This disclosure relates to sensors such as physical, chemical, and biological sensors.
Micro-electromechanical (MEMS) sensors may use microcantilevers to sense physical, chemical, and biological interactions. A microcantilever is a structure that is fixed at one end and free at the other. MEMS fabricated microcantilevers may be fabricated using silicon-based materials.
For example, microcantilever sensors may be used to sense biomolecular interactions as follows. In order to identify particular biological molecules (referred to as target molecules), a surface of a microcantilever may be functionalized with a particular probe molecule, where the probe molecule interacts with the target molecule. For example, in order to detect particular DNA material, a short single-stranded DNA (ssDNA) sequence may be used as a probe molecule for a complimentary ssDNA. Similarly, in order to detect a particular antigen, an appropriate antibody may be used as a probe molecule.
Referring to
In general, in one aspect, a sensor may include a membrane to deflect in response to a change in surface stress. A layer on the membrane may be provided to couple one or more probe molecules with the membrane. The membrane may deflect when a target molecule reacts with one or more probe molecules. The membrane may be fixed to a substrate at a first portion and a second different portion, and may span a well in the substrate.
The membrane may include a flexible material, such as a polymer. Polymers such as polyimide and parylene, or other polymers may be used. The layer may include a material to couple probe molecules to the membrane. For example, the layer may include gold. The layer may cover a portion of a first side of the membrane. The portion may be between about 5% and about 90%, or between about 10% and about 70%.
A system may include a substrate and one or more membranes coupled with the substrate. For example, the system may include a membrane spanning a well, where the membrane may have a layer to couple probe molecules to the membrane. The system may also include another membrane spanning another well, where the another membrane has a layer to couple probe molecules with the membrane. The system may include a cover to enclose the well and the another well. The system may include channels to provide fluid to the membranes.
In general, in another aspect, a method may include introducing fluid into a region proximate to a membrane, the fluid including one or more target molecules to be sensed. At least some of the target molecules may interact with the probe molecules and cause the membrane to deflect. The method may include measuring the deflection of the membrane. The deflection may be measured using optical detection methods and/or electrical detection methods.
The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims.
Like reference symbols in the various drawings indicate like elements.
Rather than using micro-cantilevers, the current disclosure provides systems and techniques for using membrane structures as physical, chemical, and/or biological sensors.
Membranes may be fabricated using materials with lower elasticity moduli than silicon-based materials that are generally used to fabricate micro-cantilevers. For example, some metal, ceramic, polymer, or other materials may be used. The elasticity moduli of these materials may be appreciably less than the moduli of materials usually used to fabricate micro-cantilevers. For example, parylene has an elasticity modulus of about 3.2 GPa, while silicon nitride (a common cantilever material) has an elasticity module of about 110 GPa, a difference of almost two orders of magnitude.
The membrane material may also be chosen to be compatible with the expected operating environment of the sensor. For example, bio-compatible membrane materials (such as Parylene) may be used for biological sensing, while appropriately compatible materials may be chosen for chemical or physical sensing.
Referring to
For example, membrane 210 may be rectangular, as shown in
Membrane 210 may have a region 240 that is modified physically, chemically, or biologically. For example, region 240 may be functionalized with one or more probe molecules for sensing one or more target molecules. Region 240 may include an intermediate layer such as a gold layer, a silicon dioxide layer, or other layer to couple probe molecules with the membrane. Using an appropriate intermediate layer, probe molecules may be coupled with the membrane surface via, for example, an intermediate thiol or cysteamine group. In some implementations, an intermediate layer may not be necessary.
Membrane 210 may act as a chemical sensor when region 240 is configured to experience a change in surface stress in response to a chemical reaction. For example, region 240 may include a thin oxide or polymer coating. Alternately, membrane 210 may comprise a metal such as gold or palladium to sense materials including, for example, hydrogen or mercury.
A net change in the surface stress on one side of membrane 210 results in an out of plane deflection of the membrane. The resulting deflection or rotation of the flexible membrane can be measured using optical techniques, piezoelectric techniques, piezoresistive techniques, or other techniques. Optical techniques include interferometry or optical beam deflection.
