CN1307001C - 平行且选择性地分散微滴的高效系统 - Google Patents
平行且选择性地分散微滴的高效系统 Download PDFInfo
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Abstract
本发明涉及一种显著增加微滴选择性分散性能的方法,用于通过在预定位置分散预定试剂产生空间和目标选择性,并提供了一种容易适应的多功能系统。本发明系统的一个实施方式包括用隔膜(3)覆盖的基底(2),用于使隔膜垂直于所述基底中形成的每一空腔变形的装置(65),其中所述空腔,在按照基质型排列形成基底的材料中蚀刻,为穿过所述基底的孔的形状,具有轴向对称的连续侧壁(11);每一孔在基底的上表面和下表面分别开口作为加料开口(12)和排出开口(14),所述加料开口的口远大于喷嘴开口(13)。
Description
本发明涉及一种平行且选择性地分散毫微升,甚至微微升的因数级的极小体积微滴的高效系统,实施这种分散的可运输的药筒和试剂盒,以及这些系统的应用,显著地在化学、生物、生物工程或制药-特别是用于生产生物芯片,用于制药、免疫或生物化学试验,用于筛选药物库或血清库,用于制备药物或其通过离子电渗疗法经皮给药,或者另外在化妆品领域,用于制备香水雾化器或气溶胶,用于喷墨打印或汽车电子学,特别是用于气体或油燃料注射器。
最近在基因组和蛋白质组的研究进展使得可以获得大量用于测定的生物和治疗分子。然而,少量可获得的生物化学产物及其高成本使得通过性能最佳化寻找试验能力的合理增加。
为此,已使用各种技术处理生物化学液体,例如带有压电驱动器的菌落转移系统或微量移液系统,以及最近的喷墨打印技术。
这些技术的目标是通过将大多数情况下预合成的生物探针(低聚核苷酸、蛋白质、肽等的)分散到不同类型的载体如玻璃、尼龙_或纤维素_上生产生物芯片。
例如从文献US 5,053,100或US 6,083,762已知,在微分散器上使用压电传感器的分散器。这种技术允许原位操作预合成或合成过的低聚核苷酸。然而,这些系统由该元件制成并且不适合高密度平行分散。
在文献US 6,028,189中,使用喷墨型微型泵进行试剂的分散,该泵是由一压电驱动器激活的。每一微型泵构建于硅团中,具有小滴加料和排出通道。为了获得原位合成,通过在循环孔排出四个微型泵释放DNA碱基,所述循环孔是在具有沿两个轴控制移动的玻璃基底上形成的。
这些系统不能根据本发明高效操作,即几百至几千滴/cm2:四个泵以几百Hz运转,根据前面文献的机器将在几百秒钟内操作100 000滴。这样,合成25个低聚核苷酸探针需要2个多小时。
与通过光刻掩蔽阻止特定分子的光化学获得的密度相比,本发明的目的在于通过大大增加平行操作的密度大大增加选择性分散微滴的性能。这种方法受到能够通过光化学固定的那些分子的限制并且基本上不能单个地处理试剂小滴。而且,用本方法原位合成限制在约25个单核苷酸。
本发明另一目的是允许选择性地通过将试剂分布于预定或计划位置,这不仅是在空间上的,而且还是靶向的通过将许多试剂中选择的一种分布于预定位置。
本发明还涉及一多功能系统,它易于以不同形式适应例如能够大量操作的生物和生物化学分析微型试剂盒。具体地说,本发明并不限于每个探针25个核苷酸的合成,而是合成达到例如70个核苷酸的长探针,同时保持高效。
这些目的是通过使用一分散头满足的,该分散头是通过高密度微电子型技术由特定形状的孔基质制成的并根据用于高输出选择性分散的特定连接加料。
更精确地,本发明目的是一种高效微滴分散系统,它包括一用膜覆盖的基底和与基底中形成的每一空腔垂直地使膜变形的装置,并且其中在形成基底的材料中蚀刻的空腔外表为孔的形状,该孔以轴向对称的侧面连续内壁横穿基底;每一孔在基底的上表面和下表面开口,并且各自作为加料开口和作为排出喷嘴打开的导管,加料开口比导管喷嘴开口要高,并且导管呈现1-20的形状比。其中所述孔以二维形状构造,孔密度达到10000/cm2并且总流速为至少1百万滴/秒钟,并且其中所述膜或所述基底具有多层结构,在不同层中三维地整合微型导管,然后微型导管通过与孔的上面开口垂直的链接件与所述孔相连。
