Title of Invention

RAPID AND SENSITIVE BIOSENSING

Abstract

A sensor device (15) for detecting magnetic particles (13) has a binding surface (40) with binding sites thereon and comprises: at Ieast one sensor dement (23) for detecting the presence of magnetic particles (13). means for attracting magnetic structures comprising at least one magnetic particle (13) toward and onto the binding surface (40) of the sensor device (15), and means for re-arranging and randomizing the position of individual magnetic particles (13) with respect to the binding sites on the binding surface (40) to give binding sites on all individual particles (13) a substantial probability to have a contact time with binding sites on the binding surface (40). With such sensor device (15), the speed of detection of target molecules in a fluid is enhanced.

Full Text

Rapid and sensitive biosensing The present invention relates to sensors, especiaüy biosensors and more particulariy to methods for a magnetically actuated 'attracting' and/or 'bmdmg' step in a biosensing process using such biosensors. Medical diagnostics. both in the central laboratory and at the bedside, is characterized by a drive towards integration and automation. The reason for this is that tests need to be easy to perform, in a reliabie and cost effective way, with minimum human intervention. At the same tiroe tbere is an ever-increasing need for higher sensitivity and specificity of detection. Magnetic biochips have been proposed as a new means to sensitively detect low concentrations of target molecules in body fluids for diagnostics. Such magnetic biochips have promising properties for bio-molecular diagnostics, in terms of sensitivity, specificity, integration, ease of use and costs. For example, sensitive magneto-resistive magnetic field sensors, such as GMR magnetic field sensors. can be combined with suitable biochemistry to selectively attach magnetic beads, resulting in a miniaturized biosensor that is suitable for detection in an array format The sensitivity and specificity of rapid tests is usually provided by dedicated capture of probe molecules, e.g. a high-affinity antibody-antigen combination. In such an immunoassay, the target molecules become sandwiched between antibodies on a solid support and a label that is detected by the sensor. Conventionally this label is a fluorophore. and a plate reader is used for detection. In the most sensitive assays, the lest is performed on magnetic bead carriers that can be actuated so the reaction rate is no longer limited by diffusion ZDQ the lest is ioeeded up. Magnetic detection naturally combines actuation and detection by using the magnetic beads as both label and carrier. Besides this natural Integration, magnetic labelling has several other advantages: body liquids do show autofluorescence, but are by nature hardly magnetic, which helps to improve the detection limit. Magnetic detection of magnetic particles requires no expensive optics. yet is fast and sensitive, and fortberrnore. it is well suited for miniaturized diagnostic sensing, due to the * direct availability of electronic Signals and the small size of the required Instrumentation. The aim of a biosensor is to detect and quantify the presence ofa biological raolecule in a sample, usually a Solution. Desired attributes are high sensitivity, high specificity, and high speed, Furthermore, the biosensor is preferably of low cost and it should be rehable and easy to use. For many decades magnetic partkies have been used in biology for Separation, extraction and purification of biological materials. In recent years, biosensors based on the use of magnetic particles for actuation as well as detection have started to develop. In these studies, magnetic particles are detected by optical methods, electric means, coils or magneto-resistive sensors. Actuation of the particles is used for stringency, to concentrate the particles near the detection surface or to enhance particle-to-particle binding. For high sensitivity and high speed in a sandwich assay, tbe foBowing protocol may be attempted: magnetic beads to target molecule, magnetising these beads with an applied magnetic field and using a Giant Magneto Resistance (GMR) sensor to detect the stray field of the magnetised beads, which stray field is dependent on the concentration. Fig. 1 shows an example of integrated excitation. A current flowing in current wire la generates a magnetic field, -»Weh magnetises a magnetic bead 2 which is attached to a target molecule 3. Hence, the beads 2 present at a binding surfece 6 of the sensor device each develop a magnetic moment m indicated by the field lines 7. The stray field fiom the magnetic bead 2 introduces an in-plane magnetisation component H«! in the GMR sensor 4, which resuhs in a resistance change ARGMROHCH). In Fig. 1, the in-plane component Hext is indicated by axrow 5. In order to achieve a short assay time, the magnetic beads 2 have to be magnetically actuated, i.e. by means of magnetic actuation attracted to the binding surfece 6. Thereafter, the binding process needs to take place as efficiently as possible. This means that (i) the particles need to be concentrated onto the binding zones with highest detection sensitivity by the sensors, and (ii) that all particles need to have Optimum possibilities to form the desired (bio)chemical bonds to the binding surface. A disadvantage of attraction by a large external permanent magnet is that the magnetic particles form large and static aggregates on the surface, which does not give Optimum binding conditions to the binding surface. In addition, magnets can give large in-plane magnetic fields 5, which influence the sensitivity of the magnetic sensor due to shifting of tbe Operation point on the non linear R(H) resistance change characteristic of the sensor. Furtbermore, the large magnetic fields may de-orientate the sensor and introduce magnetic build-up in the sensor due to its hysteric characteristic. target molecules such as e.g. proteins, antibodies, nucleic acids (e.g. DNA, RNA), peptides, oligo- or Polysaccharides or sugars, in fluids, for example, biological fluids, such as saliva, Sputum, blood, blood plasma, interstitial fluid or urine, with high sensitivity and specificity. The above objectrve is accomplished by a method and device according to the present invention. Particular and preferred aspects of the invention are set out in the accompanying independent and dependent Claims. Features from the dependent Claims may be combined with features of the independent Claims and with features of other dependent Claims as appropriate and not merely -as explicitly set out in the Claims. In a first aspect of the present invention, a sensor device, e.g. a magnetic sensor device, for detecting magnetic particles is provided, the sensor device having a binding surface with binding sites thereon and comprising: at least one sensor element for detecting the presence of magnetic particles, means for attracting magnetic structures toward and onto the binding surface of the sensor device, said magnetic structures comprising at least one magnetic particle, and means for re-arranging and randomising the position of individual magnetic particles with respect to the binding sites on the binding surfece to give binding sites on all individual magnetic particles a substantial probability to have a contact time with binding sites on the binding surface. dement such as, for example, an optica] sensor dement Hence, instead of magnetic detection of particles, the particles may also be opticaDy detected. For magnetic particles present in a sample volume, the means for re-arranging and randomising the position of the individua] magnetic particles may be adapted such that individual magnetic particles are loosened from the binding surface such that 90% of the individual magnetic particles which are part of a magnetic structure, e.g. an individual particle hself or a multi-particle stiucture, stay within 10% or less of the sample volume. Hence, during re-arrangement and randomisatkm, the magnetic particles do not go far from the binding surface in a direction substantially perpendicular to the binding surface. The magnetic particles preferably stay within 100 |im from the binding surface and more prefoably