CN1331575C - Implementation of Microfluidic Components in Microfluidic Systems - Google Patents
Implementation of Microfluidic Components in Microfluidic Systems Download PDFInfo
- Publication number
- CN1331575C CN1331575C CNB038249804A CN03824980A CN1331575C CN 1331575 C CN1331575 C CN 1331575C CN B038249804 A CNB038249804 A CN B038249804A CN 03824980 A CN03824980 A CN 03824980A CN 1331575 C CN1331575 C CN 1331575C
- Authority
- CN
- China
- Prior art keywords
- substrate
- flow path
- chamber
- microfluidic
- microchannel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Automatic Analysis And Handling Materials Therefor (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
Description
本申请要求享有于2002年12月23日提交的美国专利申请No.10/329018、于2002年9月9日提交的美国临时专利申请No.60/409489以及于2002年9月13日提交的美国临时专利申请No.60/410685的优先权,这些申请的内容通过引用结合于本文中。This application claims the benefit of U.S. Patent Application No. 10/329018, filed December 23, 2002, U.S. Provisional Patent Application No. 60/409489, filed September 9, 2002, and Priority to US Provisional Patent Application No. 60/410685, the contents of which are incorporated herein by reference.
技术领域technical field
本发明涉及一种用于在微射流级下处理流体样品的微射流系统。更具体地说,本发明涉及一种用于在微射流系统中实现微射流功能的系统和方法。The invention relates to a microfluidic system for processing fluid samples at the microfluidic level. More specifically, the present invention relates to a system and method for implementing microfluidic functions in a microfluidic system.
背景技术Background technique
微射流器件和系统提供了执行化学、生物化学和生物学分析和合成的改进的方法。微射流器件和系统允许在芯片基微化学分析系统中执行多步骤、多类型的化学操作。芯片基微射流系统通常包括传统的“微射流”元件,其尤其能够处理和分析化学和生物学样本。通常来说,本领域中的用语“微射流”是指具有通过通道相连的处理节点、腔室和储槽的网络的系统或器件,其中这些通道的典型截面尺寸处于约1.0微米到约500微米的范围内。在本领域中,具有这些截面尺寸的通道称为“微通道”。Microfluidic devices and systems provide improved methods of performing chemical, biochemical, and biological analysis and synthesis. Microfluidic devices and systems allow multi-step, multi-type chemical manipulations to be performed in chip-based microchemical analysis systems. Chip-based microfluidic systems generally include conventional "microfluidic" elements, which are especially capable of processing and analyzing chemical and biological samples. Generally, the term "microfluidic" is used in the art to refer to a system or device having a network of process nodes, chambers, and reservoirs connected by channels, wherein the channels typically have cross-sectional dimensions ranging from about 1.0 microns to about 500 microns In the range. Channels with these cross-sectional dimensions are known in the art as "microchannels".
在化学、生物医学、生物科学和制药行业中,以高度并行的方式执行大量的化学操作如反应、分离和后续检测步骤已经变得是迫切需要的。(生物)化合物的高产量的合成、筛选和分析使得能够经济地发现新的药物和候选药物,并且能实现复杂的医疗诊断设备。对于在这些应用中所需的化学操作的改进而言,重要的是提高速度,增强可再现性,降低昂贵样品和试剂的消耗,并且减少材料的浪费。In the chemical, biomedical, bioscience, and pharmaceutical industries, it has become imperative to perform a large number of chemical operations such as reactions, separations, and subsequent detection steps in a highly parallel manner. High-throughput synthesis, screening, and analysis of (bio)compounds enable the economical discovery of new drugs and drug candidates, and enable the realization of sophisticated medical diagnostic devices. Important to the improvement of the chemical manipulations required in these applications is increased speed, enhanced reproducibility, reduced consumption of expensive samples and reagents, and reduced waste of materials.
在生物技术尤其是细胞学和药品筛选的领域中,需要有高产量的粒子过滤。需要过滤的粒子的例子有各类细胞,例如血小板、白血球、肿瘤细胞和胚细胞等。在细胞学的领域中这些粒子尤其引人关注。其它粒子有(大)分子种类,例如蛋白质、酶和多聚核苷酸。在新药开发期间的药物筛选的领域中,这类粒子尤其引人关注。In the fields of biotechnology, especially cytology and drug screening, high throughput particle filtration is required. Examples of particles that need to be filtered are various types of cells, such as platelets, white blood cells, tumor cells, and blast cells. These particles are of particular interest in the field of cytology. Other particles are (macro)molecular species such as proteins, enzymes and polynucleotides. Such particles are of particular interest in the field of drug screening during the development of new drugs.
发明内容Contents of the invention
本发明提供了一种用于将微射流部件集成到微射流系统中以便使微射流系统可执行选定的微射流功能的系统和方法。本发明使用了包括有可执行微射流功能的微射流元件的封盖模块。该封盖模块堆叠在具有微射流管道的微射流衬底上,以便将微射流功能集成到系统中。The present invention provides a system and method for integrating microfluidic components into a microfluidic system so that the microfluidic system can perform selected microfluidic functions. The present invention uses a capping module comprising a microfluidic element capable of performing a microfluidic function. The capping module is stacked on a microfluidic substrate with microfluidic conduits to integrate microfluidic functionality into the system.
