CN111107937B - 包括具有薄膜晶体管和电容感测的双基底的数字微流体设备 - Google Patents

包括具有薄膜晶体管和电容感测的双基底的数字微流体设备 Download PDF

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CN111107937B
CN111107937B CN201880061705.0A CN201880061705A CN111107937B CN 111107937 B CN111107937 B CN 111107937B CN 201880061705 A CN201880061705 A CN 201880061705A CN 111107937 B CN111107937 B CN 111107937B
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microfluidic device
digital microfluidic
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I·法兰西
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Nucleoprotein Co.,Ltd.
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Abstract

一种有源矩阵介质上电润湿(AM‑EWoD)设备，其包括具有薄膜晶体管(TFT)和电容感测的双基底。如本文所描绘的，底部基底包括第一多个电极以推动各种液滴通过微流体区域，而顶部基底包括第二多个电极，其被配置为用电容感测询问液滴。在一些实施方案中，顶部基底具有高分辨率感测区域和低分辨率感测区域。

Description

包括具有薄膜晶体管和电容感测的双基底的数字微流体设备
相关申请
本申请要求于2017年10月18日提交的第62/573,846号美国临时专利申请的优先权。在本说明书中引用的所有专利和专利申请均通过引用以其整体并入本文。
背景技术
数字微流体设备使用独立的电极以在受限的环境中推进、分裂和结合液滴，从而提供“芯片实验室(lab-on-a-chip)”。数字微流体设备供选择地被称为介质上电润湿设备，或称为“EWoD”，以进一步区分该方法与依赖电泳流和/或微泵的竞争性微流体系统。Wheeler在“数字微流体(Digital Microfluidics),”分析化学年度评述(Annu.Rev.Anal.Chem.)2012,5:413-40中提供了2012年电润湿技术回顾，其通过引用整体并入本文。该技术允许使用少量的样品和少量的试剂两者进行样品制备、测定和合成化学。近年来，使用电润湿在微流体单元(cell)中的受控液滴操作已成为商业可行的；并且现在有来自大型生命科学公司如Oxford Nanopore的产品。
关于EWoD的大多数文献报道都涉及所谓的“无源矩阵”设备(也称为“分段”设备)，由此十至二十个电极用控制器直接驱动。虽然分段设备易于制造，但是电极的数量受到空间和驱动约束的限制。因此，不可能在无源矩阵设备中进行大规模的平行测定、反应等。相比之下，“有源矩阵”设备(也称为有源矩阵EWoD，也称为AM-EWoD)设备可以具有数千个、数十万个甚至数百万个可寻址电极。电极通常通过薄膜晶体管(TFT)切换，并且液滴移动是可编程的，从而AM-EWoD阵列可以用作通用目的设备，其为控制多个液滴和执行同时的分析过程提供极大的自由度。