stay within 10 (im from the binding surface in a direction substantially perpendicular to the binding surface. Randomisation of the magnetic particles may be performed e.g. by changing a magnetic gradient in time, in amplitude, in frequency (depending on the amplitude and the magnetic anisotropy of the magnetic particles) or in direction. Alternatively, in order to randomise magnetic particles they may be vibrationally excited or exposed to fluid flow. The sensor may be in the form of a disposable cartridge with a cartridge reader for providing a read-out from the sensor. The sensor may be partially or wholly integrated onto a semiconductor chip. The field generating means adapted for forming multi-parricle magnetic structures may. according to embodiments of the invention, be an on-chip magnetic field generating means, e.g. current wires, or an ofF-chip magnetic field generating means. The off-chip magnetic field generating means may be a magnetic field generating means present in the disposable cartridge for the biosensor but not on the chip, or it may be present in the cartridge reader. on-chip or an off-chip means. Tbe means for attracting said magnetic structures, e.g. individual particles or inulti-particle structures, toward and onto the binding surface of the sensor device may be an on-chip or an off-chip element having a relative permeability largei than one, i.e. the means for attractmg said roagnetic structures, e.g. individual particles or multi-particle structures, may comprise a fluxguide. The on-chip or off-chip element may be a kind of MEMS (microelectromechanical System) element which may change position or shape in order to vary a magnetic field gradient for attractmg the magnetic structures, e.g. individual particles or multi-particle structures, toward and onto the binding surface of the sensor device. In one particular embodiment of the invention, the means for attractmg the magnetic structures, e.g. individual particles or multi-particle structures toward arxi onto the binding surface of the sensor device may comprise a first current wire and at least one additional current wire. In another embodiment, the means for attracting the magnetic structures, e.g. individual particleS or multi-particle structures, may be an array of current wires. In a second aspect, the invention also provides a method for a biosensing process, the biosensing process comprising detection of magnetic particles by means of a sensor device having a binding surface with binding sites thereon. The method comprises: attracting said magnetic structures comprising at least one magnetic particle toward and onto tbe binding surface of the sensor device, and re-arranging and randomising the position of the individual magnetic particles with respect to the binding sites on the binding surface to give binding sites on all individual magnetic particles a substantial probability to have a contact time with binding sites on the binding surface. A method according to emboditnents of tbe present invention may furtbermore applying a magnetic field adapted for forming multi-particle magnetic structures having a long axis lying substantially parallel witb the binding surface of the sensor device, the multi-particle magnetic structures comprising a plurality of individual magnetic particles. Applying tbe magnetic field for generating multi-particle structures may be perfonned by applying a chain-forming magnetic field for forming cbains of magnetic particles. According to embodiments of tbe invention, attracting tbe magnetic structures, e.g. individual particles or multi-particle structures, toward and onto tbe sensor binding surface may be performed by applying an on-chip or an off-chip magnetic field. In some embodiments, attracting tbe magnetic structures, e.g. individual particles or multi-particle structures, may be performed by applying a magnetic field gradient in a direction substantially perpendicular to the binding surface of tbe sensor device. The sensor device, if itis a magnetic sensor device, may have at least one magnetic sensor element with a sensitive .direction, and attracting tbe magnetic structures, e.g. individual particles or multi-particle structures. toward and onto the binding surface may be perfonned by applying a magnetic field in the sensitive direction of the magnetic sensor element. In otber embodiments according to the invention, the sensor device may comprise at least a first and second current wire and attracting the magnetic structures, e.g. individual particles or multi-particle structures, toward and onto the binding surface may be performed by sending a first current through the first current wire and sending a second current through the second current wire. The first and the second current may be equal in magnitude. They may have opposite directions. In still further embodiments, attracting the magnetic structures. e.g. individual particles or multi-particle structures, toward and onto the binding surface may be performed by an array of current wir es. The magnetic Seid may subsequently be rotated to get maximum contact between individual magnetic partkles and tbe binding surface. These and other characteristics, features and advautages of the present invention will become apparent froro the foUowing detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention. This description is given for the sake of example only, without limiting tbe scope of the invention. The reference figures quoted below refer to the attached drawings. Fig. 1 illustraies a magnetic sensor according to the prior art ' Fig. 2 illustrates magnetic bead mteractions and chain fbrmaiion in the presence of a uniform magnetic field Fig. 3 illustrates magnetic bead columns fonned by magnetising beads in a uniform magnetic field. Fig. 4 illustrates the effect of repelling and attracting magnetic bead columns to the surface of a magnetic sensor according to an embodiment of the present invention. Fig. 5 is a top view of a current wire according to an embodiment of the present invention. Fig. 6 is an illustration of a sensor configuration according to an embodiment of the invention for attracting beads to the binding surface of a sensor device. Fig. 7 is a cross-section of the sensor configuration of Fig. 6. Fig. 8 shows the vertical magnetic force at a distance z = 0.64 jim from the binding surface, as a fiinction of the position of the beads for the sensor configuration of Fig. 6 and 7. Fig. 12 iUustrates the locaJ barometric lengtb at a distance z = 0.64 ^m from the binding surfece, for beads in tbe neighbourhood of the sensor configuration of Fig. 6 and 7. Fig. 13 is an illustration of a sensor configuration for detectmg beads according to an embodiment of the present invention. Fig. 14 shows the vertical magnetic foxce at a distance z = 0.64 \xm from the binding surface, as a fiinction of the position of the beads for the sensor configuration of Fig. 13. Fig. 15 shows the horizontal magnetic force at a distance z = 0.64 \ixn from the binding surface, as a fiinction of the position of the beads for the sensor configuration of Fig. 13. Fig. 16 shows the magnitude and phase of the magnetic force at a distance z — 0.64 (im from the binding surface, as a fiinction of the position of the beads for the sensor configuration of Fig. 13. Fig. 17 iUustrates the common mode sensitivity at a distance z = 0.64 ^m from the binding surface. for the sensor configuration of Fig. 13. Fig. 18 iUustrates the local barometric height at a distance z = 0.64 |j.m from the binding surface, for beads in the neighbourhood of the sensor configuration of Fig. 13. Figs. 19 and 20 are cross-sectional views of current wires for generating a homogenous particle distribution on the binding surface of a sensor device according" to embödiments of the present invention. Fig. 21 is a cross-sectional' view of a sensor configuration according to an embodiment of the invention. Fig. 28 illustrates a sensor device with as binding surface a porous multi-channel structure. • In the different figures, tbe same reference signs refer to the same or analogous elements. The present invention will be described with respect to particular embodiments and with reference to certain drawings but ihe inventkm is not limited thereto but only by tbe