根据本发明,术语“分布”应理解为通过瞬间平行分散几十到几千微滴的高输出排出或吸移微滴,术语“轴向对称壁”应理解为回转或圆柱形表面,例如正方形横截面,并且术语“形状比”应理解为出口导管的高度和开口之间的比。
为了获得这种性能,基底显示能够达到10 000/cm2的孔密度,其流动可以超过1百万滴/秒。
有益地,基底材料选自半导体材料如硅、砷化镓、碳化硅、锗、氧化物和绝缘成分(例如SOI,硅-氧化物-绝缘体的首字母组成)、玻璃、氮化硅、多晶硅、陶瓷、热塑性材料-例如聚甲基丙烯酸甲酯、聚碳酸酯、聚四氟乙烯、聚氯乙烯或聚二甲基硅氧烷、厚光敏性树脂(例如树脂(《SU8》)-,以及金属,例如钨或不锈钢。
优选,根据基底材料选择制备孔或微型通道的微型加工技术:
-湿或干化学蚀刻例如用于硅和玻璃的反应性离子蚀刻(缩写为RIE)或深度蚀刻(缩写为D-RIE);
-对金属进行电花切割或电成型的蚀刻;
-对热塑性材料进行浇铸和聚合;
-对大多数基底进行光刻、激光切割、超声或研磨投影(projection)。
根据优选实施方式,膜材料选自玻璃、硅、弹性体和热塑塑料;可以使用上述的蚀刻技术对膜进行蚀刻,以便产生孔加料微型通道网络;这些微型通道在两端与至少一个加料试剂罐相连。
根据特定实施方式,膜局部变形用的装置是通过电磁、磁致伸缩或压电驱动器具体实现的。也可以考虑另外的装置,例如通过双金属效应的喷墨型或热塑性的加热装置、通过位于每一孔之间的电场产生的电蒸发,或者其它静电驱动器。
所有这些变形装置可以由通过多路转换网络编程的单控制装置控制。这种装置允许同时或相继触发通过所有孔、通过一组(bloc)孔或者某些孔吸移或分散相同或不同的试剂。
根据特定实施方式,分散头具有许多为4的倍数的行和调节至所需密度的许多孔柱,以便由生产生物芯片用的四个基本核苷酸单体合成DNA探针。每行中的孔是由相同的储器通过与孔行平行并且侧面与所述行相连或者与基底平面正交的膜中形成的微型导管加料的,所述储器在膜中蚀刻或以一定距离放置并通过柔性链接与微型导管相连。
本发明还涉及本文上面定义的分散头的应用。为了实施它们中的至少一些,更有利地是制备以下形式易于使用的装置:
-分散药筒,包括至少一个预填充有试剂的分散系统并具有半导体或热塑性材料的滴定平皿,它可以显示通过微电子型蚀刻、通过切削、通过模制、通过热成型、或者调节至这种生产的任何技术形成的微型碗;
-分散试剂盒,包括至少一个分散头,它可以配备有至少一个吸移泵和至少一个滴定平皿,用或者不用试剂预填充。
这些药筒或试剂盒特别适用于通过原位合成或沉积预合成的低聚核苷酸制备生物芯片,用于收集或单个筛选生物分子或细胞,用于制备药物或用于药物试验或者用于免疫、生物化学和生物筛选。
从前面所定义的由几个孔组成的分散头可以进行通过离子电渗疗法经皮给药。在压电细胞上施加适当电位差的系统、或者任何其它电磁驱动装置,形成至少一种孔中所含或所形成的药物的校准量的给药设备。
或者说,本发明的分散系统可用于通过由适用于压电细胞的不同电位的操作系统组成的离子电渗疗法经皮给药,以给予校准量的至少一种在至少一个孔中所含或形成的药物。
本发明的分散系统还可用于在制药中筛选试验细胞,其中药物沉积在配备有极化电极的滴定平皿的微型碗中所含的细胞上,所述细胞反应性试验是光学的或电学的。
除了上述的应用之外,本发明也可用于分离和分级,例如在色谱法中通过选择性过滤。首先将相同或不同的生物细胞固定、嫁接、封闭或悬浮,通过任何已知方式,于本发明的分散头的孔(每一孔或一组孔)壁上。分散头可以整合到注射器顶端。
从以下详细说明,特别是本发明的一些非限制性实施方式实施例,并参照附图,其它特征、益处、应用也将显而易见,其中附图分别显示了:
