CN114509563A - 一种结合微流控技术的巨磁阻传感器及其制造方法与应用 - Google Patents
一种结合微流控技术的巨磁阻传感器及其制造方法与应用 Download PDFInfo
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Abstract
本发明公开一种结合微流控技术的巨磁阻传感器及其制造方法与应用,自上而下包括上盖、光刻胶层和巨磁阻芯片底片,上盖设有流体入口和流体出口,光刻胶层包括第一光刻胶层和第二光刻胶层,第二光刻胶层设置在第一光刻胶层内部,且第一光刻胶层与第二光刻胶层之间形成环形镂空,环形镂空内设有粘胶,第二光刻胶层上设有两个通孔,两个通孔之间连通形成检测区,流体入口和流体出口分别与两个通孔中心对齐且半径相等,巨磁阻芯片底片位于检测区的上表面设有巨磁阻芯片阵列,巨磁阻芯片阵列包括若干巨磁阻芯片,巨磁阻芯片为多层膜结构,且上表面固定待测抗原的捕获抗体。本发明提高了检测灵敏度,且便携性好,更加经济实用,应用前景广泛。
Description
技术领域
本发明属于传感器和生物检测技术领域,具体涉及一种结合微流控技术的巨磁阻传感器及其制造方法与应用。
背景技术
在目前的恶性肿瘤诊断与治疗中通常依赖侵入性的活组织检查和非侵入性的成像手段来追踪肿瘤的大小、扩增以及对治疗的响应。这种方法不仅会给患者带来创伤,价格昂贵,更重要的是不能实现早期诊断。影像学方法通过确定的占位性病变或明显的局部区域结构改变等物理特征来提示诊断。由于受制于空间分辨率,现有影像学方法难以检测微小病灶和实现前瞻性肿瘤防治。生物质谱技术是近年来迅速发展起来的一种鉴定生物大分子的技术。质谱技术在蛋白质组研究中主要用于蛋白质的鉴定,是蛋白质组学研究中的核心技术和重要工具,具有高灵敏度、高准确度、自动化等特点。然而,在多种肿瘤标志物的分子量非常接近的情况,通过质谱仪直接测量全段标志物分子的质量并不能实现可靠的分子识别。此外质谱检测出来的蛋白质还需要传统方法鉴定,小分子量标志物分子的检测难度大、敏感度较低和影响因素较多。常见的免疫生物分子识别方法是光或电生物信号探测。电生物分子识别技术是转换生物识别过程到一个电信号的探测。用荧光分子或荧光纳米晶体标识生物分子,其探测过程是可见的,直接、简单和可见的探测过程是生物分子光标识及探测的最大优点。然而光标识方法探测生物分子有着固有的缺点,测量容易受到背景和杂质影响,而且扫描系统通常体积大、速度慢而且价格昂贵,不能满足社区医疗、农村基层医疗与家庭对重大疾病快速早期诊断和食品安全大规模筛查的需求。半导体量子点(QuantumDot,QD)标记技术是目前备受推崇的生物标识技术,国际上广泛应用于蛋白质及DNA检测、细胞标记成像、活细胞生命动态过程示踪、活体动物体内肿瘤细胞靶向示踪等生物医学领域。由于QD的光学本征特性,QD能实现分子的标记,但难以实现标记和未标记分子的分离,更不能操纵。QD的信号提取同样依赖体积庞大、价格昂贵的光谱仪。这不能满足对大规模重大疾病防疫普查的需求。
物质在一定磁场下电阻改变的现象,称为“磁阻效应”,磁性金属和合金材料一般都有这种磁电阻现象,通常情况下,物质的电阻率在磁场中仅产生轻微的减小;在某种条件下,电阻率减小的幅度相当大,比通常磁性金属与合金材料的磁电阻值约高10余倍,称为“巨磁阻效应”(GMR);而在很强的磁场中某些绝缘体会突然变为导体,称为“超巨磁阻效应”(CMR)。