由于对电场泄漏的限制要求，大多数先进的AM-EWoD设备由多晶硅(polycrystalline silicon)(也称为多晶硅(polysilicon)，也称为多晶Si(poly-Si))构成。然而，多晶硅制造比非晶硅制造昂贵得多，非晶硅制造即用于LCD显示工业的大量制备的有源矩阵TFT中使用的类型。多晶硅制造工艺更昂贵，因为有用于处理多晶硅的独特处理和制造步骤。世界上被配置成由多晶Si制造设备的设施也更少。然而，由于多晶硅的改善的功能，Sharp Corporation已经能够在单个有源矩阵上实现包括推进、感测和加热能力的AM-EWoD设备。参见，例如，第8,419,273号、第8,547,111号、第8,654,571号、第8,828,336号、第9,458,543号美国专利，其全部通过引用整体并入本文。图1中示出了复杂的多晶SiAM-EWoD的示例。
尽管多晶Si制造技术允许实现复杂的AM-EWoD设备，但是多晶Si设备制备的成本结合全球合适制造设施的缺乏，已经阻碍了AM-EWoD技术的广泛应用。需要可以利用现有非晶硅制造能力的不同设计。这种设备可以以较低的成本和以很大的量制备，使它们适合于做普通诊断测试如免疫测定。
发明概述
本发明通过提供一种AM-EWoD的替代结构解决现有技术的缺点，该结构非常适合于由非晶硅基底的构造。在一个实例中，本发明提供了一种数字微流体设备，其包括第一基底、第二基底、间隔物以及第一控制器和第二控制器。第一基底包括耦合到第一组薄膜晶体管的第一多个电极，并且包括覆盖所述第一多个电极和第一组薄膜晶体管两者的第一电介质层。第二基底包括耦合到第二组薄膜晶体管的第二多个电极，并且包括覆盖所述第二多个电极和第二组薄膜晶体管的第二电介质层。所述间隔物将第一基底和第二基底分开，并在第一基底和第二基底之间产生微流体区域。所述第一控制器可操作地耦合到所述第一组薄膜晶体管，并且被配置为向所述第一多个电极的至少一部分提供推进电压，而所述第二控制器可操作地耦合到所述第二组薄膜晶体管，并且被配置为确定所述第二多个电极中的至少一个与驱动电极之间的电容。在一些实施方案中，所述第一电介质层是疏水的，并且在其他实施方案中，所述第二电介质层是疏水的。在优选的实施方案中，所述第一多个电极以阵列布置，例如每线性厘米至少有25个电极。在一些实施方案中，所述第二多个电极与驱动电极相互交叉。所述第二多个电极的宽度为0.01至5mm。在一些实施方案中，信号源耦合到驱动电极并且被配置为向驱动电极提供随时间变化的电压。在一些实施方案中，所述第二基底包括至少一个透光区域，该透光区域的面积可以例如为至少10mm2。所述数字微流体设备可以由非晶硅或多晶硅构成。
在一些实施方案中，所述第二多个电极以第一密度和第二密度布置，并且所述第一密度包括每100mm2至少三倍于所述第二密度的电极。所述第二多个电极的第一密度包括每线性厘米20至200个电极。所述第二多个电极的第二密度包括每线性厘米1至15个电极。所述设备的对应于所述第一密度的面积小于所述设备的对应于所述第二密度的面积。所述设备的对应于所述第二密度的面积是所述设备的对应于所述第一密度的面积的至少三倍。数字微流体设备将具有两个不同电极密度的区域，即，用于传感器电极侧的高密度(也被称为“高分辨率”)区域和低密度(也被称为“低分辨率”)区域。这样的设计将允许用户执行粒子询问(interrogation)(即，电容感测)以确定设备的一部分中的组成或尺寸，然后简单地监控设备的另一部分中的粒子的位置或存在。总体而言，这种配置简化了设备的制造，同时还简化了与感测功能相关的数据处理。
附图简述
图1示出现有技术EWoD设备，其在同一有源矩阵上包括推进和感测两者；
图2描绘通过在相邻电极上提供不同的电荷状态，水相液滴在相邻电极之间的移动；
图3示出用于本发明的EWoD设备的多个推进电极的TFT结构；
图4是第一基底的一部分的示意图，其包括推进电极、薄膜晶体管、储能电容器、电介质层和疏水层；
图5是第二基底的一部分的示意图，其包括感测电极、驱动电极、薄膜晶体管、电介质层和疏水层；
图6示出用于感测电极和驱动电极的TFT结构，其被配置为用于微流体液滴的电容感测和评估；
图7说明其中感测电极和驱动电极相互交叉作为第二基底的一部分的实施方案；
