WO2011128807A1

WO2011128807A1 - Heating of magnetic particles in a biosensor cartridge

Info

Publication number: WO2011128807A1
Application number: PCT/IB2011/051452
Authority: WO
Inventors: Jeroen Veen; Jeroen Hans Nieuwenhuis
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2010-04-15
Filing date: 2011-04-05
Publication date: 2011-10-20

Abstract

The present invention relates to a biosensor and method of heating a liquid contained in a measurement chamber (10) of a biosensor, wherein a time-varying magnetic field is provided by electromagnets (20) in the measurement chamber (10). The time-varying magnetic field is applied in a manner to obtain an at least substantially spatial homogenous distribution of the time-varying magnetic field in the measurement chamber (10). Thereby, the temperature or shell temperature of particles (e.g. labels or beads) provided in the liquid of the measurement chamber can be directly increased to effectively heat the liquid and control the temperature of bio-chemical reactions on or near the particle label surfaces.

Description

HEATING OF MAGNETIC PARTICLES IN A BIOSENSOR CARTRIDGE

FIELD OF THE INVENTION

The present invention relates to a heating device and method for heating a magnetic label in a sensing device.

BACKGROUND OF THE INVENTION

In the field of diagnostics, especially in biomedical diagnostics, such as medical and food diagnostics for both in vivo and in vitro application, but also for animal diagnostics, diagnostics on health and disease, or for quality control, the usage of biosensors or biochips is well known. These biosensors or biochips are generally used in the form of micro-arrays of biochips enabling the analysis of biological entities such as e.g. DNA (desoxyribonucleic acid), RNA (ribonucleic acid), proteins or small molecules, for example hormones or drugs. Nowadays, there are many types of assays used for analysing small amounts of biological entities or biological molecules or fragments of biological entities, such as binding assays, competitive assays, displacement assays, sandwich assays or diffusion assays. The challenge in biochemical testing is presented by the low concentration of target molecules (e.g. pmol.l and lower) to be detected in a fluid sample with a high concentration of varying background material (e.g. mmol.l ). The targets can be biological entities like peptides, metabolites, hormones, proteins, nucleic acids, steroids, enzymes, antigens, haptens, drugs, cell components, or tissue elements. The background material or matrix can be urine, blood, serum, saliva or other human- derived or non-human-derived liquids or extracts. Labels attached to the targets improve the detection limit of a target. Examples of labels are optical labels, colored beads, fluorescent chemical groups, enzymes, optical barcoding or magnetic labels.

Biosensors may employ a sensing surface with specific binding sites equipped with capture molecules. These capture molecules can specifically bind to other molecules or molecular complexes present in the fluid. Other capture molecules and labels facilitate the detection. Targets and labels are allowed to bind to the binding sites of the biosensor sensing surface in a specific manner which may hereinafter be called "specifically attached". Bio-active entities (e.g. capture molecules or binding sites) may be sketched or described as being directly coupled to a solid carrier (e.g. sensor surface or label). Such bio-active layers amay be linked to a solid carrier via intermediate entities, e.g. a buffer layer or spacer molecules. Such intermediate entities are added to achieve a high density and high biological activity of molecules on the surface. In contrast to this biological attachment to the sensing surface, labels can also attach to the sensing surface in a non-specific or non-biological manner, i.e. bind to the surface without mediation of the specific target molecules.

The use of magnetic labels in biological assays offers several advantages for use in point-of-care diagnostics tests. They are fast, since the magnetic beads provide a large surface area and because they can be homogeneously dispersed in the sample the distance that needs to be covered by diffusion can be minimized. By actuating the beads and attracting them to the sensor surface an upconcentration of target molecules (bound to magnetic labels) takes place. This speeds up the binding to the detector surface.

Furthermore, they are reliable. Once beads are attracted towards the sensor surface a bound- free separation needs to take place. Conventionally this is done by fluidic washing, which generally causes variations in the outcome of the assay. By applying accurate forces via magnetic field gradients a reliable result can be obtained. Additionally, they are easy to use. The use of magnetic beads allows manipulation of the magnetic labels (by applying proper actuation fields) in order to eliminate conventional steps in the assay procedure. One example is the fluidic washing. This significantly simplifies the cartridge.

While performing the measurements, the liquid temperature is important. Depending on the molecules to be tested and liquid viscosity an optimal temperature window exists. Reaction kinetics and viscosity both are a function of temperature.