微流体技术以其便携性、小型化、自动化、多通道样品检测、有害物质的最小处理和成本节约为检测应用提供了强大的工具。与传统方法相比,微流体的最大优势是创建了一个受控的微环境,可以精确地驱动和控制微通道中的微流体流动,从而提高了检测灵敏度。此外,所有分析过程,包括样品制造,反应,分离和检测,都集成到单个微流控芯片中,用于现场测试应用。许多新兴的微流控芯片已经成功开发用于检测食源性病原体。通过结合调谐的微流体阀和实时光学检测,可以通过根据其物理形状和大小捕获和分类细菌来执行病原体分类。
磁性纳米粒子则是近年来发展起来的一种新型材料。超顺磁性、高矫顽力、低居里温度与大范围磁化率是磁性纳米粒子重要的磁学特性。独特的生物相容性、物理和化学稳定性、廉价的生产和安全环保性使磁性纳米粒子特别适合生物分子的标识。磁性纳米粒子分子识别的基本原理,是利用高性能的磁场传感器来测量标记生物分子的磁性纳米粒子在磁化下的边缘场目前用于小磁场测量的传感系统有磁各相异性(AMR)、Hall效应、基于超导量子干涉器件(SQUID)和自旋电子共振(SER)等技术。AMR和Hall效应低的敏感度限制他们在生物分子检测中的应用。虽然SQUID和SER具有高的敏感特性,但SQUID和SER庞大的体积使他们便携性差,且费用高昂。
发明内容
解决的技术问题:针对上述技术问题,本发明提供一种结合微流控技术的巨磁阻传感器及其制造方法与应用,能有效解决上述检测灵敏度低、便携性差和费用高昂等不足之处。
技术方案:一种结合微流控技术的巨磁阻传感器,自上而下包括上盖、光刻胶层和巨磁阻芯片底片,所述上盖设有流体入口和流体出口,所述光刻胶层包括第一光刻胶层和第二光刻胶层,所述第二光刻胶层设置在第一光刻胶层内部,且第一光刻胶层与第二光刻胶层之间形成环形镂空,所述环形镂空内设有粘胶,所述第二光刻胶层上设有两个通孔,两个通孔之间连通形成检测区,所述流体入口和流体出口分别与两个通孔中心对齐且半径相等,所述巨磁阻芯片底片位于检测区的上表面设有巨磁阻芯片阵列,所述巨磁阻芯片阵列包括若干巨磁阻芯片,所述巨磁阻芯片为多层膜结构,且上表面固定待测抗原的捕获抗体。
一种结合微流控技术的巨磁阻传感器的制造方法,包括如下步骤:
S1、采用磁控溅射技术制造巨磁阻芯片多层膜结构,得到晶圆,具体过程为:采用磁控溅射技术在硅晶片上依次沉积Ta、NiFeCr、PtMn、CoFe、Ru、CoFe、纳米氧化物层NOL、CoFe、Cu、CoFe、NiFe、Cu和Ta,且厚度依次为1.5nm、3nm、12nm、1.8nm、0.85nm、1nm、1.3nm、2nm、2.1nm、0.8nm、1.5nm、0.8nm和1.2nm;
S2、在步骤S1制得的晶圆上采用半导体技术制成巨磁阻芯片;
S3、在步骤S2得到的巨磁阻芯片底片上集成微流控通道;
S4、在步骤S2得到的巨磁阻芯片上表面固定待测抗原的捕获抗体。