图8说明数字微流体设备的俯视图，其中感测电极被布置为具有变化的高密度区域和低密度区域。图8所示的电极布置为许多分析功能提供必要的功能(液滴尺寸确定和移动跟踪)，同时降低设备的复杂性和制备成本；
图9说明包括透光区域的供选择的实施方案，在该透光区域中，液滴可以被电磁辐射即光询问。应当理解，探测光和所产生的信号两者都可以通过同一透光区域进入/离开；
图10示出感测电极的供选择的布置，该感测电极布置有变化的高密度区域和低密度区域；
图11示出感测电极的供选择的布置，该感测电极布置有变化的高密度区域和低密度区域；
图12示出包括细长感测电极的供选择的布置，该细长感测电极布置有变化的高密度区域和低密度区域；
图13示出包括细长感测电极的供选择的布置，该细长感测电极布置有变化的高密度区域和低密度区域。
详述
如上所指出，本发明提供了一种有源矩阵介质上电润湿(AM-EWoD)设备，该设备包括具有薄膜晶体管(TFT)和电容感测的双基底。如本文中所描绘，“底部”基底包括多个电极以推动各种液滴通过微流体区域。“顶部”基底包括多个电极，以提供信号并用电容感测检测液滴的存在和/或大小和/或组成。“顶部”和“底部”的使用仅是一种惯例，因为可以切换两个基底的位置，并且可以以多种方式对设备进行定向，例如，顶部板和底部板可以大致平行，而整个设备被定向，使得基底垂直于工作表面(与如图所示平行于工作表面相反)。顶部或底部基底可以包括另外的功能如电阻加热和/或温度感测。因为设备包括基于TFT的传感器，所以这些设备比已知的无源设备具有高得多的灵敏度和分辨率。另外，因为电容感测所需的两个电极都在同一基底上，所以顶部电极和底部电极不需要对准，并且与推进电极相比，感测像素可以具有不同的尺寸或配置。另外，该设计可以用非晶硅实现，从而将制备成本降低到设备可以用后即丢弃的程度。也可以将非晶Si TFT用于底部板，以从它们更高的操作电压中受益，并且在顶部板上使用多晶Si TFT，用于更高的灵敏度感测。
在图2的剖面图中说明EWoD设备的基本操作。EWoD 200包括填充有油202和至少一个水液滴204的单元(cell)。单元间隙范围通常为50至200μm，但间隙可以更大。在基本配置中，如图2所示，多个推进电极205设置在一个基底上，并且单个顶部电极206设置在相对的表面上。单元另外包括在接触油层的表面上的疏水涂层207，以及在推进电极205和疏水涂层207之间的电介质层208。(上基底也可以包括电介质层，但未在图2中显示)。疏水层防止液滴润湿表面。当在相邻电极之间未施加电压差时，液滴将保持球形，以最小化与疏水表面(油和疏水层)的接触。因为液滴不润湿表面，所以它们不太可能污染表面或与其他液滴相互作用，除非当期望这种行为时。
尽管可以具有用于介电功能和疏水功能两者的单个层，但是这种层通常需要厚的无机层(以防止针孔)，其具有所得的低介电常数，因此需要超过100V用于液滴移动。为了实现低电压驱动，最好有薄的无机层以获得高电容，并且无针孔，顶部有薄的有机疏水层。通过这种组合，可以用+/-10至+/-50V范围的电压进行电润湿操作，该电压范围处于常规TFT阵列可以提供的范围。
当在相邻电极之间施加电压差时，一个电极上的电压吸引在电介质-液滴界面处的液滴中的相反电荷，并且液滴朝该电极移动，如图2所示。可接受的液滴推进所需的电压取决于电介质层和疏水层的特性。使用交流驱动以减少液滴、电介质和电极通过各种电化学作用的降解。用于EWoD的操作频率可以在100Hz至1MHz的范围，但是优选将1kHz或更低的较低频率用于操作速度有限的TFT。
如图2所示，顶部电极206是通常设置为零伏或公共电压值(VCOM)的单个导电层，以考虑推进电极205上的偏移电压，该偏移电压是由于用于切换电极上的电压的TFT的电容性反冲造成的(见图3)。顶部电极也可以施加方波以增加液体两端的电压。这样的布置允许用于TFT连接的推进电极205的较低的推进电压，因为顶部板电压206对于由TFT提供的电压是额外的。
