SENSOR SYSTEM, IN PARTICULAR FOR DETERMINING A GLUCOSE CONCENTRATION

Abstract

A medical sensor system (1) for determining a feature in a human or animal body includes magnetic measurement nanoparticles (10) configured to form reversible chemical bonds with a binding substance, and experience a change in their magnetic relaxation behavior dependent on the formation of such bonds. The sensor system (i) further includes magnetic reference nanoparticles (20) having lesser (and preferably no) binding affinity to the binding substance.

Claims

1. A medical sensor system (1) for determining a feature in a body (K), the system including: a. magnetic measurement nanoparticles (10) having magnetic relaxation behavior dependent on their formation of reversible chemical bonds with a binding substance (3); and b. magnetic reference nanoparticles (20) which: (1) do not form chemical bonds with the binding substance (3), or (2) have a lower binding affinity to the binding substance (3) than the magnetic measurement nanoparticles (10).

2. The sensor system of claim 1 wherein: a. the feature is the concentration of an analyte (2); b. the magnetic measurement nanoparticles (10) are configured to form reversible chemical bonds with the binding substance (3) in the presence of the analyte (2) in dependence on the concentration of the analyte (2), the bonds resulting in changes in the magnetic relaxation behavior of the magnetic measurement nanoparticles (10).

3. The sensor system of claim 2 wherein the analyte (2) is glucose.

4. The sensor system of claim 2 wherein: a. the binding substance (3) is a receptor for: (1) the analyte (2), and (2) an analog (4) of the analyte (2), b. the magnetic measurement nanoparticles (10) each include a magnetic core (11), the cores (11) having the analog (4) thereon, whereby the magnetic measurement nanoparticles (10) reversibly chemically bind to the receptor (3) of the analyte (2) and the analog (4) in dependence on the concentration of the analyte (2).

5. The sensor system of claim 4 wherein: a. the analog (4) is dextrin), and/or b. the binding substance (3) is concanavalin A.

6. The sensor system of claim 2 wherein: a. the binding substance (3) is a receptor for the analyte (2), and b. the magnetic measurement nanoparticles (10) each include a magnetic core (11) coated with a receptor (3) of the analyte (2), whereby the magnetic measurement nanoparticles (10) reversibly chemically bind to the analog (4) in dependence on the concentration of the analyte (2).

7. The sensor system of claim 6 wherein: a. the analog (4) is dextrin), and/or b. the binding substance (3) is concanavalin A.

8. The sensor system of claim 7 wherein the analyte (2) is glucose.

9. The sensor system of claim 1 wherein the magnetic reference nanoparticles (20) each include a magnetic core (21) coated with polyethylene glycol.

10. The sensor system of claim 1 wherein the magnetic measurement nanoparticles (10) each bear an analog (4) of an analyte (2) thereon, wherein the analog (4) forms the reversible chemical bonds with the binding substance (3).

11. The sensor system of claim 10 wherein the feature is the concentration of the analyte (2).

12. The sensor system of claim t: a. further including the binding substance (3), b. wherein the measurement nanoparticles (10), reference nanoparticles (20), and the binding substance (3) are provided as a signal pick-up unit (100) configured for implantation into a human or animal body (K).

13. The sensor system of claim 12 further including a signal processing unit (200) spaced from the signal pick-up unit (100), the signal processing unit (200) including: a. a transmitter (201) configured to emit an alternating magnetic field which magnetically interacts with the magnetic measurement nanoparticles (10) and the reference particles (20) of the signal pick-up unit (100), b. a receiver (202) configured to receive a relaxation response signal from the signal pick-up unit (100), the relaxation response signal being dependent on the magnetic interaction with the magnetic measurement nanoparticles (10) and the reference particles (20) of the signal pick-up unit (100).

14. The sensor system of claim 13 wherein the signal processing unit (200) includes a calculation unit (50) configured to calculate: a. the imaginary part of the dynamic susceptibility (χ) of: (1) the magnetic measurement nanoparticles (10), and (2) the reference nanoparticles (20), from the relaxation response signal; and b. a relationship between: (1) the amplitude (A.sub.1) of a peak (P1) in the imaginary part of the dynamic susceptibility (χ) of the reference nanoparticles (20), and (2) the amplitude (A.sub.2) of a peak (P2) in the imaginary part of the dynamic susceptibility (χ) of the measurement nanoparticles (10).

