The invention relates to a measurement method for the reduction or suppression of unwanted background in imaging techniques based on a contrast agent employing an optical interrogation that exploits the orientation-dependent optical scattering and/or absorption characteristics of the contrast agent with respect to light, which method comprises the steps of:

- providing a sample to be analyzed in an optical path between a light source and a detector,

- providing as contrast agent nano- or microparticles with magnetic and/or electric properties within the sample, generating a magnetic and/or electric, preferably electrostatic field of at least one spatial direction at the location of the sample,

- generating at least two signals of the detector receiving light from the light source passing the sample, wherein in one signal there is a minimum of a signal of the contrast agent and in the other a maximum of the signal of the contrast agent exploiting an orientation dependent polarization characteristics of the contrast agent,

- subtracting one signal from the at least one other signal to eliminate the background noise. The invention also relates to a measuring arrangement for measurement of optical properties of a sample to be investigated, as well as of analytes contained in the sample, in imaging techniques, comprising a measuring cell with the sample, a light source, a detector and an electromagnetic device set up to generate a magnetic or electric field, and a signal acquisition unit configured to control the light source, the detector and the electromagnetic device, wherein the measuring cell is placed in an optical path between the light source and wherein the detector is set up to detect scattered light coming from the light source having interacted with the sample, wherein the sample comprises a contrast agent, which contrast agent consists of particles that are able to be aligned spatially depending on the presence of the predetermined magnetic or electric field generated by the electromagnetic device. There are a number of optical measurement methods employed for the visualization of material structures and chemical compositions or for the detection of target analytes. Examples for imaging techniques are optical coherence tomography (OCT) and photoacoustic imaging (PAI), while Raman spectroscopy can be employed for the sensitive detection of molecular species. For all mentioned methods, nano- and microparticles with specific optical properties (e.g. plasmon resonance) are used as contrast agents to enhance the signal-to-noise ratio [Ref. 1 to 4], Despite the use of a contrast agent, a background signal is present due to the material surrounding the particles. This background always smears out the signal of interest. In order to be able to distinguish the signals that are generated by a contrast agent from the background, signals (or images) are compared in practice before and after the addition of the contrast agent [Ref. 5]. On the one hand, this is time-consuming and resourceintensive, and, on the other hand, it is prone to even small changes in the background.

Another method uses magnetic particles as a contrast agent for imaging [Ref. 6 to 10]. Contrary to the method presented here, the signal generation is limited to the movement of the nanoparticles and does not exploit any optical effects of the nanoparticles themselves. The generation of signals is based on causing the surrounding tissue to vibrate, which can then be detected.

It is accordingly an object of the invention to provide a measurement method for the reduction or suppression of unwanted background in imaging techniques, which overcomes the above-mentioned disadvantages of the prior art methods. The method should provide for a simple and affordable solution.

Document US 2012/1 18052A1 shows a method and a device for detecting magnetic target objects within a moving fluid. AT503845A1 discloses a method and a device for molecular detection.

With the foregoing and other objects in view there is provided, in accordance with the invention, a measurement method for the reduction or suppression of unwanted background in imaging techniques wherein the nano- or microparticles used as contrast agent have optical anisotropic behavior and wherein the optical scattering is inelastic.

Additionally, the nano- or microparticles are non-spherical particles with an aspect ratio of at least 1.2 in at least two dimensions. This option results in easily obtainable particles that exhibit anisotropic behavior.

In an embodiment of the invention cylindrical rod-shaped nano- or microparticles are used, in particular cylindrical rods with a length of about 30-200 nm and a diameter of about 3-100 nm.

More preferable, the cylindrical rod-shaped nano- or microparticles have a length of about 80 nm and a diameter of about 6 nm.

Alternatively, the nano- or microparticles contain magnetic and noble metal substructures, preferably a magnetic core and a noble metal shell. This is for having particles with suitable ferromagnetic properties to control their orientation in space with an external field.