优选的,步骤S2的具体过程为:在步骤S1制得的晶圆上旋涂光刻胶后,用光刻机曝光掩模来定义条纹传感器的形状,然后在离子刻蚀机中进行干法蚀刻以将图案转移到晶圆上;经过清洗剥离后进行第二次光刻,在晶圆上显影用于定义电极模板的第二个光刻胶剥离掩模;使用电子束蒸发器沉积金层,金剥离再次用光刻胶图案将TiO2层溅射到晶片表面,使用抗蚀剂去除剂实现TiO2剥离,通过等离子体增强化学的气相沉积法把氮化硅层沉积在电极和传感器控制区域,最后再清洗剥离去除光刻胶,制成巨磁阻芯片。
优选的,步骤S3的具体过程为:对二氧化硅基片依次进行清洗烘干、涂底、旋涂光刻胶、软烘、对准曝光、后烘、显影、硬烘、刻蚀、检测后形成光刻胶层,将光刻胶层贴在步骤S2得到的巨磁阻芯片底片上,然后在光刻胶层上粘贴上盖,使得流体入口与流体出口之间形成微流控通道。
进一步的,所述旋涂光刻胶采用负光刻技术。
进一步的,所述微流控通道采用蠕动泵从流体入口向检测区提供反应试剂,所述蠕动泵与流体入口通过管道连接。
优选的,步骤S4采用物理吸附法或共价偶联法固定待测抗原的捕获抗体。
一种结合微流控技术的巨磁阻传感器在癌胚抗原检测中的应用,检测时使用三明治结构,即癌胚抗原CEA被夹在两个抗体之间的捕获检测方法,一抗(或捕获抗体)结合在巨磁阻芯片表面,与生物素功能化的二抗称为检测抗体;随后加入链霉亲和素标记的磁性纳米粒子,通过链霉亲和素与生物素相互作用使磁性纳米粒子与检测抗体结合,组成探针,测定带有CEA的GMR传感器的磁阻环路。
有益效果:本发明提供的一种结合微流控技术的巨磁阻传感器,通过在巨磁阻芯片上表面固定不同待测抗原的捕获抗体,可以实现多种抗原的检测;巨磁阻芯片阵列与微流控的结合,可以有效提高检测灵敏度;采用微流控技术加入样本,大大节约了样本使用量;每个巨磁阻传感器可单独工作,亦可串联或并联进行工作,使用灵活度高;整个巨磁阻传感器体积小,便携性高,可推广和延伸到生物、医学的基础研究、食品安全、病毒检验、环境检测和监测等科学研究和应用领域。
附图说明
图1为一实施例巨磁阻传感器结构示意图;
图2为一实施例巨磁阻传感器原理图;
图3为一实施例中巨磁阻芯片的多层膜结构;
图4为一实施例中巨磁阻芯片光刻图;
图5为一实施例中微流控通道实物设计图;
图6为一实施例中传感器阵列俯视图;
图7为一实施例中癌胚抗原检测结果图;
图中序号:1、上盖,1-1、流体入口,1-2、流体出口,2光刻胶层,2-1、第一光刻胶层,2-2、第二光刻胶层,2-3、环形镂空,2-4、检测区,3、巨磁阻芯片底片,3-1、巨磁阻芯片,4、磁性纳米粒子。
具体实施方式
下面结合附图和具体实施例对本发明作详细说明:
实施例1
如图1和图2所示,一种结合微流控技术的巨磁阻传感器,自上而下包括上盖1、光刻胶层2和巨磁阻芯片底片3,所述上盖1设有流体入口1-1和流体出口1-2,所述光刻胶层2包括第一光刻胶层2-1和第二光刻胶层2-2,所述第二光刻胶层2-2设置在第一光刻胶层2-1内部,且第一光刻胶层2-1与第二光刻胶层2-2之间形成环形镂空2-3,所述环形镂空2-3内设有粘胶,所述第二光刻胶层2-2上设有两个通孔,两个通孔之间连通形成检测区2-4,所述流体入口1-1和流体出口1-2分别与两个通孔中心对齐且半径相等,所述巨磁阻芯片底片3位于检测区2-4的上表面设有巨磁阻芯片阵列,所述巨磁阻芯片阵列包括若干巨磁阻芯片3-1,所述巨磁阻芯片3-1为多层膜结构,且上表面固定待测抗原的捕获抗体。该操作方式与酶联免疫吸附测定法 (ELISA) 类似。首先,把捕获抗体固定在巨磁阻芯片3-1的表面上,待测抗原选择性地与捕获抗体结合,检测是通过引入用外部可观察标签标记的检测抗体来完成。ELISA的标签通常是荧光分子,而GMR生物传感检测依赖于磁性纳米粒子标签,通过高性能传感器检测磁性纳米粒子4的边缘场来实现。
