CN104736470B - 用于制造微载体的方法 - Google Patents
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Abstract
本发明涉及一种用于制造微载体的方法,其包含下列步骤:(a)提供一种具有夹层结构的晶片(6),其包含底层(7),顶层(8)和位于所述的底层和顶层(7,8)之间的绝缘层(9),(b)蚀刻掉顶层(8)以勾画微载体的本体(11)的侧壁(12),(c)至少在本体(11)的上表面(14)上沉积第一活性层(13),(d)将连续的聚合物层(16)涂覆在第一活性层(13)上,(e)蚀刻掉底层(7)和绝缘层(9),(f)去除聚合物层(16)以释放微载体。
Description
技术领域
本发明涉及一种制造微载体的方法以及一种微载体。本发明尤其涉及适用于进行科研与临床实验室中生物和/或化学分析的微载体。
背景技术
本发明的范围内,微载体或微粒子分别指任何类型的微小尺寸的载体或粒子,典型的最大尺寸为100nm至300μm,优选为1μm至200μm。
根据本发明,术语微载体是指一种功能化的,或适于功能化的微粒子,其包含,或适于包含,一种或多种连接在微载体的表面或浸渍入其本体的配体或功能性单元。广谱的化学和生物分子可作为配体与微载体连接。一个微载体可具有多种功能单元和/或配体。此处,术语功能性单元可定义为改性,连接,添加,覆盖,或共价或非共价的连接于所述微载体表面或浸渍入其本体的任意一种功能性单元。这些功能性单元包括在高通过量筛选技术和诊断学中常规使用的所有功能单元。
新药的发现或筛选以及DNA测序通常要涉及对大量化合物或分子的分析。这些分析典型地包括,例如,用于关注的化合物或特殊的目标分子的筛选化学库,或用于所关注的分子间的化学和生物反应的测试。这些分析经常需要进行数以千计的单独的化学和/或生物反应。
操作如此大量的单独反应会引发许多实际问题。其中,最为显著的问题可能是需要标记和追踪每个单独反应。
追踪反应“身份”的一种常规方法是通过在微量滴定板(微阵列)上物理性地分离每个反应来实现。然而,微量滴定板的使用会带来一些缺点例如,尤其是,所使用的微量滴定板尺寸的物理性限制,也因此限制了可在滴定板上进行的不同反应的数量。
考虑到微阵列使用中的限制,现在用功能性编码微粒(Functionalized encodedmicroparticles)有利地替代微阵列来进行化学和/或生物分析。每个功能性编码微粒具有一个编码用以唯一地识别与其表面连接的特定配体。这种功能性编码微粒的使用适用于随机处理,即数以千计的唯一功能性编码微粒可全部混合并同时进行分析。国际专利申请WO00/63695中描述了上述功能性编码微粒的例子并展示在图1中。
国际专利申请WO 2010/072011中描述了一种至少具有可用作反应室的微流体通道的分析设备,在微流体通道内,可填充大量的功能性编码微粒或微载体1(图1)。微流体通道具有可用作过滤器的阻断装置,其在允许包含化学和/或生物试剂的液体溶液流过的同时阻断其中的微载体1。选择所述微流体通道的几何高度和所述微载体1的尺寸使得所述微载体1在每个微流体通道内部典型地以单层排列方式进行排列以防止所述微载体1彼此重叠。
可在其上连接的配体与流经的化学和/或生物试剂之间显示出所关注的有利反应的这些功能性编码微载体1其自身的编码之后被读取,从而导致配体被识别而产生有利反应。
该编码可包含有大量穿越孔2的独特图案,也可包括一种非对称取向标记,例如,L型标记3(如图1所示)或三角形。这种非对称取向标记能够区分微载体1的上表面4和下表面5。
术语微流体通道是指一个封闭的通道,即,用于流体的细长通道,具有微小尺寸的横断面,即横断面的最小直径典型的为约1至500微米,优选为约10至200微米。微流体通道的纵向不一定是直线,其相当于微流体通道内流体流动的方向,即在假定流体为层流态时,优选相当于流体平均流速的矢量方向。