15. The sensor system of claim 12 wherein: a. the signal pick-up unit (100) further includes a hydrogel (5), and b. the measurement nanoparticles (10), the reference nanoparticles (20), and the binding substance (3) are disposed within the hydrogel (5).

16. The sensor system of claim 12 wherein: a. the signal pick-up unit (100) further includes a permeable shell (100a), and b. the measurement nanoparticles (10), the reference nanoparticles (20), and the binding substance (3) are disposed within the permeable shell (100a).

17. The sensor system of claim 12 wherein the signal pick-up unit (100) is at least partially biodegradable.

18. A method for determining a feature in a body (K) using the medical sensor system (1) of claim 1, the method including the steps of: a. emitting an alternating magnetic field onto the measurement nanoparticles (10) and reference nanoparticles (20), b. measuring a relaxation response signal, the relaxation response signal being dependent on the magnetic interaction of the alternating magnetic field with the magnetic measurement nanoparticles (10) and the reference particles (20).

19. The method of claim 20 further including the steps of calculating: a. the imaginary part of the dynamic susceptibility (χ) of: (1) the magnetic measurement nanoparticles (10), and (2) the reference nanoparticles (20), from the relaxation response signal; and b. a relationship between: (1) the amplitude (A.sub.1) of a peak (P1) in the imaginary part of the dynamic susceptibility (χ) of the reference nanoparticles (20), and (2) the amplitude (A.sub.2) of a peak (P2) in the imaginary part of the dynamic susceptibility (χ) of the measurement nanoparticles (10).

20. The method if claim 19 wherein the calculated relationship is a ratio of the amplitudes (A.sub.1, A.sub.2).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG. 1 schematically illustrates an exemplary sensor system according to the invention.

[0039] FIG. 2 schematically illustrates a competitive binding system usable in the invention.

[0040] FIG. 3 shows the measured imaginary part of the dynamic susceptibility of the measurement nanoparticles and reference particles plotted against the frequency of the exciting alternating magnetic field for various concentrations of the analyte (here glucose).

[0041] FIG. 4 shows the amplitude ratio A.sub.1/A.sub.2 of the peaks of the imaginary part of the dynamic susceptibility for various analyte (glucose) concentrations.

DETAILED DESCRIPTION OF EXEMPLARY VERSIONS OF THE INVENTION

[0042] FIG. 1 schematically illustrates a medical sensor system 1 for determining a feature, such as the concentration of an analyte, in a human or animal body. The following discussion will assume glucose is the analyte in question, and that glucose concentration is the feature being measured, but other analytes and features could be measured instead.

[0043] 20

[0044] In FIG. 1, the sensor system 1 includes a signal pick-up unit 100 including magnetic measurement nanoparticles 10, whose magnetic relaxation behavior changes when they form reversible chemical bonds with a binding substance 3 (here a receptor for glucose), and in particular concanavalin A (“ConA”).

[0045] As seen in FIG. 2, a competing binding system can be used wherein the magnetic cores 11 of the measurement nanoparticles 10 are coated with an analog 4 of the (glucose) analyte 2, e.g., dextran. The dextran analog 4 preferably has a molecular weight between 40,000 Da and 200,000 Da.

[0046] If the concentration of the glucose analyte 2 is low in the region of the signal pick-up unit 100, the ConA receptors (or other binding substance) 3 reversibly bind(s) to a greater degree to the dextran analog 4, as seen at the left side of FIG. 2. As a result, the hydrodynamic radius of the measurement nanoparticles 10 increases, which impacts the Brown relaxation. At a comparatively high glucose analyte 2 concentration, the glucose analyte 2 reversibly bind(s) to the ConA receptors 3, and the hydrodynamic radius r.sub.H of the measurement nanoparticles 10 accordingly decreases, as seen at the right side of FIG. 2

[0047] The signal pick-up unit 100 also includes magnetic reference nanoparticles 20, which do not form the chemical bond with the ConA receptors 3, or at least form this bond to a lesser degree than the glucose analyte 2 and/or the dextran analog 4. The reference nanoparticles 20 may be, for example, magnetic cores coated with PEG, preferably PEG300 (i.e., PEG having a chain length of 300 monomers).