For biosensor applications typically heating is considered as a means to influence the temperature, since most bio-chemical processes work optimally at a temperature of about 37 °C: a temperature above ambient. Furthermore, to include cooling in a handheld device is typically rather difficult.

To heat the biosensor cartridge, Joule heating may be used. Furthermore, to save energy, only the volume of interest may be heated. In this case this means that the cartridge or the liquid sample in the cartridge is heated. When this is to be accomplished by Joule heating, electrical components in the cartridge and electrical connections to the cartridge are required, which increases costs. The cartridge itself can be made of plastic, which is a rather poor thermal conductor. So heat generation in the reader and transfer to the cartridge is not trivial either.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a way to perform a non- contact heating of the liquid contained in the channel or measurement chamber of the cartridge.

In a first aspect of the present invention a method of heating a liquid contained in a measurement chamber of a biosensor is presented, the method comprising the steps of:

- providing a time-varying magnetic field in said measurement chamber; and

- applying said time- varying magnetic field in a manner to obtain an at least substantially spatial homogenous distribution of said time- varying magnetic field in said measurement chamber.

The invention is based on the idea to directly raise the temperature or shell temperature of particles (e.g. labels or beads) provided in the liquid of the measurement chamber of a biosensor or bio-assay. The proposed direct label or bead heating is structurally different from other known heating methods in bio-assays, since typically an external heat source is used to warm the sensor volume, while the present invention suggests raising the temperature or surface temperature of the labels or beads directly. In typical applications of biosensors, the bio-chemical reactions of which the temperature must be controlled, actually take place on the surface of the particle labels. An advantage is therefore that heating of the assay happens at the right spot. Moreover, the small heat capacity of the labels or beads would allow for very rapid thermal cycling.

In general, a time-varying magnetic field is suggested to be applied to the magnetic particles (e.g. labels or beads), with an operation frequency chosen such that power dissipation due to reorientation of the bead magnetization is maximized, thus causing heating of the magnetic particles.

Moreover, in some applications conventional magnetic fields which may be intended for excitation and/or sensor detection exhibit a large gradient so that particles are forced into or out of a sensing zone, whereas the proposed spatial homogenous magnetic field allows direct particle heating, without or with only moderate particle movement.

A preferred embodiment may further comprise the step of applying the time-varying magnetic field in a manner such that the surface temperature of magnetic labels provided in the liquid is raised directly by power dissipation within the magnetic labels. Thus, the physical process behind, but also the application of, the proposed heating effect caused by power dissipation within the particles (e.g. labels or beads) of the liquid is advantageous over conventional heating effects of the sensor chip caused by high currents flowing through excitation wires or sensor.

Another preferred embodiment may further comprise the step of choosing an operating frequency of the time- varying magnetic field such that power dissipation due to reorientation of magnetization of magnetic labels provided in the liquid is maximized. Different methods are typically used to detect the magnetic beads. Among these are optical detection, magnetic detection and mechanical detection. In case of magnetic detection, it can be advantageous to provide a heating magnetic field which is different from the detection magnetic field.

A further preferred embodiment may further comprise the step of controlling the time- varying magnetic field independently of a sensor reading operation. The proposed direct heating may provide a parameter that can control heating of the bio- assay, independently of the sensor reading, which is necessary to decouple the control of the assay and its read-out. Application of the homogeneous magnetic field for heating will causes magnetisation of the beads, which will cause them to attract each other. Therefore, it is advantageous even in case of non-magnetic detection, to coordinate heating with a sensor readout action.

A still further preferred embodiment may further comprise the step of generating the time- varying magnetic field outside of the measurement chamber. An external field is preferred to realize label or bead heating, because to generate a relatively homogeneous field, typically magnets with relatively large dimensions are needed.

A still further preferred embodiment for the exemplary case of magnetic sensing may further comprise the step of generating inside the measurement chamber an additional time- varying magnetic field for at least one of excitation and reading of said biosensorThe constraints on the magnetic fields intended for detection, actuation, and heating are different, therefore it is preferred to generate different magnetic fields. A still further preferred embodiment may further comprise the step of providing in the liquid granular single-domain particles of magnetite embedded in a biocompatible polymer shell.

