U.S. patent application number 15/959670 was filed with the patent office on 2018-10-18 for magnetically controlled permeability membranes.
The applicant listed for this patent is KING ABDULLAH UNIVERSITY OF SCIENCE AND TECHNOLOGY. Invention is credited to Niveen KHASHAB, Jurgen KOSEL, Amir ZAHER.
Application Number | 20180296469 15/959670 |
Document ID | / |
Family ID | 49477912 |
Filed Date | 2018-10-18 |
United States Patent
Application |
20180296469 |
Kind Code |
A1 |
KOSEL; Jurgen ; et
al. |
October 18, 2018 |
MAGNETICALLY CONTROLLED PERMEABILITY MEMBRANES
Abstract
A bioactive material delivery system can include a
thermoresponsive polymer membrane and nanowires distributed within
the thermoresponsive polymer membrane. Magnetic activation of a
thermoresponsive polymer membrane can take place via altering the
magnetization or dimensions of nanowires dispersed or ordered
within the membrane matrix.
Inventors: |
KOSEL; Jurgen; (Thuwal,
SA) ; KHASHAB; Niveen; (Thuwal, SA) ; ZAHER;
Amir; (Thuwal, SA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KING ABDULLAH UNIVERSITY OF SCIENCE AND TECHNOLOGY |
Thuwal |
|
SA |
|
|
Family ID: |
49477912 |
Appl. No.: |
15/959670 |
Filed: |
April 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13800564 |
Mar 13, 2013 |
9968549 |
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15959670 |
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61614814 |
Mar 23, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61M 37/00 20130101; A61K 9/0009 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 37/00 20060101 A61M037/00 |
Claims
1-10. (canceled)
11. A method of making a delivery device comprising: forming a
thermoresponsive polymer membrane in contact with the plurality of
nanowires whereby permeability of the thermoresponsive polymer
membrane is altered by exposure to a magnetic field such that a
bioactive passes through the membrane in the altered condition and
not in the unaltered condition.
12. The method of claim 11, wherein forming the membrane includes
mixing the thermoresponsive polymer with the plurality of nanowires
and casting the membrane.
13. The method of claim 11, further comprising growing a plurality
of nanowires on a substrate.
14. The method of claim 13, further comprising depositing the
thermoresponsive polymer on the substrate.
15. The method of claim 11, further comprising cross-linking the
thermoresponsive polymer.
16. The method of claim 11, further comprising contacting the
thermoresponsive membrane with a structure configured to contain
the bioactive material and pumping mechanism.
17. A method of delivering a bioactive material comprising:
administering a delivery device including a thermoresponsive
polymer membrane including plurality of nanowires, whereby
permeability of the thermoresponsive polymer membrane is altered in
the presence of the magnetic field such that a bioactive material
passes through the membrane in the altered condition and not in the
unaltered condition, to a patient; and applying the magnetic field
to the portion of the delivery device, and releasing the bioactive
material to the patient.
18. The method of claim 17, wherein applying the magnetic field
includes subjecting the thermoresponsive polymer membrane to a
magnetic field strength effective to alter porosity to the
thermoresponsive polymer membrane, wherein the thermoresponsive
polymer membrane is substantial non-porous to a bioactive material
prior to applying the magnetic field and the thermoresponsive
polymer membrane is substantially porous to the bioactive material
when the magnetic field is applied to the membrane, and passing a
bioactive material through the membrane to the patient.
19. The method of claim 17, further comprising introducing the
device to the patient.
20. The method of claim 17, wherein applying the magnetic field
increases the average pore size in the thermoresponsive polymer
membrane.
21. The method of claim 17, wherein applying the magnetic field
includes generating the magnetive field inside the patient.
22. The method of claim 17, wherein applying the magnetic field
includes generating the magnetive field external to the patient.
Description
CLAIM OF PRIORITY
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/800,564, filed on Mar. 13, 2013, entitled "Magnetically
Controlled Permeability" which claims priority to U.S. Patent
Application Ser. No. 61/614,814, filed on Mar. 23, 2012, the entire
contents of which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates to magnetically controlled
permeability membranes.
BACKGROUND
[0003] A major challenge in the development of advanced drug
formulations involves the elaboration of delivering systems
providing controlled release of bioactive materials such as drugs
or biologics. In order to achieve controlled release, the bioactive
materials can be embedded in a polymer matrix or in layered
structure. In the latter, layer dissolution rate determines the
release rate of the bioactive material. Despite significant
research efforts, challenges continue to exist for controlled drug
delivery.
