U.S. patent application number 13/188840 was filed with the patent office on 2011-11-17 for device for moving magnetic nanoparticles through tissue.
This patent application is currently assigned to NanoBioMagnetiacs, Inc.. Invention is credited to Charles E. Seeney, William A. Yuill.
Application Number | 20110279944 13/188840 |
Document ID | / |
Family ID | 37083418 |
Filed Date | 2011-11-17 |
United States Patent
Application |
20110279944 |
Kind Code |
A1 |
Seeney; Charles E. ; et
al. |
November 17, 2011 |
Device For Moving Magnetic Nanoparticles Through Tissue
Abstract
The movement of magnetically responsive nanoparticles through a
membrane is significantly enhanced by varying the direction of the
magnetic field gradient at the membrane. A device for generating
the varying-gradient magnetic field includes a primary magnet
having a primary magnetic field gradient direction, one or more
secondary magnets directed at an acute angle relative to the
primary magnetic field gradient direction, and a controller
connected to at least the secondary magnets. The controller is
operable to repetitively vary the direction of the resultant
magnetic field gradient in a pulsating manner.
Inventors: |
Seeney; Charles E.; (Edmond,
OK) ; Yuill; William A.; (Edmond, OK) |
Assignee: |
NanoBioMagnetiacs, Inc.
|
Family ID: |
37083418 |
Appl. No.: |
13/188840 |
Filed: |
July 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11400620 |
Apr 6, 2006 |
8001977 |
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13188840 |
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60669681 |
Apr 8, 2005 |
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11400620 |
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Current U.S.
Class: |
361/147 |
Current CPC
Class: |
A61N 2/12 20130101 |
Class at
Publication: |
361/147 |
International
Class: |
H01F 7/00 20060101
H01F007/00 |
Claims
1. A device for generating a varying-gradient magnetic field for
moving magnetically responsive nanoparticles through a membrane,
the device comprising: a primary magnet having a primary magnetic
field gradient direction; one or more secondary magnets directed at
an acute angle relative to the primary magnetic field gradient
direction; and a controller connected to at least the secondary
magnets and operable to repetitively vary the direction of the
resultant magnetic field gradient at the membrane in a pulsating
manner.
2. The device of claim 1 further comprising a positioning means for
positioning the one or more magnets proximate the membrane.
3. The device of claim 1, wherein at least one of the secondary
magnets is an electromagnet connectable to a power source.
4. The device of claim 3 wherein the controller comprises an
electrical switch for oscillating power to the at least one
electromagnet.
5. The device of claim 3 wherein the controller is adapted to
oscillate the magnetic field intensity on and off.
6. The device of claim 1 comprising two secondary
electromagnets.
7. The device of claim 6 wherein the primary magnet is a permanent
magnet.
8. The device of claim 6 wherein the primary magnet is an
electromagnet.
9. The device of claim 6 wherein the controller is adapted to
alternately pulse the two secondary electromagnets.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/400,620 filed Apr. 6, 2006, which claims
priority to U.S. Provisional patent application Ser. No. 60/669,681
filed Apr. 8, 2005, the entire contents of which are hereby
incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND
[0003] 1. FIELD OF THE INVENTION
[0004] The present invention relates generally to delivery of
substances through membranes or tissue within a body, and more
particularly, to a method and device for delivery of particles
through membranes and tissue within a body.
[0005] 2. BACKGROUND OF THE INVENTION
[0006] Nanoparticles generally refer to particles having at least
one dimension of about 100 nanometers or less. Magnetic
nanoparticles offer many possible medical treatment possibilities
due to their very small size and the ability to manipulate their
movement using an externally applied magnetic field gradient. A
major goal in medical applications using magnetic nanoparticle
carriers is to increase deposition in a specific target area so as
to increase the dose in the affected area and to allow less dosage
in non-affected areas. For example, the particles may be used as
carriers for pharmaceuticals, such as anticancer drugs, and the
carrier particles may be magnetically targeted to a specific area
of the body such as a tumor. Other applications may involve
directing the particles toward and embedding the particles in a
target organ tissue in order to impart magnetic properties to the
target.
[0007] In many applications of this technology, what is needed is a
method for improving the rate and extent of penetration of magnetic
nanoparticles through a membrane or tissue. These and other
objectives will be better understood with reference to the
following disclosure.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to moving magnetically
responsive nanoparticles, and more specifically, to moving
magnetically responsive nanoparticles through a membrane within a
body. A device of the present invention generates a
varying-gradient magnetic field for moving magnetically responsive
nanoparticles through a membrane. The device comprises one or more
magnets for producing a magnetic field at the membrane. At least
one magnet is connected to a controller which operates to vary, in
a repetitive manner, the magnetic field gradient produced at the
membrane by the one or more magnets.