In a further aspect of the present invention a biosensor is presented, which comprises:

- a measurement chamber containing a liquid;

- heating means for providing a time- varying magnetic field in said measurement chamber, wherein said heating means are adapted to apply said time- varying magnetic field in a manner to obtain an at least substantially spatial homogenous distribution of said time- varying magnetic field in said measurement chamber.

In another preferred embodiment, the detecting means may be provided inside the measurement chamber and the heating means may be provided outside the measurement chamber.

In a further preferred embodiment, the heating means may comprise electromagnetic elements (e.g. coils) placed both above and below the measurement chamber.

It shall be understood that the heating method of claim 1 and the biosensor of claim 9 have similar and/or identical preferred embodiments as defined in the dependent claims.

It shall be understood that a preferred embodiment of the invention can also be any combination of the dependent claims with the respective independent claim.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter. In the following drawings:

Fig. 1 shows a schematic biosensor in which the present invention can be implemented; and

Fig. 2 shows a schematic block diagram of a biosensor according to a first embodiment with a corresponding magnetic field strength distribution;

Fig. 3 shows a schematic block diagram of a biosensor according to a second embodiment; and Fig. 4 shows a schematic block diagram of a biosensor according to a third embodiment.

DETAILED DESCRIPTION OF EMBODIMENTS

Embodiments of the present invention will now be described based on a biosensor application as schematically depicted in Fig. 1.

Fig. 1 shows a biosensor sensing surface 1 to which capture molecules are coupled providing binding sites 2 to other biological entities, e.g. the target molecules 6 or targets 6. A fluid, liquid or solution 5 provided in a measurement chamber (not shown in Fig. 1) contains targets 6 and magnetic labels or beads 4 to which further capture molecules or receptor molecules 3 are coupled. The targets 6 and beads 4 are allowed to bind to the binding sites or analyte molecules 2 of the biosensor sensing surface 1 in a specific manner. In Fig. 1, bio-active entities (e.g. receptor molecules 3 or analyte molecules 2) are sketched as being directly coupled to a solid carrier (e.g. sensor surface 1 or label 4). Such bio-active layers may be linked to a solid carrier via intermediate entities, e.g. a buffer layer or spacer molecules. Such intermediate entities are added to achieve a high density and high biological activity of molecules on the surface. For clarity and simplicity, the intermediate entities are omitted in Fig. 1. In contrast to this biological attachment to the sensing surface 1, the beads 4 can also attach to the sensing surface 1 in a non-specific or non-biological manner, i.e. bind to the surface 1 without mediation of the specific target molecules 6.

The concentration of at least one sort of the targets 6 in the liquid 5 and containing at least one sort of the polarizable or polarized magnetic labels or beads 4 using a magnetic, optical or mechanical sensing device comprising a sensing surface 1. The liquid 5 comprising at least one sort of the magnetic beads 4 over the sensing surface 1 , wherein the magnetic beads 4 are pulled towards the surface and a signal that is generated by the beads 4 is determined.

According to the embodiments, the liquid or liquid sample in the measurement chamber or cartridge can be heated by applying a time- varying magnetic field to the particle labels in the sample. In typical applications of the biosensor, the analyte molecules 2 react with the receptor molecules 3 on the particle label surfaces, which is the case in e.g. catch and inhibition assays. Furthermore, the bio-molecules on the particle surface again react with molecules on the sensor surface 1. So all the biochemical processes of which the temperature should be controlled actually take place on the particle labels 4. For the purpose of optimization of the assay temperature, it is therefore beneficial to use the labels 4 themselves as a supply of heat to the assay.

As an example, superparamagnetic particle labels or beads may be used, which consist of an ensemble of granular single-domain particles of magnetite embedded in a biocompatible polymer shell. The fine granular particles which may be of several to tens of nanometres in diameter transform the energy of an external alternating magnetic field into heat by several physical mechanisms. Transformation efficiency depends strongly on the frequency of the external field. The heating is thereby mainly achieved due to loss processes during the reorientation of the magnetization of the single-domains in the alternating magnetic field (Neel relaxation), or factional losses if the

superparamagnetic particle labels can rotate in an environment of sufficiently low viscosity (i.e. Brownian relaxation). The specific losses due to magnetization

reorientation may depend on the type of remagnetization process. In case of

superparamagnetic particles in a typical sample fluid the above first loss process dominates, where the energy supplied by the external field is dissipated when the particle moment relaxes to its equilibrium orientation. It is noted that inductive heating of magnetite, i.e. via eddy currents, is negligible here.