In a further embodiment the nano- or microparticles possess ferromagnetic or superparamagnetic behavior. This enhances the contrast effect of the particles.

In another embodiment, the nano- or microparticles comprise a porous shell, in particular molecularly imprinted polymer. This is advantageous since it allows the analyte molecules to be trapped near the particle’s surface, which results in signals of higher quality.

In a further embodiment of the invention the excitation of the sample and of the nano- or microparticles is conducted with polarized light.

It is also possible to control the polarization in a predefined way. It is furthermore possible to use non-polarized light for excitation in combination with a polarization filter before or after the sample.

In a further embodiment of the invention nano- or microparticles show plasmon resonances.

It is also possible to generate a magnetic and/or electric, preferably electrostatic field of at least one spatial direction at the location of the sample includes generating an external homogenous low-gradient magnetic field by two permanent magnets, preferably located equidistant to the sample or by a pair of coils, preferably arranged in a Helmholtz geometry.

It is furthermore possible to time-modulate the magnetic field.

Alternatively, the time-modulated field is provided by one pair of Helmholtz coils which is fed by an alternating current.

More preferable, the time-modulated field is provided by two orthogonal pairs of Helmholtz coils which are fed by sinusoidal input currents that are phase shifted by 90° to generate a rotating magnetic field. This allows further properties of the nano- and microparticles to be determined, which serve to improve the signal or image.

In an embodiment of the invention said generating a magnetic and/or electrostatic field of at least one spatial direction at the location of the sample includes generating an external homogenous low-gradient electric field by two electrodes located equidistant to the sample.

In a further embodiment of the invention the electric field is a time-modulated field.

It is also possible to conduct the signal detection with simultaneous knowledge of the current orientation of the nano- or microparticles. It is furthermore possible that the detection method is a light scattering-based detection scheme.

It is also possible that the detection method is surface enhanced Raman spectroscopy.

Alternatively, the measurement method is supplemented with steps of optical coherence tomography. This combines the advantages of two measurement methods in a single procedure using one measurement setup.

With the foregoing and other objects in view there is provided, in accordance with the invention, a device for measurement of optical properties of a sample to be investigated, as well as of analytes contained in the sample, in imaging techniques wherein said signal acquisition unit is configured to generate a magnetic and/or electric, preferably electrostatic field of at least one spatial direction at the location of the sample, generate at least two signals of the detector receiving light from the light source passing the sample, wherein in one signal there is a minimum of a signal of the contrast agent and in the other a maximum of the signal of the contrast agent exploiting orientation dependent polarization characteristics of the contrast agent, subtracting one signal from the at least one other signal to eliminate the background, wherein the nano- or microparticles used as contrast agent have optical anisotropic behavior and wherein the optical scattering is inelastic.

In an embodiment of the invention the at least one electromagnetic device is a pair of electromagnetic coils located equidistantly to the sample, preferably arranged in a Helmholtz geometry.

Alternatively, the electromagnetic device comprises two pairs of electromagnetic coils in a Helmholtz geometry, said two coil pairs are perpendicular to each other. This enables the system to generate time-modulated fields for a better control of the nano- or microparticles. It is also possible that the electromagnetic device is a pair of two permanent magnets located equidistant to the sample. This makes the measuring arrangement inexpensive to manufacture and easy to control.

Alternatively, the device comprises a polarization filter wherein said polarization filter is placed in an optical path before or after the sample. This makes it possible to work with non-polarized light in a simpler device and still use separation effects from polarized light.

The following detailed description of preferred embodiments of the invention is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. The invention will be described with reference to the following figures, which are provided by way of explanation only.

Fig. 1 shows a schematic measuring arrangement.

Fig. 2 shows a measuring arrangement with two symbolic outcomes.