-在图1中,限于本发明系统的基本孔环境的分散头的部分透视图;
-在图2中,从图1中具有填充储器的分散头的II-II线所做的横截面图;
-在图3中,具有8个分散孔的本发明系统的分散头的透视图;
-在图4中,根据前面图的IV-IV线所做的横截面图;
-在图5中,具有16个分散孔的本发明系统的分散头的透视图;
-在图6中,根据前面图的V-V线所做的横截面图;
-在图7和8中,根据图5的系统和一变体的分散头的下表面的两个鸟眼图;
-在图9中,具有远程试剂分散装置的图5系统的透视图;
-在图10中,具有四个单核苷酸的远程分散装置以在移动平皿上形成探针的图5系统的透视图;
-在图11中,描述了分散孔的选择性驱动原理的本发明分散系统的横截面示意图;
-在图12a和12b中,描述了通过电磁选择性驱动装置的孔的两个驱动相的横截面图;
-在图13a和13b中,描述了分别通过电磁和压电选择性驱动装置的选择性驱动的本发明分散系统的横截面图;
-在图14中,用于制备本发明分散药筒的以通过试剂吸移填充的相的分散头的横截面图;
-在图15中,在滴定平皿上进行细胞处理的本发明分散系统的横截面图;
-在图16中,在基因试验中进行杂交测定的本发明分散系统的横截面图;
-在图17中,进行经皮给药的本发明分散系统的横截面图。
在所有图中,相同的附图标记代表相同或技术上相当的元件。膜看上去透明以便于显现所显示的整个元件。
图1中描述了分散头1的一个实例,它受限于围绕分散孔10的环境。每一孔10通过光刻蚀刻,接着在覆盖有pyrex_膜3的硅基底2中进行湿化学蚀刻,所述膜和基底通过阳极焊接装配形成头1。
孔10具有一倒置的金字塔形状,并根据硅的晶面1-1-1定义的四个连续倾斜壁11垂直穿过硅基底2。孔的上面开口12,与膜3相通,形成一尺寸比下面导管13大的正方形,以便加速小滴的排出。用于从孔加料试剂或排放试剂的微型通道20机械加工于膜3中。
在实现本实施例时,孔尺寸如下:
-上面开口边长:500μm
-下面导管边长:10-50μm(约30μm)
-膜厚:10-50μm
-基底厚度:360μm
在取自线II-II的图2横截面图中,可以看出,微型导管13与试剂加料或贮存储器4相通。在该图中还显示了基底2中通常平的下表面2i围绕孔10的侧壁11凸出以便将这些壁延伸形成导管14。这些导管是通过机制下表面获得的。具有边长C,开口13的边长的这种导管的高度H,测定形状比在本实施例中约等于3,这样提高了微微升级体积的微滴的成型性。形状比的值受到技术约束的限制,根据材料和所用蚀刻技术,良好的折中是希望在1-20之间。而且,两个孔之间的平均距离典型地约为550μm。
在图3中,分散头1的透视图由8个孔10组成,它们各自与8个储器4通过8个微型导管20相通。这种头的典型尺寸是:
-长:3mm
-宽:5mm
-厚度:根据储器的厚度为1mm
图4所示的,取自前面图的面IV-IV所做的横截面图,清楚地显示了储器4允许分散或吸移不同试剂5a或5b的独立性。
作为变体,下面图5和6分别显示了取自面V-V的鸟眼图和横截面图,分散头由16个孔10组成,它们各自与16个储器4通过16个微型导管20相连。这种构造有利于用于分散16种不同试剂。
图5和6的分散头的基底2的通常平的下表面2i,以图7的鸟眼图显示并在图8中有一变体。在图7中,孔10的壁可以看到凸起为金字塔形状。这种倾斜形状的侧面是有利的,因为它防止了试剂聚集并因此防止了其滞留。而且,从水动力学角度,它使得能够较好地充满连续分布的压力和速度。在图8中,这些相同的壁11显示为透明的圆柱形,直径为100微米,通过中心顶端6延伸,具有与孔相同的圆柱形,直径为20微米。
当单一试剂分散或吸移同时通过孔时,图9所示的膜结构有利地投入使用。在该结构中,膜3具有单一开口30,能够在所有孔10上加料或吸移相同试剂,而不使用微型导管。将这种试剂通过与穿过膜3的单一微毛细管40相连的柔性管7从远的储器(未显示)运输或者吸移到远的储器。