根据本发明的第一方面,提供了一种微射流系统,包括:形成于衬底中的第一微通道;将第一微通道与衬底表面相连的第一连通端口;形成于衬底中的第二微通道;形成于衬底中的第三微通道;以及封盖模块,其具有形成于其中的凹槽,以及覆盖了凹槽以便形成腔的用于通过尺寸排斥来分离物质的半渗透性薄膜,该薄膜形成了所述腔的壁,封盖模块包括形成于其中的通到腔的入口和通到腔的出口,其中封盖模块可堆叠在衬底上,使得腔的入口设置成与第一微通道连通,腔的出口设置成与第二微通道连通,并且薄膜设置成与第三微通道连通,这样,经过薄膜的滤液进入到第三微通道中,从而将微射流过滤功能引入到微射流系统中。According to a first aspect of the present invention, a microfluidic system is provided, comprising: a first microchannel formed in a substrate; a first communication port connecting the first microchannel with the surface of the substrate; a second microchannel; a third microchannel formed in the substrate; and a capping module having a groove formed therein, and a semi-conductor for separating substances by size exclusion that covers the groove to form a cavity. a permeable membrane forming a wall of the chamber, a capping module comprising an inlet to the chamber and an outlet to the chamber formed therein, wherein the capping module is stackable on the substrate such that the inlet to the chamber is disposed To communicate with the first microchannel, the outlet of the chamber is set to communicate with the second microchannel, and the membrane is set to communicate with the third microchannel, so that the filtrate through the membrane enters into the third microchannel, thereby filtering the microjet Functionality introduced into the microfluidic system.
根据本发明的第二方面,提供了一种用于微射流系统的封盖模块,包括:衬底,其具有形成于衬底表面中的凹槽;设于衬底上的用于通过尺寸排斥来进行物质过滤的半渗透性薄膜,该薄膜覆盖了凹槽以便形成腔;形成于衬底中的通到所述腔的入口;形成于衬底中的源于所述腔的出口;其中,封盖模块可堆叠在其中形成有微通道的微射流系统上,使得所述腔设置成经由入口与微通道连通,从而将过滤功能引入到微射流系统中。According to a second aspect of the present invention, there is provided a capping module for a microfluidic system, comprising: a substrate having a groove formed in the surface of the substrate; A semi-permeable membrane for material filtration, the membrane covering the groove to form a cavity; an inlet to the cavity formed in the substrate; an outlet from the cavity formed in the substrate; wherein, The capping module may be stacked on the microfluidic system in which the microchannel is formed, such that the cavity is arranged to communicate with the microchannel via the inlet, thereby introducing a filtering function into the microfluidic system.
根据本发明的第三方面,提供了一种微射流系统,包括:具有多个形成于其中的微通道的衬底,其中各微通道包括一个或多个用于将微通道与衬底表面相连的连通端口;多个微射流封盖模块,各模块具有设置在凹槽上以便在相应的封盖模块内形成腔的用于执行微射流过滤功能的半渗透性薄膜、通到所述腔的入口以及通到所述腔的出口;其中,微射流封盖模块中的第一个堆叠在衬底上,并通过与一个或多个微通道相关联的连通端口而使第一个微射流封盖模块的入口和出口中之一与所述一个或多个微通道流体式连通,从而将第一微射流过滤功能结合到系统中,微射流封盖模块中的第二个堆叠在所述衬底上,并通过与另外一个或多个微通道相关联的连通端口而使第二个微射流封盖模块的入口和出口中之一与所述另外一个或多个微通道流体式连通,从而将第二微射流过滤功能结合到系统中。According to a third aspect of the present invention, there is provided a microfluidic system, comprising: a substrate having a plurality of microchannels formed therein, wherein each microchannel includes one or more a plurality of micro-fluidic capping modules, each module has a semi-permeable membrane for performing a micro-fluidic filtering function that is arranged on a groove so as to form a cavity in the corresponding capping module, a port leading to the cavity an inlet and an outlet leading to the cavity; wherein a first of the microfluidic capping modules is stacked on the substrate, and the first microfluidic capping module is enabled through communication ports associated with one or more microchannels. One of the inlet and outlet of the capping module is in fluid communication with the one or more microchannels, thereby incorporating a first microfluidic filtration function into the system, a second of the microfluidic capping modules stacked on the liner and one of the inlet and outlet of the second microfluidic capping module is in fluid communication with the other one or more microchannels through a communication port associated with the other one or more microchannels, thereby Incorporate a second microfluidic filtration function into the system.
根据本发明的第四方面,提供了一种微射流系统中的微制造的过滤系统,包括:封盖模块,其包括用于将物质分离成第一和第二组分的薄膜;用于传送物质通过微射流系统的第一流动路径,其中在封盖模块堆叠在衬底上时,封盖模块与第一流动路径相交;第一储槽,其形成于封盖模块中并处于薄膜之上,具有用于接受所述物质的与第一流动路径连通的入口,以及用于将第一组分从第一储槽中传送出来的与第一流动路径连通的出口;第二储槽,其形成于衬底中并用于接受所述物质的第二组分;用于接受所述物质的第二组分的与第二储槽流体式连通的第二流动路径;以及用于诱发物质流动的与第一流动路径连通的第一流体源,其中封盖模块堆叠在衬底上,使得第一储槽与第二储槽连通,并通过薄膜与第二储槽分隔开,沿着第一流动路径传送的物质被分成第一组分和第二组分,其中第一组分沿着第一流动路径流经第一储槽,而第二组分沿着第二流动路径流经薄膜。According to a fourth aspect of the present invention there is provided a microfabricated filtration system in a microfluidic system comprising: a capping module comprising a membrane for separating a substance into first and second components; a first flow path of a substance through the microfluidic system, wherein the capping module intersects the first flow path when the capping module is stacked on the substrate; a first reservoir formed in the capping module above the membrane , having an inlet in communication with the first flow path for receiving the substance, and an outlet in communication with the first flow path for delivering the first component out of the first storage tank; a second storage tank, which formed in the substrate for receiving a second component of the substance; a second flow path for receiving the second component of the substance in fluid communication with a second reservoir; and for inducing flow of the substance a first fluid source in communication with the first flow path, wherein the capping module is stacked on the substrate such that the first reservoir communicates with the second reservoir and is separated from the second reservoir by the membrane, along the first The substance conveyed by the flow path is divided into a first component and a second component, wherein the first component flows along the first flow path through the first reservoir and the second component flows along the second flow path through the membrane.