An ensemble of nano- or microparticles are used as contrast agents for imaging or in sensor technology. The nano- or microparticles have a minimum equivalent sphere diameter of about 10 nm and a maximum of about 100 pm. They also show a well- defined shape that differs from a sphere with a minimum aspect ratio of 1 .3. Standard deviations of the geometry parameters are less than 50% of the mean values. The particles have a high geometric uniformity (the measurement of the optical absorption/scattering of the particles in solution shows characteristic peaks). Potential control of the spatial orientation of the particles is achievable so that the evaluation of the alignment ratio of an ensemble of these particles reveals a minimum value of 30%.

Hence, the nano- or microparticles have a well-defined shape that differs from a sphere and are designed in such a way that their spatial orientation can be controlled. The particles have a high geometric uniformity to allow measurements with a large number of particles in parallel (ensemble-based measurement). Excitation with polarized light can be used to generate a signal that depends on the orientation of the particles in relation to the direction of polarization of the excitation light. This means that at least two signals (or images) can be generated.

In this context, an image consists of one or more signals. The detector and the controller such as a signal acquisition unit ultimately process signals into images, with noise effects and their treatment affecting signals as well as images.

In one signal there is a minimum of the signal of the contrast agent and in the other a maximum of the signal of the contrast agent. The different signal intensities result from different spatial orientations of the contrast agent in relation to the polarization direction of the exciting light. However, both signals have background noise. By subtracting one signal from the other, the background can then be eliminated, and a signal is obtained that is free from background.

In the state of art, this works only for imaging modalities with high optical resolution and/or low concentration of the contrast agent. In the case of the method presented here, all nano- or microparticles have the same shape and can therefore be viewed as an ensemble, which allows for a higher particle concentration and, thus, for ensemblebased measurements. This is the only way to obtain higher signal intensities and signal-to-noise ratios. Within the resolution limit of the chosen detection scheme (either optical or acoustical) a larger number of particles can be used. The proposed method therefore provides a significant signal-to-noise improvement for light scattering-based detection, OCT, photoacoustic imaging, Raman spectroscopy.

Essential features of the invention are, thus, that a measurement method for the reduction or suppression of unwanted background is provided based on non-spherical nano- or microparticles employing an optical interrogation that exploits the orientationdependent optical scattering and/or absorption characteristics of the nano- or microparticles with respect to polarized light. The non-spherical nano- or microparticles do have a well-defined shape with high geometric uniformity, which is a prerequisite for ensemble-based measurements. Such nano- or microparticles as non-spherical particles show an aspect ratio of at least 1 .2 in at least two dimensions. The higher the aspect ratio the stronger the contrast effect. Experiments have shown that particles with an aspect ratio lower than 1 .2 in at least two dimensions show no sufficient effect.

The optical scattering may be elastic. The advantage of inelastic optical scattering is that information on the molecular structure of molecules in the particle proximity can be obtained. A setup producing inelastic scattering and a measuring method exploiting effects of inelastic scattering do not exclude regular occurrence of elastic scattering, but ignore it.

Advantages of additional optional features:

• Nano- or microparticles that show plasmon resonances:

Plasmon resonances strongly increase absorption and scattering characteristics of micro- and nanoparticles. In case of Raman spectroscopy, the plasmons provide a field enhancement close to the particle surface, which strongly increases the Raman scattering efficiency.

• Nano- or microparticles with magnetic properties:

Magnetic properties of nano- or microparticles allows the manipulation of their orientation in an external magnetic field.

• Excitation light that is polarized: o Control of the polarization of the excitation light:

Instead of changing the orientation of the particles, it is also possible to change the orientation of the polarization axis. This avoids the implementation of rotatable external magnetic or electric fields and therefore can simplify the measurement setup. o Alternatively, non-polarized light can be used for excitation in combination with a polarization filter 3 after the sample 5 (in the case of OCT or other light scattering-based detection schemes):

In the case that a non-polarized light source is used, this configuration offers an alternative to positioning the polarization filter 3 in front of the sample 5. This is only possible if the resulting optical output signal is correlated to the particle orientation.