For typical superparamagnetic particle labels or beads, the specific loss power (SLP) may for example equal tens to hundred of Watts per gram for a field amplitude of 14 kA/m and 300 kHz frequency. Restrictions of the field strength and frequency as for example in medical treatments by magnetic fluid hyperthermia to prevent damage to healthy tissue or physiological functions, do not apply in the proposed heating of the sample in the cartridge, and the field magnitude and frequency may be increased.

The frequency dependent power dissipation of fine magnetic particles equals:

Ρ = μ₀ π/χ" \Η\ ², (1)

where μο is the permeability of vacuum and \H\ is the magnetic field magnitude. The imaginary part χ " of the complex susceptibility = χ '+j χ " can be expressed as

χ" = χ₀Φ / (1+ Φ²), (2)

with Φ = f τ„. The Neel relaxation time constant τ„ is typically in the order of tens to hundreds of nanoseconds, depending on the grain sizes in the ensemble. In the superparamagnetic regime, i.e. for frequencies up to tens of megahertz's (Φ«1), the specific loss power increases with the square of frequency and field magnitude. E.g. by using a ten times higher field frequency with strength of tens of kilo amperes per metre, the SLP can be boosted to several kilowatts per gram.

In a typical biological assay, only 1.5e-6 g of beads is present. Assuming a 2/3 mass fraction of grains inside the polymer shell of a particle label, the fluid sample contains an approximate total of le-6 g of magnetite. This amount of magnetic material may be insufficient to heat the entire liquid sample to e.g. 37 °C within a reasonable time span and with a practical magnetic field strength. However, the local temperature at the polymer shell of the particle label is easily raised above the ambient temperature. As reported in numerous publications on hyperthermia treatment, the particle shell temperature is sustained at a temperature above 42 °C in order to burn cancerous tissue. This temperature raise can be achieved practically with magnetic field strengths of several kilo Amperes per meter at several hundreds of kilohertz's. Label heating for the optimisation of biochemical reaction efficiency is therefore feasible.

Fig. 2 shows a schematic arrangement of a biosensor according to a first embodiment. A spatial homogenous magnetic field with a small spatial gradient, as depicted in the upper part of Fig. 2, is applied by upper of and lower electromagnets 20 arranged above and below a cartridge or measurement chamber 10 with labels or beads in a sample fluid. The parameter z indicates the height dimension of the measurement chamber 10. In such a homogenous field, energy will be dissipated in the magnetite, but there is hardly any external magnetic force exerted on the particles. The required time- varying homogenous field can be realized by the electromagnets 20 (e.g. coils) or any other kind of electromagnetic or elements placed above and under the sample holding or measurement chamber 10. By simultaneously operating the electromagnets 20, a close to homogenous field distribution can be achieved in the measurement chamber 10.

In the upper part of Fig. 2, the magnetic field strength vs. the height z is shown for a configuration with two typical electromagnets 20 placed above and under the measurement chamber 10, when a current of e.g. 1A is applied. The diagram shows that a magnetic field strength of hundreds of kA/m can be realized in this implementation. The gradient along the sample chamber height is however small, so that the force exerted on the magnetic labels beads is also small, thus preventing unintended actuation of the labels or beads. It is noted that various magnet actuation schemes (such as pulsed actuation) can be implemented in order to minimize the influence of the proposed heating concept on the assay properties.

Fig. 3 shows a schematic block diagram of a biosensor with magnetic sensing according to a second embodiment. The biosensor comprises a measurement chamber 10 which contains the solution or liquid as described in connection with the above first embodiment. Additionally, an on-chip field generation element 30 (e.g. an electromagnet, a coil, or simple wire(s)) is provided for sensor or bead excitation so that the stray fields can be detected by a magnetic sensor (not shown). The on-chip field generation element 30 is provided within or inside the measurement chamber 10 and is controlled by an integrated or remote sensing control unit 35. In addition, external electromagnets 20 are placed above and under the measurement chamber 10 and provided for direct heating of the labels or beads contained in the measurement chamber 10.

Similarly, the external electromagnets 20 are controlled by an integrated or remote heating control unit 25, which might as well be integrated with the sensing control unit 35.

