Measurement of liquid flows in a living organism

A method of measuring liquid flows in a living organism comprises the steps of applying an applied magnetic field to a living organism, introducing a time-varying quantity of a magnetizable fluid into a flow of liquid in the living organism, and measuring the variation in an induced magnetic field emanating from the living organism as a measure of the flow of the magnetizable fluid and the liquid within the living organism. The measurement of the induced magnetic field is preferably accomplished with at least two magnetic field sensors positioned at different locations relative to the living organism, whose outputs are detected with SQUID detectors. A cross correlation of the outputs of the magnetic field sensors permits the flow of liquid to be deduced as a function of time and location.

BACKGROUND OF THE INVENTION 
The present invention relates to the measurement of liquid flow in a living 
organism, and, more particularly, to such measurements performed using 
magnetic field measurements. 
The flow and circulation of liquids in the body of a living organism are an 
important aspect of the health of the organism. The principal liquid 
flowing in the body is blood, which carries nutrients and oxygen to cells 
and returns waste from the cells. Irregularities in the flow of blood 
through the heart and blood vessels indicate the presence of constrictions 
or malfunctions. The irregularities in blood flow in turn often lead to 
other problems. 
Health care workers have long monitored the flow of blood in the body, and 
there are a variety of techniques that can be used for this purpose. A 
stethoscopic examination can determine some aspects of blood flow, but 
this approach is quite limited. Blood flow can be monitored by injecting 
X-ray absorbing dyes or radioactive tracers, followed by measurements of 
the progress of the dyes or tracers with X-rays or radioactivity counters, 
respectively. These approaches, while operable, have the disadvantage of 
low spatial resolution, possible destruction of cells, and, in some cases, 
the need to inject relatively large amounts of tracer material due to the 
relatively low sensitivity of the techniques. 
There is therefore a need for an approach that permits monitoring the flow 
of liquids in the body which is of high sensitivity and which produces 
essentially no adverse side effects. The present invention fulfills this 
need, and further provides related advantages. 
SUMMARY OF THE INVENTION 
The present invention provides an approach for monitoring liquid flows 
through the body of a living organism such as a human being or an animal. 
Although the approach of the invention requires the introduction of a 
fluid into the body, the method has high sensitivity and therefore 
requires a minimal introduction of the fluid. The approach is operable for 
monitoring any liquid flow in the body, such as that of blood, urine, and 
injected liquids. 
In accordance with the invention, a method of measuring liquid flows in a 
living organism comprises the steps of applying an applied magnetic field 
to a living organism, introducing a time-varying quantity of a 
magnetizable fluid into a flow of liquid in the living organism, and 
measuring the temporal or spatial variation in an induced magnetic field 
emanating from the living organism as a measure of the flow of the 
magnetizable fluid and the liquid within the living organism. 
The magnetizable fluid is preferably a suspension of small magnetite 
particles in a carrier fluid. Such fluids are paramagnetic (also sometimes 
termed "superparamagnetic") and can be magnetized to exhibit an induced 
magnetic field of greater magnitude than the applied magnetizing field. 
Such fluids are available commercially. 
A magnetizing field is applied to the living organism to be studied. The 
applied magnetizing field may be constant or varying in time or spatially 
varying, as may be appropriate to the variation of the technique to be 
used. A small quantity of the magnetizable fluid is introduced into the 
liquid to be studied, diluting the magnetizable fluid in that liquid. The 
amount of the magnetizable fluid injected varies as a function of time, 
either by changing the amount of the magnetizable component of the fluid 
or the total amount of introduced fluid, as a function of time. For 
example, if the flow of blood in a particular region of a leg is to be 
studied, a small quantity of the magnetizable fluid is injected into an 
artery leading to that region. The magnetizing field applied to the body 
induces an induced magnetic field in the magnetizable fluid as it flows 
through the blood vessels. Although conceivably it would not be necessary 
to apply a magnetic field to the magnetizable fluid due to the presence of 
the earth's magnetic field, the present invention requires the use of an 
applied magnetic field to induce magnetism in the flowing magnetizable 
fluid. 