根据本发明的第五方面,提供了一种微射流系统中的微制造的过滤系统,包括:衬底;位于衬底中的用于传送物质的第一流动路径;形成于衬底中的用于接受和传送物质的滤后组分的第二流动路径;形成于衬底中并与第二流动路径连通的凹槽;限定了保留物腔的盖子,该盖子堆叠在衬底上,使得保留物腔设置成与第一流动路径连通;固定在盖子上以覆盖了保留物腔的薄膜,其中该薄膜的尺寸制成为可将所述物质分离成滤后组分和保留组分,并且在盖子堆叠在衬底上时设置在凹槽之上,从而限定了处于薄膜下方的过滤腔,这样便可通过薄膜将第二流动路径设置在第一流动路径的附近并与之分隔开;形成于衬底中并与保留物腔连通的第三流动路径,用于接受和传送来自保留物腔中的所述物质的保留组分。According to a fifth aspect of the present invention, there is provided a microfabricated filtration system in a microfluidic system, comprising: a substrate; a first flow path for transporting substances located in the substrate; A second flow path for receiving and delivering the filtered component of the substance; a groove formed in the substrate and communicating with the second flow path; a cover defining a retentate cavity stacked on the substrate so that the retentate The material chamber is arranged to communicate with the first flow path; the membrane fixed on the lid to cover the retentate chamber, wherein the membrane is sized to separate the material into a filtered component and a retained component, and is fixed on the lid When stacked on the substrate, it is arranged above the groove, thereby defining a filter cavity under the membrane, so that the second flow path can be arranged adjacent to and separated from the first flow path by the membrane; formed in A third flow path in the substrate and in communication with the retentate chamber for receiving and delivering retained components of said species from the retentate chamber.
根据一个方面,本发明提供了一种微射流芯片中的微过滤系统,其用于将经过毛细尺寸的封闭通道系统的物质如化合物分离成不同的组分。本发明的过滤系统提供了过滤模块,其可以较低的成本来装配,同时能提供每单位时间过滤较大量化合物的精确手段。微过滤系统将传统的薄膜过滤技术集成到由玻璃、塑料或其它适当材料形成的微射流系统中。微制造的过滤系统可包括设计用于插入到标准的微射流系统中以提供片上过滤的子系统。一个示例性的过滤系统包括被薄膜分隔开的两条流动路径,薄膜通过尺寸判定分离出了流经第一流动路径的物质。在薄膜的两侧形成有与流动路径相通的储槽。在薄膜上连接了微制造的盖子,从而限定了薄膜上方的储槽。According to one aspect, the present invention provides a microfiltration system in a microfluidic chip for separating substances such as compounds passing through a capillary-sized closed channel system into different components. The filtration system of the present invention provides filtration modules that can be assembled at relatively low cost while providing an accurate means of filtering relatively large quantities of compounds per unit of time. Microfiltration systems integrate conventional membrane filtration technology into microfluidic systems formed from glass, plastic or other suitable materials. Microfabricated filtration systems may include subsystems designed to be inserted into standard microfluidic systems to provide on-chip filtration. An exemplary filtration system includes two flow paths separated by a membrane that size separates material flowing through the first flow path. A reservoir communicating with the flow path is formed on both sides of the membrane. A microfabricated lid is attached to the membrane, defining a reservoir above the membrane.
根据另一方面,可采用其中形成有电磁阀部件的封盖结构来将电磁阀集成到微射流系统中。电磁阀部件包括用于选择性地阻挡经过衬底中的一个或多个连通端口的流动的薄膜,以及用于控制薄膜位置的促动组件。According to another aspect, the solenoid valve may be integrated into the microfluidic system using a cover structure in which the solenoid valve component is formed. The solenoid valve assembly includes a membrane for selectively blocking flow through one or more communication ports in the substrate, and an actuation assembly for controlling the position of the membrane.
附图说明Description of drawings
图1显示了微射流系统,其包括有用于将微射流功能集成到微射流系统中的封盖结构。Figure 1 shows a microfluidic system including a cap structure for integrating microfluidic functionality into the microfluidic system.
图2显示了适用于包括有根据本发明一个示例性实施例的微过滤系统的诊断微射流芯片。Figure 2 shows a diagnostic microfluidic chip suitable for use with a microfiltration system according to an exemplary embodiment of the present invention.
图3是根据本发明一个示例性实施例的图2所示芯片中的微过滤系统的透视截面图。3 is a perspective cross-sectional view of a microfiltration system in the chip shown in FIG. 2 according to an exemplary embodiment of the present invention.
图4是图3所示微过滤系统上的薄膜的详细视图。FIG. 4 is a detailed view of a membrane on the microfiltration system shown in FIG. 3. FIG.
图5显示了图3所示微过滤系统的微制造的盖子。FIG. 5 shows the microfabricated cover of the microfiltration system shown in FIG. 3 .
图6是图3所示微过滤系统的顶视图。FIG. 6 is a top view of the microfiltration system shown in FIG. 3 .
图7是在装配微过滤系统之前的图2所示诊断芯片的顶视图。Figure 7 is a top view of the diagnostic chip shown in Figure 2 prior to assembly of the microfiltration system.
图8是在装配微过滤系统之后的图2所示诊断芯片的顶视图。Figure 8 is a top view of the diagnostic chip shown in Figure 2 after assembly of the microfiltration system.
