Note: Descriptions are shown in the official language in which they were submitted.
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USE OF ELECTRIC FIELDS TO MINIMIZE
REJECTION OF IMPLANTED DEVICES AND MATERIALS
FIELD OF THE INVENTION
This invention relates to the use of electric current to reduce fibrous
capsule formation
adjacent to the surface of implanted medical devices. Reduced capsule
formation facilitates the
transfer of fluids into or out of an interior lumen of an implanted device and
the surrounding tissue
or between the surface of an implanted device and surrounding tissue. Medical
devices employing
such electric currents may be part of a drug delivery system/device or a
biofluid sampling
system/device intended for use witliin a mammalian body. The invention
provides for methods and
apparatus to supply electric currents as either stand alone apparatus or as
part of larger medical
devices or systems.
BACKGROUND OF THE INVENTION
Limiting the lifetime of devices implanted within the body of a mammalian
subject is the
body's rejection reaction to these materials, termed the "foreign body
response". In this context, the
foreign body response consists any or all of those events initiated by the
body in reaction to
introduced material. This includes, but is not limited to, inflammation
response, migration of
macrophages or other wound/repair cells to the location, altered cell type of
the surrounding tissue,
deposition of fibrous proteins and related materials not normally observed
within the particular
tissue in those forms or levels, and the walling off or encapsulation of the
device by the body by a
fibrous capsule.
For those devices which can support this rejection response, e.g. those
devices which can
'reside in a fully functional state when encapsulated, the body's foreign body
response is not as
hindering. For devices such as catheters, ports, or other fluid transfer
points, which require as part
of their function, minimal obstruction of the passage of fluids or other
materials into or out of an
interior or lumenal space within a device and the surrounding tissue is an
important concern.
However, in both classes of devices, minimization of the rejection response
may be a means to
possibly extend device useful lifetime within the body.
To date this minimization has been accomplished by use of composition of the
materials in
contact with the body, selective coatings and/or modifications of the surface
of devices to promote
acceptance by the body. For instance, Joseph and Torjman (US Pat. No.
6,471,689) teach the use of
bilayer membranes to encourage neovascularization and minimize capsule
formation. Such passive
means to control the rejection response by themselves have not always proved
effective.
In considering the body's reaction to introduced foreign materials and
substances, the
cascade of events is considered to follow the biological events associated
with a wound healing
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response. Applied electric fields have been employed successfully to
accelerate the processes
associated with wound healing. Miller (US 4,846,181) teaches the use of pulsed
electrical
stimulation of varying polarities throughout the treatment cycle to enhance
soft tissue wound
healing. A variety of techniques are available as means to accelerate or
enable both soft tissue and
bone healing processes. (See, for example, Chapter 21, Sussman, C and Byl, NN,
"Electrical
Stimulation for Wound Healing" in Wound Care, 2 d Edition, Sussman C and Bates-
Jensen, BM,
editors, Aspen Publishers, Gaithersburg, MD 2001, and references cited
therein.) To date however,
the use of electrical currents to retard or diminish wound healing response
(and by implication,
subsequent fibrous capsule formation) has not been described.
Use of electric fields as a means of diminishing the wound healing response is
supported by
the work of J.D. Reich, et al. (J Amer Acad Derm 1991;25:40-6) whereby they
demonstrate a
twofold reduction in mast cell infiltrate in cutaneous wounds using applied
electric fields to the
dermis.
In a different application of electrical forces, Rise (US Pat. No. 5,853,424)
teaches the use
of static surface charges upon surfaces of implanted devices to retard or
prevent tissue ingrowth in
infusion catheters. Such charges are created using chemical means or by
electrical means through
the application of source of electrical potential.
In spite of these previous efforts, tissue ingrowth and encapsulation of
implanted devices
remains a significant problem, and there remains a need for improved methods
and apparatus to
minimize the body encapsulation response about medical devices and systems
located beneath the
surface of the skin.
SUMMARY OF THE INVENTION
The invention includes a method of using electric fields to reduce the body's
rejection
response to materials, devices or systems placed in part or in whole
subdermally, the method
comprising passing an electric current from one or more first electrodes
located proximate to a
critical structure or feature of a device introduced into the body to one or
more second electrodes
located elsewhere. The electrical current may be substantially DC in nature,
or may be pulsatile.
The current density of one or more first electrodes may be between 0.01 mA/cm2
and 100 mA/cm2.