Referring to
When membrane 310 is undeflected, the reflected light is received at a region A of detector 380. When membrane 310 is deflected, the reflected light is received at a region B of detector 380. The relative location of regions A and B provide a measure of the deflection of membrane 310.
Referring to
Referring to
Referring to
For improved sensitivity, a large deflection/rotation of the sensing element is desired. Silicon materials may provide less than optimum deflection due to their high elasticity modulus. Polymers such as parylene, polyimide, etc., may provide a better choice.
Referring to
A layer 530 is provided on a surface region of membrane 510. For example, layer 530 may be a gold layer that is compatible with thiol chemistry for attaching probe molecules to the surface of membrane 510. Other layer materials may be used; for example, layer 530 may be a silicon dioxide layer.
Referring to
Referring to
Referring to
Referring to
Fluid may be provided to and/or removed from regions proximate to sensors 710A and 710B using channels (not shown) that may be formed, for example, in substrate 700 or in cover 730. Fluid may be provided to sensors 710A and 710B for functionalization; that is, to provide probe molecules for detecting target molecules. First sensor 710A and second sensor 710B may be functionalized to detect different target molecules, or to detect the same target molecules. Alternately, at least one of first sensor 710A and second sensor 710B may be used for common mode rejection, and may not be functionalized.
For common mode rejection, the deflection of a reference sensor may be monitored. The deflection of the reference sensor may change over time due to, for example, a drift in temperature. Since the same drift may be occurring in other sensors proximate to the reference sensor and introducing noise into the measurements, the change in deflection of the reference sensor may be used to subtract noise from the other sensors.
Fluid may be provided to sensors 710A and/or 710B to determine whether the fluid (i.e., gas or liquid) includes one or more target molecules. The same fluid may be provided to sensors 710A and 710B, or different fluids may be provided.
Table 1 below includes a list of parameters used in the analysis below.
The following calculations illustrate the benefits that may be obtained using a composite membrane such as a parylene membrane with a gold layer. First, the change in curvature of the gold-covered portion of the membrane as a result of the surface stress change is evaluated. To facilitate calculation, an equivalent membrane made of gold was used for a model for the gold-covered portions of the membrane, as shown in
Referring to
y−=−
y+=t1+t2−
ε+=Ky+ Equation (4)
ES=−γε+w2=−γKy+w2 Equation (5)
The elastic strain energy of the membrane due to bending per unit length of the membrane is given by Equation (6). The width of the membrane as a function of y is given in Equations (7A) and (7B). The curvature K is obtained by minimizing the total energy of the system, given in Equation (8), as shown in Equation (9).
w(y)=w1 (t1−
ET=ES+EB Equation (8)
The vertical deformation of the center of the membrane is evaluated using energy minimization and superposition methods. Referring to
Referring to
Referring to
Referring to
δm=δ1−δ2 Equation (14)
The net angle is constrained to be zero, as shown in Equation (15). Using this relationship, the moment M may be calculated, as shown in Equation (16).
θ1−θ2=0 Equation (15)
Material properties and dimensions for an exemplary composite membrane are given in Table 2 below. The membrane center deformation is a function of the membrane length and the length of the gold-covered portion.
A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. For example, different materials may be used for the membrane. Different layer materials may be provided on the membrane. Further different methods for providing probe molecules may also be used.
Although rectangular membranes have been shown, other shapes may be used. For example, circular membranes may be used. The shape of the membrane need not be regular or symmetric; a membrane shape that deflects in response to a change in surface stress may be used. The placement of a layer on the membrane need not be symmetric. Further, the membrane may be attached to the one or more support structures (e.g., the substrate) differently than shown. Accordingly, other embodiments are within the scope of the following claims.
This application claims priority to U.S. Provisional Application Ser. No. 60/426,851, filed Nov. 15, 2002, entitled “MULTIPLEXED BIOMOLECULAR ANALYSIS,” which is hereby incorporated by reference.
This invention was made with Government support under Grant (Contract) No. R21 CA86132-01 awarded by the National Institutes of Health/National Cancer Institute and Contract No. DE-FG03-98ER14870 awarded by the United States Department of Energy. The Government has certain rights in this invention.
