Abstract:
A biosensor includes a magnetic structure having grooved surface to biologically bond magnetic labels to a biological substance within the grooves. The grooves are positioned within the magnetic structure so that stray magnetic fields from the magnetic structure magnetize magnetic labels within the groove. The magnetic labels may be magnetic nanoparticles or magnetic microbeads. The techniques may reduce or eliminate the usage of any external magnetic field generator, e.g., electromagnets or current lines.

Description:
[0001]    This application claims the benefit of application No. 61/534,636, filed Sep. 14, 2011, the entire content of which being incorporated herein by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    This invention relates to magnetic biosensors. 
       BACKGROUND 
       [0003]    Bioassays that detect and quantify biomolecues at ultra-low quantity, with point-of-care settings, are of great need in many fields, including basic medical science, disease control and diagnostics, drug discovery and environment monitoring. Bioassays can be used for disease or pathogen detection based on the principle of specific interactions between oligonucleotides, such as DNA-DNA or RNA-RNA interaction, small-molecule-biomolecule interaction, aptamer-biomolecule interactions, protein interactions, and others. Various types of interactions can be used with biosensors. As noted, antibody-antigen interaction is one example of a specific interaction between biomolecules which can be used. Other examples of biomolecule interactions, include those interactions between oligonucleotides, such as DNA-DNA or interaction, small-molecule-biomolecule interaction, aptamer-biomolecule interactions and protein interactions. 
         [0004]    Magnetic biosensors include giant magnetoresistive (GMR) sensors, magnetic tunnel junction (MTJ) sensors, Hall biosensors or Giant magneto impedance (GMI) biosensors. Magnetic biosensing, which combines the magnetic biosensor and the magnetic nanoparticle (MNP), has been intensively studied. In existing magnetic biosensing schemes, when the targeted biomolecues are present, they bond to the biologically-functionalized surface of an individual magnetic field sensor or a sensor-array. Functionalized MNPs bond to these targeted biomolecues. The dipole field from the specifically bond magnetized MNPs will change the overall effective magnetic field on the sensing layer of the magnetic biosensor. This causes the change of the magnetization configuration of the magnetic biosensor, thus generating an electrical signal from the biosensor, which can be quantitatively correlated with the number of the MNPs. 
         [0005]    Conventionally, as shown in  FIGS. 7 and 8 , an externally-applied magnetic field is used to magnetize the MNPs. Hence, an external magnetic field generator is typically used, which not only downplays the promised portability feature for magnetic biosensors but also increases the power consumption of the whole system. 
         [0006]    Magnetic field from built-in current lines on the biosensor has been proposed for magnetizing the MNPs. This can eliminate the usage of the electromagnet; however, the requirement for large power consumption still exists. The presence of a large current on a sensing chip, such as tens of milliampers, is typically required to produce a large enough magnetic field for magnetizing the MNPs. Such large current causes heating effects and also may result in a dielectric break down between the protection layer and the biological sample. 
       SUMMARY 
       [0007]    In general, magnetic biosensing techniques are described that utilizes stray field from the magnetic biosensor to magnetize and bond magnetic labels, such as magnetic nanoparticles (MNPs) or slightly larger magnetic particles including magnetic magnetic microbeads. The techniques may reduce or eliminate the usage of any external magnetic field generator, e.g., electromagnets or current lines. The techniques may utilize a specific patterned structure, e.g. a groove, in the magnetic biosensor. The specific patterned structure may be fabricated using an ion milling and other lithograph processes. 
         [0008]    More specifically, a magnetic nanoparticle detection scheme is described that avoids the requirement of any externally generated magnetic field. Traditional magnetic biosensing scheme employs an external applied magnetic field generator to magnetize the superparamagnetic MNPs. This results in extra power consumption, which may be critical for point-of-care applications. The detection scheme described herein introduces a patterned groove structure in the biosensor, utilizes the magnetic stray fields from the magnetic device to magnetize the MNPs. 
         [0009]    An example is described below based on a spin-valve giant magnetoresistane (GMR) sensing device. For this structure, the stray field from the free layer is used to magnetize the MNPs, which locate inside the groove and near to the free layer. Micromagnetic simulations are performed to calculate the signal level of this detection scheme. A maximum signal of 8.9×10 −5  magnetoresistive ratio (MR) change from one iron oxide magnetic nanoparticle with 8 nm in radius is obtained from the simulation. This signal level is high enough for the detection of about 10 such nanoparticles if using the state-of-art electronic circuit for signal processing. This new detection scheme is not limited to GMR device and is applicable for other spintronic and magnetic sensing devices such as magnetic tunnel junction (MTJ), Hall sensor with sandwiched structure and giant magneto impendence (GMI). 
         [0010]    The biosensor may utilize, for example, GMR sensing device having the spin valve structure, an MTJ sensing device having the spin valve structure, a GMI sensing device having the spin valve structure or a Hall sensing device having the spin valve structure. The biosensor may include a magnetic sensing device that has a soft magnetic layer underneath a Hall sensing layer. In this example, the soft magnetic layer responds to the sensing current and generates the magnetic field. For some magnetic sensing schemes, like the Hall sensor or a semiconductor layer, a single layer may only be needed. A single soft magnetic layer underneath the sensing layer may be utilized to generate the magnetic field. 
         [0011]    The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 
     