当分散几种试剂时,例如分散4种单核苷酸A、C、T、G,在图10的透视图中显示的这种情况下,上面的膜被3个横断物31分开以便形成4个独立的试剂加料或吸移管道32。这些管道与4个微毛细管41相连,通过膜3和4个弹性管7与4个远的储器(未显示)偶联。这种结构特别适用于分散4个基本核苷酸,以在被硅化合物83层覆盖的平皿82上形成用于制备微型芯片的探针9,从而能够嫁接第一个核酸金属化物。平皿82按照轴XYZ受到定位装置86的支持。
为了以选择性方式分散微滴50试剂,即通过使用与其它独立的每一孔,膜3局部处理,如图11的横截面图所示。通过施加力F由局部变形膜3的装置选择性地驱动分散孔10。
在图12a和12b的横截面图中,显示了通过局部变形由电磁驱动装置激活的膜激活孔10的两个驱动相。这些装置是通过由产生电流的激发电路组成的基本电磁体60具体实施的,特别包括与气隙中心64偶联的线圈63。所述电磁装置还包括磁性芯片65,固定在垂直于孔的膜3上并且能够受电磁体极化。该芯片另外可以是永久磁铁,或者由抗磁性或顺磁性材料制成。
当电流62循环时,中心63对芯片65施加吸引力F。然后膜3朝电磁体变形并在开口13使液体51的流动停止(图12a)。通过颠倒电极使电流62以另一方向循环时,中心63对磁性芯片65施加一排斥力F。膜以中空形状弯曲并将液体51以微滴50通过排出管道的开口13排出(图12b),同时体积通过管道的尺寸以及通过施加的电信号的振幅和持续时间校准和控制。
另外,小滴排出可以通过施加脉冲电流或者通过以膜的共振频率施加交流电流进行。
为了进行微滴的选择性分散,也就是说对每一孔的控制是独特的,通过一系列驱动装置进行局部变形。图13a和13b描述了这种分别通过电磁装置和压电装置具体实施的装置的横截面。
电磁装置包括许多电磁体60和许多磁铁65,以基质形状与每一孔4垂直放置,并且压电装置包括一些压电芯片70,与用于电磁装置的类型相同的激发电路61偶合。微滴50的压电触发器(图13b)以通过关闭电路61电磁触发的情况下激发相同的方式(图12和13a)激发,开关66打开将使小滴50的流动停止。当使用压电激活装置时,电信号为这种情况下施加到压电元件电极的电位差。
这套激活装置是通过偶联或多路转换网络可编程的控制单元(未显示)控制的,并且其实施对本领域技术人员为已知。这种单元能够同时或相继触发唯一试剂或不同试剂通过孔的吸移或分散。
因此可以获得小滴的高排出流动,例如对单一孔为100滴/秒。因此对1000个孔可以获得100000的流量,同时膜的变形受到外面信号的控制。事实上,液体基本上是不能压缩的,在孔的上面开口和排出开口之间的液体运行速度之间的比与各自表面之比成反比。在所述实施例中,开口面之比是约15,小滴的排出速度为膜变形的约15倍。
为了制备本发明的分散药筒,如图14的横截面图所示,将试剂吸移到分散头中。就发生的这种吸移而言,试剂含在根据相应于孔10的尺寸蚀刻于平皿81上的微型碗80中。这种平皿包括间隔为0.6mm的9600微型碗的情况。可以类似地制备几千个碗/cm2,而目前所用的滴定平皿通常仅包括1-4个碗/cm2。
平皿通过微米调整(方向Z)朝基底2移动直到它贴到微型碗80的边缘固定的téflon_防水接头82。另外可以使用其它材料形成接头:硅、vuiton_、聚合物、弹性体或适应的热塑性材料。
然后通过触发安装于与孔10的排放导管相连的排放管7上的泵8将试剂吸移到孔中,如本文上面所述的。平皿81还可以按照方向XY移动,以便能够从允许试剂混合物的微型碗的其它吸移到相同孔中。平皿放置在定位台XYZ(图10中所示)。
根据其应用,试剂可以是各种类型:DNAc、低聚核苷酸、基因、细胞、RNAm、蛋白质、DNA或通过PCR(是聚合酶链反应的缩写形式)扩增的RNA序列、抗原和抗体、治疗分子、血清等。