The invention additionally comprises an apparatus for the delivery of electric
fields to
reduce the body's rejection response to devices placed in part or in whole
subdermally comprising
one or more first electrodes subdermally located in the close proximity of a
critical structure or
feature of a device introduced into the body and one or more second electrodes
located elsewhere.
Also provided are control circuitry and a power supply coupled to at least one
of the first electrodes
and at least one of the second electrodes to produce an electrical current
through tissue from at least
one of the first electrodes to at least one of the second electrodes.
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This invention may be embodied in many different forms and should not be
construed as
being limited to the embodiments described herein. In addition, various
embodiments of the
invention may combine one or more additional aspects as part of the scope of
the overall invention.
Those skilled in the art will readily understand the basis and means of the
invention as described by
the embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 - Model of the electrode / electrolyte interface depicted as a
portion of an electric
circuit.
Figure 2 - Illustration of one form of a semipermeable structure segregating
an electrode
from surrounding tissue. The semipermeable structure also serves as a site for
fluid delivery into surrounding tissue.
Figure 3 - Diagram of one embodiment of control circuitry for the generation
of pulsatile
electrical currents.
Figure 4 - Diagram of one embodiment of a catheter-like device, employing the
apparatus
of this invention having both first and second electrodes upon the device
surface.
Figure 5 - Cross-sectional view of a portion of the embodiment shown in Figure
4.
Figure 6 - Illustration of an alternate embodiment of a catheter-like device
utilizing the
apparatus of this invention. A first set of electrodes is incorporated into
the
structure of the device with the second electrode being independently
positioned
in adjacent tissue.
Figure 7 - Cross sectional diagram of one embodiment of a fully implantable
device for the
delivery of drugs and therapeutic agents also incorporating the apparatus of
this
invention.
DEFINITIONS
1. Biofluids - Fluids found in extracellular environments, e.g. interstitial
fluid, cerebrospinal fluid,
throughout the body of the subject which may contain a variety of materials,
including but not limited to, proteins, hormones, nutrients, electrolytes,
catabolic
products, or introduced foreign substances.
2. Critical structures / features of devices - Any portion of a device where
the presence of cells,
proteins, fibrous encapsulation or other flow restriction or blockage
diminishes
intended device performance. These portions may, for example, be associated
with
fluid inlets or outlets, sensor locations, and the like.
3. Device - Device in the context of this invention refers to apparatus,
instruments, systems,
structures, materials or other objects non-native to the host body and may be
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inorganic or organic in composition which are placed either in part or in
whole in one
or more subdermal regions of a subject.
4. Electrophoresis - The movement of molecules or particles (possessing a net
charge) under the
influence of an electric field.
5. Subdermal - Beneath the slcin. In the context of this invention, this
region may include, but is
not limited to, tissues, organs, cavities, fluids, vascular or connective
structures
located within the body of a subject. In this context, subdermal also includes
regions
of the dermis that would be pierced or otherwise penetrated by devices such as
microdelivery needles.
6. Subject - A human or mammalian subject who has one or more devices in
and/or on their body.
DETAILED DESCRIPTION OF THE INVENTION
The invention generally relates to novel use of electric fields to diminish
the body's
rejection response to implanted drug delivery and biofluid sampling devices.
The present invention
specifically relates to the method of delivering electrical current and
apparatus for the delivery of
these currents, in a variety of forms, amplitudes or periodicities. The
invention described herein
provides for methods and devices enabling long term continuous or periodic
monitoring of
physiological conditions by subdernnal systems or the administration of
therapeutic agents by
subdennal systems.
As described in more detail below, embodiments of the invention may include
the location
of one or more first electrodes in the vicinity of critical structures or
features of the implanted
medical device, the positioning of one or more second or counter electrodes in
a region not critical
to device performance, the activation of at least one critical structure
electrode and at least one
counter electrode completing a circuit and the subsequent mobilization of
charged molecules and/or
the direction of cell and cellular material associated with the body's
rejection response or impaired
device function from the critical locations upon passing an electrical current
from at least one
critical structure electrode to at least one counter electrode. In the context
of this invention,
structures or features of medical devices critical for device performance may
include those surfaces
or regions of the device exposed to the surrounding tissue requiring either
fluid passage between the
device and the tissue or having the need to access the surrounding tissue,
e.g. optically sense, and
which the presence of a fibrous encapsulation diminishes optimal device
performance.