WO 2010/072011中描述的分析设备,所关注反应的测定可基于微流体通道内存在的每个编码微载体1的荧光强度的连续读数,如图2所示。换句话说,分析中存在的目标分子将会触发预定的荧光信号。然而,由于强背景荧光的存在,该预定荧光信号很难被检测。
已知可使用光学层来增加微载体涂层分析中发出的荧光强度以达到可检测的水平。例如,图2显示了通过文献WO 2011/044708中描述的方法获得的一组已涂层的微载体1,其中光学层沉积在微载体1上。
然而,图2中展示的生物分析的结果,显示了由涂层微载体1发出的荧光信号的不同模式。尤其是,一些微载体1a发出了均匀的可检测的荧光信号而另一些微载体1b发出了不完全的或不均匀的荧光信号,微载体1b时常具有新月形状(下文称为“阴影效应”)。此外,一些微载体由于被它们表面的光学层免除而不发出任何可检测荧光。
这些缺陷使得难以在分析中提取到精确的定量信息。
一些微载体1b上光学层的缺失或部分沉积是源于文献WO 2011/044708中所涉及的处理。实际上,这种处理不能在光学层沉积前以及沉积过程中避免一些微载体1之间部分或完全的重叠。这种重叠显示在图3中,其中微载体1的上表面4的区域A将被光学层涂覆,而所述微载体1的上表面4的区域B由于被另一个微载体1’遮盖而无法被所述光学层涂覆。
此外,在WO 2011/044708中描述的处理过程中,一些微载体会在涂层前翻滚因此导致涂层在错误的表面上。
另外,不可能在进行荧光分析前将部分涂层的微载体1b或未涂层的微载体从涂层完好的微载体1a中分离出来。实际上,微载体上光学层的存在只能在荧光分析过程中通过发出的荧光信号识别。
发明内容
本发明的目标在于补救上述全部或部分缺点。
为了这个目标,本发明提供一种用于制造微载体的方法,其包含下列步骤:
(a)提供一种具有夹层结构的晶片,其包含底层,顶层以及位于所述底层和顶层之间的绝缘层,
(b)蚀刻掉顶层以勾画微载体本体的侧壁,
(c)至少在本体的上表面上沉积第一活性层,
(d)将连续聚合物层涂覆在第一活性层上,
(e)蚀刻掉底层和绝缘层,
(f)去除聚合物层以释放微载体。
因此,在根据本发明的方法中,当微载体仍连接在晶片上时完成第一活性层的沉积,以防止发生上述翻滚或重叠现象。第一活性层均匀地沉积在本体的整个上表面上以避免在分析过程中发生上述的“阴影效应”。因此,保持了关于流经微通道的配体和目标分子的精确定量信息的数据完整性。
微载体在释放之前连接在一起,因此避免微载体在用于制造它们的设备的敏感部分例如在涡轮泵中,被分散。
可选地,在上述步骤(a)和(b)之间进行沉积第一活性层的步骤(c)。在一个变化例中,步骤(a)至(f)连续地进行。
根据一种实施方式,步骤(e)通过首次蚀刻和二次蚀刻进行,首次蚀刻在保留绝缘层的同时对底层进行选择性蚀刻,例如通过使用蚀刻槽来完成,以及二次蚀刻用于蚀刻绝缘层,例如通过干蚀刻来完成。
如果底层包含单晶硅,则蚀刻槽可以为氢氧化钾槽。另外,如果绝缘层包含二氧化硅,干蚀刻可通过CHF3(三氟甲烷)的等离子蚀刻或CF4的等离子蚀刻进行。
聚合物层也可通过干蚀刻去除。例如,如果聚合物层包含聚对二甲苯,其可通过氧等离子体进行蚀刻。
另外,例如,在步骤(b)和(c)之间,可将一种区别性标记例如一种编码雕刻在微载体上。
相同的区别性标记可归因于大量的微载体,例如属于相同组别的所有微载体。
因此,在分析的过程中,不同类型的微载体可混合在一起同时使用,每种类型具有自己的区别性标记并且可携带一种或多种配体。在这种情况下,特异性的标记能够在分析中识别每个微载体和其连接的配体的类型。
当在沉积第一活性层(步骤c)之前雕刻该区别性标记时,要选择所述活性层的厚度与所述区别性标记的尺寸以便该区别性标记经由第一活性层是可读取的。
另外,底层和/或顶层可包含单晶硅,绝缘层可包含二氧化硅以及聚合物层可包含聚对二甲苯。根据另一个实施方式,聚合物层是胶层用于将支撑层粘结到晶片上。
通过已知的蚀刻方法例如选择性氢氧化钾槽蚀刻可容易且高效地蚀刻掉单晶硅层。