就制备探针以生产生物芯片而言,在图15的横截面图中显示了低聚核苷酸或蛋白质沉积到滴定平皿上或者移动带上。分散头由储器并按照图10在泵的作用下加料。各种治疗试剂52-56分散于孔中。待处理的细胞沉积在滴定平皿81的微型碗中。头和平皿借助参照点(未显示)精确地对准。滴定平皿是通过注入热塑性材料如聚甲基丙烯酸甲酯或聚碳酸酯制成的。
这些探针通过激活设备的控制单元的编程需要以及带的移动成型,因此在该移动的同时立即形成探针:探针9的形成时间最佳化,这样相对于形成现有技术的连续层的形成方面能够节省大量时间。用本发明的分散系统获得的高流速能够使探针可以达到例如用于功能基因组和基因表达所需的60-70个核苷酸。平皿或带通过微米调整按照方向XY移动以定位具有待压印区域的排出开口。
在检测遗传试验中杂交的应用的另一实施例中,如图16的横截面所示,带82,如前面图制备的,通过患者90的DNA流动扫描。患者的DNA通过嫁接大理石91或者通过荧光预先磁性标记,所述大理石嫁接在现有技术中用于使磁场中的分子停止。
本方案具有再次使用分散驱动装置的增加的益处,能够通过检测进行试验的读取,这能够减少所用电材料的量,而在现有技术中,在滴定碗中必须有读数线圈。
杂交或免疫相互作用使得能够将患者的DNA固定在一些探针9上。这些杂交的检测是通过在与杂交的探针垂直的电路61中形成感应电流或者通过光学测定进行的。这种测定能够通过精确探针定位并通过以下事实进行:在磁性标记的情况下,相同的电路61确保了探针分散和杂交的测定。
在离子电渗疗法应用中,参照图17的横截面图,从分散头到分散孔10进行经皮给药。在该孔中,药物按照上面所述的方法分布。通过电压发生电路61在压电细胞(cell)70上施加几毫伏的电压以使膜3变形。然后可以在给定时间内给予预校准量的药物50。孔的两个相对壁11也可以极化以通过引起皮肤毛孔扩张促进吸收药物。
本发明并不限于所述和所代表的实施方式。
除了基质中之外,例如可以进行孔、激活装置和滴定碗的构造:同心环形或螺旋形构造同样适宜。
微型导管可以蚀刻在基底上或者可以蚀刻在膜上。可以使膜或基底具有多层结构,使得在不同层中将微型导管三维整合。微型导管然后可以通过与孔上面开口垂直的链接件与孔相连。
而且,可以使用其它技术触发膜的局部变形,通过使用热塑性或磁致伸缩效应的双金属带效应:双金属带型材料热塑性变形沉积以在膜上形成与孔垂直的带。每一带可以通过铁磁性材料层和通过导电材料层(在Cu、Al、Au等中)形成,所述铁磁性材料在电磁体产生的磁场的影响下变形。也可以使用气动装置,通过电蒸发、或者通过施加静电场。
而且,可以借助例如Foucault电流产生膜的变形力或其加热。通过使膜变形或者通过振动导管顶端可以使膜共振。
而且,允许其它修改以满足特定应用。例如,就制药中试验细胞筛选而言,参照图15,滴定平皿81的微型碗80配备有极化电极87。细胞反应性试验可以是光学的,即通过荧光和/或光谱,或者是通过电或电化学阻抗测定的电学的试验。也可以相反地在这些电极之间施加适宜值的电位差,以在这些细胞中产生极化并因此有助于细胞上的治疗效果。
本发明分散系统的另一应用涉及通过如上所述的平行和相继加料将试剂分散于表征化合物的质谱柱中。这种应用同样适用于色谱法。
Claims (25)
1、高效分散微滴的系统,包括基底(2),具有上下表面并用膜(3)覆盖;和装置(65,70),用于使膜垂直于所述基底(2)中形成的每一空腔(10)变形,其中所述空腔,在包括基底的材料中蚀刻,外观为穿过所述基底的孔的形状,具有轴向对称的连续侧壁(11),每一孔在基底的上表面和下表面分别开口作为加料开口(12)和以排出喷嘴(13)开口的导管(14),所述加料开口呈现开口高于导管的喷嘴(13),并且所述导管呈现1-20的形状比,其中所述孔以二维形状构造,孔密度达到10000/cm2并且总流速为至少1百万滴/秒钟,并且其中所述膜或所述基底具有多层结构,在不同层中三维地整合微型导管,然后微型导管通过与孔的上面开口垂直的链接件与所述孔相连。