    
     DETAILED DESCRIPTION 
       [0012]      FIG. 1  shows a magnetic biosensing scheme using a spin valve structure. As shown in  FIG. 1 , a magnetic nanoparticle (MNP) is biologically bonded to the surface of magnetic biosensor. In a conventional configuration, an external magnetic field is needed so that the superparamagnetic MNP is magnetized. The magnetized MNP generates a dipole magnetic field, which exerts on the free layer of the spin valve. 
         [0013]    Before the MNP bonds to the sensor surface, the effective field H eff  on the free layer is: 
         [0000]        H   eff   =H   ext   +H   stray-pinned   (1),
 
         [0000]    where H ext  is the external applied magnetic field and H stray-pinned  is the stray field from the pinned layer. After bonding to the surface of the sensor, the MNP is magnetized by the external applied field. Both the stray fields from the free layer and pinned layer are very small and can be ignored for the conventional magnetic biosensing scheme. The magnetic charges from the free layer (two ends of the long axis of the sensor) are far from most of bond MNPs because of the large dimension of the sensor along the long axis. The magnetic charges from the fixed layer (two ends of the short axis of the sensor) are far from most of bond MNPs because of the distance from the pinned layer to sensor top surface. Due to the superparamagnetic property of the MNP, at external field H, its magnetization can be expressed as: 
         [0000]    
       
         
           
             
               
                 
                   
                     M 
                     = 
                     
                       
                         M 
                         s 
                       
                       × 
                       
                         L 
                          
                         
                           ( 
                           
                             
                               
                                 m 
                                 0 
                               
                                
                               
                                 μ 
                                 0 
                               
                                
                               H 
                             
                             
                               
                                 k 
                                 B 
                               
                                
                               T 
                             
                           
                           ) 
                         
                       
                     
                   
                   , 
                 
               
               
                 
                   ( 
                   2 
                   ) 
                 
               
             
           
         
       
     
         [0000]    where M s  is the saturation magnetization, m 0  is the magnetic moment of a single particle, μ 0  is the magnetic permeability of vacuum, H is the applied magnetic field, k B  is the Boltzmann constant, T is the absolute temperature, and L is the Langevin function. Thus, the dipole field from the MNP on the free layer can be written as: 
         [0000]    
       
         
           
             
               
                 
                   
                     
                       H 
                       dipole 
                     
                     = 
                     
                       
                         
                           3 
                            
                           
                             ( 
                             
                               m 
                               · 
                               r 
                             
                             ) 
                           
                            
                           r 
                         
                         
                           r 
                           5 
                         
                       
                       - 
                       
                         m 
                         
                           r 
                           3 
                         
                       
                     
                   
                   , 
                 
               
               
                 
                   ( 
                   3 
                   ) 
                 
               
             
           
         
       
     
         [0000]    where m is the magnetic moment of the MNP, r is space vector from the center of the MNP to the free layer. Therefore, the effective field on the free layer is then expressed as: 
         [0000]        H   eff   =H   ext   +H   stray-pinned   +H   dipole   (4),
 