Claims. Any reference signs in tbe Claims shall not be construed as limiting tbe scope. The drawings described are only schematic and are non-lhniting. In the drawings, tbe size of soroe of the elements may be exaggerated and not drawn on scale for illustrative purposes. Where the term "comprising" is used in tbe present description and Claims, it does not exclude otber elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. na" or "an", "tbe", this includes a plural ofthat noun unless something eise is specifically stated Furthermore, the terms first. second third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of Operation in otber sequences than described or illustrated herein. inserBon into the biosensor (e.g. diluted digested degraded biochemically modified, fiftered, dissolved into a bufFer). The original fluids can be for example, biologica] fluids, such as saliva, sputum, blood, blood plasma, interstitial fluid or urine, or other fluids such as drinking fluids, environmental fluids, or a fluid that results from sample pre-treatment The fluid can for example comprise elements of solid sample maierial, e.g. from biopsies, stooL, fbod, feed, environmental samples. The surface of the sensor device may be modified by attaching molecules to it wbich are suitable to bind the target molecules wtrich are present in the fluid. The surface of the sensor can also be provided with organisms (e.g. viruses or cells) or fractions of organisms (e.g. tissue fractions, cell fractions, membranes). The surface of biofogical binding can be in direct contact wiih the sensor chip, but there can also be a gap between the binding surfece and the sensor chip. For example, the binding surface can be a material that is separated from the chip, e.g. a porous material. Such a material can be a lateral-flow or a flow-througb material, e.g. consisting of microchannels in Silicon, glass, plastic, etc. The binding surface can be parallel to the surface of the sensor chip. Alternatively, the binding surface can be under an angle with respect to, e.g. perpendicular to, the surface of the sensor chip. Before the magnetic particles or the target molecules/magnetic particles-, combination can be bound to the surface of the sensor device, they have to be attracted towards that surface. Embodiments of the present invention now provide a metbod for improving the speed of biosensing by improving the speed of at least one of the 'attracting' and/or the 'binding' phases in the assay protocol as described in the background section. Accordiag to embodiments of the present invention, the attracting phase may be speeded up by magnetic actuation of target molecules/magnetic particles combinations. The *bind! process may be optimised by increasing the contact cfficiency (to maximise 1he rate of specific biologica] binding y*ben'the bead is dose to the binding surface) as well as the contact time (the total time that individifäl beads are in contact with the binding surfece. In the following. focus will be laid on a binding assay, more in particular a sandwicb assay, but tbe describcd methods are not limited to this assay type. In a biosensor assay, tbe 'attract1 and "bind' phases need to be made as efficient and as fast as possible. In the 'attract1 phase tbe beads are concentrated from tbe bulk of tbe fluid to a zone near tbe sensor binding surface. The time needed to attract the particles toward the binding surface should be as low as possible, lower than 30 minutes, preferably lower than 10 minutes, and more preferred lower than 1 minute. In the Tjind* phase, the resulting bead ensemble is brought even closer to tbe binding surface in a way to optimise tbe occurrence of desired (bio)chemical binding to tbe capture or binding area on the sensor, i.e. the area where there is a high detection sensitivity by the sensors, e.g. magnetic sensors, and a high biological specificity of binding- It is not trivial to optimise the 'bind' process. Therefore, there is a need to rncrease the contact efficiency (to maximise tbe rate of specific biological binding when the bead is close to the binding surface) as well as the contact time (the total time that individual beads are in contact with the binding surfece). First, the contact efficiency will be discussed The contact efficiency deals with the contact between the surface of the beads that are closest to the sensor and the surface of tbe binding region on the sensor. Ideally, the distance between the biological molecules on the surface of tbe beads and the biological molecules on surface of the binding region of the sensor should be in the order of the size of the biological molecules. for example, a distance of 0-100 nm. wherein I is the current through the current wire and r is the distance between the magnetic bead and the current wire. As an example, a current of 10 niA at a distance of 0.5 ^im from tbe bead may generate, at tbe level of the bead, a field gradient of 8.103 T/m. As another example, the magnitude of the magnetic field gradient in the vicmity of magnetic material embedded in the sensor surfece is calculated The example is * taken that magnetic beads are embedded in tbe material. The magnitude of the magnetic field gradient at a distance r away from the centre of a spherical bead with moment m is approximately given by: (8) For simplicity, the angle dependency of the gradient which may give diffenences of a factor two, has been ignored in equation (8). For example, a 300 um bead with magnetic moment m - 10"16 Am2 may generate a gradient of about 2.103 T/m at a distance of 400 nm. For example, assuming a field gradient of 103 T/m. From equation (6) it can be calculated that for a magnetic moment m, resulting fix>m a Single bead structure (or from a multi-bead structure as in the second aspect of the present invention), of 10" Am" or more, a distance of approach or attraction C can be achieved of 4 nm (if m = 10" Am ) or less (if m is larger than 10~1:> Am2) at room temperature. This mcans that very small distances can in principle be achieved already by using practica! magnetic field gradients, e.g. in the ränge between 10 T/m and 10000 T/m, so that efficient biological binding can take place. result the beads will expose a significant part of their surface area to the binding surface. The surface-to-surface exposure will allow the formation of specific biochemical bonds. According to the prescnt invention, the raagnetic particles may be randomised regularly or irregularly, e.g. by removing and re-applying the magnetic fields attracting the individual magnetic particles to the binding surface of the sensor device, or by rotational excitation of the beads, or by the application of fluid motion such as stirring or acoustic vibratkms. With randomised is meant that magnetic particles which are attracted to the binding surface but which do not bind to the binding surface are shorüy moved away from tbe binding surface but never get very fax frorn the binding surface. i.e. they stay within a short distance from the binding surface in the z-direction, Le. a direction perpendicular to tbe binding surface. Preferably, they stay within 100 \xm frorn the binding surface and more preferably tihey stay within 10 Jim from the binding surface in a direction substantially perpendicular to the binding surface. Acconüng to the invention, the particles are moved away frorn the binding surface such that 90% of the magnetic particles which are attracted to the binding surface stay within 10% or less of the sample volume. Particles do not disperse back into the complete sample volume. The repeated attractions and randomisations ensure that biological material coupled to magnetic beads have a high probability to be at least once in contact with the binding sites on the binding surface of the sensor device during the total assay, i.e. that all targets have a substantial probability to have a contact time with binding sites on the binding surface of the sensor device. The magnetic particles or beads are thus attracted toward and onto the binding surface by means of a magnetic field gradient. The assay should be designed to achieve maximum specific binding (by attraction of the beads toward the binding surface) and minimum hindering of binding (all beads should have a significant