Number | Name | Date | Kind |
---|---|---|---|
4502938 | Covington et al. | Mar 1985 | A |
4882627 | Keesen et al. | Nov 1989 | A |
RE33581 | Nicoli et al. | Apr 1991 | E |
5055265 | Finlan | Oct 1991 | A |
5294804 | Kajimura | Mar 1994 | A |
5341215 | Seher | Aug 1994 | A |
5372930 | Colton et al. | Dec 1994 | A |
5427915 | Ribi et al. | Jun 1995 | A |
5448399 | Park et al. | Sep 1995 | A |
5491097 | Ribi et al. | Feb 1996 | A |
5510481 | Bednarski et al. | Apr 1996 | A |
5620854 | Holzrichter et al. | Apr 1997 | A |
5653939 | Hollis et al. | Aug 1997 | A |
5658732 | Ebersole et al. | Aug 1997 | A |
5719324 | Thundat et al. | Feb 1998 | A |
5776324 | Usala | Jul 1998 | A |
5807758 | Lee et al. | Sep 1998 | A |
5833603 | Kovacs et al. | Nov 1998 | A |
5852229 | Josse et al. | Dec 1998 | A |
5908981 | Atalar et al. | Jun 1999 | A |
5918110 | Abraham-Fuchs et al. | Jun 1999 | A |
5918263 | Thundat | Jun 1999 | A |
5923421 | Rajic et al. | Jul 1999 | A |
5929440 | Fisher | Jul 1999 | A |
5945605 | Julian et al. | Aug 1999 | A |
5955659 | Gupta et al. | Sep 1999 | A |
6005400 | Thundat et al. | Dec 1999 | A |
6016686 | Thundat | Jan 2000 | A |
6030581 | Virtanen | Feb 2000 | A |
6050722 | Thundat et al. | Apr 2000 | A |
6096559 | Thundat et al. | Aug 2000 | A |
6118124 | Thundat et al. | Sep 2000 | A |
6181422 | Veltze | Jan 2001 | B1 |
6203983 | Quate et al. | Mar 2001 | B1 |
6212939 | Thundat | Apr 2001 | B1 |
6229609 | Muramatsu et al. | May 2001 | B1 |
6237399 | Shivaram et al. | May 2001 | B1 |
6251343 | Dubrow et al. | Jun 2001 | B1 |
6263736 | Thundat et al. | Jul 2001 | B1 |
6268161 | Han et al. | Jul 2001 | B1 |
6289717 | Thundat et al. | Sep 2001 | B1 |
6319469 | Mian et al. | Nov 2001 | B1 |
6338968 | Hefti | Jan 2002 | B1 |
6436647 | Quate et al. | Aug 2002 | B1 |
6475750 | Han et al. | Nov 2002 | B1 |
6480730 | Darrow et al. | Nov 2002 | B2 |
6514689 | Han et al. | Feb 2003 | B2 |
6521109 | Bartic et al. | Feb 2003 | B1 |
6526828 | Dayan et al. | Mar 2003 | B1 |
6631638 | James et al. | Oct 2003 | B2 |
6647796 | Beach et al. | Nov 2003 | B2 |
6654625 | Say et al. | Nov 2003 | B1 |
6668627 | Lange et al. | Dec 2003 | B2 |
20020092340 | Prater et al. | Jul 2002 | A1 |
20020102743 | Majumdar et al. | Aug 2002 | A1 |
20020137084 | Quate et al. | Sep 2002 | A1 |
20020180979 | Chou et al. | Dec 2002 | A1 |
20030092016 | Wiggins et al. | May 2003 | A1 |
20040211251 | Lee et al. | Oct 2004 | A1 |
Number | Date | Country |
---|---|---|
WO 9502180 | Jan 1995 | WO |
WO 9850773 | Nov 1998 | WO |
WO 2004052046 | Jun 2004 | WO |
Number | Date | Country | |
---|---|---|---|
20040096357 A1 | May 2004 | US |
Number | Date | Country | |
---|---|---|---|
60426851 | Nov 2002 | US |