         [0000]    The change of H eff  on the free layer before and after the MNP bonding will change the orientation of the free layer magnetization M free  which leads to an electrical signal change of the magnetic biosensor. 
         [0014]      FIG. 2  illustrates the proposed external-field-free detection scheme. In this detection scheme, a groove structure is purposely created on the magnetic sensor, so that the MNPs can bond into the groove where the magnetic charges from both free layer and pinned layer are close to the MNP thus the stray fields from the magnetic films (free and pinned layer) H stray-film  are strong. In this configuration, before the MNP bonding, the effective field on the free layer is only the stray field from the pinned layer, without the presence of the external applied field: 
         [0000]        H   eff   =H   stray-pinned   (5),
 
         [0000]    The MNP, after bonding into the groove, will be magnetized by the stray fields from both the free and pinned layers. Hence its magnetization can be expressed by: 
         [0000]    
       
         
           
             
               
                 
                   
                     M 
                     = 
                     
                       
                         M 
                         s 
                       
                       × 
                       
                         L 
                          
                         
                           ( 
                           
                             
                               
                                 m 
                                 0 
                               
                                
                               
                                 μ 
                                 0 
                               
                                
                               
                                 H 
                                 
                                   stray 
                                   - 
                                   film 
                                 
                               
                             
                             
                               
                                 k 
                                 B 
                               
                                
                               T 
                             
                           
                           ) 
                         
                       
                     
                   
                   , 
                 
               
               
                 
                   ( 
                   6 
                   ) 
                 
               
             
           
         
       
     
         [0000]    where H stray-film  is the stray fields from the free and pinned layers of the magnetic biosensor. Combining the dipole field that generates by the MNP, the effective field on the free layer after the MNP bonding should be written as: 
         [0000]        H   eff   =H   stray-pinned   +H   dipole   (7),
 