SUMMARY
[0004] A delivery device can include a thermoresponsive polymer
membrane and a plurality of magnetic nanowires distributed within
the thermoresponsive polymer. The plurality of magnetic nanowires
can respond to a magnetic field whereby permeability of the
thermoresponsive polymer membrane is altered by exposure to a
magnetic field such that a bioactive material passes through the
membrane in the altered condition and not in the unaltered
condition. The thermoresponsive polymer membrane can be, for
example, poly(N-isopropylacrylamide) (PNIPAAm) or
poly(D,L-lactic-co-glycolic acid), and any combination thereof. In
another embodiment, the device includes a reservoir configured to
contain the bioactive material in contact with the thermoresponsive
polymer membrane. In another embodiment, the reservoir can be made
of the thermoresponsive polymer membrane.
[0005] The plurality of magnetic nanowires in the thermoresponsive
polymer membrane can be distributed in the membrane in a variety of
different ways in order to achieve different delivery profiles. In
one embodiment, the plurality of magnetic nanowires can be oriented
within the thermoresponsive polymer membrane. In another
embodiment, the plurality of magnetic nanowires can be randomly
distributed within the thermoresponsive polymer membrane. In
another embodiment, the plurality of nanowires can have a patterned
distribution within the thermoresponsive polymer membrane.
[0006] In another embodiment, the plurality of magnetic nanowires
can form a pattern within the thermoresponsive polymer membrane.
The pattern can include a first region having a first density of
nanowires and a second region having a second density of nanowires.
The first density of nanowires can be higher than the second
density of nanowires.
[0007] In certain embodiments, a majority or substantially all of
the plurality of magnetic nanowires are magnetic. In another
embodiment, at least a portion of the plurality of magnetic
nanowires can be magnetostrictive.
[0008] In another aspect, a method of making a delivery device can
include forming a thermoresponsive polymer membrane in contact with
the plurality of magnetic nanowires, whereby permeability of the
thermoresponsive polymer membrane is altered in the presence of the
magnetic field such that a bioactive material passes through the
membrane in the altered condition and not in the unaltered
condition. In certain embodiments, forming the membrane can include
mixing the thermoresponsive polymer with the plurality of nanowires
and casting the membrane.
[0009] A plurality of nanowires can be grown on a substrate. The
thermoresponsive polymer can be deposited on the substrate. In
another embodiment, the method can include removing the
substrate.
[0010] In another embodiment, the method can include cross-linking
the thermoresponsive polymer. In other embodiments, the method can
include contacting the thermoresponsive membrane with a reservoir
configured to contain the bioactive material. The nanowires can be
magnetic or magnetostrictive. In another embodiment, the
thermosensitive polymer can include the reservoir.
[0011] In another embodiment, a method of delivering a bioactive
material can include administering a delivery device including a
thermoresponsive polymer membrane including plurality of magnetic
nanowires to a patient, and applying the magnetic field to the
portion of the delivery device, and releasing the bioactive
material to the patient. Permeability of the thermoresponsive
polymer membrane is altered in the presence of the magnetic field
such that a bioactive material passes through the membrane in the
altered condition and not in the unaltered condition.
[0012] In another embodiment, applying the magnetic field can
include subjecting the thermoresponsive polymer membrane to a
magnetic field strength effective to alter porosity to the
thermoresponsive polymer membrane, wherein the thermoresponsive
polymer membrane is substantial non-porous to a bioactive material
prior to applying the magnetic field and the thermoresponsive
polymer membrane is substantially porous to the bioactive material
when the magnetic field is applied to the membrane, and passing a
bioactive material through the membrane to the patient.
[0013] In another embodiment, the method can include introducing
the device to the patient. In another embodiment, applying the
magnetic field can increase the average pore size in the
thermoresponsive polymer membrane. In another embodiment, applying
the magnetic field can include generating the magnetive field
inside the patient. In another embodiment, applying the magnetic
field can include generating the magnetive field external to the
patient.
[0014] The bioactive material can be a drug, small molecule,
protein, peptide, antibody, prodrug, small molecule, vitamin, DNA,
RNA, siRNA, chemotherapeutic, immunotherapeutic, or other
therapeutic compound.
[0015] Other aspects, embodiments, and features will be apparent
from the following description, the drawings, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a diagram depicting a delivery device.