probability to interact with binding sites on the binding surface of the sensor device), and minimum unwanted unbinding (due to forces breaking the desired bonds between beads and binding surface). Solution and/or to extract this material. Secondty. when magnetic particles are rotated with respect to another body, for example the surtace of a biochip or the surface of a cell, the interaction and binding rate between the labe! and the other body can be enhanced. The increase of the binding rate may particularly be of importance when the surfece area of the labe! is large with respect to the size of the relevant molecular binding region on the magnetic particle. This is, for example, the case in low-concentration assays, when a catching or fishmg step yields magnetic particles with only very httle biologieal material of interest on the magnetic particle surface. For reference, some calculations on the role of orientation and rotation in biomolecular kinetics can be found in "K.S. Schmitz and J. M. Schurr. "The role of orientation constraints and rotation dtffiision in biomolecular Solution kinetics', J. Phys. Chem., voL 76, p. 534 (1972)". The ideal rotation speed is given by an optimal binding rate at acceptable unbinding rate for the biochemical bond that needs to be forraed in the given assay time. In other words, the rotation is optimised for sensitivity as well as speeificity. To avoid removal of the desired specific bindings, the applied forces need to be below 1 nN. In a second aspect the present invention furthermore proposes the use of multi-particle magnetic struetures, such as e.g., but not limited thereto, chains or eoliimns of magnetic particles or beads, e.g. for achieving enhanced speed in biosensing, More particularly. aecording to the invention, multi-particle struetures are used to increase the speed of the process steps 'attract' and/or 'bind' in a biosensing protocol. It has to be noted that magnetic particles can be used in various types of assays, e.g. a binding or unbinding assay, sandwich assay, displacernent assay. Inhibition assay, or competition assay. In the foüowing, focus will be laid on a binding assay, more in particular a sandweh assay, but the described methods are not limited to this assay type. according to the second aspect o^the present invention may comprise a corobination of large and small particles but may.also bc structures comprising particles with simüar size. Typically, multi-particle structures may comprise 5 to several 1000 magnetic particles or beads, but even higher numbers are also possible. In the following description the second aspect of the invention will be described by means of chains or columns of magnetic particles. It has, however. to be understood that this is only for the ease of explanation and that this is not linüting to the invention. Other multi-particle structures can also be used according to the second aspect of the invention, e.g. Clusters of magnetic particles, or Single or multiple loops, or rings of magnetic particles. Thus, one example of a multi-particle strueture which can be used according to the second aspect of this invention is a cfaain 10 of magnetic particles or beads. It is known that magnetic particles or beads form chains 10 when the inter-bead magnetic forces exceed the thermal motion. Magnetising magnetic particles or beads in a magnetic field has the effect of inducing a dipole-dipole interaction between neighbouring beads, which, if the interaction energy exceeds the thermal energy of the particles, results in the formation of chains 10 of magnetic particles in the dixection of the magnetic field lines. Over time. the chains 10 interact with each other to form columns. In. for example, a uniform magnetic field without field gradients, the chains and columns can arrange in regulär pattems due to repulsion caused by the dipole moments: This is illustrated in Fig. 2, which shows magnetic bead interactions and formation of chains 10 in the presence of a uniform magnetic field in a Square capillary tube 11 of 50 pm [Baudiy et al., I Pbys. Cond. Matt. 16, "R469 (2004)]. rnagnetic field is removed Furthermore. rnagnetic particles initial!}7 ordered as chains can form loops or rings when the field is removed In the following description, the second aspect of tbe present invention will be fiuther deseribed by means of chains 10 of beads. This is only for the ease of explanation and is not limiting to the invention. In the following, the formation of chains 10 of particles will be discussed. The ratio X of interaction energy of two parallel dipoles in contact and the thermal energy is given by: (2) wberein U is energy of interaction between rnagnetic beads, k the Boltzmann-constant 138054 10"23 J/K and T the temperature in Kelvin. Tbe energy of interaction U can also be deseribed by: (3) wberein (io is the permeability of vaeuum (47t. 10" H/m), mi and rr>2 the rnagnetic moment of a first respeclively a second rnagnetic particle or bead r the center-to-center distance of the rnagnetic particles or beads and f is the unit vector in the direction of the path between two centres of particles. This can be broadened to particles with dissimilar radii. For example. in case of a mixture of large beads with large moments and small beads with small moments. . tbe beads with larger moment will more strongly attract each other for a given center-to-center distance. As a consequence, the large particles can form chains while the particles 'having a smaller moment will collect around or as close as possible to the poles of the larger particles. Manipulating the larger particle chain directly manipulates the smaller particles. Combination of equations (2) and (3) with ml=m2 leads to: decreases. the motional freedom of the beads in the chain 10 increases and tbe chains 10 show shape fluctuations. Tbe chains 10 dissociate wben the ratio becomes smaller than unity. The force of interaction or attraction Fi^between magnetic particles or beads in attractive alignment (unlike wben poles of tbe same nature are touching) can be represerrted by tbe following equation: (5) wberein F« is expressed in N. Preferably, according to tbe second aspect of tbe present invention, supeiparamagnetic particles or beads may be used. Superparamagnetic particles or beads are ferromagnetic beads so small tbat they quickly lose tbeir magnetic moment in absence of an externa! magnetic field. Superparamagnetic particles or beads are readily magnetised to large magnetic moments, facilitating detection, yet tbe rnutual magnetic attraction can be switched off, preventing irreversible aggregation. In general, superparamagnetic particles or beads with a diameter of, for example, about 300 nm rnay require a field of only 4 to 10 mT to form chains 10 of beads. The speed of chain fbrmation and the chain length may be determined by the particle or bead concentration and the.particle or.bead magnetic moment [Zhang, Phys. Rev. E51, 2099 (1995)]. The chains 10 according to embodiments of the present invention may. for example, have a length in the order of about 100 particles. The surface of the magnetic particles or beads may be prepared to allow reversible aggregation, i.e. the formation of multi-particle structures in the presence of a magnetic field and the dissociation of the multi-particle structures when the magnetic fields are subsequently removed. It is shown by experiments that reversible chain fbrmation is possible with e.g. 300 nm particles obtainable from Ademtecb. The surface of the beads may In the 'bind* phase. the resulting bead ensemble is brougbt even closer to tbe binding surface in a way to optimise tbe occurrenceof desired (bio)chemical binding to the capture or binding area on the sensor. i.e. the area where there is a high detectiorj sensitivity by tbe sensors, e.g. magnetic sensors, and a high biological specificity of binding. It is not trivial to optimise the "bind' process. Therefore, there is a need to increase the contact efficieocy (to maximise the rate of specific biological binding when tbe bead is close to the binding surface) as well as the contact time (the total time that individual beads are in contact with the binding surface). Contact efficiency and contact time have been discussed above with respect to the first aspect of