包含二氧化硅的绝缘层能够在使用蚀刻槽蚀刻底层的同时保护微载体。
聚对二甲苯层是能够在释放前保持微载体的高抗蚀层。
粘结到晶片上的支撑层的使用提供提高的机械性能以利于在制造微载体的过程中对晶片操作。
根据本发明的一个实施方式,例如在步骤(e)和(f)之间,至少在微载体本体的下表面上沉积第二活性层。
通过这种方法制造的微载体包含两个相对的活性层,分别为在本体的上表面上的第一活性层和在本体的下表面上的第二活性层。
第一活性层和/或第二活性层可包含具有光学或磁学特性的材料,多晶硅和/或聚四氟乙烯,或具有高反射率的金属层。
使用具有光学特性的材料将大幅地提高由微载体的相应表面发出的荧光信号。例如,具有磁学特性的材料可用于将微载体定位在希望的方向上。多晶硅的使用增大本体相应表面的孔隙率从而增强所述表面的有效涂层区域。最后,聚四氟乙烯可用于在分析中减少微载体与其所放置的表面之间的摩擦。
第一活性层和/或第二活性层可包含氧化物或氮化物,例如二氧化硅,或金属层。
二氧化硅可用于使本体的相应表面平滑并且增加所述表面上非特异性分子的滑动。因而由连接在所述表面的分子发出的特异性信号被增强而由非特异性分子发出的干扰信号被较大程度地减弱。
本发明也涉及根据本发明的方法获得的微载体,其包含本体,所述本体具有覆盖有第一活性层的上表面和覆盖有第二活性层的下表面。
当本体的上表面和下表面均被包含具有光学特性的材料的活性层(光学层)覆盖时,无论微载体的取向如何均能进行可靠的分析。
附图说明
通过非限制实施例结合附图,本发明和下述说明书中的其他细节、特征和优点可以被更好地理解,其中:
图1:展示了根据现有技术的微载体的顶部透视图;
图2:展示了在分析中观察到的根据现有技术的微载体上的荧光发射量;
图3:展示了根据现有技术的微载体制造方法中在光学层沉积之前一组微载体的顶部透视图;
图4至12:展示了根据本发明的一个实施方式制造微载体的方法的连续步骤;
图13至17:展示了本发明的另一个实施方式
图18:展示了在分析中观察到的根据本发明的微载体上的荧光发射量。
具体实施方式
下文将参考图6至17描述根据本发明来制造微载体的方法。该方法包含下列连续步骤:
第一步,如图4所示,包括提供一种具有夹层结构的晶片6,该晶片6包含底层7,顶层8和位于所述的底层与顶层7,8之间的绝缘层9。
例如,所述晶片6是SOI(在绝缘体上的硅)晶片,其具有直径为100mm、厚度为380μm的底层7,厚度为1μm的绝缘层9和厚度为10μm的顶层8。顶层8和底层7由单晶硅制成,绝缘层9由二氧化硅制成。
第二步,如图5所示,包括在顶层8上涂覆光致抗蚀剂层10。为了勾画微载体的轮廓表面,使用紫外灯经由掩模(图中未显示),例如铬/玻璃掩模照射光致抗蚀剂层10。
掩模中对应于微载体轮廓的开口图案提供了空间选择性紫外照射。抗蚀剂层10上被空间选择性照射的地方发生光引发反应并且开始聚合。然后使用特殊的化学试剂去除未曝光和未反应的抗蚀剂。硬化的抗蚀剂的保留图案勾勒出了微载体的外部形状。
在本文的优选实施方式中,硬化的抗蚀剂的保留图案在微载体的本体11上进一步勾勒了编码例如包括一系列穿越孔的二进制编码,类似于图1中所示的孔2和3。
该光致抗蚀剂层10可以是正性光致抗蚀剂或负性光致抗蚀剂。正性抗蚀剂的一个例子为由Shipley公司提供的MICROPOSIT S 1805PHOTO RESIST而负性抗蚀剂的一个例子为由Gersteltec工程解决方案公司提供的GM1040SU-8PHOTO EPOXY。可通过本领域中已知的不同技术,例如喷涂,或优选旋涂将该光致抗蚀剂层10涂在晶片6上。
第三步,如图6所示,包括蚀刻掉顶层8以勾画微载体的本体11的侧壁12。这可以通过深反应硅蚀刻(DRIE),例如通过基于DRIE(深反应离子蚀刻)的用于深度硅蚀刻的波希法来完成。
