Electricity: measuring and testing – Magnetic – Fluid material examination
Reexamination Certificate
2001-02-16
2003-02-11
Strecker, Gerard R. (Department: 2862)
Electricity: measuring and testing
Magnetic
Fluid material examination
C324S071400, C324S235000, C422S068100, C436S526000
Reexamination Certificate
active
06518747
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to sensing the presence of magnetic particles, and more particularly to quantitatively measuring accumulations of such particles by means of DC magnetic excitation and sensing of the amplitude of the resulting excitation of the magnetic moments of the particles.
2. Discussion of Related Art
Much attention has been given to techniques for determining the presence, and possibly the level of concentration, of minute particles in a larger mixture or solution in which the particles reside. It is desirable in certain circumstances to measure very low concentrations of certain organic compounds. In medicine, for example, it is very useful to determine the concentration of a given kind of molecule, usually in solution, which either exists naturally in physiological fluids (for example, blood or urine) or which has been introduced into the living system (for example, drugs or contaminants).
One broad approach used to detect the presence of a particular compound of interest is the immunoassay technique, in which detection of a given molecular species, referred to generally as the ligand, is accomplished through the use of a second molecular species, often called the antiligand or the receptor, which specifically binds to the ligand of interest. The presence of the ligand of interest is detected by measuring, or inferring, either directly or indirectly, the extent of binding of ligand to antiligand.
A good discussion of several detection and measurement methods appears in U.S. Pat. 4,537,861 (Elings et al.). The patent is directed to several ways to accomplish homogenous immunoassays in a solution of a binding reaction between a ligand and an antiligand which are typically an antigen and an antibody. The teaching of Elings is to create a spatial pattern formed by a spatial array of separate regions of antiligand material attached to a solid substrate. The corresponding ligand, which has been previously labeled by attaching to it a molecule or particle which has a particular physical characteristic, is then dispersed over the solid substrate such that the labeled ligand can produce a binding reaction with the antiligand in the spatial patterns. After the labeled bound complexes have been accumulated in the spatial patterns, equipment is used to scan the solid substrate, thereby measuring the physical characteristic of the labels to provide the desired immunoassay. The scanner may be based on fluorescence, optical density, light scattering, color and reflectance, among others. In addition, Elings further teaches that the magnetic particles may also be attached to either the ligand or the labeled ligand for the purpose of accumulating the labeled bound complexes within the solution or onto the prepared substrate surface, after which the scanning techniques previously described are employed.
Indeed, magnetic particles made from magnetite and inert matrix material have long been used in the field of biochemistry. They range in size from a few nanometers up to a few microns in diameter and may contain from 15% to 100% magnetite. They are often described as superparamagnetic particles or, in the larger size range, as magnetic beads. The usual methodology is to coat the surface of the particles with some biologically active material which will cause them to bond strongly with specific microscopic objects or particles of interest (proteins, viruses, cells, DNA fragments, for example). The magnetic particles then become “handles” by which the objects can be moved or immobilized using a magnetic gradient, usually provided by a strong permanent magnet. The Elings patent is an example of this use of magnetic particles. Specially constructed fixtures using rare-earth magnets and iron pole pieces are commercially available for this purpose.
Although these magnetic particles have been used primarily for moving or immobilizing the bound objects, some experimental work has been done on using the particles as tags for detecting the presence of the bound complexes. Historically the detection and quantification of the bound complexes has been accomplished by means of radioactive, fluorescent, or phosphorescent molecules which are bound to the complexes of interest. These prior tagging techniques have various important weaknesses. Radioactive methods present health and disposal problems of the resulting low-level radioactive waste, and they are also relatively slow. Fluorescent or phosphorescent techniques are limited in their quantitative accuracy and dynamic range because emitted photons may be absorbed by other materials in the sample (see Japanese patent publication 63-90765, published Apr. 21, 1988, Fujiwara et al.). Furthermore, the signal from the fluorescent or phosphorescent molecules normally decays over a period of hours or perhaps days, at the most.
On the other hand, since the signal from a tiny volume of magnetic particles is exceedingly small, it has been natural that researchers have tried building detectors based on Superconducting Quantum Interference Devices (SQUIDs), which are well known to be the most sensitive detectors of magnetic fields for many applications. There are several substantial difficulties with this approach, however. Since the pickup loops of the SQUID must be maintained at cryogenic temperatures, the sample must be cooled to obtain a very close coupling to these loops. This procedure makes the measurements unacceptably tedious, and is inappropriate for many biotechnology applications. In addition, the general complexity of SQUIDS and their associated cryogenic components renders them extremely expensive and generally unsuitable for use in an inexpensive desktop instrument. Even a design based on “high Tc” superconductors does not completely overcome these objections, and would introduce several new difficulties, as discussed in Fujiwara et al.
More traditional approaches to detecting and quantifying the magnetic particles have typically involved some form of force magnetometry, in which the sample is placed in a strong magnetic gradient and the resulting force on the sample is measured. In a force-balance magnetometer, for example, the force is measured as an apparent change in the weight of the sample as the gradient is changed. An example of this technique is shown in Rohr U.S. Pat. Nos. 5,445,970 and 5,445,971. A more sophisticated technique measures the effect of the particle on the deflection or vibration of a micromachined cantilever (see Baselt et al.,
A Biosensor based on Force Microscope Technology
, Naval Research Lab., J. Vac. Science Tech. B., Vol 14, No. 2, 5pp, April 1996). These approaches are all limited in that they rely on converting an intrinsically magnetic effect into a mechanical response, which must then be distinguished from a large assortment of other mechanical effects such as vibration, viscosity, and buoyancy, which can substantially interfere with the intended measurement.
In U.S. Pat. No. 6,046,585, Simmonds describes a technique employing a small region (the “gap”) in a toroidal magnetizer, within which one places a pair (or multiple pairs) of inductive detection coils and generates a high-frequency oscillating magnetic field (the “drive field”). In this implementation, the individual detection coils are carefully matched in size but counter-wound, so that in the absence of any other magnetic materials (such as magnetic particles which are part of magnetic bound complexes) the pair of coils produces a zero output voltage. In other words, the drive field couples exactly the same but with opposite polarity to each of the counter-wound coils, so that the voltages from the individual coils algebraically sum exactly to zero.
When an accumulation of magnetic particles on a solid substrate is placed in the gap in close proximity to the detection coils, the oscillating drive field produces a corresponding oscillating magnetization in the magnetic particles, which can then be detected by the detection coils. In the Simmonds patent, the physical size of the partic
Black Randall C.
Diederichs Jost H.
Jensen Kurt G.
Sager Ronald E.
Simmonds Michael B.
Quantum Design, Inc.
Strecker Gerard R.
The Maxham Firm
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