The progress of the magnetizable fluid through the blood vessels is 
preferably measured externally to the body by a biomagnetometer. This 
instrument includes one or more, usually a plurality of, magnetic field 
sensors such as single-loop magnetometers or gradiometers. Passage of a 
time-varying induced magnetic field through the sensor produces an 
electrical current, which in turn is detected by a sensitive electrical 
detector. Present biomagnetometers utilize Superconducting QUantum 
Interference Device ("SQUID") detectors coupled to the magnetic field 
sensors to detect the small currents resulting from very small magnetic 
field fluxes. 
Magnetic field sensor/SQUID detector combinations are highly sensitive to 
magnetic field variations. They can therefore record the movement of the 
magnetizable fluid in the living organism, even when the concentration of 
the magnetizable fluid in the organism is very low. The geometry of the 
sensor system can be varied depending upon the nature of the study being 
performed. However, typically there would be several sensors and 
associated SQUIDs at varying locations selected so that the passage of the 
magnetizable fluid through the region can be monitored from the sensed 
induced magnetic field changes. 
The present invention provides an advance in the field of monitoring liquid 
flows in living organisms. Other features and advantages of the invention 
will be apparent from the following more detailed description of the 
invention, taken in conjunction with the accompanying drawings, which 
illustrate, by way of example, the principles of the invention.

DETAILED DESCRIPTION OF THE INVENTION 
FIG. 1 schematically depicts the practice of the present invention as used 
to measure blood flow in a human body 10 and identify and locate 
impediments to that blood flow. The blood 12 flows through a blood vessel 
14 that is below a surface 15 of the body 10. To illustrate the use of the 
invention, it is assumed that the blood vessel 14 is of generally constant 
internal cross-sectional area over most of its length, but has an internal 
constriction 16 over a portion of its length. 
In accordance with a preferred embodiment of the invention, an applied 
magnetic field is applied to the body 10 by a magnet 18 positioned 
externally to the body. The magnet 18 may be a permanent magnet that 
produces a constant applied magnetic field, or, as depicted, an 
electromagnet that can produce either a constant applied magnetic field or 
a time-varying applied magnetic field. 
A time-varying quantity of a magnetizable fluid 20 is introduced into the 
blood 12 in the blood vessel 14 at a location remote from a measurement 
region of interest 21, through a needle 22. The magnetizable fluid mixes 
with the blood (or other liquid in the body) and flows along with the 
blood. The needle 22 is preferably placed at a distance upstream from the 
measurement region of interest 21 sufficiently far that the magnetizable 
fluid is uniformly distributed across the width of the blood vessel 14 by 
the time that it reaches the region of interest 21. Also, displacement of 
the point of introduction upstream reduces the magnetic interference of 
the injection on the magnetic field measurements. 
The magnetizable fluid is preferably a paramagnetic ferrofluid consisting 
of a suspension of 100 Angstrom diameter magnetite particles in water, 
stabilized with an anionic surface active agent. Such a fluid is available 
as Ferrofluid Type EMG507 from Ferrofluidics Corp., Nashua, N.H. This 
particular magnetizable fluid is superparamagnetic with a magnetic 
susceptibility of 0.5 to 5, saturates at an applied magnetic field of 
100-400 Gauss, and exhibits no magnetic hysteresis. 
A flow of blood, because it contains iron, exhibits a small magnetic field 
even without the presence of the magnetizable fluid. A flow of the 
magnetizable fluid also exhibits a small magnetic field even without the 
application of a magnetic field by the magnet 18. However, these fields 
are so small that they are not practically utilized for measurements of 
liquid flows in the living organism, unless a very high concentration of 
the magnetizable fluid is used. The present invention provides that the 
magnetizable fluid is induced to exhibit a higher induced magnetic field 
as a result of the applied magnetic field of the magnet 18. The higher 
induced magnetic field makes measurements of the liquid flow in the body 
practical with very small additions of the magnetizable fluid, which in 
turn do not produce substantial side effects and permit extended studies. 