[0048] FIG. 1 schematically depicts the measurement nanoparticles 10, reference nanoparticles 20, and the receptor 3 provided in a hydrogel 5, with these components 10, 20, 3, and 5 collectively providing the signal pick-up unit 100, which can be easily implanted or injected into the human or animal body K. The analyte 2 within the body can then diffuse into the hydrogel 5 of the signal pick-up unit 100, so that the reactions depicted in FIG. 2 can occur in the signal pick-up unit 100.

[0049] In an alternative version, the signal pick-up unit 100 includes a surrounding membrane or other permeable shell 100a, which permanently encloses the measurement nanoparticles 10, reference nanoparticles 20, and the receptor 3, and which can be penetrated by the glucose or other analyte 2. In this case, the analyte 2 diffuses from the surroundings through the shell 100a and into the :interior of the signal pick-up unit 100 implanted in the body K, so that the reactions depicted in FIG. 2 can occur in the signal pick-up unit 100.

[0050] In addition to the signal pick-up unit 100, the sensor system 1 preferably also includes a signal processing unit 200 (FIG. 1), which can be disposed spatially separated from the signal pick-up unit 100, in particular outside the body K. The signal processing unit 200 includes a transmitter 201 and a receiver 202, wherein the transmitter 201 is designed to emit an alternating magnetic field to act on the magnetic measurement nanoparticles 10 and reference nanoparticles 20 of the signal pick-up unit 100. The receiver 202 is designed to receive a response signal in the form of a relaxation signal of the signal pick-up unit 100, which can be generated by the magnetic interaction of the alternating magnetic field with the magnetic measurement nanoparticles 10 and the magnetic reference nanoparticles 20 of the signal pick-up unit 100. For generating the alternating magnetic field, the transmitter 201 can include a transmitting coil 201a, which can be suitably connected to an AC voltage source 30. The receiver 202 can further include two receiving coils 202a, 202b for receiving the magnetic relaxation signals, wherein these receiving coils 202a, 202b can be connected in a known manner to a lock-in amplifier 40 for evaluating the relaxation signals. The amplifier 40 multiplies the signals of the receiving coils 202a, 202b with the la excitation frequency 30 of the AC voltage signal.

[0051] Referring to FIG. 1, the distance A between the signal pick-up unit 100 and the transmitter 201 (particularly the transmitting coil 201a) can he, for example, in the range of 1 to 10 mm, preferably within 1-2 mm of 5 mm. The generated alternating magnetic field can have an amplitude in the range of (for example) 0 to 600 μT.

[0052] The diameters/dimensions of the nanoparticles 10, 20 are preferably selected such that the Neel relaxation time at a body temperature of 37° C. is greater by three orders of magnitude than the Brown relaxation time. This is typically achievable if the diameters of the nanoparticles 10, 20 are greater than approximately 11.2 nm.

[0053] In an exemplary version of the invention, the measurement nanoparticles 10 include a core 11 made of ferromagnetic elements such as iron, cobalt, nickel, and/or of a chemical compound of these elements. The core 11 is coated with a dextran analog 4, wherein the diameter of the resulting nanoparticle 10 is on average approximately 80 nm. The dextran preferably has a molecular weight between 40,000 Da and 200,000 Da. The reference nanoparticles 20 have a core 21 made of iron oxide, which is coated with PEG300, thereby providing coated reference nanoparticles having an average diameter of approximately 130 nm.