图9a是根据本发明一个备选实施例的两端口式直接微过滤系统的顶视图。Figure 9a is a top view of a two-port direct microfiltration system according to an alternative embodiment of the present invention.
图9b是图9a所示微过滤系统的透视截面图。Figure 9b is a perspective cross-sectional view of the microfiltration system shown in Figure 9a.
图10a是根据本发明一个备选实施例的三端口式直接微过滤系统的顶视图。Figure 10a is a top view of a three-port direct microfiltration system according to an alternative embodiment of the present invention.
图10b是图10a所示微过滤系统的透视截面图,其中微制造的盖子被取下。Figure 10b is a perspective cross-sectional view of the microfiltration system shown in Figure 10a with the microfabricated cover removed.
图11显示了根据本发明一个实施例的结合到微射流系统中的电磁阀。Figure 11 shows a solenoid valve incorporated into a microfluidic system according to one embodiment of the present invention.
具体实施方式Detailed ways
本发明提供了一种用于允许对样品进行片上过滤、净化或分离的微制造的过滤系统。微制造的过滤系统可用在许多种应用中,包括但不限于血液分离和过滤、微量渗析、需要过滤或渗析子系统的微化学分析和合成应用,以及其它微射流应用。在下文中将针对一个示例性实施例来描述本发明。本领域的技术人员可以理解,本发明可在多种不同的应用和实施例中实施,并且不能将其应用具体地限制在本文所述的特定实施例中。The present invention provides a microfabricated filtration system for allowing on-chip filtration, purification or separation of samples. Microfabricated filtration systems can be used in a variety of applications including, but not limited to, blood separation and filtration, microdialysis, microchemical analysis and synthesis applications requiring filtration or dialysis subsystems, and other microfluidic applications. Hereinafter, the invention will be described with respect to an exemplary embodiment. Those skilled in the art will appreciate that the present invention may be practiced in many different applications and embodiments and is not specifically limited in application to the specific embodiments described herein.
本文所使用的用语“微射流的”指一种用于装卸、处理、喷出和/或分析流体样品的包括有至少一个具有微量尺寸的通道的系统或器件。As used herein, the term "microfluidic" refers to a system or device for handling, processing, ejecting and/or analyzing a fluid sample that includes at least one channel having microscale dimensions.
本文所使用的用语“通道”和“流动通道”指一种形成或贯穿于介质中并允许流体如液体和气体运动的路径。微射流系统中的通道优选具有处于约1.0微米到约500微米范围内的截面尺寸,其更理想地处于约25微米到约250微米的范围内,最好处于约50微米到约150微米的范围内。本领域的普通技术人员具备确定流动通道的合适体积和长度的能力。这些范围包括上述值作为上限或下限。流动通道可具有任何选定的形状或设置,它们的例子包括线性或非线性的构造,以及U形构造。As used herein, the terms "channel" and "flow channel" refer to a path formed in or through a medium that allows the movement of fluids, such as liquids and gases. The channels in the microfluidic system preferably have cross-sectional dimensions in the range of about 1.0 microns to about 500 microns, more desirably in the range of about 25 microns to about 250 microns, most preferably in the range of about 50 microns to about 150 microns Inside. Those of ordinary skill in the art are well within the ability to determine the appropriate volume and length of the flow channel. These ranges include the above values as upper or lower limits. The flow channels may have any chosen shape or arrangement, examples of which include linear or non-linear configurations, and U-shaped configurations.
本文所使用的用语“微射流元件”指用于执行微射流功能的微射流系统中的部件,其包括但不限于:被动止回阀、主动阀、压力传感器、连接通道、薄膜过滤单元、用于外部连接管的螺纹塞、压缩腔、泵,以及本领域的普通技术人员已知的其它部件。As used herein, the term "microfluidic element" refers to components in a microfluidic system used to perform microfluidic functions, including but not limited to: passive check valves, active valves, pressure sensors, connecting channels, membrane filtration units, Threaded plugs for externally connected tubing, compression chambers, pumps, and other components known to those of ordinary skill in the art.
本文所使用的用语“薄膜”或“过滤器”指可用来通过尺寸排除或其它措施来分离或过滤物质的任何适当成分和大小的材料。As used herein, the terms "membrane" or "filter" refer to any material of suitable composition and size that can be used to separate or filter matter by size exclusion or other means.
本文所使用的用语“衬底”指其中形成有用来传送流体的通道的支撑结构。As used herein, the term "substrate" refers to a support structure in which channels are formed for conveying fluids.
本文所使用的用语“盖子”或“封盖模块”指一种具有与衬底相同大小或稍小一些的尺寸、具有由任何选定材料形成的任何选定尺寸或形状并且具有微射流元件的结构。封盖模块构造成堆叠在衬底上或可与之通信,从而完全地或部分地完成流体路径。As used herein, the term "lid" or "capping module" refers to a device of the same size or slightly smaller than the substrate, of any selected size or shape formed of any selected material, and having microfluidic elements. structure. The capping module is configured to be stacked on or in communication with the substrate to complete or partially complete the fluidic pathway.
本文所使用的用语“物质”指用在微射流工艺中的任何材料,包括但不限于化合物、分子、病毒、细胞、粒子、珠粒、缓冲剂,或者任何其它可用在微射流工艺中的材料。As used herein, the term "substance" refers to any material used in microfluidic processes, including but not limited to compounds, molecules, viruses, cells, particles, beads, buffers, or any other material that can be used in microfluidic processes .