波希法公开在文献“J.K.Bhardwaj,H.Ashraf,Proc.SPIE,2639,224(1995);A.Schilp,M.Hausner,M.Puech,N.Launay,H.Karagoezoglu,F.Laermer,在硅微加工制造环境中用于高蚀刻率深反应离子蚀刻的先进蚀刻工具(Advanced etch tool for high etch rate deepreactive ion etching in silicon micromachining production environment),Proceeding MST2001,Dusseldorf”中。深反应离子蚀刻公开在文献“Madou MJ,2002,微加工的基础(Fundamentals of microfabrication),CRC出版社”中。
如图7所示的第四步中,该光致抗蚀剂层10在湿化学池中被去除。因此,它保留了勾画有根据微载体的设计被图案化的一系列本体11的清晰单晶硅层。
第五步,如图8所示,包括在本体11的上表面14上沉积第一活性层13。在沉积过程中,第一活性层13也沉积于在侧壁12之间形成的凹陷部分15的底部。
第一活性层13是具有光学特性的层,例如含二氧化硅的氧化层。当使用红色荧光标记时第一活性层13的厚度约在90至120nm之间。也可使用任何其它的介电材料,例如氮化物或金属层。
可使用不同类型的氧化沉积方法,例如PECVD(等离子体增强化学气相沉积法),蒸发法,或溅射法(Madou MJ,2002,微制造的基础(Fundamentals of microfabrication),CRC出版社)。为了通过PEVCD技术来沉积二氧化硅,典型地,可在几百毫托至几托压强下使用气体如二氯甲硅烷或硅烷与氧气的混合物。在室温至300℃温度范围内进行二氧化硅的沉积。
第六步,如图9所示,包括在第一活性层13上涂聚合物层16,例如聚对二甲苯层或由参考分别由Brewer Science,Microchemical和AllresistPro TEK公司提供的Pro TEK、AZPC 520D或SX AR-PC 5000/40的已知材料制成的层。所述聚合物层16的厚度可为1μm至100μm。该聚合物层例如通过化学气相沉积法(CVD)或旋涂技术涂层。第七步,如图10所示,包括蚀刻掉底层7和绝缘层9。
底层7的蚀刻去除通过研磨底层7的主要部分并通过槽蚀刻法蚀刻底层7的剩余部分来进行,该槽蚀刻法包括将SOI晶片浸渍在氢氧化钾槽中。然后,通过CHF3(三氟甲烷)的等离子体蚀刻或CF4的等离子体蚀刻完全地蚀刻掉绝缘层9。绝缘层的蚀刻率为可控的。为了制造双层微载体,根据本发明的第一实施方式的方法包含第八步,如图11所示,其包括在微载体的本体11的下表面18上沉积第二活性层17。该第二活性层17也具有光学特性,例如含二氧化硅的氧化层。当使用红色荧光标记时第二活性层17的厚度约在90至120nm之间。也可使用任何其它的介电材料,例如氮化物或金属层。
第二活性层17可使用与沉积第一活性层13相同的方法进行沉积。
然后通过例如氧等离子体蚀刻掉聚合物层16用以分离并释放双层微载体19,如图12a所示。该蚀刻率为可控的。通过这种方法获得的微载体19包含本体11,本体11具有在其上表面14上的第一活性层13以及在其下表面18上的第二活性层17。每个活性层13,17均匀且连续地覆盖在本体11的对应表面14,18上。
图13至17展示了根据本发明的方法的另一个实施方式。
在该实施方式中,通过相同的5个步骤获得图8所示的晶片6。
然后,在第六步(图13)中,支撑层21被胶层22覆盖。该支撑层21为例如由硅,石英或玻璃制成的晶片且其厚度为约300至700μm。该胶粘物为例如参考WaferBONDHT10.10或CR200由Brewer科技公司提供的树脂。胶层22的厚度为约10至100μm,优选为约50μm。
在第七步中,如图14所示,支撑层21经由与第一活性层13接触并粘贴在一起的胶层22与晶片6粘结。这种粘结优选通过对晶片6,支撑层21与胶层22加压加热来完成。
在一个变化例中,胶层22被直接涂在第一活性层13上而支撑层21被涂在胶层22上。
