(在7个包覆的吸收物的情况下减少37％，并且在11个包覆的吸收物的情况下减少70％)中的多柔比星积累的显著减少。随着包覆的吸收物的数目增加(即包覆的吸收物的表面积增加)，心脏和肾脏中的多柔比星积累减少。其他器官诸如脾和肺也示出类似的趋势，但为了简洁起见，此处未示出。
上文的讨论集中于去除输注治疗中过量的化疗药物。如先前所提及的，这仅是应用的一个实例，并且不意图限制权利要求的范围。使用这些吸收物可以去除其他类型的药物和物质。此外，吸收物的技术和结构可以用于在***后释放局部药物或其他治疗剂。
将理解，上文公开的变型以及其他特征和功能、或其替代方案可以被结合到许多其他不同的***或应用中。本领域技术人员随后可以做出多种目前未预见的或未预料到的本文中的替代、修改、变型或改进，这些替代、修改、变型或改进也意图被所附权利要求涵盖。
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Claims (23)
1.一种吸收和释放化合物的化学吸收物，包括：
晶格的多孔支架；
在所述晶格的至少一个表面上的表面修饰，其中所述表面修饰基于与特定化合物结合或释放特定化合物中的一种的能力来选择；和
在所述支架中容纳导丝的中央孔。
2.如权利要求1所述的化学吸收物，其中所述吸收物包含弹性材料，所述弹性材料允许改变所述支架的化学性质和机械性质中的至少一种。
3.如权利要求1所述的化学吸收物，其中所述表面修饰包括涂层。
4.如权利要求1所述的化学吸收物，其中所述表面修饰包括添加到所述晶格的所述至少一个表面的官能团。
5.如权利要求4所述的化学吸收物，其中所述官能团包括选自由以下组成的组的至少一种：强阳离子交换基团；弱阳离子交换基团；强阴离子交换基团；弱阴离子交换基团；DNA链；生物配体；蛋白质；抗体；酶；纳米颗粒；微米颗粒；磁性颗粒；以及其任何组合。
6.如权利要求1所述的化学吸收物，其中所述表面修饰包括具有多个层的表面修饰。
7.如权利要求1所述的化学吸收物，其中所述吸收物的尺寸、形状和机械性质由血管尺寸、位置和在所述吸收物的期望位置中的血流来确定。
8.如权利要求1所述的化学吸收物，其中所述吸收物包括护套和导丝。
9.如权利要求8所述的化学吸收物，其中所述护套和所述导丝的表面也具有表面修饰。
10.如权利要求1所述的化学吸收物，其中所述晶格和所述支架包含基于聚(乙二醇)的聚合物。
11.如权利要求1所述的化学吸收物，其中所述晶格具有包括以下中的至少一种的几何形状：立方体状、六边形、准周期性结构、在前面和后面具有不同几何形状的非周期性结构、以及连续变化的几何形状，其中所述变化的几何形状是径向或轴向中的一种，在一些位置处具有较宽的支柱，并且在其他位置处具有较窄的支柱。
12.一种制造化学吸收物的方法，包括：
形成具有中央孔的晶格的三维多孔支架；和
修饰所述支架和所述晶格中的至少一种的至少一个表面以引入官能团，其中所述官能团基于与特定化合物结合的能力来选择。
13.如权利要求12所述的制造方法，其中形成所述晶格的三维多孔支架包括使用弹性材料形成所述晶格的三维多孔支架。
14.如权利要求12所述的制造方法，其中形成所述晶格的三维多孔支架包括使用基于聚(乙二醇)的聚合物形成所述晶格的三维多孔支架。
15.如权利要求12所述的制造方法，其中形成所述晶格的三维多孔支架包括印刷所述多孔支架或注射模制所述多孔支架中的一种。
16.如权利要求12所述的制造方法，其中修饰至少一个表面包括通过化学反应修饰所述至少一个表面。
17.如权利要求16所述的制造方法，其中通过化学反应修饰所述至少一个表面包括通过聚合、催化反应、表面包覆、蚀刻、多巴胺包覆和交联中的一种来修饰所述至少一个表面。
18.如权利要求12所述的制造方法，其中所述官能团选自由以下组成的组：强阳离子交换基团；弱阳离子交换基团；强阴离子交换基团；弱阴离子交换基团；DNA链；生物配体；蛋白质；抗体；酶；纳米颗粒；微米颗粒；磁性颗粒；以及其任何组合。
19.如权利要求12所述的制造方法，其中所述修饰所述至少一个表面包括用聚合物包覆所述至少一个表面，所述聚合物包括以下中的至少一种：包含所述官能团的第一聚合物和将所述第一聚合物粘附到所述支架的第二聚合物的组合、包含功能单体和粘附单体的无规共聚物、或包含官能单体和粘附单体的接枝共聚物。
20.如权利要求12所述的方法，还包括将所述吸收物附接至导丝并且将所述吸收物封闭在护套中。
21.如权利要求20所述的方法，还包括修饰所述导丝和所述护套中的至少一种的表面。
22.如权利要求12所述的方法，其中形成所述晶格的三维多孔支架包括基于血管尺寸、位置和在期望的位置中的血流速率来形成具有尺寸、形状和机械性质的所述三维多孔支架。
23.一种将化学吸收物引入到身体内的方法，包括：
通过所述化学吸收物中的中央孔***导丝；
将所述化学吸收物附接至所述导丝；
将所述化学吸收物***到导入护套中；
将所述导入护套***到所述身体的血管中；和
将所述化学吸收物放置到静脉中，从所述静脉中排出来自肿瘤的血液。
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| PCT/US2019/029979 WO2019213123A1 (en) | 2018-04-30 | 2019-04-30 | Three-dimensional printed scaffold for capturing toxins and releasing agents |
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| EP3768192A1 (en) | 2021-01-27 |
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