the present invention. With regard to contact time, wben a large number of beads or particles is attracted to the binding surface of a sensor device and the complete binding surface becomes covered with magnetic particles, the multi-particle structure will be very dense but also static and rigid. Due to translational constraints, a large fraction of particles cannot reach the binding surface and will not have a chance to form a desired specific biochemical bond. This causes a loss of signal in the biosensor and thus a false reading or an unnecessarily long assay time. ■ . The above analysis leads to the conclusion that multi-bead structures do generale a high contact area with the binding surface. but cannot be beneficially used in a magnetic biosensor due to the low translational dynamics inside the multi-bead structure. However. the inventors have realised that there is a way to solve this. Therefore, it must be realised that inside the multi-bead structures, individual beads maintain a freedom of rotation. For example. superparamagnetic beads have a very weak magnetic anisotropy, so a very but neverget very far from the binding surfece. i.e. they stay mithin a short distance from the binding surfece in the z-direction. Preferably, tbey stay within 100 p.m from the binding surfece and more preferably they stay within 10 Jim from the binding surfece in a direction ^ubstantially perpendicular to the binding surfece. According to the invention, the particles are moved away from the binding surfece such that 90% of the magnetic particles which are part of a multi-particle structure stay within 10% CHT less of the sample vohrme. Particles do not diverse back into the complete sandle vohnne. The repeated attractions and randomisarions ensure that biological material coupled to magnetic beads have a high probability to be at least once in contact with the binding sites on the binding surfece of the sensor device during the total assay, i.e. that all targets have a substantial probability to have a contact time with binding sites on the binding surfece of the sensor device. The magnetic particles or beads are thus attiacted toward and onto the binding surfece by means of a magnetic field gradient. The beads involved in the binding process will be part of multi-bead structures, characterised in that the beads have a probability larger than 80% to have the surfece of at least one other bead in their vicinity, i.e. within a bead-surface to bead-surfece distance of two times the bead diameter. In conclusion, the assay should be designed to achieve maximum specific binding (by attraction of the beads toward the binding surfece) and minimum hindering of binding (all beads should have a significant probability to interact with binding sites er, the binding surfece of the sensor device), and minimum unwanted unbinding (due to forces breaking the desired bonds between beads and binding surfece). when a catching or fishing step yields magnetic particles with only very lhtie biobgical material of interest OD the magnetic particle surface. For reference, some calculations OD the role of orientation and rotation in biomolecular kinetics can be found in "K.S. Schmitz and J. M. Schurr. 'The role of orientation constraints and rotation diffusion in biomolecular solutbn kmetics\ J. Phys. Chem., voL 76, p. 534 (1972)". The ideal rotation speed is gjven by an optimal binding rate at acceptable unbinding rate for the biochemical bond that needs to be formed in the gjven assay time. In other words, the rotation is optimised for sensitivity as well as specificity. To avoid removal of the desired specific bindings, the applied forces need to be below 1 nN. According to a first embodhnent of the second aspect of the present invention, the use of magnetic fields which are oriented essentially peipendicularly to the sensor surface 14 of the sensor device 15, i.e. according to the orientation axes mentioned in the drawings, oriented in the z-direction, is described. This is illustrated in Fig. 3. A uniform magnetic field, indicated by arrow 12, induces the formation of particle or bead chains 10. comprising a phirahty of magnetic particles or beads 13, as described earlier. Then, a magnetic field gradient may be generated for attracting the magnetic particle or bead chains 10 toward the surface 14 of the sensor device 15. The magnetic field gradient may be provided by at least one magnetic field gradient generating means 16. In the example illustrated in Fig. 3 the magnetic field gradient is generated by means of an external coil 16 which is positioned under the sensor device 15 and which is used to generate forces toward and from the sensor surface 14. In embodiments of the present invention, the sensor device 15, which may be used according to the present invention. may cornprise at least one magnetic sensor dement and at least one magnetic field generating means for generating a magnetic field foi forming bead chains 10. Tne magnetic sensor dement may preferably be a magneto-resistive sensor along the z-axis, i.e. along the long axis of the bead chains 10 which are represented as open circles. The z-oriented field generates the bead chains 10. The local current wire generates a field gradient in the middle of tbe loop 30. When the field generated by the loop 30 has the same orientation as the externa! field, the field is larger inside the loop 30 than outside the loop. Therefore, the chains 10 are attracted into the middle of the loop 30. When the current is reversed, the field generated by the loop 30 will oppose the external field in tbe middle of the loop 30, and as a consequence the chains 10 will be pushed out of the loop 30. Simüariy, Fig. 27, which is a top view along the long axis of the bead chains 10 of a configuration comprising two current wires with a sensor in the middle, illustrates how currents in current wires can be used to concentrate bead chains 10 onto a sensor binding region. It has to be noted that the presence of a magnetic sensor or other magnetic materials in a chip can influence the fields near the sensor, due to magnetostatic or flux guiding properties. An advantage of the out-of-plane chain orientation is that flux guiding is low due to the in-plane shape anisotropy of magnetic thin films. The magnetic field gradient may be modulated in-phase with the modulation of the chain-foiming magnetic field 12, which results in attraction of bead chains 10 to the sensor surface 14. When the modulation is applied in anti-phase, the field gradient is reversed and as a result the bead chains 10 may be repelled from the sensor surface 14. This is illustrated in Fig. 4 which shows the effect of repelling (reference number 17) and attracting (reference number 18) magnetic particle or bead chains 10 from and to the surface 14 of a sensor device 15 respectively. Repelling the bead. chains 10 may generale stringency,-which ma)' differentiate between (strongly) bound and weakly bound beads or particles 13 on the sensor surface 14. In case the binding surface 40 is parallel to the sensor surface 14, located on or near the sensor surface 14, the above-described embodiment has the disadvantage that not all magnetic particles 13 can come very close to the binding surface 40 due to the multi-particle structures 10 having their long axis in a plane perpendicular to the plane of the binding surface 40. However, in case the binding surface 40 is a porous medium with walls essentially perpendicular to the sensor surface 14, the beads 13 in the multi-partiele strocture 10 wirich are lying in a plane substantially parallel to the binding surface 40 can make good contact to the binding surface 40. This is iDustrated in Fig. 28, where the binding surface 40 is provided on walls of a porous multi-channel structure, whkh walls are oriented perpendicularly with respect to the sensor surface 40. The Channels in the multi-charmel structure may e.g. be tubes or shts. The multi-particle structures 10 may attracted to fhe binding surface 40 e.g. by means of a magnetic gradient in a direction perpendicular to the binding surface 40, in the embodiment shown parallel to the sensor surface 14. After the 'attract' phase, a 'binding' phase takes place, i.e. binding sites on particles 13 in the multi-particle structures 10 