By activating at least one first electrode in close proximity to a critical
structure or feature
of a subcutaneous device or material, e.g. a fluid infusion site, and having
at least one second
electrode apart from this location, charged signaling peptides, proteins, or
certain cell types such as
fibroblasts, macrophages, mast cells, etc., associated with a walling off,
encapsulation, clogging or
foreign body response to the device will be physically moved or directed from
the critical structure,
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thereby limiting the extent to which the rejection processes initiated by
these charged species will
detrimentally affect the medical device.
As this electrophoretic technique is substantially different from the passive
approaches
previously employed to minimize rejection, e.g. surface modification, local
static charge, it may be
employed by itself or in combination with one or more of these other
techniques in order to
minimize rejection and/or encapsulation of the medical device or portions
thereof.
The basis for minimizing the rejection response and subsequent fibrous
encapsulation is to
employ electric fields as a novel active means to limit this activity. In
particular, to use the
technique of electrophoresis is employed for this purpose. Electrophoresis is
well known to those in
the art as the basis for several analytical tools in biochemistry and related
disciplines. In this
invention, electrophoresis is employed as a means for mobilizing or directing
biomaterials
(typically proteins and modified proteins, or certain cell types) associated
with the rejection
response away from critical device locations, surfaces and surrounding areas.
Electrophoresis is the movement of molecules or particles (possessing a net
charge)
under the influence of an electric field. The forces underlying
electrophoretic migration and
mobility are well understood. This technique has been applied to devices and
methods for the
delivery of charged species to both intracellular and extracellular fluids.
However, electrophoresis
has not been used as means for limiting or preventing the body's foreign body
response to
introduced materials, structures or devices.
By preventing or diminishing the localization of these biomaterials, e.g.
proteins, signaling
peptides, or specific cell types associated with the wound healing cascade
and/or foreign body
response including fibrous capsule formation, in the vicinity of critical
structures or features by the
use of electrophoresis, the rejection response (encapsulation) or clogging
will be restricted or
eliminated entirely enabling longer useful lifetimes for implanted devices or
materials.
Typically, proteins and molecules such as signaling peptides possess a net
charge at
physiological pH (pH 7.0-7.5). Signaling peptides or molecules in this context
refer to those
molecular entities which initiate a cascade of events, e.g. acting as chemo-
attractants causing cell
migration to vicinity of the device or the triggered deposition of collagens
or other materials
associated with rejection, etc. The systems described herein can mobilize all
or a portion of these
charged biomolecules associated with clogging or impaired function away from
those critical
device locations which govern either device performance or overall device
lifetime within the body.
More precisely, electric fields are employed to mobilize charged
molecules/cell types that either by
themselves would build up and occlude critical features or which are
associated with the rejection
response of the body towards foreign objects.
In general, the rate of migration depends upon the applied electric field, and
is inversely
proportional to the viscosity of the solution. It should be further noted that
the migration of proteins
and peptides (or other charged biomolecules associated with the rejection
response) is also
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dependent of a number of factors beyond the applied electric field and
solution viscosity. In
particular, the composition of the biomolecule, e.g. the amino acids or other
charged moieties and
their location within the three dimensional structure, determines the
biomolecule's net charge at a
given local pH as well as the biomolecule's overall size and shape. That is,
electrophoretic mobility
of a biomolecule is also proportional to the biomolecule's net charge and
inversely proportional to
its size (and may also depend on shape).
In addition to the above considerations, the ion composition of the
surrounding medium
determines the effect of the electric field upon the biomolecule in question.
That is, in low ionic
strength medium, movement of a charged molecule, e.g. a negatively charged
protein, results in a
separation from its counter ions, (typically Na+ ions). In this circumstance,
charge separation forces
tend to counteract electrophoretic migration of the biomolecule thus hindering
its migration through
the solution. In contrast, in high ionic strength mediums, such as
interstitial fluid, numerous
counterions, typically cations such as Na+, are present. In this environment,
migration of the
biomolecule is not be hindered by loss of counter ions since large quantities
are present in solution.
However, the presence of such large quantities of counter ions results in an
ion "cloud" shielding
the biomolecule from the electric field, thereby reducing the force upon the
biomolecule and hence
its observed velocity. In certain instances, the ionic species themselves,
e.g. Mg++ or Ca++, may
govern or influence the motility of cell types associated, either directly or
indirectly, with capsule
formation. Thus, the electrical current may influence the nature and relative
quantities of signaling
molecules, peptides, ions and other mediators of the wound healing cascade and
ultimately of
fibrous capsule formation.