         [0000]    Therefore, the difference of the effective field on the free layer changes the magnetization configuration of the free layer. By utilizing the strong stray fields from the free and pinned layers to magnetize the MNP, the external applied field is no longer needed in this novel detection scheme. 
         [0015]    In various examples, the free layer typically ranges from 1 to 10 nm in thickness, the spacer layer may generally be 1-10 nm in thickness, while the pinned layer typically ranges from 5 to 50 nm. Although not shown, the substrate may take the form of one or more layers including a physical substrate, an adhesion layer, a seed layer, and underlayer spacing and insulation layers, and the like. 
         [0016]    In some examples, the groove is formed with a width that accommodates multiple magnetic labels, e.g., two to three times the diameter of particles to bond. For example, the magnetic biological sensor may be designed to bond MNPs, which typically range from a few nanometers to less than 100 nanometers, and more typically on the order of 1 to 10 nanometers. In such an example, the groove may be formed as 50 or 100 to 300 nanometers in width. As another example, the biological sensor may be configured to bond magnetic microbeads, which may be on the order of sub-one micron up to two microns (100 to 2000 nanometers). In such an example, a groove having a width of several microns, (e.g., 1-5 microns) may be used. As another example, the biological sensor may be configured to bond magnetic objectives with shapes different from sphere or cube, which could be rod or wire or tube on the order of sub-micron in length and width (50 nm-1000 microns). In such an example, a groove having a width and a length of several times larger than the dimensions of the magnetic objectives. 
         [0017]    Further, the groove may be formed with sufficient depth to contain the biological substance so that biological bonding of the magnetic label still occurs within the groove. The groove may be formed to extend through the free layer and a portion of the pinned layer, e.g., to the underlying substrate. In this case, the groove may range from 1 to over 100 nanometers in depth for MNPs. Moreover, the groove may be formed so as to have a depth such that, upon biologically bonding to the biological substance within the groove, the center of the magnetic label may be generally vertically aligned with a center of the free layer, as shown in  FIG. 2B . In general, the groove may be formed such as to have a large bonding surface within the magnetic structure without compromising the magnetic performance of the free layer and the pinned layer. 
         [0018]    Micromagnetic simulation is performed for the proof of concept. Because of the large lateral dimensions (one or more micrometers) vs. the ultra thin magnetic layers (typically on the order of 1-10 nanometers) for a typical spin valve type magnetic biosensor, micromagnetic simulation can be carried out using a two dimension (2D) model. In this paper, we use a well-established 2-D Micromagnetic simulation software, the object-oriented micromagnetic framework (OOMMF), to simulate the magnetization behavior of the free layer under the stay field from the pinned layer and the dipole field from the MNPs. In the simulation, both free and pinned layer with a groove structure are divided into small magnetic cells with the same size (5 nm). Each magnetic cell has its own magnetic moment and interacts with all other cells. Before the MNP bonding, the effective field on the free layer is the sum of the stay field from all the magnetic cells of pinned layer. With the MNP sitting in the groove, for simplicity, we assume the center of the MNP is the same level with the center of the free layer as shown in  FIG. 2   b . The MNP is magnetized by the total stay fields from all the magnetic cells of the free and pinned layers. The dipole field from the MNP is discretized and incorporated into the OOMMF input file as well as the stay field from the pinned layer on the free layer. The averaged magnetization orientations of the free layer are computed from the magnetization distribution of the magnetic cells by OOMMF. 
         [0019]      FIG. 3  shows a definition of the dimensions for one example sensor having a groove structure as described herein. In this example, the size of the magnetic biosensor is 3 μm long (L s ) by 0.5 μm wide (W s ), while the groove dimension (length L g  and width W g ) varies for optimization. A biosensor of these dimensions was simulated. A commercially available iron oxide MNP was also simulated to explore the maximum sensitivity of the technique described herein, which locates at the center of the groove structure. The iron oxide magnetic nanoparticle has saturation magnetization value of 480 emu/cc and size of 8 nm in radius. The signal from the MNP is represented by the change of the magnetoresistive ratio (MR) with and without the presence of the MNP. 
         [0020]      FIGS. 4   a  and  4   b  show the MR change due to the MNP for different groove dimensions. In  FIGS. 4   a  and  4   b , the width of the groove is fixed at 100 nm and 200 nm, respectively, while the length of the groove varies from 100 nm to 700 nm. As shown in  FIG. 4   a , the signal is at the maximum when the groove length is 100 nm in this simulation. The results indicate the strong stray fields from the free and pinned layers acting on the MNP and the strong interaction between MNP dipole field the free layer. The signal then decreases rapidly to the minimum with 200 nm groove length and increases as the length increases, suggesting a complex interaction between the stray fields, MNP dipole field and free layer. 
         [0021]      FIG. 4   b  shows a maximum signal (8.9×10 −5 ) with 100 nm groove length structure in this simulation. The signal then decreases dramatically with 200 nm groove length and increases slowly with a longer groove structure. In comparison, for a groove structure with a length longer than 200 nm, the simulated biosensor having a 200 nm width shows a more stable signal change than the simulated biosensor with a 100 nm width. This may be due to the fact that there is less magnetic material left on the magnetic biosensor after formation of the groove. As demonstrated by the experimental data, which shows a noise level around 10 −5  MR change using a spin valve biosensor, a sensitivity (around 40 dB) of ten nanoparticles detection can easily be achieved using the detection method described herein. 