本文所使用的用语“微射流功能”指对微射流系统中的流体或样品执行或施加的任何操作、功能或工艺,包括但不限于:过滤、渗析、泵送、流体流动调节、控制流体流量等。As used herein, the term "microfluidic function" refers to any operation, function or process performed or applied to a fluid or sample in a microfluidic system, including but not limited to: filtration, dialysis, pumping, fluid flow regulation, controlling fluid flow wait.
本文所使用的用语“端口”指可在两个元件之间提供流体连通的结构。As used herein, the term "port" refers to a structure that can provide fluid communication between two elements.
本文所使用的用语“泵”指用于吸入和排出流体的装置,其可具有不同的尺寸,包括微量尺寸,这里称为“微泵”。As used herein, the term "pump" refers to a device for drawing and expelling fluid, which may be of various sizes, including microscale sizes, referred to herein as a "micropump".
本发明允许采用具有可执行微射流功能的微射流元件的封盖模块来将不同的微射流功能实现在微射流芯片中。如图1所示,适于实现本发明一个实施例的微射流芯片10包括衬底11,其具有一个或多个设于其中的显示为微通道的流动通道3。流动通道可传送流体经过微射流系统10,以便对流体样品进行处理、装卸和/或执行任何其它合适的操作。微射流系统10可包括任何适当数量的用来传送流体经过微射流系统10的流动通道3。The present invention allows different microfluidic functions to be implemented in a microfluidic chip by using a capping module with microfluidic elements capable of performing microfluidic functions. As shown in FIG. 1, a
如图1所示,流动通道3形成于衬底11中,并可经由一个或多个连通端口13a,13b与衬底表面相连。在衬底11上设有封盖模块15以形成封闭的流体路径,该封盖模块包括用于执行微射流功能的微射流元件18,例如过滤器、一个或多个阀、压力传感器或其它部件。根据一个备选实施例,封盖模块可包括用于再次引导流体流经另一结构周围的微通道的连接通道。该示例性衬底11包括两个连通端口13a,13b,各端口将流动通道3的不相连部分3a,3b与衬底表面相连,然而本领域的技术人员可以认识到,可在连通端口和流动通道的大小、数量和结构方面进行修改。As shown in FIG. 1 , the
该示例性封盖模块15可包括与衬底的连通端口交界的连接端口,和/或用来在第一连接端口和第二连接端口之间提供射流路径的腔12或通道。本领域的技术人员可以认识到,封盖模块可具有其它的结构,并不限于图1所示的实施例。The
采用封盖模块15就可将例如过滤、渗析、泵送、流动控制等微射流功能集成到微射流系统10中,不需要对衬底11进行显著的改进。包括有任何数量或设置的用来传送流体的导管或通道3的衬底可变换成功能性射流回路,这是通过选择一个或多个带有功能性微射流元件18的封盖模块15并将其设置在衬底即芯片上来实现的。根据一个示例性实施例,可采用与用来制造集成电路的相同的自动化“拾放(pick and place)”表面安装设备技术并利用各种封盖结构来在具有微通道的衬底上形成射流回路。适当的拾放设备例如可以由Manncorp,Inc.(Huntingdon Valley,PA)制造。Microfluidic functions such as filtration, dialysis, pumping, flow control, etc. can be integrated into the
为了制造射流回路,衬底11中的通道3可由芯片微制造技术来制造。通道或管道可这样来制出,即在第一衬底中蚀刻出半通道,然后粘合和/或层压第二衬底以封闭这些半通道,从而形成微通道。如果需要更复杂的射流网络的话,衬底可由含有蚀刻通道的一层或多层形成。然后可在衬底中制出连通端口,以便将微通道与衬底的外表面相连。用于制造连通端口的适当技术包括钻孔、激光蚀刻、粉末爆破或本领域中已知的其它技术。在制造了衬底和连通端口之后,将具有所需功能性的封盖模块粘合到衬底上,形成较大微射流回路中的微射流部件。To manufacture the fluidic circuit, the
可将不同数量和尺寸的封盖模块粘合到衬底上,以便施加各种微射流功能而形成微射流系统。封盖模块可被取下和更换,以便能够重新使用衬底。Capping modules of different numbers and sizes can be bonded to the substrate in order to apply various microfluidic functions to form a microfluidic system. The capping module can be removed and replaced to enable reuse of the substrate.
根据一个示例性实施例,封盖模块具有处于约1毫米到约5厘米之间的截面尺寸,然而本领域的技术人员可以认识到,本发明并不限于这一范围。封盖模块可由任何适当的材料形成,包括但不限于塑料、玻璃、硅和本领域已知的其它材料。According to an exemplary embodiment, the capping module has a cross-sectional dimension between about 1 millimeter and about 5 centimeters, although those skilled in the art will recognize that the present invention is not limited in this scope. The lid module may be formed from any suitable material including, but not limited to, plastic, glass, silicon, and others known in the art.
图2显示了可根据本发明的内容而制出的一个示例性微射流诊断芯片的体系结构。诊断芯片20可包括一个或多个微射流部件,其可单独地或组合起来地构造成能够促进样品的处理。例如如图所示,诊断芯片20包括微过滤系统100,其可分离溶液中的物质,例如从细胞或悬浮液中分离出选定的粒子或其它粒子。诊断芯片20还可包括一个或多个用于存储和供应样品、试剂或其它化合物给系统的储槽90,以及一个或多个用于聚集样品废液的废液储槽91。诊断芯片还可包括一个或多个测定用量、混合和培育部件,例如片上样品稀释系统,其用于处理样品,例如执行特定量样品和试剂的混合。例如该示例性系统包括混合部件60和培育区域61。芯片还可包括用于分析来自微过滤系统100中的滤后物的检测器70。检测器70可利用任何适当的检测手段,包括但不限于荧光、电化学分析、介电电泳、表面血浆共振(SPR)、射频、热分析及其组合。芯片10可采用用来选择性控制经过通道的流体流量的阀,以及一个或多个设置在芯片上或芯片外的用来驱动流体运动经过芯片上的通道3的驱动单元。本领域的技术人员可以认识到,微射流系统并不限于图2所示的诊断芯片,根据本发明,可以对各种微射流部件的结构、位置、数量和组合进行修改。Figure 2 shows the architecture of an exemplary microfluidic diagnostic chip that can be fabricated in accordance with the teachings of the present invention.