When a time-varying quantity of a magnetizable fluid moves through an 
applied magnetic field, a varying current and thence a varying induced 
magnetic field results. The varying induced magnetic field is detected and 
measured by a biomagnetometer 30 positioned externally to the body. The 
time variations in the induced magnetic field sensed by the various 
sensors of the biomagnetometer 30, and a cross correlation of the signals 
produced by the various sensors leads to an understanding of the 
environment through which the magnetizable fluid is moving. 
(There are two magnetic fields involved in the present invention, and must 
be carefully distinguished. The applied magnetic field is created within 
the region of interest 21 by the operation of the magnet 18. The induced 
magnetic field is that which results from the presence and movement of the 
magnetizable fluid in the region of interest 21, and is measured 
externally by the biomagnetometer 30.) 
Biomagnetometers suitable to the practice of the present invention are 
available commercially from Biomagnetic Technologies, Inc., San Diego, 
Calif. The structure and operation of such biomagnetometers are well known 
to those skilled in the art. FIG. 1 depicts a biomagnetometer that has 
been adapted to be particularly useful in measurements of liquid flows in 
living organisms. This biomagnetometer is preferably of the type disclosed 
in U.S. Pat. No. 5,061,680, whose disclosure is incorporated by reference, 
although more conventional biomagnetometers can also be used. 
This biomagnetometer 30 includes at least two, and typically a plurality, 
of magnetic field sensors, here indicated as sensors 32, 34, 36, 38, 40, 
and 42. The sensors are distributed through space in an arrangement 
selected to yield the required information. In the case of an 
investigation of blood flow through a blood vessel 14, the sensors are 
typically arranged along the length of the blood vessel, as illustrated. 
The use of the present invention is not limited to measurements of a blood 
flow in a long blood vessel lying near the surface of the body, which is 
used in the illustration for convenience. Movement of blood in deeply 
buried vessels can be measured, as for example blood vessels within the 
brain and within organs such as the heart. 
Each sensor includes a pickup coil that may be a planar-loop magnetometer, 
such as illustrated for the sensors 32 and 34, or a three-dimensional 
gradiometer, such as illustrated for the sensors 36, 38, 40, and 42. In 
each case, when magnetic flux penetrate the sensor, an electrical current 
is produced. The electrical current is typically very small, because the 
concentration of the magnetizable fluid 20 is selected to be as small as 
possible to avoid side effects. The resulting induced magnetic fields are 
small, on the order of less than 10,000 femtotesla. 
In the biomagnetometer constructed in accordance with the '680 patent, the 
sensors 32, 34, 36, 38, 40, and 42 are made of a superconductor and are 
placed in an insulated enclosure 44 that is filled with a cryogenic 
coolant appropriate to the superconductor, such as liquid nitrogen or 
liquid helium, to maintain the sensors in the superconducting state. Loss 
of current due to electrical resistance is thereby avoided. The respective 
signal of each of the sensors is conveyed through a lead 46 to a 
superconducting quantum interference device ("SQUID") 48. (In FIG. 1 only 
a single lead and SQUID are shown to reduce clutter in the drawing, but in 
practice there is typically a dedicated lead system and SQUID for each of 
the sensors.) The SQUID 48 may be placed in the same container as its 
sensor, or, as shown, may be placed in another insulated container 50 
filled with a cryogenic gas. The advantage of placement of the SQUID in a 
separate container is that the container 50 may be maintained at a lower 
cryogenic temperature than the container 44, such as at liquid helium 
temperature, to improve the electronic performance of the SQUID 48. 
The SQUID 48 detects the small electrical current flow produced when a 
magnetic flux penetrates the sensor 40, and produces an output signal. 
That output signal is transmitted to conventional ambient-temperature 
SQUID electronics 52, and the output of the SQUID electronics 52 is 
gathered, stored, and processed by a microcomputer 54. SQUID design and 
electronics are well known in the art, and are described, for example, in 
U.S. Pat. Nos. 4,386,361, 4,403,189, 3,980,076, and 4,079,730, whose 
disclosures are incorporated by reference. 