2、如权利要求1的微滴分散系统,其中,所述孔构建成矩阵形状、同心圆形状、螺旋形、或者这些构型的组合而不是二维形状。
3、如权利要求1或2的微滴分散系统,其中用于变形的整个装置由可编程控制单元经由多路交换网络控制,从而同时或相继触发孔、一组预选择孔或某些预选择的孔吸移或排出相同或不同试剂。
4、如权利要求1或2的微滴分散系统,其中基底或膜的材料选自半导体材料、多晶硅、玻璃、氮化硅、陶瓷、热塑性材料、弹性体、厚光敏性树脂和电成型或电腐蚀性金属。
5、如权利要求1的微滴分散系统,其中基底或膜的蚀刻选自化学蚀刻、光刻、通过电腐蚀或电成型蚀刻、模制和聚合、激光切割、超声或研磨投影。
6、如权利要求5的微滴分散系统,其中所述化学蚀刻是RIE或D-RIE。
7、如权利要求5或6的微滴分散系统,其中膜经过蚀刻产生微型导管网络以加料所述孔,所述微型导管在顶端与至少一个试剂加料储器相连。
8、如权利要求1的微滴分散系统,其中用于局部变形膜(3)的装置(65,70)由电磁、压电、磁致伸缩、静电驱动器或通过电蒸发组成。
9、如权利要求1的微滴分散系统,其中膜上的变形力是通过开启膜(3)的共振或者通过振动导管(14)的顶端产生的。
10、如权利要求1的微滴分散系统,其中基质构型的每一行中的孔是由相同储器(4)通过与孔(10)的行平行并与行侧相连或者与基底(2)的面正交的膜中形成的微型导管(20)加料的,所述储器在膜中蚀刻或者以一定距离定位并通过柔性链接件与微型导管相连。
11、如权利要求1的微滴分散系统,其中分散头(1)具有许多为4的倍数的行,以便由4个单核苷酸(A,C,T,G)合成DNA探针用于制备生物芯片,并且其中每一行中的孔由相同储器(4)通过在与行平行的膜(3)中形成的微型导管(32)加料,所述储器在膜中蚀刻或者以一定距离定位并通过柔性链接件(7)与微型导管相连。
12、分散药筒,包括如权利要求1或2的分散系统,用试剂(51)预填充,并具有滴定平皿(81),所述平皿可以显示通过微电子型蚀刻、通过机制、通过模制和通过热成型形成的微型碗(80)。
13、如权利要求12的分散药筒,其中滴定平皿显示配备有极化电极的微型碗,所述细胞反应性试验是光学或电学的。
14、如权利要求12或13的分散药筒,其中在所述滴定平皿的所述电极之间施加一电位差以便在细胞中产生极化并有助于细胞上的治疗效果。
15、分散试剂盒,包括如权利要求1或2的分散系统,配备有至少一个吸移泵(8)和至少一个滴定平皿(81),它们可以用试剂预填充。
16、如权利要求15的分散试剂盒,其中滴定平皿显示配备有极化电极的微型碗,所述细胞反应性试验是光学或电学的。
17、如权利要求15或16的分散试剂盒,其中在所述滴定平皿的所述电极之间施加一电位差以便在细胞中产生极化并有助于细胞上的治疗效果。
18、如权利要求12或13任一项的分散药筒制备生物芯片的应用,通过原位合成或沉积预合成的低聚核苷酸,从而筛选生物、化学分子,或者在细胞上,制备药物或者药物试验或免疫、生物化学或基因筛选。
19、如权利要求15或16任一项的分散试剂盒制备生物芯片的应用,通过原位合成或沉积预合成的低聚核苷酸,从而筛选生物、化学分子,或者在细胞上,制备药物或者药物试验或免疫、生物化学或基因筛选。
20、如权利要求1或2的分散系统的应用,用于通过由适用于压电细胞(70)的不同电位的操作系统组成的离子电渗疗法经皮给药,以给予校准量的至少一种在至少一个孔中所含或形成的药物。
21、如权利要求1或2的分散系统在制药中筛选试验细胞的应用,其中药物沉积在配备有极化电极的滴定平皿(81)的微型碗(80)中所含的细胞上,所述细胞反应性试验是光学的或电学的。
22、如权利要求20或21的应用,其中在所述电极之间施加适宜值的电位差以便在细胞中产生极化并因此有助于细胞的治疗效果。
23、如权利要求1或2的分散系统的应用,通过孔或一组孔将相同或不同生物细胞或生物化学化合物固定在分散头的孔的壁上用于选择性过滤。