• Signal detection with simultaneous knowledge of the current orientation of the particles: The local dependence of the hydrodynamic resistance of the particles with respect to their surrounding can be exploited for extracting additional information out of the measurement signal such as viscosity.

The method is based on nano- or microparticles which have a non-spherical shape (anisotropic geometry) leading to optical anisotropic behavior. In addition, the method is based on the use of polarized light. The anisotropic geometry of the particles and the use of polarized light make it possible to obtain scattering and/or absorption of the particles depending on their relative spatial orientation with respect to the polarization direction.

The alignment of the particles takes place via an external magnetic or electric field. The external field requires to be homogenous, i.e. with a low-gradient to avoid movement of the particles and to allow for a larger field of view. A homogenous low- gradient magnetic field can be generated by two permanent magnets located equidistant to the sample or by a pair of coils 10A, 10B (preferably arranged in the Helmholtz geometry). A homogenous low-gradient electric field can be generated by two electrodes located equidistant to the sample 5.

Polarized light is used to achieve an optical interaction with the particles that depends on their orientation. The high geometric uniformity of the particles ensures that all particles in the ensemble have the same orientation with respect to the externally applied magnetic or electric field. The optical measurement beam 2 can therefore excite many particles in parallel resulting in an increased signal strength without smearing out the orientation dependent effect.

The scattering and absorption strength of the particles depends on the alignment of the main axis to the polarization direction - parallel alignment of the main axis to the polarization provides a maximum of the optical effect and perpendicular alignment a minimum. In both cases, however, there is always background noise that is independent of the particles used. If one now measures the optical effects in both orientations, one can subtract them from one another and thus eliminate all noise and all background effects. On the one hand, this can be done statically by recording a signal in the case of a particle alignment, then rotating the alignment of the particles and recording a signal again. On the other hand, this can also be done dynamically by modulating the particle orientation and recording a current signal. A rotating magnetic or electric field can be used to generate a rotation of the particles, which leads to a measurement signal that is modulated with the excitation frequency (or a multiple thereof). One can then extract exactly the signal from the total signal that corresponds to the excitation frequency, which again filters out noise.

Specific application examples

Cylindrical rod-shaped nano- or microparticles can be employed as contrast agent. The particles are ferromagnetic with their magnetic moment oriented along the long cylinder axis. They also may show superparamagnetic features that are known to be special characteristics of nano particles and can be exploited in measurement procedures.

The nanoparticles are dispersed in solution or a biological medium. If an external homogenous magnetic field is switched on, the nano- or microparticles’ magnetic moment and therefore, the long axis of the particles, will be oriented parallel to the external magnetic field. The orientation of the particles depends on the direction of the external magnetic field.

For the optical measurement, linearly polarized light is used for optical excitation. The scattering and absorption strength of the particles depends on the alignment of the main nano- or microparticles cylinder axis to the polarization direction - parallel alignment of the main axis to the polarization provides a maximum of the optical effect and perpendicular alignment a minimum.

Example 1 and 2:

If photoacoustic microscopy is carried out, the intensity of the photoacoustic signal depends on the optical absorption of the nano- or microparticle contrast agent. This means that a maximum of the photoacoustic signal is observed for particles aligned parallel to the direction of polarization and vice versa. Here, orthogonal pairs of coils means that the common central axis of the first pair of coils is perpendicular to the axis of the second pair of coils. A prerequisite for this mode is that the sampling rate of the OCT is much higher than the rotational frequency of the magnetic field (e.g. 100x higher). Here, the excitation light of the OCT measurement setup can be provided by a laser of 5 mW output power with a wavelength of 1300 nm and is linearly polarized with a polarization extinction ratio of 20 dB. The beam diameter at the focal plane is 2pm. A standard OCT measurement setup can be employed including a reference arm and a dual balanced photodetector. The rotation of the external magnetic field induces a rotation of the nanoparticles and, thus, a modulation of the scattering signal. The modulation frequency of the optical scattering signal in case of cylindrical nanoparticles is two times the frequency of the external magnetic field (parallel alignment of the nanoparticles every 180 ° of the external rotating magnetic field and, thus, a doubling of the frequency of the external magnetic field). Thus, the frequency of the detected sinusoidal OCT signal is 2000 Hz. By comparing the orientation of the external magnetic field and the actual nanoparticle orientation measured by OCT, one can calculate the phase lag between the nanoparticle and the external magnetic field. The voltage via a shunt resistor in the electronic circuit feeding the coils with input current can be employed as reference to determine the momentary orientation of the external magnetic field. A lock-in amplifier technique can be employed to measure the phase lag by feeding the optical signal into the sample input and by providing the shunt resistor voltage to reference input. The Lock-in amplifier needs to work at its 2F mode (i.e. doubling the frequency of the reference signal). This phase lag depends on the drag of the nanoparticles and thus, on their volume. Binding of the analyte protein results in a change of the nanoparticle volume and its drag, which itself results in an increased phase lag between the external magnetic field and the nanoparticles. Measurements of the frequency-modulated OCT signal allow to determine the phase lag, which indicates the presence of the analyte molecule. From the phase lag, the concentration of the analyte molecule can be derived (the higher the number of analyte molecules bound to the nanoparticle surface the higher the increase of the phase lag). In addition, the tomography measurement modality allows to deduce the location and allows to conduct a concentration mapping of the analyte. The overall measurement principle also works for small analyte molecules in a competitive assay format where the nanoparticles are pre-loaded with a bigger molecule (e.g. a spherical nanoparticle or a high-molecular-weight polymer). Here, the analyte molecules replace the bigger pre-bound species. This results in the decrease of the observed phase lag. The presence and the concentration, including a concentration mapping, of the analyte molecule is only accessible due to the proposed measurement mode.

Example 3:

The measurement of a specific analyte molecule in solution and a reduction of background signal can also be targeted by surface-enhanced Raman spectroscopy (SERS). Here, the nano- or microparticles act as signal enhancing factor for the Raman scattering signal. To that end, the plasmonic particle properties are exploited. Enhancement of the Raman signal is achieved due to the local electric field enhancement in close vicinity of the nanoparticle surface. The sample 5 can be a liquid sample (e.g. water) containing the analyte molecule. The latter can be a small molecule showing Raman activity (e.g. polychlorinated biphenyls). Nano- or microparticles can be composed of a magnetic core with a noble metal shell.

Nano- or microparticles can be of cylindrical shape. They can have a length of about 30 to 200 nm and a diameter of about 3 to 100 nm. Preferably, in this example, they have a length of 80 nm and a diameter of 6 nm and can be composed of cobalt to show ferromagnetic properties. The standard deviation of both, the length and the diameter can be 10% of the mean value. The particle possesses a shell of gold with a mean thickness of 5 nm and 10% standard deviation. The nano- or microparticles need to be functionalized with a porous shell (e.g. molecularly imprinted polymer) that allows the analyte molecule to be trapped near the particle surface. Here, the excitation light of the measurement setup can be provided by a laser of 5 mW output power with a wavelength of 785 nm and is linearly polarized with a polarization extinction ratio of 20 dB. The beam diameter at the focal plane is 2pm. A standard Raman measurement setup can be employed including a diffraction grating and a CMOS camera as spectrometer and an optical filter in front to block the excitation wavelength. Cylindrical particles exhibit two plasmon resonance modes (parallel and perpendicular to the main cylinder axis). Both plasmon resonance modes result in the formation of hot spots (spots close to the nanoparticle surface with high electric field enhancement). Thus, the orientation of the nanorods allows for exciting a specific plasmon resonance mode and therefore, the formation of distinct hot spots. Alignment of the cylindrical particle parallel to the polarization of the incoming light favors the formation of hot spots on the tips of the cylinder, while a parallel orientation favors the formation of hot spots along the side surface of the cylinder. Raman-active molecules present in the hot spot regions generate characteristic Raman scattering spectral fingerprints. The particle surface coating allows to bind a target molecule close to the particle surface so that the analyte molecule is concentrated in the region of the plasmonic hot spot. The signal intensity of the Raman signal depends on the orientation of the nano- or microparticle. This can be exploited in analogy of Example 1 and Example 2 either by static external fields and the subtraction of the background, or by using rotating external fields and by inducing a frequency modulation of the Raman signal. For the latter, the resulting Raman signal for each detected wavelength can be frequency filtered (e.g. Fourier analysis of the time dependent signal for each wavelength) to deduce the part of the signal that corresponds to the nano- or microparticle motion. This results in background-free visualization of the Raman spectrum of the chosen analyte and minimizes autofluorescence background.