[0017] FIG. 2 is a diagram depicting a delivery device including a
reservoir. FIG. 2A is a diagram depicting the delivery device in a
closed state. FIG. 2B is a diagram depicting the delivery device in
an open state.
[0018] FIG. 3 is a diagram depicting a method of making the
delivery device.
[0019] FIG. 4 is a diagram depicting a system including the
delivery device.
DETAILED DESCRIPTION
[0020] A delivery device for a bioactive material can include
magnetic nanowires in a thermoresponsive polymer matrix, which can
form a membrane that controls bioactive material delivery. The
device, and methods of delivering a bioactive material, can rely on
control of the permeability of the thermoresponsive polymer
membrane. The nanowires can be used to adjust or alter the
permeability of the thermoresponsive polymer by, for example,
creating spots of local heating, which can alter the porosity of
the membrane. The nanowires can create spots of local heating by
applying a magnetic field. For example, magnetic activation of a
thermoresponsive polymer membrane, via the actuation of
magnetostrictive nanowires dispersed and ordered within the
membrane matrix, can activate the membrane to change its
permeability for water, thereby acting like a valve that opens
(permeable) and closes (non-permeable). Magnetic activation can
mean that the membrane permeability is changed remotely upon the
application of a magnetic field. By altering the permeability of
the thermoresponsive polymer membrane including nanowires, delivery
of bioactive material through the membrane can be controlled, for
example, allowing for sustained release or timed release of the
bioactive material.
[0021] There are a number of ways to implement a remotely
controlled membrane. For example, the remotely controlled membrane
can be used to control the release of bioactive materials from an
implantable delivery device. The delivery device can include the
remotely controlled membrane, such as a magnetically activated
membrane, a passive pump (e.g., controlled by the valves) based on
osmotic pressure differences, a microfluidic channel (e.g., for
drug flow control), or a biocompatible device capsule.
[0022] In general, the device operates by applying a magnetic field
to actuate the nanowires. For example, the magnetic field applied
to magnetostrictive nanowires cause the nanowires to extend and
contract (e.g., oscillation or vibration). The magnetic field can
be constant or oscillated. The vibration can cause heat generation
in the polymer due to friction within the polymer matrix. The
thermoresponsive membrane contracts or expands in the regions of
heating, altering the permeability of the membrane. By properly
designing the nanowire lengths and diameters, the resonant
frequency at which each type of nanowire responds to the magnetic
field can be altered, thereby allowing for selective triggering of
different membranes, or different regions within the same membrane
fabricated with different nanowires, within the device.
[0023] Surprisingly, the tunability of the physical properties of
the nanowires makes them uniquely suited for creating controlled
permeability membranes. Specifically, the application of magnetic
nanowires, and their magnetostrictive properties, allow for
specific activation of a thermoresponsive polymer membrane,
allowing for complete control of porosity of the membrane.
[0024] The properties and structure of the thermoresponsive polymer
membrane can be sensitive to a variety of physical and chemical
conditions of the surrounding media. Sensitivity to a magnetic
field can affect the thermoresponsive polymer membrane. In this
case, magnetic activation can mean that the membrane permeability
is changed remotely upon the application of a magnetic field.
[0025] Implantable delivery trigger methods that allow for remote,
repeatable, and controllable bioactive material dosage delivery can
greatly improve the efficiency of treatments of numerous medical
conditions and can have a large impact on the biotechnology market
in the near future. An ideal device for on-demand bioactive
material delivery should safely contain a large quantity of
bioactive material, release little or no bioactive material in the
off state, be repeatedly switchable to the on state (open state)
without mechanically disrupting the device, and be triggered
remotely and noninvasively to release a controlled dose demanded by
a patient (e.g. local pain relief) or prescribed by a doctor (e.g.
localized chemotherapy). Despite the clear clinical need, few such
bioactive material delivery devices have been developed so far.
Most of them rely on "on-chip" power supply provided by, e.g., a
battery. This increases the size of the device considerable making
it unattractive for implantation. Others are limited by ineffective
trigger systems and an inability to dynamically adjust bioactive
material dosing. A method for triggering the osmotic pumping and
release of a bioactive material can allow for remote, passive, and
controlled activation via magnetic field applied by an external
electromagnet.