Alternatively, the application of electrical currents through the tissue may
directly influence
the motility of certain cell types. That is, the orientation and strength of
electric fields generated by
the passage of an electrical current have been shown to guide the migration of
select cell types such
as endothelial cells and fibroblasts in vitro and in vivo. Fibroblasts in
particular have been shown to
migrate towards the cathode under the influence of an applied current.
Fibroblasts are also
considered responsible for the generation of the bulk of the collagen forming
the fibrous capsule
surrounding implants.
Thus, to minimize the infiltration of fibroblasts in the vicinity of critical
device features, in
one embodiment of the invention, one or more first electrodes in close
proximity to critical features
of a device serves as anodes (positive bias) with one or more second
electrodes (counter electrodes)
serving as the cathode (negative bias). Overall, the actions of the applied
electrical current may
either affect certain lcey signaling molecules in the wound healing cascade
directly or the electric
fields engendered by the passage of this current may influence the motility of
cells involved in the
wound healing cascade. The exact form, amplitude and polarity of the currents
applied are
determined by the tissue/cell types involved and the functional requirements
of the medical device
and the scope of this invention is not limited to any one embodiment of these.
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The process of running an electric current through a solution may result in
several possibly
detrimental side effects, dependent upon the nature and extent of applied
current and the
dimensions/types of electroactive surfaces, e.g. electrodes, einployed. Chief
among these effects
are: the generation of acid and base at the anode and cathode (respectively);
the highly reactive
electrolysis zone immediately adjacent to the electrode surface; and the
possible formation of gas
bubbles at the electrodes. The ability to deal with these potentially
detrimental effects represents
additional novel and unobvious aspects to the invention described herein.
The introduction of an electrical current at an electrode/electrolyte
interface is typically
modeled as a capacitor in parallel to a resistance (FIGURE 1). In this model,
the boundary between
the electrode (5) and the surrounding fluid or electrolyte (20) is represented
by the dashed line (25).
The capacitor (15) represents the capacitance of the double layer of
electrolytes formed at the
boundary (25) and the resistance (10) represents the faradaic reaction(s) of
chemical species at the
electrode surface. Based upon this simple model, one effective means to reduce
or minimize
possibly detrimental activities in to introduce the current in a pulsatile
fashion, analogous to the'
passage of high frequency electrical signals through capacitors. By doing
such, the faradaic
reactions are minimized, lessening the generation of the deleterious agents.
Pulsatile currents are typically characterized by the pulse amplitude, pulse
frequency and
the on/off percentage of time during the pulse frequency period (otherwise
known as the duty
cycle). In addition, the composition and viscosity of the surrounding
electrolyte fluid, e.g. body
fluids such as interstitial fluid, cerebrospinal fluid, etc., as well as the
electrode material and current
density influence the nature and extent of the formation of electrolysis by-
products.
In a preferred embodiment of the invention, plusatile DC currents are utilized
to minimize
possible deleterious products. In this embodiment of the invention, the pulse
frequency is generally
between 0.1 Hz and 1000 Hz, the duty cycle is generally between 0.1% and 10%
and the current
density is generally between 0.01 mA/cm2 and 100 mA/cm2. However, the broader
scope of this
invention is not intended to be limited by these embodiment and conditions. It
is noted that other
conditions, materials and structures may be employed such as those described
by in the following
sections that permit wider current limits and parameters, including continuous
application of direct
current.
pH- Electrophoretic activity may result in the electrolysis of water, forming
either acid or
base in the vicinity of the electrode (typically acid, H+, at the anode and
base, OH", at the cathode).
In certain situations, the generated base or acid may overwhelm the
surrounding fluid's buffering
capacity, substantially altering the local pH and potentially adversely
affecting the surrounding
tissues and cells. One embodiment to ameliorate this generation of acid or
base is to employ a
modified form of electrophoresis whereby the polarity of the electrodes is
reversed periodically.
That is, although electrophoresis is substantially DC in nature, by altering
the polarity of the
electrodes intermittently, an electrode which had been the site of acid
generation now becomes a
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source of base generation, and vice versa. This switching of polarity, if
performed with the
appropriate periodicity, will substantially eliminate adverse pH effects yet
will have minimal effects
upon the net migration of the charged species, e.g. the polarity reversal is
for such a short period
that the charged biomolecules do not migrate substantially back to their
initial location. In one
embodiment of this invention, the polarity is reversed in an asymmetric
fashion, such as by time of
pulse period or by current amplitude, to achieve neutralization of generated
acids or bases.