[0009] In one embodiment the device includes an electromagnet with
a controller varying the power to the magnet in a repetitive
manner. In another embodiment, the physical position of the magnet
is repeatedly changed with time.
[0010] The present invention also includes a system for moving
magnetically responsive nanoparticles through a membrane. The
system comprises a means for introducing magnetically responsive
nanoparticles into a body, and a magnetic field generator. The
magnetic field generator is adapted to produce a
repetitively-varying magnetic field gradient for moving the
nanoparticles through the tissue.
[0011] The present invention additionally includes a method of
moving magnetically responsive nanoparticles through a membrane
within a body comprising the following steps. The magnetically
responsive nanoparticles are introduced into the body. The
anaoparticles are then moved through the membrane using a
repetitively-varying magnetic filed gradient.
[0012] Other features and advantages of the present invention will
be readily apparent to those skilled in the art upon a reading of
the description of preferred embodiments which follows when taken
in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a diagrammatic illustration showing the use a
device of the present invention.
[0014] FIGS. 2A-2D are diagrammatic representations of magnet
arrangements useful in the present invention.
[0015] FIG. 3 is a diagrammatic illustration of the fixed-magnetic
field experimental setup.
[0016] FIG. 4 is a diagrammatic illustration of a
repetitively-varying magnetic field gradient experiment using a
permanent magnet.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] In proposed medical treatment applications, magnetic
nanoparticles are first caused to travel through the bloodstream.
Once the particles have reached the target area, it is then
desirable for the particles to penetrate the vessel wall and often
to penetrate additional tissue. The rate and extent of penetration
are important parameters for the success of these applications.
[0018] Conventional procedures to pull magnetically responsive
particles through a fluid or tissue use fixed magnets to pull
continuously in the same direction. Using a fixed magnet, the
particles can be moved through a membrane, but the movement is
relatively slow. The discovery outlined by this invention is that
the rate of movement of superparamagnetic nanoparticles through a
membrane is significantly faster using a magnetic field that
oscillates or varies repetitively in direction and/or in strength,
and particularly when using a field in which the direction of the
magnetic field gradient varies repetitively with time. Thus, the
method of the present invention comprises introducing magnetically
responsive nanoparticles into the body, and moving the
nanoparticles through a membrane using a repetitively-varying
magnetic field directed at the membrane.
[0019] The phrase "repetitively-varying magnetic field" as used
herein and in the appended claims is defined as "a magnetic field
having repetitive changes or perturbations in the direction and/or
strength of the magnetic field gradient." Varying the direction of
the magnetic field gradient causes the force acting upon magnetic
particles to vary in direction so as to aid particles in moving
around individual molecules or fibers making up a vascular membrane
and tissue. The particles can also be periodically relaxed by the
magnetic field so as to disengage from the structure of the tissue
and be free to move in the gradient when it is reestablished. These
theories are believed to reflect actual mechanisms; however, the
devices and methods of the invention do not depend on the accuracy
of these theories.
[0020] Referring to FIG. 1, a magnetic field generating device 10
is shown for producing a varying-gradient magnetic field 12,
illustrated by field lines, for moving magnetically responsive
nanoparticles 14 through a membrane 16. One or more magnets 18 are
needed for producing the magnetic field 12 at the membrane 16. A
magnetic field gradient variation controller 20 is connected to at
least one magnet and is operable to vary the magnetic field
gradient of that magnet to cause a variation in the direction of
the resultant gradient at the membrane 16. A positioning means 22
is connected to the magnets 18 and allows for positioning of the
magnets 18 with respect to the membrane 16.
[0021] It is anticipated that movement of the particles can be
optimized by modifying the composition and properties of the
magnetic nanoparticles used. The magnetically responsive
nanoparticles 14 preferably comprise ferromagnetic particles, more
preferably superparamagnetic particles, and most preferably
superparamagnetic particles comprising magnetite. The nanoparticles
14 may include a biocompatible shell and be used as carriers for
bioactive substances such as pharmaceuticals or other materials
such as gene or stem cells needed at a specific location in a body
24. For example, the particles could carry cancer treating drugs
and be carried in a carrier fluid 26 such as the blood stream to a
target tumor. In this case the particles must be moved from the
bloodstream through membranes such as the wall of a blood vessel
including the endothelium, as well as the membrane or tissue
containing and surrounding the tumor cells. The term "nanoparticle"
is used herein and in the appended claims to refer to all such
particles, whether coated or carrying other chemicals, and
regardless of whether the particles are present individually or in
cemented clusters or agglomerates. The term "membrane" is used
herein and in the appended claims in a broad sense to include
arterial and vein walls as well as any tissue covering, lining,
containing or separating target organs, tumors, cells, and the like
in the body.