实施例2
一种结合微流控技术的巨磁阻传感器的制造方法,包括以下步骤:
S1、采用磁控溅射技术制造巨磁阻芯片多层膜结构,得到晶圆;
一般使用Ni、Co、Fe等材料或其合金材料作为GMR的磁性层,Cu等非磁性材料作为GMR的非磁性层,如图3所示,采用溅射系统Veeco在硅晶片上依次沉积Ta、NiFeCr、PtMn、CoFe、Ru、CoFe、纳米氧化物层NOL、CoFe、Cu、CoFe、NiFe、Cu和Ta,且厚度依次为1.5nm、3nm、12nm、1.8nm、0.85nm、1nm、1.3nm、2nm、2.1nm、0.8nm、1.5nm、0.8nm和1.2nm;沉积室的真空度为1x10-11Torr,沉积在室温下进行;在所有磁性层的沉积过程中,沿横向施加300Oe的磁场用于硬层(PtMn/CoFe)沉积,对于自由层(顶部CoFe/NiFe层)沿纵向施加10Oe磁场,NOL是由CoFe层上的等离子体辅助氧化形成的;为了提高检测灵敏度,沉积的GMR薄膜进行两次退火,首先在270℃和1000Oe磁场下退火5小时,然后在150℃和500Oe垂直磁场下退火一小时。
S2、步骤S1制得的晶圆上采用半导体技术制成巨磁阻芯片;
在步骤S1制得的晶圆上旋涂光刻胶后,用光刻机曝光掩模来定义条纹传感器的形状,然后在离子刻蚀机中进行干法蚀刻以将图案转移到GMR薄膜上。经过清洗剥离后进行第二次光刻,在晶圆上显影用于定义电极模板的第二个光刻胶剥离掩模。接下来,使用电子束蒸发器沉积200nm金层作为电极,金剥离在丙酮浴中用超声波进行,形成了电极引线,传感器的激活尺寸为150µm×200µm。再次用光刻胶图案将100nm厚的TiO2层溅射到晶片表面,以保护功能传感器区域,使用抗蚀剂去除剂实现TiO2剥离。为了防止电极和传感器被表面生物功能工艺化学物质覆盖,通过等离子体增强化学的气相沉积法(PECVD)把Si3N4层沉积在金电极和传感器控制区域,去除光刻胶后,制造的 GMR 芯片阵列的光学图像如图 4 所示。
S3、在步骤S2得到的巨磁阻芯片底片上集成微流控通道;
通过光刻技术制造微流控通道,对二氧化硅基片依次进行清洗烘干、涂底、旋涂光刻胶、软烘、对准曝光、后烘、显影、硬烘、刻蚀、检测形成光刻胶层,将光刻胶层贴在步骤S2得到的巨磁阻芯片底片上,然后在光刻胶层上粘贴上盖,使得流体入口与流体出口之间形成微流控通道。光刻技术分为正光刻与负光刻,具体区别曝光显影过程不同,正性胶在曝光区间显影,负性胶则相反,负性胶和正性胶边界漫射光形成的轮廓不同。负性胶由于曝光区间得到保留,漫射形成的轮廓使显影后的图象为上宽下窄的图像;而正性胶相反,为下宽上窄的图像,此处采用负光刻技术。结构设计和集成方式如图5和图6所示,图5为微流控通道实物设计图,图6为传感器阵列俯视图,可以根据使用需要求,将多个传感器组成传感器阵列;微流控通道采用蠕动泵从流体入口向检测区提供反应试剂,所述蠕动泵与流体入口通过管道连接。