come into contact and bind with binding sites on the binding surface 40. According to the present iiiventioru the position of individual magnetic particles 13 in the multi-particle structures 10 is randomised with respect to the binding sites on the binding surface 40 to give the binding sites on the individual particles 13 in the multi-particle structures 10 a substantial probability to have a contact time with binding sites on the binding surface 40. This randomisation may be done by changing the magnetic field gradient in a direction perpendicular to the binding surface 40. After the binding phase. the multi-particle structures 10 are no longer attracted to the binding surface 40, unbound particles 13 are washed away and detection of particles bound onto binding surface 40 can take place. This detection can e.g. be a magnetic detection or an optical detectiorL Typically in biological tests When.the binding surface 40 is essentially parallel to the sensor surface 14, in particular the-binding surface 40 is part of the sensor surface 14, to achieve a srnall distance between most of tbe particles or beads 13 in a chain 10 and the binding surface 40. it is advantageous to align the bead chains 10 along the binding surface 40, i.e. to apply magnetic fields with strong in-plane components, i.e. in the x- or y-direction. This is described in a second embodiment of the present invention. Magnetic fields with strong in-plane compor>ents xnay be applied by off-chip as well as by on-chip field-generating means. On-chip fieki generaiion has the strong advantage that tbe unavoidable magnetic crosstalk to the magnetic sensing element, e.g. a GMR, is well defined 1 Hence, according to the second aspect of the present invention, a magnetic field generaiing means is adapted to form multi-particle magnetic structures 10 which have a long axis lying parallel to the binding surface 40. A magnetic field is applied with a strong in-plane component parallel with the binding surface 40 of the sensor device 15, e.g. by placing the device near a permanent magnet and/or a coil. Multi-particle magnetic structures, in the example given chains 10. are formed and attracted towardthe binding surface 40. According to this second embodiment preferably, at least one current wire 19 may be positioned close to and underneath the binding surface 40 of a sensor device 15, preferably within 3 mm, more preferably within 30 micrometer and most preferred within 3 micrometer. The formed particle or bead chains 10 then Orient substantially parallel to the surface 14 of the sensor device, in a direction substantially perpendicular to the direction of the current in tbe at least one current wire 19, and will be pulled toward the binding surface 40, as is sketched in Fig. 5. In this figure, the current direction in the current wire 19 is indicated by arrow 20 and the orientation of the particle or bead chains 10 is indicated by arrow 21. have the highest magnitude above the sensor) multi^partkle magnetic structores or magnetic bead chains 10 may then be detected by at least one magnetic sensor dement by applying currents in the at least two current wires 22a, 22b in the same direction, in that way effectively measuring the amount of beads or particles 13 present on the binding surface 40. Alternatively, the multi-particle structures may be detected by e.g. an optical detection element Also, fields oriented essentially along the x- or y-axis may be used according to the present invention, i.e. for in-plane orientation of the magnetic multi-particle structures. A magnetic force may be generated along the z-axis by applying cuirents in at least one cmrent wire 22. The force will be attractive when the fields from the current wire 22 increase the local field above the surface, thus generating a positive Seid gradient toward the sensor surfece 14. A disadvantage of applying in-plane fields is that these are along the sensitive direction of the magnetic sensor and will influence the properties of a magnetic sensor device 15. One Solution is to time-separate the two processes: sequentially actuate and detect the particles. Fig. 6 shows a possible configuration of a magnetic sensor device 15 for integrated attraction and detection of magnetic beads or particles 13 oriented in multi-particle magnetic structures. The magnetic sensor device 15 in this example may comprise a magnetic sensor element 23 and at least a first and second current wire 22a resp. 22b. This may be a preferred sensor configuration for altracting magnetic beads or particles 13 in multi-particle magnetic structures 10 close to the binding surface 40. A same current but in opposite directions is applied to the first and second wires 22a, 22b positioned at both sides A, B of ■ the magnetic sensor element 23. The benefit of this will be described hereinafter. For the ease of explanation. the following discussion will be done by rneans of a single bead 13 and with > fields" generated only by local on-chip wires. It is. however, to be understood that this may also be applied to the multi-particle magnetic structures 10 of the present invention and can be generalized when more field-generating means are added. Fig. 7 shows a cross-section of the sensor device 15 of Fig. 6, A magnetic sensor eleroent 23 and a first and second current wire 22a, 22b are positioned on top of a Substrate 24. Tbe dashed line, indicated by reference number 14, represents the sensor surface of the sensor device. A portion of the sensor surface 14 is the binding surface 40 comprising binding sites (not represented in detail). A co-ordinate system has been introduced in Fig. 7 in order to make tbe following explanation more clear. Fig. 8 shows the vertical magnetic force F^g^x) (see equation (12)), i.e. the magnetic force in the direction perpendicular to tbe sensor surface 14, the z-direction as indicated by the co-ordinate system in Fig. 7. as a function of the position of the magnetic particle or bead 33 in the sensitive directioD of the sensor. the x-direction. For the particles 13-wilI be attracted more closely toward tbe edges of the current wires 22a, 22b than toward the centre or middle of the current wires 22a. 22b (see further). Fig. 9 shows the corresponding horizontal magnetic force Fmag^x) (equation (11)), Le. tbe magnetic förce in the sensitive direction of tbe magnetic sensor device 15, tbe x-direction as ülustrated in Fig. 7 by tbe co-ordinate System, and this as a ftmction of tbe Position of tbe magnetic beads 13 in tbe x-direction. Agaio, for tbe constmction of Fig. 9, Fmp^x) is determined at a distance of 0.64 pm from tbe binding surface 40 (i.e. z = 0.64 lan). It can be seea from Fig. 9 tbat the horizontal magnetic force FTm^IVC(x) is much bigger in tbe middle of tbe fest and second current wires 22a resp. 22b than it is at the edges of tbe current wires 22a, 22b. This means tbat magnetic particles or beads 13 located above the centre of tbe current wires 22a, 22b will be more transported in the x-direction than magnetic particles or beads 13 located above the edges of the current wires 22a, 22b. The same happens to tbe formed multi-particle magnetic structures 10. Forces acting on a multi-particle magnetic strukture 10 are larger than forces acting on a Single bead 13 (if tbe multi-particle magnetic structure 10 e.g. comprises a plurality of beads 13 of tbe same type as tbe one compared to), due to the larger magnetic moments of a multi-particle magnetic structure 10. Fig. 10 shows the magnitude, indicated by curve 25, and phase, indicated by # curve 26. of the resulting magnetic force (combination of Fnagn^(x) of Fig. 8 and Fmagnjc(x) of Fig. 9). From Fig. 10 it is clear tbat above the centre oflhe current wires 22a, 22b tbe magnetic field is perfect in-plane oriented (0°). The curves depicted in Fig. 8, Fig. 9 and Fig. 10 are obtained under the condition that no multiple-particle structures are formed and that no externa] magnetic field is applied. Because of the above-described forces, tbe magnetic particles or beads 13 are transported over tbe sensor surface 14 towards the edges of the first and second current wire 22a, 22b. (14) The distance of approach or the barometric beight distribution % is illustrated in Fig. 11, which illustrates the barometric height due to the