[0022] Other applications of the inventive technology include the
embedding of superparamagnetic particles into the tissue of an
organ in order to impart magnetic properties to that tissue and
subsequently allow the organ to function with the aid of a magnet.
Examples of this type application potentially include hearing
devices and valves.
[0023] Suitable magnets include both permanent magnets and
electromagnets. Commercially available permanent magnets include
magnetic metallic elements, composites such as ceramics and
ferrites, and rare earth magnets. Electromagnets are also readily
available commercially.
[0024] In a preferred embodiment, the device comprises at least one
electromagnet such that the magnetic strength can be oscillated or
pulsed. (The term "oscillate" and all its forms are used broadly to
include a pulse.) Design of electromagnets suitable for
applications requiring oscillation and pulsing is well known to
those skilled in the art.
[0025] The controller 20 may vary the physical position or movement
of a magnet, or it may control the magnetic strength. For example,
a controller may mechanically rotate one or more permanent or
electromagnets. Preferably, controller 20 controls the power from a
power source 28 to an electromagnet. More preferably, the
controller comprises a timer 30 and a switch 32 for pulsing the
power to the electromagnet by turning it off and on in a timed,
repetitive fashion. Mechanical controller and electromagnet power
controller design and manufacture are well known to those skilled
in the art.
[0026] Many different arrangements of magnets can be utilized to
achieve a variable magnetic field gradient. A single electromagnet
pulsed on and off can be used to provide a relaxation and
reorientation time for the nanoparticles as described above. FIG. 1
and FIG. 2A show a preferred arrangement in which two
electromagnets, 34 and 34', are alternately pulsed off and on while
the strength of a main magnet 36 is constant. This arrangement
provides variation in the direction of the magnetic field gradient.
Main magnet 36 can be an electromagnet or a permanent magnet and is
directed generally perpendicular to the membrane 16 while the
electromagnets 34 and 34' are directed at an angle to this
perpendicular.
[0027] FIGS. 2B-2D show other preferred configurations for
electromagnets, permanent magnets, and combinations of
electromagnets and permanent magnets. For example, a preferred
magnet configuration shown in FIG. 2C comprises electromagnets 34
clustered symmetrically around a center point and directed in
parallel. The direction of the magnetic field is varied by varying
or pulsing, preferably not in unison but rather alternately, the
strength of the individual electromagnets. As above, alternate
pulsing causes a variation in the direction of the resultant
gradient at the membrane, causing the force acting upon magnetic
particles to vary in direction so as to aid particles in moving
through the membrane. Another preferred arrangement is shown in
FIG. 2B wherein a number of electromagnets 34 are clustered around
a central magnet. As previously described, the electromagnets 34
are preferably pulsed alternately in a repetitve manner while the
electromagnetic field from the main magnet 36 may remain
constant.
[0028] A device for changing the direction of the magnetic field
repetitively and continuously using only a mechanical device is
shown in FIG. 2D. The eccentric rotating permanent magnet 38
comprises a rotating magnetic cap 40 on top of the magnet base 42.
The cap 40 has a high magnetic susceptibility but is not
symmetrical about the main axis of the magnet. Rotating the cap 40
on the magnet 38 causes the direction of the magnetic field passing
through the targeted region to vary continuously as the cap is
rotated.
[0029] The arm 22 can be modified such that the configurations
shown FIGS. 2A-2C include independent and repetitive mechanical
motion of the magnets to, for example, repetitively change the
angle of the magnetic field at any point in the field. The devices
shown in FIGS. 2A-2D can actually be modified in a number of ways
to vary, in a repetitive manner, the overall strength of the
magnetic field gradient and/or the direction of the magnetic field
gradient. It is anticipated that the effectiveness of varying the
strength or direction of the field will depend on the specific
application. For example, if the particles are being pulled from a
flowing stream it may be more effective to vary the direction but
to always have a field acting so that particles that have not
entered the membrane are not swept past the targeted location. In
other cases, the space available for the magnets may be limited in
the vicinity of the targeted area, so a system with a single magnet
may be more suitable for the application.