S4、在步骤S2得到的巨磁阻芯片上表面固定待测抗原的捕获抗体,采用物理吸附或共价偶联的方法。
实施例3
一种结合微流控技术的巨磁阻传感器用于癌胚抗原CEA(CarcinoembryonicAntigen)的检测
首先,选择5个传感器组成传感器检测阵列用于检测CEA,其中CEA浓度为1ng/mL;采用三明治结构,即CEA被夹在两个抗体之间的捕获检测方法。一抗结合在传感器表面(称为捕获抗体),二抗(称为检测抗体)与生物素功能化。随后加入链霉亲和素标记的磁性纳米粒子,通过链霉亲和素与生物素相互作用与检测抗体结合,组成探针。另一组由5个传感器构成传感器检测阵列用牛血清白蛋白(BSA)而不是捕获抗体功能化,形成对照组。使用BSA涂层的目的是阻止磁性粒子停留在对照组以免除对校准传感器的影响。传感区域在链霉亲和素标记纳米粒子后,分别测定了带有CEA和被牛血清白蛋白阻断的GMR传感器的磁阻环路,测量电流为5 mA,采用恒流模式。
为检测磁传感信号与浓度的定性定量关系,我们进行了一系列定量CEA浓度检测。将CEA分析物在PBS缓冲液中稀释,以产生从1ng/mL(摩尔浓度5pM)到1pg mL(摩尔浓度5fM)的大范围分析物浓度梯度。 磁性生物阵列通过一个探针(抗原CEA)和一个对照(BSA)功能化。所施用的5个样品掺染了5fM至500pM的CEA分析物(在传感器上加标),在五个传感器上移液了同一个浓度。将CEA浓度与传感器信号进行线性拟合,得到线性曲线方程y=0.8450x+14.85,相关系数R2=0.9747,如图7所示。在没有任何生物扩增的情况下,CEA的检测下限可达飞摩水平。5毫微摩尔CEA的信号电压为500μV,明显大于BSA阻挡的传感器上15μV的信号。预计这种灵敏度足以从10nL或更低的体液样品中检测所有已知的潜在生物标志物。更重要的是,所施加的CEA量与高达5pM的GMR传感器检测到的磁性信号之间存在剂量-响应的拟线性关系。CEA分析物进一步增加到5pM以上将导致信号饱和。这种线性度的动态范围超过了迄今为止报告的大多数其他基于GMR的检测系统,使得精确定量成为可能。
测试结果表明,基于GMR阵列的生物阵列的检测灵敏度比传统的ELISA(4pM)高出三个数量级。基于磁原理的GMR生物分子分析技术有大量潜在的应用场景和克服目传统的荧光光学检测方法的不足。在临床肿瘤诊断中,监测血液和细胞裂解液中肿瘤标志物分子的动态变化代表着癌症诊断的未来。研究存在广泛浓度范围的整个标记物群的能力,将使临床拥有强有力的早诊手段,和在治愈阶段对治疗效果进行及时诊判,如检测肿瘤对化疗的反应。通过研究化疗前后肿瘤标记物表达谱的变化,可预测肿瘤对特定治疗的反应及抗药性,优化治疗方法和选择更高效的药物。此外,测量方法的高灵敏度、大的线性动态范围和抗干扰能力,将能够在包括尿液和唾液在内的非血清生物体液的生物标志物检测中,获得比血清中低几个数量级,但侵入性更小的效果。磁生物分子检测方法在单个芯片上检测多个生物标志物的能力,结合灵敏度、可扩展性和易用性,使这种蛋白质测定方法成为早期诊断手段的辅助方法。