24、如权利要求23的分散系统的应用,其中分散头与注射器顶端整合。
25、如权利要求1或2的分散系统的应用,用于平行或相继加料质谱术或色谱术的柱。
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- 2001-06-15 DK DK01945453T patent/DK1289660T3/da active
- 2001-06-15 AT AT01945453T patent/ATE317299T1/de not_active IP Right Cessation
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- 2001-06-15 JP JP2002510191A patent/JP2004503389A/ja active Pending
- 2001-06-15 AU AU6767301A patent/AU6767301A/xx active Pending
- 2001-06-15 ES ES01945453T patent/ES2258533T3/es not_active Expired - Lifetime
- 2001-06-15 DE DE60117146T patent/DE60117146T2/de not_active Expired - Fee Related
- 2001-06-15 US US09/882,308 patent/US6833112B2/en not_active Expired - Fee Related
- 2001-06-15 KR KR1020027016885A patent/KR100780971B1/ko not_active IP Right Cessation
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CN107433244A (zh) * | 2017-08-31 | 2017-12-05 | 北京工业大学 | 电磁膜片式按需微滴制备装置 |
Also Published As
Publication number | Publication date |
---|---|
ATE317299T1 (de) | 2006-02-15 |
IL153216A (en) | 2007-02-11 |
US20020121529A1 (en) | 2002-09-05 |
DE60117146T2 (de) | 2006-10-19 |
EP1289660B1 (fr) | 2006-02-08 |
AU6767301A (en) | 2001-12-24 |
EP1289660A1 (fr) | 2003-03-12 |
US6833112B2 (en) | 2004-12-21 |
KR100780971B1 (ko) | 2007-11-29 |
DE60117146D1 (de) | 2006-04-20 |
CN1436099A (zh) | 2003-08-13 |
KR20030016286A (ko) | 2003-02-26 |
WO2001096019A1 (fr) | 2001-12-20 |
JP2004503389A (ja) | 2004-02-05 |
ES2258533T3 (es) | 2006-09-01 |
IL153216A0 (en) | 2003-07-06 |
CA2311622A1 (en) | 2001-12-15 |
AU2001267673B2 (en) | 2006-05-25 |
DK1289660T3 (da) | 2006-06-12 |
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