[0026] The porosity of the membrane may be altered by changes in
the membrane itself or changes in the plurality of nanowires
distributed within the thermoresponsive polymer membrane. The
plurality of nanowires can respond to a magnetic field whereby the
average pore diameter in the thermoresponsive polymer membrane can
be altered in the presence of the magnetic field such that a
bioactive material passes through the pore. Magnetic activation of
a thermoresponsive polymer membrane can take place via altering the
dimensions or orientation of nanowires dispersed or ordered within
the membrane matrix.
[0027] The thermoresponsive polymer membrane can be fabricated by
mixing one or more thermoresponsive polymers in a formulation
suitable to form a porous membrane. In another approach, the
thermoresponsive polymer membrane can be cast polymer film, an
engineered assembly of polymers, a hydrogel, or other suitable
structure. The membrane covers a reservoir, for example, and
impermeable polymer reservoir.
[0028] A large variety of synthetic thermoresponsive polymers with
different properties, lipids, or polysaccharides can be used to
form the membrane. See, for example, B. Philipp, et al., Prog.
Polym. Sci., 1989, 14, 91, which is incorporated by reference in
its entirety. The thermoresponsive polymer membrane can include,
e.g., poly(N-isopropylacrylamide) (PNIPAAm) or
poly(D,L-lactic-co-glycolic acid) and any combination thereof. This
provides many possibilities to tune the release properties of the
thermoresponsive polymer membranes together with ensuring
biocompatibility. The thermoresponsive polymer can be high
molecular weight compounds or macromolecules. The membrane can be
reversibly permeable to low molecular weight compounds or small
molecules having a molecular weight of less than 10,000 Da,
preferably less than 5.000 Da and more preferably less than 1,000
Da.
[0029] A variety of different substances, such as synthetic and
natural polymers, biopolymers, proteins, nucleic acids, magnetic
and fluorescent inorganic nanoparticles, or lipids can be blended
with the thermoresponsive polymer to form the membrane. The
thickness of the membrane can depend on the conditions of its
preparation. The thickness of the membrane on a substrate can be
adjusted in the nanometer range, e.g. by adsorption of varying
numbers of thermoresponsive polymer layers, which can give the
structure semipermeable properties. See, for example, G. B.
Sukhorukov, et al., J. Phys. Chem. B 1999, 103, 6434 and G. B.
Sukhorukov. et al., J. Microencapsulation, 2000, 17, 2, 177-185,
each of which is incorporated by reference in its entirety. The
thermoresponsive polymer membrane walls can be permeable for small
molecules such as small organic molecules while they exclude
compounds with a higher molecular weight. See, for example, E.
Donath, et al., Nach. Chem. Tech. Lab., 1999, 47, 400, which is
incorporated by reference in its entirety.
[0030] Activation of the membrane means changing its permeability
for an active material, such as a drug, or solvent, such as water
(for example, by altering the material), thereby acting like a
valve that opens (permeable) and closes (non-permeable). In some
circumstances, it can be desirable to provide systems having
controllable or adjustable loading as well as release properties.
In particular, the method can be favorable to allow the loading or
release of materials into and from the thermoresponsive polymer
membrane by modifying the membrane permeability. For some
applications, a defined and controllable permeability of the
membrane can be required in order to control the process of loading
the device as well as any subsequent release under specific
conditions. Due to the fact that the loading is preferably fast,
but the release should be in most applications slow, it is further
desired that the permeability be switchable. Therefore, it can be
desirable to provide methods to influence, vary or switch
properties of a membrane.
[0031] The permeability of thermoresponsive polymer membrane can be
determined, varied or controlled by parameters of the membrane. The
permeability to high molecular weight compounds as well as low
molecular weight compounds can be adjusted according to the needs
in different applications. The permeability control can offer a
unique tool for entrapping molecules within the device and
releasing them in a predetermined manner, e.g. over an extended
period of time or at a desired, predetermined site or time
point.
[0032] The method permits a reversible alteration of the
permeability of membranes. This enables specifically charging the
device with desired active substances or specifically releasing
active substances entrapped in the device, respectively, by
applying a magnetic field. For example, a permeability increase can
make it possible to later charge the finished device with active
substances in an "open condition." After the device has been loaded
with active material, for example, during storage or transport or
another time when the device is not intended to release the active
substance, the permeability of the membrane to the entrapped active
substance can be reduced by adjusting of suitable conditions so
that no active substance can leave the device. Such a "closed
condition" of the membrane prevents possibly undesired substances
from entering the device. At the desired time and site of release,
respectively, the active agent can be released in a defined way,
for example, delayed delivery, pulsed delivery or other periodic
delivery, by increasing the permeability of the membrane. In this
way, it is possible to release materials from the device only after
the device has been placed in position for a predetermined amount
of time prior to a targeted time for delivery in certain areas of
an organism. The increase in permeability can be simply induced by
applying magnetic field to the membrane.