本发明的微过滤系统100利用封盖模块将传统的薄膜过滤技术集成到微射流芯片中。过滤系统可插入到现有的微射流芯片中,以便对悬浮液中的粒子、细胞或其它物质进行过滤,不需要对芯片结构进行显著的或成本昂贵的改进。The
图3、4和6显示了根据本发明一个实施例的适用于实现在图2所示微射流系统中的微制造的过滤子系统100。图5显示了用来制造根据本发明一个实施例的过滤系统100的封盖模块15。过滤子系统用来通过薄膜110分离物质,例如包含有粒子和流体的混合物的样品,并之后收集被分离出来的组分。根据一个示例性实施例,采用过滤子系统来从血浆中分离血细胞,然而本领域的技术人员可以认识到,本发明还包括有其它应用。根据其它的应用,可采用该过滤系统来从细胞中分离病毒,从细胞中分离珠粒,以及分离化合物、分子或其它可用薄膜来分离的物质。如图所示,过滤子系统100直接形成在微射流芯片上,从而为芯片增添了过滤性能,而不要求进行显著的或成本昂贵的改进。Figures 3, 4 and 6 illustrate a
过滤子系统100利用传统的薄膜过滤器110来在衬底11中分离出两个流动路径,以便提供样品的微小体积控制过滤。该示例性过滤系统是四端口式横向过滤器,其包括用来向过滤系统提供物质、例如粒子和流体的混合物的第一流体流动路径120,以及用来接受和传送来自过滤系统的滤后物(即滤液)的第二流体流动路径130。第一流体流动路径120包括第一连通端口,其显示为在第一入口121a处与过滤系统相交的第一入口通道121。第一流体流动路径120包括第二连通端口,其显示为第一出口通道122,它包括源于过滤腔的出口122a,用来接受和传送来自过滤系统的保留物质。第二流体流动路径包括在第二入口处与薄膜110下方的过滤腔相交的入口通道131,以及用来传送来自过滤系统的滤后物的第二出口通道132。第二流体流动路径130可包括用来传送滤后物的载流流体。流体源驱动混合物流经过滤系统,以实现经过薄膜的组分分离。流体源可包括芯片外部的注射泵、微制造的蠕动泵、微制造的注射器,或者本领域已知的任何适当的流体源,例如在题为“微射流系统和部件”的美国临时专利申请No.60/391868(代理人档案号CVZ-019-2)中所述的那些流体源,该申请的内容通过引用结合于本文中。
该示例性微制造的过滤系统100具有较小的底面积(小于约1平方毫米),导致了紧凑的结构、较低的成本和相对简单的制造。该粒子分离器还提供了具有很少或没有堵塞的相对较低的变形率。如果需要的话,所保持的流体量可以很大,另外如果需要的话,该设计可针对额外的分析步骤按比例缩放和重复。The exemplary
本发明的过滤子系统可通过提供包括有两个流动通道120,130的相交部分101的微射流芯片来形成。装配工艺仅为集成批量制出的部件,其相对简单,并且可在大容量下实现低成本。根据一个示例性实施例,芯片形成有在相交部分101处与第二流动路径130相通的凹槽140。第一流动路径120最初通过凹槽140被分离或分开。采用适当的粘合剂或其它适当的连接机构来将适当的薄膜110附着在微射流芯片上,以便覆盖凹槽,从而在薄膜的下方形成了用来容纳滤后物并传送滤后物经过第二流动路径130的储槽。该薄膜可包括本领域已知的任何适当的过滤薄膜。The filtration subsystem of the present invention can be formed by providing a microfluidic chip comprising an
图5所示的该示例性微制造的封盖模块15固定在薄膜110的上方,从而形成了一个与第一流动路径120相通的过滤腔161。盖子15可采用适当的粘合剂或其它适当的连接机构来连接。该示例性封盖模块15包括与过滤腔连通的入口162和出口163,以便将第一流动路径120与过滤腔161相连,并实现待过滤组合物经由薄膜上方的过滤腔的流动。或者,薄膜110直接固定在封盖模块15上,而封盖模块连接在衬底上,从而将过滤系统集成在衬底上。本领域的技术人员可以认识到,封盖模块并不限于该示例性实施例,可根据本发明的内容而进行变更。The exemplary
图7显示了微射流系统10,其包括在装配具有薄膜110的封盖模块15之前便形成于其中的通道3。图8是具备过滤性能的封盖式微射流系统10的顶视图。FIG. 7 shows a
待过滤组合物从入口通道引入到过滤子系统中,并进入过滤腔中和薄膜110之上。物质的组分被薄膜110所分离,较小的组分如血浆流经薄膜进入到凹槽140中,并流经第二流动路径130。其余部分如血细胞流经过滤腔而到达第一流动路径120的出口。The composition to be filtered is introduced into the filtration subsystem from the inlet channel and into the filter cavity and onto the
根据该示例性实施例,微射流芯片的衬底可由玻璃、塑料、硅、石英、陶瓷或任何其它适当的材料形成。在由玻璃制成的微射流芯片中,芯片可包括两层,即芯片和固定到芯片上以形成过滤子系统的盖子。在由塑料形成的微射流芯片中,这些部件可压制到塑料衬底中。According to this exemplary embodiment, the substrate of the microfluidic chip may be formed of glass, plastic, silicon, quartz, ceramic, or any other suitable material. In microfluidic chips made of glass, the chip may comprise two layers, a chip and a cover secured to the chip to form the filtration subsystem. In microfluidic chips formed from plastic, these components may be pressed into a plastic substrate.