[0054] The dynamic susceptibility of the measurement or reference nanoparticles 10, 20 for the Brown relaxation present here is:

[00001]$\chi =\frac{{\chi }_0}{1+i.Math..Math.{\mathrm{\omega \tau }}_B}$$\mathrm{wherein}$${\tau }_B=\frac{4.Math.\pi .Math..Math.r_H^3.Math.\eta }{k_B.Math.T}$

is the Brown relaxation time. The particle 10, 20 rotates mechanically against the viscous forces of the surrounding medium. The Brown relaxation time is proportional to the third power of what is known as the hydrodynamic radius r.sub.H of the particles, which is plotted in FIG. 2, and which is decisively influenced by the binding of the measurement nanoparticles 10 to the receptor 3. In the case of a low glucose analyte 2 concentration, an accordingly high number of ConA receptor molecules 3 bind to the measurement nanoparticle 10, whereby its hydrodynamic radius r.sub.H increases (schematically depicted at the left side of FIG. 2). In contrast, at a high glucose concentration, the hydrodynamic radius r.sub.H decreases, since now the ConA receptors 3 are bound to a greater extent by the glucose analyte 2.

[0055] The foregoing competitive binding can be evaluated by measuring the magnetic relaxation behavior of the measurement nanoparticles 10 or reference nanoparticles 20. For this purpose, the receiver 202 preferably includes two receiving coils 202a, 202b disposed coaxially with one another (as seen in FIG. 1). The alternating magnetic field induces a voltage V.sub.Coil1, V.sub.Coil2 in the receiving coils 202a, 202b, whereby the difference of these voltages V.sub.m=V.sub.Coil1−V.sub.Coil2 can be measured

[0056] A voltage V.sub.Excitation is induced in the receiving coils 202a, 202b of the receiver 202, with V.sub.Excitation being dependent on the alternating magnetic field, as well as a voltage V.sub.Particles, which stems from the magnetization of the measurement or reference nanoparticles 10, 20. As a result, V.sub.Coil=V.sub.Excitation−V.sub.Particles.

[0057] Where the receiver coils 202a, 202b are disposed in the transmitter coil 201a, as in FIG. 1, the induced voltage V.sub.Excitation is the same for the two coils 202a, 202b, so that V.sub.m includes only the particle contributions. If the signal pick-up unit 100 is not present, V.sub.m vanishes.

[0058] When a signal pick-up unit 100 is present, the lock-in amplifier 40 may be used to determine portions of the voltage V.sub.m which are in phase with the alternating magnetic field (i.e., the real part of V.sub.m), and which are phase shifted 90° thereto (i.e., the imaginary part of V.sub.m). The imaginary part of the dynamic susceptibility thus results as

[00002]$\chi =C.Math.\frac{V_m}{\omega }$

wherein V.sub.m is the imaginary part of the voltage V.sub.m measured by way of the receiver coils 202a and 202b; ω is the frequency of the alternating magnetic field; and C is a constant.

[0059] It has been found that long particle chains form in the binding system of FIG. 2 at low glucose concentrations, resulting in sedimentation of these chains. This sedimentation phenomenon has been found to be reversible, and is reflected in the measured amplitude of the imaginary part of the dynamic susceptibility, shown in FIG. 3 for the nanoparticles 10, 20 for various glucose concentrations (5 mM, 10 mM, 15 mM and 20 mM).

[0060] In detail, the following sample compositions were used:

TABLE-US-00001 Measurement Reference Molar nanoparticles 10 nanoparticles 20 ratio c.sub.p Glucose (80 nm dextran) (130 nm PEG) ConA/nano- [mM] [mg/ml] [mg/ml] particles 0-20 6 4.8 165

[0061] The individual sample volumes used had the following compositions (components 80 nm dextran (25 mg/ml), 130 nm PEG (10 mg/ml), PBS (phosphate-buffered saline solution), and glucose (in PBS, 100 mM)):

TABLE-US-00002 80 nm 130 nm Total dextran PEG PBS ConA Glucose volume [μL] [μL] [μL] [μL] [μL] [μL] 4.80 9.60 4.00 1.60 — 20.00 4.80 9.60 3.00 1.60 1.00 20.00 4.80 9.60 2.00 1.60 2.00 20.00 4.80 9.60 1.00 1.60 3.00 20.00 4.80 9.60 — 1.60 4.00 20.00

[0062] However, the measured signal (or the amplitude of the imaginary part of the dynamic susceptibility) of FIG. 3 also includes information about the distance of the receiver 202 from the signal pick-up unit 100, the dilution of the particles, the number of the particles, and the viscosity, in addition to the sedimentation.