第八步,如图15所示,包括蚀刻掉底层7和绝缘层9。该蚀刻步骤与图10中进行的那个类似。
然后可在微载体的本体11的下表面18上沉积第二活性层17(图16)。
然后,通过去除胶层22使支撑层21从晶片6上分离。这种去除可通过加热胶层22或通过使用溶剂来进行。于是,双层微载体19被分离并被释放,如图17所示。
支撑层21提供增强的机械性能以利于在制造微载体的过程中操作晶片6。
如图13所示,在分析过程中,每个微载体19的功能化表面将发出均匀的荧光信号以避免产生上述的“阴影效应”。因此使用这种微载体19能够在分析中提供精确的定量信息。
当在分析过程中难以控制微载体的取向时使用双层微载体19是有效的。
相反地,如果微载体的取向可被控制,则可仅使用活性层13覆盖本体11的上表面14。
为了这个目的,根据本发明方法的另一个实施方式建议在第七步后直接蚀刻掉聚合物层,如图10所示,或与图15中所示的步骤一起直接去除胶层22(为了从晶片6上分离支撑层21)。
在该实施方式中,如图12b所示,只具有一个活性层13的微载体20被释放。该实施方式涉及更简单的方法,能够制造较低廉的微载体20。
在每个实施方式中,在用于分析前,释放的微载体19,20可悬浮地保存在液体箱或容器中。每个微载体19,20优选定型为圆盘形式,其直径在1至200μm之间,例如40μm。
参考本文公开的本发明的说明书和实施例,本发明的其它实施方式对本领域的技术人员来说是显而易见的。说明书和实施例仅被认为是示范性的,本发明的范围和主旨由下文的权利要求指明。
Claims (18)
1.一种用于制造微载体(19,20)的方法,其包含下列步骤:
(a)提供一种具有夹层结构的晶片(6),该晶片(6)包含底层(7),顶层(8)和位于所述的底层和顶层(7,8)之间的绝缘层(9),
(b)蚀刻掉顶层(8)以勾画微载体(19,20)的本体(11)的侧壁(12),
(c)至少在本体(11)的上表面(14)上沉积第一活性层(13),
(d)将连续的聚合物层(16,22)涂覆在第一活性层(13)上,
(e)蚀刻掉底层(7)和绝缘层(9),
(f)去除聚合物层(16,22)以释放微载体(19,20)。
2.如权利要求1所述的方法,其特征在于,步骤(e)通过首次蚀刻和二次蚀刻进行:首次蚀刻用于选择性蚀刻底层(7);二次蚀刻用于选择性蚀刻绝缘层(9)。
3.如权利要求2所述的方法,其特征在于,首次蚀刻通过使用蚀刻槽进行。
4.如权利要求2所述的方法,其特征在于,二次蚀刻通过干蚀刻进行。
5.如权利要求1或2所述的方法,其特征在于,聚合物层(16)通过干蚀刻去除。
6.如权利要求1或2所述的方法,其特征在于,在步骤(b)与(c)之间,将区别性标记刻在微载体(19,20)上。
7.如权利要求6所述的方法,其特征在于,所述区别性标记为编码(2,3)。
8.如权利要求1或2所述的方法,其特征在于,底层(7)和/或顶层(8)包含单晶硅。
9.如权利要求1或2所述的方法,其特征在于,绝缘层(9)包含二氧化硅。
10.如权利要求1或2所述的方法,其特征在于,聚合物层(16)包含聚对二甲苯。
11.如权利要求1或2所述的方法,其特征在于,聚合物层是胶层(22),其将支撑层(21)粘结到晶片(6)上。
12.如权利要求11所述的方法,其特征在于,所述支撑层(21)为由硅、石英或玻璃制成的晶片。
13.如权利要求1或2所述的方法,其特征在于,在步骤(e)与(f)之间,至少在微载体(19)的本体(11)的下表面(18)上沉积第二活性层(17)。
14.如权利要求1或2所述的方法,其特征在于,第一活性层(13)和/或第二活性层(17)包含具有光学或磁学特性的材料,或多晶硅和/或聚四氟乙烯。
15.如权利要求14所述的方法,其特征在于,所述具有光学或磁学特性的材料为具有高反射率的金属层。
16.如权利要求1或2所述的方法,其特征在于,第一活性层(13)和/或第二活性层(17)包含氧化物或氮化物、或金属层。