如图3所示，推进电极的有源矩阵可以被布置为由数据线和栅极(选择)线驱动，这与液晶显示器中的有源矩阵非常相似。扫描栅极(选择)线以一次寻址一条线，同时数据线承载待传送到推进电极用于电润湿操作的电压。如果不需要移动，或者如果液滴旨在远离推进电极移动，则将0V施加到该(非目标)推进电极。如果液滴旨在朝着推进电极移动，则将AC电压施加到该(目标)推进电极。
图4示出非晶硅、TFT开关的推进电极的结构。电介质408必须足够薄并且具有与低压AC驱动兼容的介电常数，诸如可以从用于LCD显示器的常规图像控制器获得。例如，电介质层可以包括顶部罩面涂覆有200-400nm等离子体沉积的氮化硅的大约20-40nm SiO2层。供选择地，电介质可以包括2至100nm厚、优选20至60nm厚的原子层沉积的Al2O3。使用本领域技术人员已知的方法，通过沿着各种电极线产生不同掺杂的非晶硅结构的交替层来构造TFT。疏水层407可以由诸如
Figure GDA0003522977260000061
AF(Sigma-Aldrich,Milwaukee,WI)和来自Cytonix(Beltsville,MD)的FlurorPelTM涂料的材料构造，该材料可以旋涂在电介质层408上。
在本发明中，构造具有TFT功能的第二基底以提供电容感测能力，并且用间隔物分隔两个层，该间隔物在两个层之间产生微流体区域。液滴的电容感测使用两个电极，如图6所示。通常，AC信号被施加到驱动电极506，由此AC信号在附近的感测电极505上产生电容耦合的电压。电容耦合的信号由外部电路测量，并且信号的变化指示驱动电极506和感测电极505之间的材料。例如，由于材料之间相对介电常数的差异，所以取决于电极之间是油202还是水液滴204，耦合电压将明显不同。(硅油的相对介电常数εr＝2.5，乙醇的相对介电常数εr＝24，水的相对介电常数εr＝80。)
图5示出包括TFT开关的感测电极505和驱动电极506的非晶硅感测层的结构。用于驱动电极的AC信号水平运行，并且一次激活仅一条线，以最小化与读出线和“关闭”感测电极的电容耦合。TFT并不是完美的开关，并且即使在“关闭”状态下也有一些小的电导。这意味着大量的关闭线可能具有与一个“开启”像素相似的信号。由于这个原因，最好通过仅在被驱动行上具有交流电压来最小化来自被驱动行上方和下方的交流电压的电容信号。
如图6所示，感测电极和驱动电极产生共面的间隙单元。一个主要优点是两个板不需要精确对准，甚至不必具有相同的像素间距，因此简化了两个板系统的制造。使用叉指间隙单元对液滴进行电容感测的另外详情可见于例如“芯片实验室设备中跨绝缘叉指电极的微流体两相流引起的电容变化(Capacitance Variation Induced by Microfluidic Two-Phase Flow across Insulated Interdigital Electrodes in Lab-On-Chip Devices)”,T.Dong,CBarbosa,传感器(Sensors),15,2694-2708,(2015)，其通过引用整体并入。用于检测电容信号的电路可以包括各种电子部件，包括放大器、多路复用开关。先进的设计可以包括耦合到多通道电荷传感器如用于数字X射线成像的那些的非晶Si TFT阵列。参见“用于成像探测器的前端电子设备(Front-end electronics for imaging detectors)”,G.DeGeronimo等人,物理研究中的核仪器与方法A(Nuclear Instruments and Methods in Physics Research A),471第192–199页,(2001)，其通过引用整体并入。