The data acquired from the sensors may then be processed by processing 
techniques available in the art, such as the approach disclosed in U.S. 
Pat. No. 4,977,896, whose disclosure is incorporated by reference. To 
improve the signal-to-noise ratio of the results, the living organism 
under study, the magnet, the sensors, and the SQUID detectors may be 
placed in a magnetically shielded room 56, indicated schematically in FIG. 
1. Such magnetically shielded rooms are disclosed, for example, in U.S. 
Pat. Nos. 3,557,777 and 5,043,529, whose disclosures are incorporated by 
reference. 
FIG. 2 illustrates the type of results that would be produced by the 
arrangement of FIG. 1, when operating in the manner discussed previously. 
The magnetizable fluid 20 is injected through the needle 22 at a time to, 
and flows through the blood vessel 14 from left to right in the drawing of 
FIG. 1. At a time t1 after introduction of the magnetizable fluid, sensor 
32 detects the increased induced magnetic field produced by the leading 
edge of the flow of the magnetizable fluid. Sensor 34 detects the leading 
edge of the flow of the magnetizable fluid a short time t2 later. Sensor 
40 detects the leading edge at a time t3 later (this discussion omits 
sensors 36 and 38, but they would show similar patterns), and sensor 42 
detects the leading edge at a time t4 later. The presence of the 
constriction 16 restricts the total flow rate (volume per unit time) of 
blood in the blood vessel 14 to the same value at all locations. However, 
the velocity of flow (distance per unit time) varies as a function of 
position. Upstream of the constriction 16 the flow velocity is relatively 
slow, and downstream of the constriction 16 the flow velocity is 
relatively faster. Accordingly, the time t4 is less than the time t2 
(assuming that the sensors are equally spaced for this example). Moreover, 
the faster flow past the sensors 40 and 42 produces an induced magnetic 
field of greater magnitude than the slower flow past the sensors 32 and 
34. Thus, two aspects of the measurement of the sets of sensors permits 
one to deduce the presence of the constriction 16 in the blood vessel 14, 
somewhere between the sets of sensors. 
The operability of the present approach has been verified by measurements 
of an anesthetized rat. The study was performed in a magnetically shielded 
room using a Model 607 biomagnetometer available from Biomagnetic 
Technologies, Inc. and with an applied magnetic field of the magnet 18 of 
about 0.2 microtesla. For this feasibility study the instrument had a 
non-optimized circular array of seven second-order gradiometers, not the 
linear array of FIG. 1. 
The right femoral vein of the rat was cannulated for an infusion of 
ferrofluid. Magnetic data was collected for 30 seconds, after which 0.3 cc 
(cubic centimeters) of diluted magnetizable fluid having a particle 
concentration of 0.085 volume percent was injected. Measurement signals 
generally similar to those depicted in FIG. 2 were obtained. The signals 
of the seven sensors were cross correlated, and showed that the flow rate 
of the magnetizable fluid and the blood was consistent with the flow 
pattern of blood through the body of the rat. To reach more quantitative 
conclusions would require optimization of the sensor coil arrangement, as 
shown in FIG. 1. The injection of magnetizable fluid was repeated three 
times, except that in the three subsequent injections a smaller amount, 
about 0.1 cc. of the same particle concentration magnetizable fluid was 
used. These subsequent injections proved that the concentration of the 
magnetizable fluid could be made quite small, and also that the results 
were repeatable. After the study was complete, the cannula was removed and 
the rat returned to its cage. The rat suffered no seizures or other 
apparent abnormalities resulting from the procedure. 
The present invention provides an apparatus and method for determining the 
flow of liquids within a living organism. Although particular embodiments 
of the invention have been described in detail for purposes of 
illustration, various modifications may be made without departing from the 
spirit and scope of the invention. Accordingly, the invention is not to be 
limited except as by the appended claims.