         [0022]      FIG. 5  is a graph demonstrating an example signal produced by the biosensor based on the particle position inside the groove structure. The parameters of the particle used in this simulation were the same as those used in above-described simulation. As shown in  FIG. 5 , the signal from one iron oxide nanoparticle becomes larger when the particle locates closer to a corner of the groove structure, i.e., a corner of the groove along the surface of the magnetic structure. This may be due to a stronger interaction between the particle and the free layer because of the larger stray fields from both fixed and free layers on the corner of the groove structure. 
         [0023]    To explore the detection dynamic range in this detection scheme, the signal dependence on the particle number in the groove structure was studied. In order to obtain a wide dynamic range, groove structure of 700 nm length and 200 nm width was chosen due to the large groove structure area to accommodate more nanoparticles. Iron oxide nanoparticles with same dimension and saturation magnetization as the above simulation are used here. The maximum number of nanoparticles for the simulation was set to 500, so that the distance between each nanoparticle is in a reasonable range for minimizing the particle interaction. The nanoparticles were modeled as being uniformly distributed in the groove structure. As shown in  FIG. 6 , the signal from the biosensor increase as the number of particles bonded within the groove structure increases (black dot curve in  FIG. 6 ). Compared with the extended linear dependence from a single particle signal (top curve in  FIG. 6 ), the simulated signal from multiple particles tends to decrease. However, there is only 30% signal drop in 500 nanoparticle case, which indicates the signal does not reach a plateau before the number of nanoparticles reaches the maximum. Therefore, in this detection scheme, the maximum particle detection limit may be determined by physical accommodation of nanoparticles in the groove structures. 
         [0024]    In this manner, a magnetic biosensing scheme is described that may be utilized without requiring an external magnetic field generator. This may provide many benefits, including, for example, system miniaturization and power consumption control of biosensing systems. In one example, the detection scheme utilizes a groove structure in the biosensor, and employs the stray fields from free and pinned layers of the magnetic biosensor for MNP magnetization. 
         [0025]    As described above, micromagnetic simulations were carried out for a theoretical study of this detection scheme. Signals from different groove structures were calculated. The results showed a good signal level and an example maximum 8.9×10 −5  MR change from one 8 nm radius iron oxide magnetic nanoparticle locating on the center of the groove structure. The signal dependence on the nanoparticle position in the groove structure was investigated. The results suggested an increased signal level on the corner of the groove structure. The dynamic detection range of example biosensors using this detection scheme was explored by simulating signal from multiple nanoparticles in the groove structure. The results demonstrated that the signal increases as more nanoparticles are bonded in the groove structure. Moreover, the simulation showed that uniformly distributed 500 nanoparticles does not saturate the sensor signal. As such, the detection scheme may be limited only by the physical accommodation of nanoparticles in the groove structure. 
         [0026]      FIG. 9  illustrates an example handheld device that utilizes the detection scheme described herein. The handheld device may be possibly the size of a cell phone or smaller and comprises a magnetic sensing chip, controller to receive and process the electrical signal from the sensing chip, an a display screen to provide a user interface and present any sensed output to a user. The controller may be a field programmable gate array (FPGA), a general purpose processor, a digital signal processor or other suitable electronic component. The handheld device may include a computer-readable medium to store software instructions (e.g., a memory) for execution by the processor to perform the sensing techniques described herein. In some embodiments the sensing chip is incorporated into an electronic component that may be coupled, mounted on, tethered or otherwise connected to a handheld device. 
         [0027]      FIG. 10  illustrates two example configurations of a field-free magnetic sensor. A strip-type magnetic biosensor is shown in which a grooved pattern is formed to include a plurality of parallel linear grooves. Other patterns may be formed, such as a pattern of curved grooves, a pattern of sawtooth grooves, or combinations thereof. A second example is shown in which the magnetic sensor having a pattern of notches, each of the notches forming a single, short groove into the magnetic surface of the biosensor. 
         [0028]      FIG. 11  illustrates example flow of direction of magnetic labels (nanoparticles, microbeads) through an example sensing chip having a grooved pattern formed from a plurality of notches. 
         [0029]      FIG. 12  illustrates further details of the field-free surface detection scheme. As shown, magnetic labels are bonded on the surface of notched magnetic biosensor, and magnetized by the stray field from biosensor films (free layer and pinned layer), generating dipole field to interact with free layer, leading to output of an electrical signal. As shown, the sensor may provide three-dimensional detection of the magnetic labels, i.e., surface detection and edge detection within the groove. 
         [0030]      FIGS. 13 and 14  are top views showing two examples of the electric sensing chip formed with a plurality of electrodes electrically connected to the magnetic structure having the grooved pattern. The electrodes provide electrical connections for reading the electrical signal produced by the sensing chip. 
         [0031]    For another example, the grooves could be filled or partially with materials (e.g. SiO 2 , Al 2 O 3 , SiN, etc) thus the surface of groove areas and the magnetic sensor areas are in the same level or close to the same level. The surface functionalization molecules (e.g. antibody) can be printed locally on the surface of the groove areas or close to the groove areas. 
         [0032]    Various embodiments of the invention have been described. These and other embodiments are within the scope of the following claims.