vertical magnetic force F^ag^x) phis gravitation. This curve is obtained under the conditkm that DO multi-particle structures are formed and that DO external magnetic field is applied. From this figure it can be conckided that for the configuration with the dimensions described in Figs. 6 to 12, in the iange -3 \xm The above-obtained ränge (-3 \im . This embodiment of tbe invention has tbe advantage that both means for. attraction of beads 13 and means for detection of beads 13 are integrated on the magnetic sensor Substrate 24. In this embodirnent no externa] actuation means is required for attraction of the beads 13. However, according to a further embodiment of the invention, additional externa! magnetic fields may be applied to the sensor device 15 as described in the former embodiment for e.g. realising a still fester attraction of magnetic particles or beads 13 froin tbe bulk toward the binding surfece 40 or for stirring. An additional external magnetic field with low gradient, however, does not realise the fotce required for attracting the magnetic particles or beads 13 close to the binding surface 40. Preferably, AC fields may be used for tbese additional external magnetic fields. DC fields, which may originale froro e-g, permanent rnagnets, will shift the R(H) resistance change characteristic from the magnetic sensor eleraent 23 and introduce gain variations. On the contrary, AC fields will only introduce additional frequency components, which may or may not interfere with the detection mechanism and may or may not introduce gain errors. Therefore, preferably AC fields may be used which have a frequency such that the detection mechanism is not affected Furthermore, the attack and decay of the envelope of such additional external magnetic fields should be relatively slow compared to the actual frequency in order to not generate magnetic build-up in the sensor 10. Abrupt switching of magnetic fields will introduce remnant magnetic fields in the sensor. By slowly increasing and decreasing the amplitude, this effect mav be avoided. may be used several times, where the tightly bonded beads are not removed but used as a starting (calibration) point for a next measurement For sensor devices 15 with a non-uniform sensitivity across the sensor surface 14 the applied magnetic fields should be arranged in a way to give the highest density of bound paxticles or beads 13 in the high-sensitivity regions of the sensor device 15 (see further). Hereinabove, calculations of distribution of force have been shown and compared to the areas of highest sensitivity. Magnetic structores, such as individual magnetic particles or multi-particle magnetic structores or magnetic bead chains 10, will be attracted to the binding surface 40 where the particles or beads 13 can be detected by the detector or sensor element 23. According to embodiments of the invention, the attractive force (Fma^z) may be strong enough to bring the particles or beads 13 to the sensor surface 14 within a ränge in the order of nanometers, i.e. in the ränge of the size of biological molecules the sensor surface 14 may be modified with in order to form the binding surface 40 so as to bind the target molecules present in the fluid to be analysed, which are bound to magnetic particles or beads 13. For sensor devices 15 with a uniform sensitivity across the binding surface, the surface coverage by magnetic particles or beads 13 should be as uniform as possible, i.e. magnetic struetureä, such as individual magnetic particles or multi-particle magnetic structures or magnetic bead chains 10, should not be attracted only to the edges of the sensor devices. A uniform particle distribution can be achieved under the following conditions: wherein equation (20) is derived from Maxwell equation VB == 0. According to embodiments of the present invention, possible arrangements of current wires 22 which may be used according to the present invention lo generale such flelds ^ * * which lead to a uniform attraction across the sensor surface 14 are sketcbed in Fig.' $9 and 20, which show cross-sectional views of possible current wire configurations to generale a homogenoife particle distribution OD the sensor surface 14 of the sensor device 15. In this figures, the cunents in the current wires 22 ran in a direction perpendicular to the plane of tbe paper. According to embodiments of the invention, the Variation of magnetic field gradient in the xnlirection (and thus the magnetic force in the x-direction) may be reduced by introducing additional current-wires 21, for example by adding a current wire 27 below the current wire 22 (Fig. 19) or by adding current wires 27a, 27b next to the current wire 22 (Fig. 20). Alternatively added current wires may be a plurality of current wires, a so-called segment of current wires. dement 23. Current wire 22 may have a lower electrica] resist2nce than sensor dement 23r so . that the current wixe 12 is more suited for the generation of magnetic fields. As explained above with respect to the second aspect of the present invention, an in-plane magnetic field may create in-plane multi-particle magnetic structures or magnetic bead chams 10. These multi-particle magnetic structures or magnetic bead chains 10 may, in some embodiments, be attracted to the sensor surface 14 by magnetic field gradients oriented in a dnectkm sobstantially perpendicular to the sensor surface 14 inducedby, ibr example, current wires 22 close to the sensor surface 14. the magnetic field gradients induced by current wires 22 may, in the case of a circular current wire 22 and disregarding matrix effects of the surrounding, be essentially axially symmetrica!. This means that there is also an in-plane gradient which exerts forces substantially perpendiculariy to tbe axis of the multi-particle magnetic structures or magnetic bead chains 10 at the sensor surface 14. This will lead to a non-homogeneous distribution of the multi-particle magnetic structures or magnetic bead chains 10. The Solution ibr this problem is to use a 1D array 28 of current wires 22a, 22b. 22c and address these current wires 22a, 22b, 22c in a sequential manner. This is illustrated in Fig. 22. The right hand part of this drawing shows a cross-section of the array 28 of current wires 22a, 22b, 22c. The in-plane gradient is varied. The multi-particle,magnetic structures or magnetic bead chains 10 are volling over the sensor surface 14 in order to create a continuous rollrng motion and in this way improvethe binding kinetics as all parts of the multi-particle magnetic structures or magnetic bead chains 10 get in close contact with the binding surface 40 in this rolling motion. The main directkm of the magnetic field is indicated by arrow 29. A further embodiment according to the present invention is an advantageous combination of the first and second embodiments. Magnetoresistive sensors Clements 23 > for example, are sensitive to in-plane fields. In case large fields are needed for particle manipulation, these are preferably applied oct'-of-plane. may be induced causing the multi-particle magnetic structures or magnetic bead chains 10 of particles or beads 13 (formed in an extemally applied out-of-plane field) to rotate and He flat with respect to the binding surface 40. The magnetic field gradiert attracts the multi-particle magnetic structures or magnetic bead chains 10 to the sensor surface 14 of the sensor device 15. In other embodiments according to the present inventiorL, uniform external fields, MMMmiftHTO external fields or on-chip current wires may be used to Staate the magnetic particles 13. Fig. 24 ilhistrates examples of sequences of Signals to drive the different field-generating means. Curve 30 ülustrates on-chip currents in current wires 22a, 22b for the attraction of magnetic particles or beads 13 toward the sensor surface 14. Curve 31 illustrates the excitation sequence of a small external coiL Part 31a of curve 31 represents the attraction of the beads from the bulk to the sensor surfece 14 and part 3 lb represents the repelling fbrce into the bulk. Curve 32 illustrates the excitation sequence for a large coil to magnetise the particles or beads 13 and form columns or chains 10. The present invention has been described mainly by using magneto-resistive