An alternate embodiment of the invention is to provide additional buffering
materials or
compounds either as part of the structure or as delivered solutions. That is,
the structure of the
device may be composed of materials which function in part as a binder to the
acid/base such that
the acid or base 'generated is immediately bound to the material, thereby
neutralizing these reactive
species. Such materials may include structural carbonates or coatings of ion
exchange resins.
Alternatively, solutions may be supplied which have additional buffering
capacity, adjusted to
physiological pH such that the generated acid or base will be adsorbed by this
additional buffering
capacity. This method may be used alone or in combination with the alternating
polarity mentioned
above to negate the effects of generated acid or base.
However, it may be in some circumstances that an altered pH in the surrounding
tissue may
be beneficial to maintaining device function, e.g. aiding the breaking of
ionic bonds, salt bridges or
weak covalent bonds of surrounding structures, etc. In such embodiments of the
invention, the need
to buffer generated acid or base would be unnecessary or otherwise qualified
and the generation of
either acid or base a desired outcome.
Electrolysis Zone - The process of electrolysis or breaking down of water
molecules creates
a highly reactive zone extending from the surface of the electrode into the
overlaying space, up to
several hundred nanometers, dependent upon, among other factors, the structure
of the electrode,
the electrode potential and the composition of the solution. This zone may be
harmful to the
surrounding tissue directly or the process of electrolysis induces a rejection
response through the
formation of radicals which generate antigenic species. In one form of the
invention, the electrodes
may have one or electrically active surfaces positioned on the electrode
surface away from the
surrounding tissue at a sufficient distance to mitigate the effects of
electrolysis, e.g. a distance
generally greater than 1 micron, and thereby segregating the tissue from this
highly destructive
environment. In one embodiment of this form of the invention, the electrodes
are physically
separated from the tissue by an overlying semipermeable structure or gel. A
semipermeable
structure in the context of this invention is a structure, membrane, mesh or
gel, which provides fluid
and small molecule access to the electrode surface while physically distancing
the electrode from
contact with surrounding tissue. Therefore the dimensionality of the pores of
such a structure
should be less than the dimensionality of the surrounding cells and tissues.
In general, this indicates
a pore size that is less than 10 microns in diameter is desirable. In
alternate embodiments of the
invention larger pore dimensions is offset by increased fluid path length or
tortuousity thereby
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permitting the use of meshes or polymers with pore sizes considerably larger
in diameter, e.g. 1
rriin.
This semipermeable structure may also serve as the division between the
interior or lumenal
space of the device and the exterior of the device. In yet other embodiments
of this invention, the
semipermeable stracture may provide addition roles within the device, e.g. as
a means or site of
fluid delivery (FIGURE 2) or as a mechanical structure providing a support for
surrounding tissue
ingrowth and neovascularization.
In FIGURE 2, one end of a fluid delivery device (80), e.g. a catheter like
device, is shown
having a lumenal space (50). Positioned within this lumenal space and beneath
a semipermeable
structure (70) is a first electrode (60). This first electrode is connected to
a power supply/control
unit by means of an insulated wire (63). On the outer aspect of the device, is
a second electrode
(65), likewise connected to the same power/control unit as the first electrode
by means of an
insulated wire (68). Upon activation of the electrodes, the electrical current
passes from the surface
of the first electrode (60) into fluid present in the lumenal space, traverses
through the
semipermeable structure (70), through the surrounding tissue (55) and
completes the circuit at the
second electrode (65). It should be noted that no orientation or polarity of
activation is implied by
this description of the electrical pathway. The semipermeable structure also
serves as the site of
fluid delivery from the interior lumenal space of the device, as indicated by
the arrow (75). Fluid
passing down the lumenal space of the catheter will exit from the device (80)
through the
semipermeable structure (70) in pass into the surrounding tissue (55).
Alternative embodiments may include but are not limited to the positioning of
the
electrodes within structures, e.g. narrow channels or grooves, on, the
exterior surface of the device.
Alternatively, the electrodes may be positioned within the device so that the
surrounding tissues or
cells are not in direct contact with the electrolysis zone.
Gas Generation - Another by=product of electrophoresis is gas generation at
the electrodes.