[0033] As an alternative to altering permeability of the membrane
to the active material, the permeability of the membrane to
solvent, or water, can be altered. When in the higher permeability
state, the solvent can pass into the device and can dissolve the
active material, causing it to be released from the device.
[0034] The nanowires can be magnetic in that the nanowires can
change directions or orientation of their magnetization in response
to a magnetic field. At least a portion of the plurality of
nanowires can be magnetostrictive. The nanowires can be
magnetostrictive in that the nanowires can change length in
response to a magnetic field. See, for example, WO 2011/138676,
which is incorporated by reference in its entirety.
[0035] Nanowires generally include at least one substantially
crystalline or amorphous material. In certain embodiments, the
nanostructure can include a core of a first material and at least
one shell of a second (or third etc.) material, where the different
material types are distributed radially about the long axis of a
nanowire, a long axis of an arm of a branched nanowire, or the
center of a nanocrystal, for example. Depending on the application
and other design parameters, nanowires can have an aspect ratio
(length-to-width ratio) of, for example, 1, 5, 10, 100, 250, 500,
800, 1000 or higher. Nanowires structures with a diameter in the
range of approximately 5 nm to approximately 200 nm, with lengths
in the range of approximately 10 nm to approximately 100 .mu.m, can
be formed.
[0036] Nanowires can be produced by electrodeposition, chemical
etching, vapor-liquid-solid (VLS) synthesis or solution-phase
synthesis, to name a few examples.
[0037] The nanowire can be substantially crystalline or
amorphous.
[0038] Nanowires can have various cross-sectional shapes,
including, but not limited, to circular, square, rectangular and
hexagonal. In each case, the term "diameter" is intended to refer
to the effective diameter, as defined by the average of the major
and minor axis of the cross-section of the structure. Magnetic
nanowires can be made of pure metals including rare earth metals or
alloys, consisting of, e.g., cobalt, nickel, iron, gallium,
terbium, dysprosium and combinations thereof. The use of different
metals or of alloys allows for the tailoring of the magnetic
responses under applied magnetic fields for a given region of
thermoresponsive polymer.
[0039] By characterizing a dose delivery and magnetic field
relationship for different nanowire and thermoresponsive polymer
structures, in addition to characterization of nanowires for
various shape and magnetic alloys compositions, design of the
controlled permeability membranes can be optimized for specific
applications, including treatment of specific diseases and
physiologic conditions. For example, the magnetic field may be
applied either internal or external to the patient. If external,
the magnetic field must still be near enough to the patient to
alter the porosity of the thermoresponsive polymer membrane. The
design flexibility can allow for a precise dose-control mechanism
for implantable bioactive material delivery systems to be developed
which can be used to treat pain, cancer, diabetes, or Alzheimer's,
as well as other conditions. The device can be produced with low
cost materials with relatively small device sizes and significantly
improved dose control. The membrane is controlled like an on/off
switch, with no appreciable leakage through the membrane.
[0040] FIG. 1 depicts a delivery device 4 including a
thermoresponsive polymer membrane 6 and a plurality of nanowires 8.
The nanowires 8 can be randomly distributed in the membrane. The
plurality of nanowires can be randomly distributed within the
thermoresponsive polymer membrane. The plurality of nanowires can
be in a patterned distribution within the thermoresponsive polymer
membrane. The plurality of nanowires can form a pattern within the
thermoresponsive polymer membrane. When the magnetic field is
applied to the membrane, the pattern of the plurality of nanowires
can cause a change in porosity only in the area of the
thermoresponsive polymer membrane wherein the pattern is located.
The pattern can include a region having a density of nanowires that
is different from another region having a density of nanowires. One
region of the thermoresponsive polymer membrane can have a higher
density of nanowires than a different region that has a lower
density of nanowires.