[0030] Modification of the magnetic field using a magnet in a C or
H configuration may also be beneficial in some cases. One pole
could be a single pole and the other a configuration similar to
those shown in FIGS. 2A-2C. It may also be beneficial to have both
poles similar to the configuration shown in FIGS. 2A-2C with the
pulsing or variation of the magnets being synchronized between the
two poles where "pole" refers to the arrangement of magnets or
mechanical devices shown in FIGS. 2A-2C rather than the end of a
single, simple magnet.
[0031] The positioning means 22 is preferably a mechanical arm
adjustably attaching the magnet(s) and providing stability and
controlled positioning with respect to the membrane. Such
positioning means are well known to those skilled in the art and
are used, for example, in angioplasty procedures for remote
guidance of intravascular catheters.
[0032] A system of the present invention for moving magnetic
nanoparticles through a membrane comprises a means for introducing
magnetically responsive nanoparticles into a body and a magnetic
field generating device as described above. Means for introducing
the magnetically responsive nanoparticles include, but are not
limited to, injection of the particles into a person via the
circulatory system and magnetic guidance to the membrane.
[0033] A method of the present invention for moving magnetically
responsive nanoparticles through a membrane within a body comprise
the steps of introducing the magnetically responsive nanoparticles
into the body as described above, and moving the nanoparticles
through the membrane using a varying-gradient magnetic field as
described above.
[0034] In order to further illustrate the devices, systems and
methods of the present invention, the following examples are
given.
EXAMPLE
[0035] It was speculated that magnetic particles show a slow
response to a continuous magnetic field when pulled through a
membrane due to simple misalignment with pores in the membrane.
Particles could also become trapped on the wall of channels going
through the membranes, or in fibrous membranes, the particles could
become entangled in the fibers as they move through. Changing
direction of particle movement could assist particles to realign,
to move past matter that accumulates in front of the particles, or
to move off the wall of the pores as the particles are being pulled
through the membrane.
[0036] Also, the probability of the particles becoming attached to
the wall of a pore is greater when the maximum magnetic gradient is
at a significant angle to the axis of pore. Therefore, changing the
angle of the magnetic gradient should result in moving the
particles off the wall of pore. Similarly, shutting off the
magnetic field should allow the particles to diffuse off the wall
of the pore and thus become free to move through the tissue.
[0037] Laboratory tests using a fixed, constant strength magnet
were performed to determine the base case feasibility of moving
magnetic particles through membranes. A test apparatus was arranged
as shown in FIG. 3. The objective of the test was to pull magnetic
nanoparticles present in the first chamber 46 through the porous
membrane 52 and into the second chamber 48. A stationary
electromagnet 18' was used to pull magnetite nanoparticles from the
carrier fluid 26 in chamber 46, across porous membrane 52, and into
a clean fluid 50 in second chamber 48. Power to the electromagnet
remained constant and the test ran for several hours. The results,
evaluated visually, established that very few particles penetrated
the membrane. It was concluded that the particles moved relatively
slowly through the membrane.
[0038] A second test was then performed using a magnetic field that
varied in strength. This test also utilized a test apparatus as
shown in FIG. 3 except that the electromagnet 18' was operated in a
pulsing or on/off mode. This was achieved by connecting the
electromagnet to a controller having a switch and timer to turn the
electromagnet on and off. The pulsation presumably allowed the
particles to be released from membrane fibers or the walls of pores
by diffusion.
[0039] A third laboratory test was run in which the direction of
the magnetic gradient was varied. The assembly is shown in FIG. 4.
In this modification a permanent magnet 18 was attached to a steel
rod 54 having two right angle bends 56. One end of the rod 54 was
then attached to an electric motor 58 so that the magnet could be
rotated at an estimated 30 to 60 rpm. Rotation of the magnet causes
the components of magnetic gradient parallel to the face of the
magnet to vary.
[0040] The second and third tests were also performed for several
hours. The results were that significant quantities of particles
appeared on the second chamber side of the membrane in both the
second and third test. Also, significant quantities of particles
were pulled to the bottom of the second laboratory chamber 48 in
the third test. It was concluded that pulsation of the magnetic
field and oscillating the magnetic field component perpendicular to
the direction the particles are to be moved enhances particle
movement through the laboratory porous membrane. Since varying the
direction or strength of a magnetic field gradient aids the
movement of particles through a laboratory porous membrane, it is
likely the same effect will be operative in moving particles
through living tissue or membrane.
[0041] Thus, the present inventive process(es), methodology(ies)
and apparatus(es) are well adapted to carry out the objects and
attain the advantages mentioned herein, as well as those inherent
in the present disclosure. While numerous changes may be made by
those skilled in the art, such changes are encompassed within the
spirit of this invention as described herein and by the appended
claims.
* * * * *