17.如权利要求16所述的方法,其特征在于,所述氧化物为二氧化硅。
18.通过如权利要求13所述的方法获得的微载体(19),其包含具有顶面(14)和底面(18)的本体(11),顶面(14)上覆盖有第一活性层(13),底面(18)上覆盖有第二活性层(17)。
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EP12177718.9A EP2690059A1 (en) | 2012-07-24 | 2012-07-24 | Method for producing microcarriers |
EP12177718.9 | 2012-07-24 | ||
PCT/EP2013/065442 WO2014016262A1 (en) | 2012-07-24 | 2013-07-22 | Method for producing microcarriers |
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RU (1) | RU2631526C2 (zh) |
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EP2690058A1 (en) * | 2012-07-24 | 2014-01-29 | Biocartis SA | Method for producing microcarriers and for performing biological assays |
US9978644B1 (en) * | 2016-09-07 | 2018-05-22 | Amkor Technology, Inc. | Semiconductor device and manufacturing method |
KR102348180B1 (ko) | 2019-02-19 | 2022-01-07 | 전남대학교산학협력단 | 색전술용 마이크로캐리어 및 그 제조방법 |
CN110484129B (zh) * | 2019-07-02 | 2022-01-25 | 昆山联滔电子有限公司 | 带有防护涂层的产品及其制备方法 |
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JP6277188B2 (ja) | 2018-02-07 |
US9349545B2 (en) | 2016-05-24 |
KR20150040939A (ko) | 2015-04-15 |
IN2015DN00439A (zh) | 2015-06-19 |
EP2690059A1 (en) | 2014-01-29 |
BR112015001463A2 (pt) | 2017-07-04 |
AU2013295081A1 (en) | 2015-02-05 |
EP2877423A1 (en) | 2015-06-03 |
RU2631526C2 (ru) | 2017-09-25 |
ES2787857T3 (es) | 2020-10-19 |
CN104736470A (zh) | 2015-06-24 |
RU2015101761A (ru) | 2016-08-10 |
US20150162141A1 (en) | 2015-06-11 |
AU2013295081B2 (en) | 2016-10-06 |
JP2015531691A (ja) | 2015-11-05 |
CA2879150C (en) | 2020-07-14 |
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ZA201500438B (en) | 2017-11-29 |
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