sensors 23 for the detection of magnetic particles or beads 13. It has, however, to be noted that the beads 13 may also be detected by other magnetic sensor means, such as, for example, with Hall sensors, coils, etc. As earlier described, in embodiments according to this present invention, enha^ced rotation of the beads 13 can also used to improve the speed of the 'binding' step. The second aspect of the present invention shows different advantages. Due to the larger volume and resulting larger shear forces, multi-particle structures 10 are mpre sensitive to fluid washing steps than single particles 13. This may result in more effective washing and less non-specific binding. Magnetic beads 13s as used in any of tbe frrst or second aspects of the invention, can be attracted to a sensor surface 14 from a lafge vohime sample, using magnetic forces alone or in combination with the Sedimentation and diffusion processes. Furthermore, chains 10 of magnetic bea*fc l? in accordance with the second aspect of the invention can be attracted toward tbe binding surface 40, which locally creates a high bead concentration, a good cöntact between beads and sensor binding surface 40, and thus an increased binding rate. The processes of the beads 13 near tbe sensor surface 14 (e.g. attract, bind, stringency, and their repetitions) can all be roeasured as a function of time. Tbe data are indicative of tbe kinetics of the processes. The kinetics depend on the target concentration in tbe Solution, and as sx;h the data can indicate what the target concentration was as-socm as the signal appears above the noise. Also, the measurernent of kinetics allows the measurernent in a large dynamic ränge, because a high target concentration will be detected very rapidly (e.g. in a few seconds) white low target concentrations can be detected after a much longer processing time (e.g. minutes to hours). Also, the kinetics and noise Signals can be analysed as a quality control, to check if the assay has evolved correctly and ensure for the end-user that the test result is reliable. CLAIMS: 1. A sensor device (15) for detecting magnetic particles (13), the sensor device (15) having a binding surface (40) wilh binding sites thereon and comprising: at käst one sensor dement (23) for, detecting the presenee of magnetic particles (13), means for attractmg magnetic structures toward and onto tbe binding surface (40) of tbe sensor device (15), said magnetic structures comprising at least one magnetic partkle (13), means for re-arranging and randomizing tbe position of individual magnetic particles (13) with respect to tbe binding sites on tbe binding surface (40) to give binding sites on all individual particles (13) a substantial probability to have a contact time witb binding sites on tbe binding surface (40). 2. A sensor device (15) according to claim 1, tbe magnetic particles (13) being present in sample volume, wherein said means for re-arranging and randomising the position of individual magnetic particles (13) is adapted such that individual magnetic particles (13) are loosened from the binding surface (40) such that 90% of the individual magnetic particles (13) which are part of a magnetic structure (10) stay within 10% of the sample volume. 3. A sensor device (15) according to any of the previous claims, furthermore comprising field generating means adapted for forming multi-particle magnetic stmctures (10) having a long axis substiantially parallel with the binding surface (40) of the sensor device (15), said irmiti-particie structures (10) comprising a pluralhy of individual magnetic particles (13). 4. A sensor device (15) according to claim 3. wherein the field generating means adapted for forming multi-particle magnetic structures (10) is an on-chip or an off-chip magnetic field generating means. 5. A sensor device (15) according to any of Claims 3 or 4, wherein the multi- particle structures (10) are chains of magnetic particles 6. A sensor device (15) according to any of the previous Claims, wherein tbe roeans for attracting said magnetic structures toward and onto the binding surfece (40) of the sensor device (15) is an on-chip or an off-chip means. 7. A sensor device (15) -according to claim 6. wberein the means for attracting said magnetic structures toward and onto the binding surface (40) of the sensor device (15) is an on-chip or an off-chip element having a relative permeability larger than one. 8. A sensor device (15) according to claim 7, wherein said on-chip or off-chip element changes position or shape ifi order to locally vary a generated magnetic field gradient 9. A sensor device (15) according to claim 1, wherein the roeans for attracting said magnetic structures toward and onto the binding surface (40) of the sensor device (15) comprises a first current wire (22) and at least one additional current wire (27). 10. A sensor device (15) according to claim 1, wherein the means for attracting said magnetic structures toward and onto the binding surface (40) of the sensor device (15) comprises an array (28) of current wires (22). 11. A method for a biosensing process. the biosensing process comprising detection of magnetic particles (13) by me-ans of a sensor device (15) having a binding surface (40) with binding sites thereon, the method comprising: 12. A method according to claim ] 1, magnetic particles (13) being.present in a sample volume, wberein-re-arranging and randomising the position of tbe individual magnetic particles (13) is such that individual magnetic particles (13) are loosened from.the binding surface (40) such that 90% of the particles (13) stays within 10% of the sample volume. 13. A metbod according to any of claims 11 or 12. furthexmore comprismg applying a magnetic field adapted for forming multi-particle magnetic structures (10) having a long axis substiantially parallel with the binding surface (4flL)*of the sensor device (15), said multi-particle magnetic structures (10) comprising a plurahty of individual magnetic particles (B). 14. A method according to claim 13,-wherein applying a magnetic field is performed by applying a chain fonning magnetic field for forraing chains (10) of magnetic particles. 15. A method according to claim 11, wherein attracting said magnetic structures toward and onto the binding surface (40) is performed by applying an on-chip or an off-chip magnetic field 16. A method according to claim 15. wherein attracting said magnetic structures toward and onto the binding surface (40) is performed by applymg a magnetic field gradient in a direction substantially perpendicular to the binding surface (40) of the sensor device 05). first currem wire (22a) and sending a second current through tbe second current wire (22b), the first and second current being equal in magnitude. 19. A method according to claim 15, wberein attracting said magnetic structures toward and onto tbe binding surface (40) is performed by an array (28) of current wires (22a, 22b). 20. A metbod according to claim 13, wberein applymg a magnetic field adapted * for fbnning multi-particle magnetic structures (10) having a long axis essentially in plane substantially parallel with tbe binding surface (40) of tbe sensor (15) comprises: applying a first magnetic field ibr forming of out-of-plane multi-partiele structures, and subsequently applying a second magnetic field for orienting tbe multi-particle structures so as to have a long axis essentially in-plane substantially parallel with tbe binding surface (40) of the sensor device (15).

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3363-CHENP-2007 AMENDED CLAIMS 15-07-2014.pdf

3363-CHENP-2007 AMENDED PAGES OF SPECIFICATION 15-07-2014.pdf

3363-CHENP-2007 CORRESPONDENCE OTHERS 17-03-2014.pdf

3363-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 15-07-2014.pdf

3363-CHENP-2007 FORM-3 15-07-2014.pdf

3363-CHENP-2007 OTHERS 15-07-2014.pdf

3363-CHENP-2007 POWER OF ATTORNEY 15-07-2014.pdf

3363-chenp-2007-abstract.pdf

3363-chenp-2007-claims.pdf

3363-chenp-2007-correspondnece-others.pdf

3363-chenp-2007-description(complete).pdf

3363-chenp-2007-drawings.pdf

3363-chenp-2007-form 1.pdf

3363-chenp-2007-form 26.pdf

3363-chenp-2007-form 3.pdf

3363-chenp-2007-form 5.pdf

3363-chenp-2007-pct.pdf

3363-CHENP-2007-Petition for Annexure.pdf