[0041] Referring to FIG. 2A and FIG. 2B, a device 10 can be in a
closed state (FIG. 2A) or an open state (FIG. 2B). Device 10
includes polymer membrane 6, which contains nanowires 25. Polymer
membrane 6 covers reservoir 30, which contains bioactive material
40. In the closed state, the permeability of polymer membrane 6
confines bioactive material 40 to the reservoir 30. Application of
a magnetic field causes the permeability of polymer membrane 6 to
change, rendering it more permeable. As shown in FIG. 2B, the
change in permeability permits bioactive material 40 to be released
from device 10. The plurality of nanowires can be oriented
substantially parallel to a surface of the thermoresponsive polymer
membrane, or substantially perpendicular to the thickness of the
membrane.
[0042] In FIG. 3, device 50 includes thermoresponsive polymer 52
having a plurality of nanowires 54 distributed in a regular manner
in the polymer such that there is nanowire depleted region 56 and
nanowire rich region 58. As such, the density of nanowires in one
region can be higher than another density of nanowires. In certain
circumstances, the composition, length, or diameter of the
nanowires (or combinations thereof) can differ as well. The
difference in nanowire density can lead to the area including the
higher density pattern to have more increased porosity while the
area that including the smaller density of nanowires has less
porosity than the higher density region. The higher the density of
wires in a region, the larger the thermoresponsive changes during
magnetic activation, since there are more sources of heat from the
additional wires when compared to lower densities.
[0043] In a preferred embodiment, the thermoresponsive polymer
membrane may be magnetically activated via the actuation of
magnetic nanowires dispersed within the membrane matrix. In this
context, activation of the membrane includes changing its
permeability for water, thereby acting like a valve that can change
the membrane or shell to an open state (permeable) or a closed
state (non-permeable). Magnetic activation can include that the
membrane permeability is changed remotely upon the application of a
magnetic field.
[0044] There are numerous applications for such a remotely
triggered membrane. For example, a magnetic field may be applied to
the membrane shell to control the release of bioactive material
with an implantable bioactive material delivery device. The
bioactive material delivery device can rely on several components.
These components can include a remotely triggered valve composed of
the magnetically activated membrane, a passive pump which is
controlled by the valves, with a working principle based on, e.g.,
osmotic pressure differences, microfluidic channels, which may be
useful for bioactive material flow control, and a biocompatible
device capsule.
[0045] By applying a magnetic field, an extension and contraction
of the magnetic or magnetostrictive nanowires, or a vibration, can
be generated, causing heat generation due to friction within the
thermoresponsive polymer matrix during oscillation. Alternatively,
the change in magnetization of the magnetic nanowires can cause
losses, which generate heat. In other embodiments, a combination of
the two effects may apply. The membrane contracts in the regions of
heating, rendering it porous and hence permeable (open state). By
properly designing the nanowire lengths and diameters, the resonant
frequency at which each type of nanowire responds can be
controlled, thus enabling selective triggering of different
membranes, and different regions within the same membrane
fabricated with differing nanowires, within the device.
[0046] This method for controlling the permeability of a membrane
can allow for the triggering of, e.g., an osmotic pump, which
relies on the surrounding body fluid to begin pumping. The end
result is a passive remotely triggered pumping mechanism for the
device, made possible solely by the remote magnetic triggering.
[0047] In a preferred embodiment, magnetic nanowires can be applied
specifically for achieving the activation of a thermoresponsive
polymer membrane, allowing for complete control of porosity of the
membrane. Previous work has relied on the heat generation created
using magnetic single domain particles and the constant reversal of
particle domain to control membrane porosity. See, for example,
Sanrini, J. T. Jr, et al. Angew. Chem. Int. Ed. 39; 2396-2407, 2000
and T. Hoare, et al., Nano Lett., Vol. 9, No. 10, 2009, each of
which is incorporated by reference in its entirety. It is
well-known magnetostrictive effect that a magnetic field has on
magnetic nanowires. See, for example, P. D. McGary and B. J. H.
Stadler, J. Appl. Phys. 97, 10R503 2005, which has been
incorporated by reference in its entirety. Furthermore, thermally
responsive thermoresponsive polymers, such as
poly(N-isopropylacrylamide)-based nanogels have been shown to work
and suggested for drug delivery application. See, for example, R.
Langer, D. S. Kohane, et al., Nano Lett., Vol. 9, No. 10, 2009. An
advantage of using nanowires instead of particles is the ability to
control the number, composition, pattern or distribution of the
nanowires in the membrane. This can be a critical improvement
providing predictable and repeatable results. Another advantage can
include the higher heat losses than can be produced by nanowires
compared to magnetic particles. Another advantage is the use of
wires of different resonant frequencies, which allows activating
membranes individually. Heat generation using nanowires can be used
to achieve bioactive material delivery control within such a
thermoresponsive polymer. Furthermore, the membrane can be used as
a trigger for the osmotic pump.