在一些实施方案中，不必要为AC信号提供多个独立的驱动电极。如图7所示，驱动电极可以布置成相邻的，但是与感测电极相互交叉。(图7所示的所有电极都在同一金属层中，但是以不同的颜色示出以表示其功能。)在图7中，AC信号被提供给水平横跨表面的单个驱动电极，而横跨阵列“读取”各种感测电极。通常，一次激活仅一条传感器线以最小化来自处于“关闭”模式的驱动电极和感测电极的AC信号之间的电容耦合。没有这样的逐行读出，来自多个处于“空”状态(例如，耦合到油)的感测电极的信号将看起来比适当的更大，降低了正确感测电极的信噪比。在供选择的实施方案中，顶部基底可以包括驱动电极、感测电极和接地栅格。如上所述，驱动电极和感测电极可用于液滴感测，而接地栅格提供与推进电极相对的电极表面区域，该电极表面区域对电接地具有低阻抗。
本发明将使用耦合到顶部驱动电极和感测电极的电路以提供电容感测，从而允许设备跟踪由设备操纵的液滴的位置。然而，来自在小感测电极上的液滴的电容感测的信号也相对较小，因此可能需要一百至三百行传感器电极以获得可接受的信噪比。横跨整个设备提供如此高密度的感测电极将是昂贵且不必要的。因此，对于较大的阵列(诸如用于组合化学)，优选的是在顶部板上具有有高密度感测像素的小的局部区域以用于粒子尺寸测量，而在其他地方具有较低的密度以用于移动感测。
如图8所示，可以在顶部板上的各个位置处产生具有不同密度的感测电极的AM-EWoD设备。在图8的实施方案中，阵列上有200dpi的高分辨率区域用于液滴尺寸测量，和10dpi的分辨率区域以跟踪液滴移动。在图8中，对于100条测量线，传感器将为181.61mm宽。如果感测板下方的TFT EWoD推进基底具有200dpi(每英寸电极)的均匀分辨率，则将有1430行推进电极用于控制液滴的移动、混合等。相比之下，横跨整个设备具有180dpi分辨率的限于一百个感测行的设备将只有14.1毫米宽，导致仅111行推进电极；对于复杂的分析来说可能太小了。因此，通过提供不同的密度，可以制备具有所有所需感测能力的更大的设备。一般来说，低分辨率区域将包括每线性厘米1至15个电极，而高分辨率区域将包括每线性厘米20至200个电极。通常，具有较低密度(也称为“低分辨率”)的感测电极的总面积(长度x宽度)大于具有较高密度(也称为“高分辨率”)的感测电极的总面积。例如，与高分辨率区域相比，低分辨率区域可以是高分辨率区域的三倍或更大。例如，低分辨率区域可能是其五倍或更大。例如，与高分辨率区域相比，低分辨率区域可能是其十倍或更大。
使用不同密度的感测电极的另外的好处是，顶部板的部分可以设置有透明的或否则透光的区域，以允许进一步询问液滴。例如，可以通过用光源穿过顶部基底照射液滴，然后使用检测器和任选的滤色器通过顶部基底观察所产生的荧光，观察荧光标记。在其他实施方案中，光可以通过顶部基底和底部基底两者，以允许在IR、UV或可见光波长下的吸收测量。供选择地，可以使用衰减(受抑)全内反射光谱来探测系统中液滴的含量和/或位置。
图9中示出这种系统的一个实施方案，其中感测电极905之间的间隙910为2mm的量级，允许光915从物镜920通过以照射通过的液滴930。在一个实施方案中，液滴930包含荧光分子，并且所产生的荧光信号通过物镜920被收集回来，并使用二向色滤光器(未示出)分离，以用检测器(未示出)检测。因此，该设计允许在液滴移动通过系统时收集关于液滴的不同类型的信息，例如电容和光谱信息。
如关于图8所讨论的，实施低分辨率感测的最简单方式将是具有与高分辨率区域相同的感测像素设计，但是在感测像素周围具有大的空间。这个构思在图10的不同实施方案中说明。使用图10的设计，液滴将可能在低分辨率感测像素之间通过，但是可以编写液滴控制算法以确保液滴有规律地通过感测像素，允许监控液滴的尺寸和组成。如图10所示，低分辨率像素的均匀分布使得可以显著增加可进行感测的面积，同时允许使用市售的驱动器。作为供选择的方案，任一垂直感测线上的感测像素的数量可以是恒定的，而感测像素是交错的，如图11所示。也可以采用其他图案如伪随机图案，以最大化与液滴的相互作用，同时减少必须制造和随后寻址的感测TFT的实际数量。