There are two distinct differences between the heating field generated by the external electromagnets 20 and the excitation field generated by the on-chip field generation element 30. Firstly, for bead heating, quite a large field strength of the electromagnets 20 is required, e.g. tens of kA/m, whereas the on-chip field generation element 30 is only able to produce high field strengths in a very small volume. Secondly, the excitation field generated by the on-chip field generation element 30 exhibits a strong spatial gradient, such that particles are attracted towards the sensor. In contrast thereto, the heating field generated by the external electromagnets 20 is not intended to result in particle movement, and a spatial homogenous magnetic field is applied to the labels or beads in the sample fluid of the measurement chamber 20, with a small spatial gradient. In such a homogenous field, energy will be dissipated in the magnetite, but there is hardly any external magnetic force exerted on the particles.

The heating field may be generated and controlled by the heating control unit 25 to provide a periodical signal with a fundamental frequency of several hundreds of kilohertzs, while the exact frequency depends on the properties of the particles being used. The shape of the signals is not necessarily defined, it can be sinusoidal, rectangular, etc, as long as it is periodical. The main idea is that there is some hysteresis in the magnetisation loop of the magnetic particles (e.g. labels or beads). Everytime the hysteresis loop is cycled through a certain amount of energy is dissipated, which causes heating. The optimal amplitude of the signal depend on the magnetisation characteristics of the particles used.

Magnetic actuation to attract magnetic particles to the sensor surface and to 'wash' them away in a later stage of the assay may also typically be performed with external electromagnets. The same magnets may be used for heating when driven in a different mode (other frequencies and other combinations of polarisation to create a substantially uniform magnetic field), but the invention is by no means restricted to using these actuation magnets.

It is however noted that there are various different ways to detect the presence of magnetic particles. As an example, optical detection does not need an on- cartridge structure for sensing or excitation of the magnetic labels or beads.

Fig. 4 shows a schematic block diagram of a biosensor with optical detection according to a third embodiment. Similar to the above second embodiment, the biosensor comprises a measurement chamber 10 which contains the solution or liquid as described in connection with the above first embodiment and which is sandwiched between external electromagnets 20 provided for direct heating of the labels or beads contained in the measurement chamber 10. Again, the external electromagnets 20 are controlled by an integrated or remote heating control unit 25 in a similar manner as described in connection with the second embodiment.

The detection cavity or chamber 10 may, for example, be formed by a double-sided tape , i.e. which has adhesive properties at two opposing sides, a base element and a cover element, wherein the double-sided tape is located between the cover element and the base element. The double-sided tape thus comprises a gap, in which the detection chamber 10 is formed. The base element, the cover element and the double- sided tape thus form a cartridge comprising a detection surface.

The biosensor of Fig. 4 further comprises an optical particle detection unit 52, 54 for detecting the particles on or near the detection surface. The particle detection unit comprises a light source 52, which is, for example, a laser device or a LED, for generating a light beam (bold arrow in Fig. 4), which illuminates the detection surface.

The particle detection unit further comprises a detector 54 for detecting the light reflected from the detection surface. Additionally, the particle detection unit may further comprise optical elements (not shown), which are arranged in the light beam for generating parallel light or focussing the light beam, respectively. The optical elements may be lenses, for example.

The particle detection unit shown in Fig. 4 is adapted for detecting changes at the detection surface e.g. by using the so called FTIR method (Frustrated Total Internal Reflection). The beam of light is reflected on an interface between a medium with a higher refractive index, for example, the above mentioned base element, and a medium with a lower refractive index, for example, the fluid or liquid in the measurement chamber 10. There is a certain critical angle of incidence above which there is a situation of total internal reflection (TIR). The present detection configuration (regarding refractive indices and angle of incident) is such that there is a total internal reflection of the incoming beam. Although the light is totally reflected in such a situation, there is still a penetration of the light in a very thin layer of the medium with the lower refractive index. This is the so called evanescent light, the intensity of which decays exponentially in the low refractive index medium with a characteristic penetration depth in the order of the wavelength of the light. Thus, in practise the penetration depth is preferentially less than 0.5 micrometer. If particles, in particular, magnetic particles, are bound to the detection surface, the optical properties of this very thin first fluid layer of preferentially about 0.5 micrometer are changed leading to a reduction of the reflected light beam. This is caused by absorption and scattering of the evanescent light (FTIR). As a result the signal of the detector 54 changes. This change of the signal of the detector 54 can be related to the amount of particles on the detection surface, for example, by calibration measurements. Thus, by detecting the change of the signal of the detector 54, the amount of particles on the detection surface can be determined.