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种结合微流控技术的巨磁阻传感器,其特征在于:自上而下包括上盖(1)、光刻胶层(2)和巨磁阻芯片底片(3),所述上盖(1)设有流体入口(1-1)和流体出口(1-2),所述光刻胶层(2)包括第一光刻胶层(2-1)和第二光刻胶层(2-2),所述第二光刻胶层(2-2)设置在第一光刻胶层(2-1)内部,且第一光刻胶层(2-1)与第二光刻胶层(2-2)之间形成环形镂空(2-3),所述环形镂空(2-3)内设有粘胶,所述第二光刻胶层(2-2)上设有两个通孔,两个通孔之间连通形成检测区(2-4),所述流体入口(1-1)和流体出口(1-2)分别与两个通孔中心对齐且半径相等,所述巨磁阻芯片底片(3)位于检测区(2-4)的上表面设有巨磁阻芯片阵列,所述巨磁阻芯片阵列包括若干巨磁阻芯片(3-1),所述巨磁阻芯片(3-1)为多层膜结构,且上表面固定待测抗原的捕获抗体。
2.一种基于权利要求1所述的结合微流控技术的巨磁阻传感器的制造方法,其特征在于,包括如下步骤:
S1、采用磁控溅射技术制造巨磁阻芯片多层膜结构,得到晶圆,具体过程为:采用磁控溅射技术在硅晶片上依次沉积Ta、NiFeCr、PtMn、CoFe、Ru、CoFe、纳米氧化物层NOL、CoFe、Cu、CoFe、NiFe、Cu和Ta,且厚度依次为1.5nm、3nm、12nm、1.8nm、0.85nm、1nm、1.3nm、2nm、2.1nm、0.8nm、1.5nm、0.8nm和1.2nm;
S2、在步骤S1制得的晶圆上采用半导体技术制成巨磁阻芯片;
S3、在步骤S2得到的巨磁阻芯片底片上集成微流控通道;
S4、在步骤S2得到的巨磁阻芯片上表面固定待测抗原的捕获抗体。
3.根据权利要求2所述的一种结合微流控技术的巨磁阻传感器的制造方法,其特征在于,步骤S2的具体过程为:在步骤S1制得的晶圆上旋涂光刻胶后,用光刻机曝光掩模来定义条纹传感器的形状,然后在离子刻蚀机中进行干法蚀刻以将图案转移到晶圆上;经过清洗剥离后进行第二次光刻,在晶圆上显影用于定义电极模板的第二个光刻胶剥离掩模;使用电子束蒸发器沉积金层,金剥离再次用光刻胶图案将TiO2层溅射到晶片表面,使用抗蚀剂去除剂实现TiO2剥离,通过等离子体增强化学的气相沉积法把氮化硅层沉积在电极和传感器控制区域,最后再清洗剥离去除光刻胶,制成巨磁阻芯片。
4.根据权利要求2所述的一种结合微流控技术的巨磁阻传感器的制造方法,其特征在于,步骤S3的具体过程为:对二氧化硅基片依次进行清洗烘干、涂底、旋涂光刻胶、软烘、对准曝光、后烘、显影、硬烘、刻蚀、检测后形成光刻胶层,将光刻胶层贴在步骤S2得到的巨磁阻芯片底片上,然后在光刻胶层上粘贴上盖,使得流体入口与流体出口之间形成微流控通道。
5.根据权利要求4所述的一种结合微流控技术的巨磁阻传感器的制造方法,其特征在于:所述旋涂光刻胶采用负光刻技术。
6.根据权利要求4所述的一种结合微流控技术的巨磁阻传感器的制造方法,其特征在于:所述微流控通道采用蠕动泵从流体入口向检测区提供反应试剂,所述蠕动泵与流体入口通过管道连接。
7.根据权利要求2所述的一种结合微流控技术的巨磁阻传感器的制造方法,其特征在于,步骤S4采用物理吸附法或共价偶联法固定待测抗原的捕获抗体。
8.一种基于权利要求1所述的结合微流控技术的巨磁阻传感器在癌胚抗原检测中的应用。
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