[0048] In a preferred embodiment, a bioactive material delivery
system including a thermoresponsive polymeric membrane embedded
with nanowires can be stimulated by an external electromagnet.
Stimulation of the nanowires by the electromagnet generates heat,
which causes temperature dependant motion control of the membrane
by the nanowires. Heat generated from stimulating (from an external
source) nanowires to control the porosity and permeability of a
membrane in a manner that enables the membrane to act as an on/off
switch for a bioactive material delivery system or device. The
system can provide more precise dose control for implantable
bioactive material delivery systems by enabling the membrane to
behave as a valve to control flow bioactive materials through the
membrane.
[0049] One approach to make the bioactive material delivery device
can include forming a thermoresponsive polymer membrane in contact
with the plurality of nanowires. First, a plurality of nanowires
that are responsive to a magnetic field can be grown on a
substrate. The plurality of nanowires can be grown to select
diameters, length or in specific patterns. See FIG. 3.
Thermoresponsive polymers may then be added to cover the nanowires.
Then, the substrate can be removed. See FIG. 3. Another approach to
making the bioactive material delivery device includes mixing a
plurality of nanowires with a thermoresponsive polymer to form a
mixture and depositing the mixture to form a membrane. See FIG. 3.
In certain circumstances, the thermoresponsive polymer of the
membrane can be cross-linked.
[0050] As shown in FIG. 4, a system for delivery of a bioactive
material to a subject in need of the bioactive material includes
device 60, magnetic activator 62, and a controller 64. Controller
64 is configured to regulate delivery of the bioactive material by
switching the magnetic activator 62 on or off. The device 60 is
implanted into the subject, optimally near the location in need of
the bioactive material. The bioactive material can be a drug to be
given to a patient by first administering the bioactive material
delivery device including a thermoresponsive polymer membrane
including plurality of nanowires to the patient, applying a
magnetic field to a portion of the bioactive material delivery
device, and releasing the bioactive material to the patient. The
magnetic field can be adjusted to a field strength effective to
alter porosity to the thermoresponsive polymer membrane, wherein
the thermoresponsive polymer membrane is substantial non-porous to
a bioactive material prior to applying the magnetic field and the
thermoresponsive polymer membrane is substantially porous to the
bioactive material when the magnetic field is applied to the
membrane. The magnetic field can be generated inside the patient or
external to the patient. If the magnetic field is external to the
patient, it still must be near enough to exert alter the
permeability of the thermoresponsive polymer membrane. When the
magnetic field is applied, the bioactive material can pass through
the membrane to the patient. For example, applying the magnetic
field can increase the average pore size in the thermoresponsive
polymer membrane. Magnetic field strengths for switching typically
are in the .mu.T to mT range, at frequencies ranging from some 10
Hz to about 1 MHz. Amplitudes and frequencies can strongly depend
on membrane dimensions, nanowire material, design and density, as
well as, in the case of multiple membranes for separate bioactive
materials, the discrimination between these materials during drug
release.
[0051] The size of a device employing this system can be between 50
microns and 100 mm. For example, the device can have dimensions of
between 2 and 50 mm, 4 and 25 mm, for example, 5 mm, 8 mm, 10 mm,
12 mm, 15 mm, or 20 mm. The amount of bioactive material that can
be loaded into the device can be limited by the size. A primary
benefit of this system is a significant improvement in dose control
as compared to other devices. Other benefits include improved
biocompatibility and its smaller size, which makes for a more
suitable implantable device. Bioactive materials with very high
potency can be preferred for the device due the fact that the
smaller size of the device can limit the bioactive material load
and that the bioactive material can be delivered at the exact
location where it is needed.
[0052] In one embodiment, deployment of the device is ideally
intended to be months to years. The device can be surgically
removed after deployment. The nanowires are not bioresorbable, but
can be capable of migrating from the treatment site and to and
through the appropriate tissues to be expelled along with a
patient's digestive waste, based on the size of the nanowires.
[0053] This device potentially has broad bioactive material
delivery applications including pain management, cancer, diabetes,
or Alzheimer's. The magnetic or magnetostrictive properties of
nanowires or the characteristics of specific thermoresponsive
polymeric gels can be used for bioactive material delivery.
[0054] Other embodiments are within the scope of the following
claims.
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