Thus, in the above embodiments, a time-varying magnetic field is supplied to the magnetic particles, with an operation frequency chosen such that power dissipation due to reorientation of the bead magnetization is maximized, because this causes particle heating. This is structurally different from conventional heating approaches, e.g. Joule heating, which require an external heat source to heat up the sensor volume, while in the proposed direct particle heating the temperature of the particles or particle surfaces is raised directly. The proposed direct particle heating is beneficial, since in typical applications of biosensors, the bio-chemical reactions of which the temperature must be controlled, actually take place on the surface of the particle labels or beads. The small heat capacity of the labels or beads therefore allows for very rapid thermal cycling.

Typical applications of the proposed direct particle heating include catch and inhibition immunoassays for protein or drugs testing. In addition to immunoassays, the heating technique may be applied to polymerase chain reaction (PCR) for the amplification of DNA. A specific type of PCR makes use of magnetic beads on which the DNA is multiplied. This approach then allows easy extraction of the amplification products from the solution by manipulation of the magnetic beads. For the purpose of fast PCR in a cartridge, using the magnetic beads themselves as the heat supply is beneficial, since in this case the temperature of the bead surfaces is raised directly.

In summary, a biosensor and a method of heating a liquid contained in a measurement chamber 10 of the biosensor have been described, wherein a time- varying magnetic field is provided by electromagnets 20 in the measurement chamber 10. The time-varying magnetic field is applied in a manner to obtain an at least substantially spatial homogenous distribution of the time-varying magnetic field in the measurement chamber 10. Thereby, the temperature or shell temperature of particles (e.g. labels or beads) provided in the liquid of the measurement chamber can be directly increased to effectively heat the liquid.

Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims.

In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality.

A single unit or devices may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

Any reference signs in the claims should not be construed as limiting the scope.

Claims

CLAIMS:

1. A method of heating a liquid (5) contained in a measurement chamber (10) of a biosensor, the method comprising the steps of:

- providing a time-varying magnetic field in said measurement chamber

(10); and

- applying said time- varying magnetic field in a manner to obtain an at least substantially spatial homogenous distribution of said time- varying magnetic field in said measurement chamber (10).

2. A method according to claim 1, further comprising the step of applying said time- varying magnetic field in a manner such that the surface temperature of magnetic labels (4) provided in said liquid (55) is raised directly by power dissipation within said magnetic labels (4).

3. A method according to claim 2, further comprising the step of choosing an operating frequency of said time-varying magnetic field such that power dissipation due to reorientation of magnetization of magnetic labels (4) provided in said liquid (5) is maximized.

4. A method according to claim 1, further comprising the step of controlling said time- varying magnetic field independently of a sensor reading operation.

5. A method according to claim 1, further comprising the step of generating said time- varying magnetic field outside of said measurement chamber (10).

6. A method according to claim 5, further comprising the step of generating inside said measurement chamber (10) an additional time- varying magnetic field for at least one of excitation and reading of said biosensor.

7. A method according to claim 5, further comprising the step of using the same magnetc system magnetic system for heating and for actuation of the particles.

8. A method according to claim 1, further comprising the step of providing in said liquid (5) granular single-domain particles of magnetite embedded in a

biocompatible polymer shell.

9. A biosensor comprising:

- a measurement chamber (10) containing a liquid;

- heating means (20) for providing a time- varying magnetic field in said measurement chamber (10), wherein said heating means (20) are adapted to apply said time-varying magnetic field in a manner to obtain an at least substantially spatial homogenous distribution of said time- varying magnetic field in said measurement chamber (10).

10. A biosensor according to claim 9, further comprising detecting means (30) for applying an additional time- varying magnetic field for at least one of excitation and sensor reading.

11. A biosensor according to claim 9, further comprising detecting means (30) for applying an optical radiation for sensor reading.

12. A biosensor according to claim 10, wherein said detecting means (30) is provided inside said measurement chamber (10) and said heating means (20) is provided outside said measurement chamber (10).

13. A biosensor according to claim 9, wherein said heating means comprises electromagnetic elements (20) placed both above and below said measurement chamber