如图9a和9b所示,根据一个备选实施例,微过滤子系统可包括双端口式直接过滤器180,其包括插入到流体流动路径181中的薄膜110。如图所示,双端口式直接过滤器包括形成在微射流衬底中的流体流动路径181,其被分成两个部分181a,181b。第二部分181b形成了凹槽186,薄膜110粘附在凹槽上,形成了用于接受滤后物的过滤腔。包括形成了过滤腔的凹槽186的微制造的盖子15在薄膜的上方连接到衬底上,以便与流动路径181相连。待过滤物质经由流体流动路径181传送到过滤腔中,并且流经薄膜110。薄膜110通过捕集较大的分子来分离物质,由剩余分子构成的滤后物沿着流体流动路径181流经薄膜并进入到凹槽182中,并且流出微过滤系统以供进一步的分析、处理和收集等。As shown in Figures 9a and 9b, according to an alternative embodiment, the microfiltration subsystem may include a dual port
如图10a和10b所示,根据另一实施例,微过滤系统可包括三端口式直接过滤器190。该三端口式直接过滤器190包括用来将两种样品输入到过滤腔195中的两个入口流动通道191,192,以及用来将滤后物传送出过滤器190的一个出口通道193。该三端口式直接过滤器包括限定了过滤腔的微制造的盖子15,以及将过滤腔与出口通道193分开的薄膜110。在操作中,经由入口通道191,192提供两种样品。样品在过滤腔195中混合在一起,样品混合物经薄膜过滤,该薄膜可分离样品混合物的组分。流经薄膜的滤后物被传送通过出口通道,以用于进一步的处理、分析和收集等。According to another embodiment, a microfiltration system may include a three-port direct filter 190, as shown in Figures 10a and 10b. The three-port direct filter 190 includes two inlet flow channels 191 , 192 for inputting two samples into the filter chamber 195 , and one outlet channel 193 for conveying filtrate out of the filter 190 . The three-port direct filter includes a
薄膜分离领域的技术人员可以认识到,这里所述的过滤系统可用来实现所有类型的包括薄膜的片上分离,其包括通过大小来分离分子,或者从分子中分离出珠粒,或者从大粒子中分离出小粒子,或者从细胞中分离出病毒,或者用来实现本领域的技术人员所知的其它分离。Those skilled in the art of membrane separations will recognize that the filtration systems described herein can be used to achieve all types of on-chip separations including membranes, including separation of molecules by size, or separation of beads from molecules, or separation of large particles Small particles are isolated, or viruses are isolated from cells, or used to effect other isolations known to those skilled in the art.
根据本发明的另一实施例,可采用封盖模块15来将电磁阀结合到微射流系统中。在图11中显示了用于根据本发明的内容在微射流系统中实现的容纳于封盖结构中的电磁阀的一个例子。如图所示,电磁模块150包括盖子15,其形成了内腔151、用来选择性地堵塞经由衬底中的一个或两个连通端口的流动的薄膜154,以及用于使薄膜154偏转的促动组件160。根据该示例性实施例,促动组件包括线圈162和磁体164。本领域的技术人员可以认识到,可以使用其它可使薄膜偏转的适当装置,包括压电执行机构。According to another embodiment of the present invention, a
电磁封盖模块110可堆叠在衬底11上,使得薄膜在偏转时能够阻塞连通端口13a,13b中的一个或多个。因此,电磁封盖模块110集成了用于选择性地阻塞经过通道3到微射流流动路径中的流动的阀。如上所述,电磁封盖模块可通过使用自动化的“拾放”设备或者本领域已知的任何适当装置而安放在衬底上。The
本领域的技术人员可以认识到,封盖模块不限于该示例性实施例,可采用其它元件来增添其它的微射流功能,作为过滤和流量控制的附加或替代。Those skilled in the art will recognize that the capping module is not limited to this exemplary embodiment and that other elements may be employed to add other microfluidic functions, in addition to or instead of filtration and flow control.
本发明的微过滤系统可有利地结合具备微制造/微结构的微射流系统中所固有的小体积动态流量控制的传统薄膜技术的功能和范围。本发明提供了将任何适当的聚合物薄膜与微射流网络的成本效率合算的混合。该微过滤系统增设到微射流系统上是简单且成本较低的,这是因为将微过滤系统装配到微射流芯片中的额外成本对于微射流系统本身的成本来说相对较低。The microfiltration system of the present invention can advantageously combine the functionality and scope of traditional membrane technology with the small volume dynamic flow control inherent in microfabricated/microstructured microfluidic systems. The present invention provides cost-effective mixing of any suitable polymer film with a microfluidic network. The addition of the microfiltration system to the microfluidic system is simple and inexpensive because the additional cost of assembling the microfiltration system into the microfluidic chip is relatively small compared to the cost of the microfluidic system itself.
根据本发明的微射流系统可单独地或与其它部件相结合地包括有一个或多个上述部件。The microfluidic system according to the present invention may include one or more of the above-mentioned components alone or in combination with other components.
在上文中已经针对一个示例性实施例来描述了本发明。由于可在不脱离本发明范围的前提下对上述结构进行一定的变更,因此包含在上述描述中或显示于附图中的所有上述内容均应被解释为示例性的,不具备限制性意义。The invention has been described above with respect to an exemplary embodiment. Since certain changes can be made to the above structure without departing from the scope of the present invention, all the above content contained in the above description or shown in the accompanying drawings should be interpreted as illustrative rather than restrictive.