[0063] The reference system formed by the reference nanoparticles 20 is therefore used. FIG. 3 shows, for example, that two peaks P1, P2 can be observed at a glucose concentration of 20 mM, wherein a first peak P1 occurs at approximately 250 Hz (alternating field frequency) and the second peak P2 at approximately 800 Hz. These peaks P1, P2 correspond to the measurement nanoparticles 10 and reference nanoparticles 20, with the low frequency peak P1 being created by the 130 nM PEG particles 20, and the high frequency peak P2 being created by the 80 nm dextran particles 10. The plotted lines bearing the peaks P1 and P2 represent the overlapping relaxation signals of the two particle types 10, 20, with the is increases in amplitude arising when measurement particles 10 have lesser attachment between their dextran analog coatings 4 and the ConA receptor 3 (i.e., when concentration of the glucose analyte 2 is higher). Since the measurement nanoparticle peaks P2 rise considerably more strongly than the reference nanoparticle peaks P2, the ratios of the amplitudes A1, A2 may be considered for determining the glucose concentration:

[00003]$\begin{array}{c}y=.Math.A_1/A_2\\ =.Math.\frac{\mathrm{amplitude}.Math..Math.\mathrm{measured}.Math..Math.\mathrm{at}.Math..Math.220.Math..Math.\mathrm{Hz}.Math..Math.\mathrm{in}.Math..Math.\mathrm{FIG}..Math.3}{\mathrm{amplitude}.Math..Math.\mathrm{measured}.Math..Math.\mathrm{at}.Math..Math.894.Math..Math.\mathrm{Hz}.Math..Math.\mathrm{in}.Math..Math.\mathrm{FIG}..Math.3}\end{array}$

[0064] The ratio can be evaluated in an automated fashion, e.g., by an calculation unit 50 (FIG. 1). Calculating the ratios at various glucose concentrations results in:

TABLE-US-00003 Glucose [mM] A.sub.1/A.sub.2 0 1.6048 5 1.1385 10 0.9910 15 0.9335 20 0.8920

[0065] With an appropriately calibrated sensor system 1, the ratio determination A.sub.1/A.sub.2 allows the glucose (or other analyte) concentration to be determined in the region of the signal pick-up unit 100, with the reference system reducing the effect of interferences.

[0066] The signal-to-noise ratio was determined by way of repeat measurements. The standard deviation of A.sub.1/A.sub.2 was determined to be 0.001377 (using 22 measurements),

[0067] FIG. 4 shows the foregoing A.sub.1/A.sub.2 ratio plotted against the glucose concentration, along with a curve fit to the data. The A.sub.1/A.sub.2 ratio was fit to the following function:

[00004]$\frac{A_1}{A_2}=\frac{\mathrm{aG}+b}{G+d}$

wherein G is the glucose concentration, and a, b, d are fit parameters. The illustrated curve fit has an R.sup.2 value of 0.9998, showing good agreement with the foregoing function. The nonlinearity arises because the two particle types 10, 20 interact with ConA receptor 3 and thus agglomerate or sediment.

[0068] To obtain a sensor system 1 having linear characteristics, a reference nanoparticle 20 that does not bind to the receptor 3 can be used. It is also possible to determine the superimposition of the Brown relaxation of the two particle types 10, 20 through individual measurements of the two particles 10, 20, and subtract these from each other:

[00005]$y=\frac{A_2}{A_1-a*A_2}$

[0069] The factor a then includes the influence of the measurement nanoparticles 10 (80 nm dextran) on A.sub.1 and the sedimentation of the reference nanoparticles 20 (130 nm PEG). Using the foregoing data, linear behavior is obtained for a=0.75.

[0070] The invention is not limited to the exemplary versions described above, and rather is limited only by the claims set out below. Thus, the invention encompasses all different versions that fall literally or equivalently within the scope of these claims.