还可以使用不同形状的电极产生低分辨率感测区域和高分辨率感测区域，如图12和13所示。图12示出高分辨率感测区域中的方形像素和低分辨率感测区域中的较大矩形感测像素。这种设计对于感测沿阵列的上下移动，即从一个细长电极移动到另一个细长电极将是有效的。可以实施该相同的技术以制造水平细长电极和垂直细长电极两者，这将提供具有较低分辨率的液滴跟踪。图13显示具有垂直矩形感测像素和水平矩形感应像素的低分辨率区域，以检测液滴的垂直移动和水平移动。其他几何设计如螺旋形也可以用于以更少的电极和更少的TFT促进位置感测。如图12和13所示，可以容易地将液滴从发生液滴产生、分裂或混合的低密度区域移动到可以评估那些液滴的尺寸和组成的高密度区域。
从前述内容将看出，本发明可以提供低成本的芯片实验室功能。具体地，通过使用所描述的结构，可以使用非晶硅制造设施和较低成本的驱动电子器件在电介质系统上产生电润湿。本发明有效地利用了EWoD设备的顶部和底部两者上的可用表面，但是不需要使顶部表面和底部表面上的电极对准。
对于本领域技术人员将显而易见的是，在不脱离本发明的范围的情况下，可以对上述本发明的特定实施方案进行许多改变和修饰。因此，整个前述描述将以说明性而非限制性的意义来解释。

Claims (17)

1.一种数字微流体设备，其包括：
第一基底，其包括耦合到第一组薄膜晶体管的多个推进电极，并且包括覆盖所述多个推进电极和第一组薄膜晶体管两者的第一电介质层；
第二基底，其包括耦合到第二组薄膜晶体管的多个感测电极和驱动电极，并且包括覆盖所述多个感测电极、第二组薄膜晶体管和驱动电极的第二电介质层；
间隔物，其将第一基底和第二基底分开，并在第一基底和第二基底之间产生微流体区域；
第一控制器，其可操作地耦合到所述第一组薄膜晶体管并且被配置为向所述多个推进电极的至少一部分提供推进电压，其中向所述推进电极施加AC信号，使微流体区域的流体移动；和
第二控制器，其可操作地耦合到所述第二组薄膜晶体管并且被配置为确定所述多个感测电极中的至少一个与所述驱动电极之间的电容，其中向所述驱动电极施加AC信号，在附近的感应电极上产生电容耦合的电压。
2.权利要求1所述的数字微流体设备，其中，所述第一电介质层是疏水的。
3.权利要求1所述的数字微流体设备，其中，所述第二电介质层是疏水的。
4.权利要求1所述的数字微流体设备，其还包括覆盖所述第一电介质层的第一疏水层和覆盖所述第二电介质层的第二疏水层。
5.权利要求1所述的数字微流体设备，其中，所述第一多个薄膜晶体管或所述第二多个薄膜晶体管包含非晶硅。
6.权利要求1所述的数字微流体设备，其中，所述多个推进电极以阵列布置。
7.权利要求6所述的数字微流体设备，其中，所述多个推进电极的阵列包括每线性厘米至少25个电极。
8.权利要求1所述的数字微流体设备，其中，所述多个感测电极中的每个电极与所述驱动电极相互交叉。
9.权利要求8所述的数字微流体设备，其还包括信号源，所述信号源耦合到所述驱动电极并被配置为向所述驱动电极提供随时间变化的电压。
10.权利要求8所述的数字微流体设备，其中，所述多个感测电极的宽度为0.01至5mm。
11.权利要求1所述的数字微流体设备，其中，所述第二基底包括至少一个透光区域。
12.权利要求11所述的数字微流体设备，其中，所述透光区域的面积为至少10mm2。
13.权利要求1所述的数字微流体设备，其中，所述多个感测电极以第一密度和第二密度布置，并且所述第一密度包括每100mm2至少三倍于所述第二密度的电极。
14.权利要求13所述的数字微流体设备，其中，所述第一密度包括每线性厘米20至200个电极。
15.权利要求13所述的数字微流体设备，其中，所述第二密度包括每线性厘米1至15个电极。
16.权利要求13所述的数字微流体设备，其中，所述设备的对应于所述第一密度的面积小于所述设备的对应于所述第二密度的面积。
17.权利要求16所述的数字微流体设备，其中，所述设备的对应于所述第二密度的面积是所述设备的对应于所述第一密度的面积的至少三倍。
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