应当理解,下述权利要求覆盖了这里所述发明的所有通用的和具体的特征,本发明范围的所有陈述在语言上均属于其中。It is to be understood that the following claims cover all generic and specific features of the invention described herein, to which all statements of the scope of the invention are made by language.
Claims (7)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40948902P | 2002-09-09 | 2002-09-09 | |
| US60/409,489 | 2002-09-09 | ||
| US60/410,685 | 2002-09-13 | ||
| US10/329,018 | 2002-12-23 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710128025XA Division CN101199917A (en) | 2002-09-09 | 2003-09-09 | Implementation of microfluidic components in a microfluidic system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1694756A CN1694756A (en) | 2005-11-09 |
| CN1331575C true CN1331575C (en) | 2007-08-15 |
Family
ID=35353397
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038249804A Expired - Fee Related CN1331575C (en) | 2002-09-09 | 2003-09-09 | Implementation of Microfluidic Components in Microfluidic Systems |
| CNA200710128025XA Pending CN101199917A (en) | 2002-09-09 | 2003-09-09 | Implementation of microfluidic components in a microfluidic system |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710128025XA Pending CN101199917A (en) | 2002-09-09 | 2003-09-09 | Implementation of microfluidic components in a microfluidic system |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN1331575C (en) |
| ZA (1) | ZA200502324B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008002336A1 (en) * | 2008-06-10 | 2009-12-24 | Robert Bosch Gmbh | Pinch valve and method for its production |
| CA2910734C (en) * | 2013-04-30 | 2018-11-06 | Hewlett-Packard Development Company, L.P. | Microfluidic sensing device and system |
| CN106542495A (en) * | 2016-12-12 | 2017-03-29 | 墨宝股份有限公司 | A kind of preparation method of micro-electrical-mechanical system vibration jet actuator |
| CN108745012B (en) * | 2018-06-14 | 2021-04-20 | 四川大学 | A Modular and Combinable Micro Venturi Bubble Generator |
| CN113101985B (en) * | 2019-06-26 | 2022-07-22 | 京东方科技集团股份有限公司 | Detection chip and detection system |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922210A (en) * | 1995-06-16 | 1999-07-13 | University Of Washington | Tangential flow planar microfabricated fluid filter and method of using thereof |
| US5962081A (en) * | 1995-06-21 | 1999-10-05 | Pharmacia Biotech Ab | Method for the manufacture of a membrane-containing microstructure |
| US6440725B1 (en) * | 1997-12-24 | 2002-08-27 | Cepheid | Integrated fluid manipulation cartridge |
-
2003
- 2003-09-09 CN CNB038249804A patent/CN1331575C/en not_active Expired - Fee Related
- 2003-09-09 CN CNA200710128025XA patent/CN101199917A/en active Pending
- 2003-09-09 ZA ZA200502324A patent/ZA200502324B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922210A (en) * | 1995-06-16 | 1999-07-13 | University Of Washington | Tangential flow planar microfabricated fluid filter and method of using thereof |
| US5962081A (en) * | 1995-06-21 | 1999-10-05 | Pharmacia Biotech Ab | Method for the manufacture of a membrane-containing microstructure |
| US6440725B1 (en) * | 1997-12-24 | 2002-08-27 | Cepheid | Integrated fluid manipulation cartridge |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200502324B (en) | 2006-05-31 |
| CN1694756A (en) | 2005-11-09 |
| CN101199917A (en) | 2008-06-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6878271B2 (en) | Implementation of microfluidic components in a microfluidic system | |
| US7870964B2 (en) | Implementation of microfluidic components in a microfluidic system | |
| US9205396B2 (en) | Microfluidic device | |
| EP2423667B1 (en) | Particle processing system | |
| US7497994B2 (en) | Microfluidic devices and systems incorporating cover layers | |
| US6561208B1 (en) | Fluidic impedances in microfluidic system | |
| US6742661B1 (en) | Well-plate microfluidics | |
| US6536477B1 (en) | Fluidic couplers and modular microfluidic systems | |
| JP5124054B2 (en) | Microfluidic devices and systems incorporating protective layers | |
| US6756019B1 (en) | Microfluidic devices and systems incorporating cover layers | |
| EP1946830A1 (en) | Microreactor and method of liquid feeding making use of the same | |
| US20050180891A1 (en) | Miniaturized fluid delivery and analysis system | |
| CN101223101A (en) | Microfluidic device with integrated micropump, especially biochemical microreactor, and manufacturing method thereof | |
| CN1331575C (en) | Implementation of Microfluidic Components in Microfluidic Systems | |
| EP3339867A1 (en) | Micro-channel device and method for manufacturing micro-channel device | |
| JP2013509578A (en) | Siphon aspiration as a cleaning method and device for heterogeneous assays | |
| WO2005031163A1 (en) | Implementation of microfluidic components in a microfluidic system | |
| Xie et al. | Development of an integrated bio-microfluidic package with micro-valves and reservoirs for a DNA lab on a chip (LOC) application | |
| CN114728287A (en) | Device and method for manipulating and transferring a fluid volume into a microfluidic system | |
| JP2006284451A (en) | Micro total analysis system for analyzing target material in specimen | |
| Xie et al. | Development of a disposable bio-microfluidic package with reagents self-contained reservoirs and micro-valves for a DNA lab-on-a-chip (LOC) application | |
| RU200301U1 (en) | MICROFLUID CHIP FOR MULTI-PARAMETRIC IMMUNO ASSAY |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070815 Termination date: 20090909 |