Example 4:

The above-mentioned measurement examples 1 -3 can also be realized in a modified way by keeping the external magnetic field static in one direction and by changing the direction of polarization of the interrogating light beam instead of changing the orientation of the nano- or microparticles.

Example 5:

The above-mentioned measurement examples 1 -3 can also be realized in a modified way by keeping the external magnetic field static in one direction and by using unpolarized light. This measurement mode requires a polarization filter 3 in the light path after the sample 5 has been excited.

Example 6:

The measurement of a specific analyte molecule in solution and a reduction of background signal can also be targeted by Raman spectroscopy (example 3) while in parallel a concentration mapping of the analyte is conducted with OCT (example 1 ). This is possible since both methods may use the same nano- or microparticles as contrast agent as well as an at least partly identical measurement setup. This enables a new quality in measurements exploiting both the share of elastic scattering in a scattering event and the share of inelastic scattering.

Technical sketches:

One possible measurement setup (see FIG. 1 ) consists of a light source 1 which generates a light beam 2. This light beam, if it does not already have a direction of polarization (for example by using a laser as the light source), then passes through a polarization filter 3. Hence, the polarization filter 3 is located in the light path and before the sample 5. The light beam is directed onto the measuring cell 4 and hits the sample 5 there. This sample 5 contains the particulate contrast agent, which can move freely at least around its own axis. The spatial orientation of the contrast agent can be controlled by external excitation by means of a suitable electromagnetic device 6. The optical absorption and I or scattering of the contrast agent results in a signal (optical or also acoustical), which strikes a suitable detector 9 at an angle 7 and after a signal path 8 of any length. A possible measurement method, as it is also described above as an application example (Example 1 ), is shown schematically in FIG. 2. The electromagnetic device for manipulating the spatial orientation of the contrast medium is in this case a pair of electromagnetic coils (pair 10A and pair 10B) and the contrast agent consists of elongated magnetic nano- or microparticles with a spatial orientation 1 1 . The magnet causes the nano- or microparticles to rotate and aligns them either parallel to the direction of polarization (signal "ON" path in Fig. 2) or at perpendicular angles to the direction of polarization (signal “OFF” path in Fig. 2).

A device comprising this measurement setup also comprises a signal acquisition unit (not shown) configured to control the light source (1 ), the detector (9) and the electromagnetic device (6, 10A, 10B). The signal acquisition unit is a computer or computer-like device or an assembly of electronic devices that coordinates the operation of the measurement parts and outputs results in the form of images, image sections, image parts or signals in digital form.

If an optical or acoustic detection is now carried out and an image is recorded, a maximum measurement signal is obtained on one hand and a minimum measurement signal on the other hand. Both also contain the background noise. Subsequent image processing subtracts the “OFF” signal from the “ON” signal and thus removes the background. The final image has no background noise. In the case of a continuously rotating external magnetic field, Fourier analysis of the time dependent measurement signal can be used to suppress the background components of the signal.

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List of Reference Signs

1 light source

2 light beam 3 polarizer

4 measuring cell

5 sample

6 electromagnetic device

7 angle 8 signal path

9 detector

10A electromagnetic coil

10B electromagnetic coil

11 orientation of particles