In aqueous solutions, the positively biased anode typically generates oxygen
while the negatively
biased cathode typically generates hydrogen. The amount of gas generated is
dependent upon the
current utilized. If the rate of evolution is sufficiently low per unit area,
then the generated gas will
dissolve into the surrounding fluid without bubble formation (this is
dependent, among other
factors, upon the rate of electrolysis per unit area, electrode composition,
surface roughness of the
electrode, etc.). However, if higher currents are required in order to
minimize the body's rejection
response, the overall electrode dimension, shape and number of electrodes may
be altered to
accommodate higher currents necessary to mobilize the biomolecules while
avoiding bubble
formation. Therefore, in one embodiment of the invention, gas bubble formation
is minimized by
enlarging the electrode surface area relative to the current employed in order
to facilitate diffusion
of the gas into the surrounding fluid. Such enlargement of surface area also
may benefit charge
transfer characteristics of the electrode, in general. It should be noted
that, in certain circumstances,
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it may be that the gas generation, particularly oxygen, may provide a benefit
to the surrounding
tissue and therefore electrolysis may be employed for this reason, e.g. US
Pat. Nos. 6,368,592, and
5,788,682. In one embodiment of the invention, therefore, the generation of
gas is a desired
outcome in addition to the use of electric fields to minimize capsule
formation.
An alternate embodiment by which to minimize gas bubble formation is to employ
agents
to absorb the gas as it is generated. This may be accomplished using materials
which are employed
also as electrodes. This is the case with certain metals, e.g. titanium or
platinum at positively biased
electrode (anode) which form oxides in the presence of the generated oxygen or
palladium at the
negatively biased electrode (cathode) which absorbs hydrogen. Alternatively,
these materials may
be located near to the electrodes but not necessarily serving as the
electrode, e.g. a mesh or structure
overlaying the electrode which absorbs the gas in question.
A third approach to resolving evolution of gas and subsequent bubbling is the
electrode or
structure associated with the electrode being a semi-permeable structure in
contact with body fluids
on one side and providing an escape or sequestration chamber for the generated
gas on the other.
Such a structure, e.g. a membrane, mesh or brush-like structure, which allows
passage of the
generated gas on one side and current through the fluid on the other. The gas
would either vent to
outside of the body via a conduit means or be sequestered in a reservoir. This
reservoir may contain
additional agents or materials to absorb the generated gas, thereby reducing
the volume and
pressures. A further refinement of this embodiment is that the mesh or
membrane structure also
contains additional agents, e.g. ion exchange materials, to sequester
additional by-products of
electrolysis specifically the generated acid or base.
Electrodes
The electrophoretic circuit may be completed using a one or more electrodes of
various
geometries and composition. In a preferred embodiment, there is a least one
first electrode
comprising at least part of or in close proximity to a critical structure upon
a device and at least one
second electrode or second electrode located in a region non-critical for
device function. The
electrolytes and fluid provided by the surrounding tissue providing a means of
electrical connection
between the first and second electrodes. In certain embodiments of the
invention, the second
electrode may be placed on the outer aspect of the subject's slcin or body. In
such embodiments, a
means to ensure electrical contact, e.g. saline solution or conductive gel,
should generally be
present to provide electrical contact from the second electrode to subdermal
regions.
In the context of this invention, close proximity indicates a distance
generally in the range
of immediate contact between the electrode and the critical feature, e.g. the
first electrode may
comprises a part of the critical structure of the device, or close proximity
may extend to a distance
of several centimeters separation between the first electrode and the device
critical feature or
structure. In such circumstances, in addition to factors such as current
amplitude, and device
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geometry, the electrical path through the tissue will greatly influence the
distance or spacing
between the first electrode and critical feature or structure.
In alternate embodiments of the invention, a plurality of first and second
electrodes are
utilized. ]=ii these embodiments, the activation of these electrodes may be in
defined sequences or
order involving one or more electrodes of a specific bias at any point in time
in order to facilitate
the mobilization of the biomaterials. In one form of this alternate
embodiment, a series of electrodes
are positioned as concentric bands around a tubular device, e.g. a catheter.
By sequential activation
of sets of these electrodes in a wave-like pattern, charged materials or cell
types may be "walked"
away from critical features, e.g. fluid infusion sites, towards non-critical
locations upon the device.
This operation niay be repeatedly applied in order to facilitate this movement
of materials.
Variations of such electrode embodiments include sequential activation of one
or more sets of
electrodes over a period time, e.g. days or weeks, to control fibrous capsule
formation upon the
device attributable to either continued inflamrnatory activity or mechanical
disruption. In yet other
alternate embodiments, similarly biased electrodes may be placed at the two or
more critical
features of the device and the counter electrode placed elsewhere. This
arrangement serves to
diminish rejection at multiple points simultaneously, thereby iinproving
overall device
performance.
Electrodes may be constructed from conductive or semiconductive materials
including, but
not limited to: metals such as gold, platinum, palladium, silver or titanium;
organic conductive
polymers; conductive gels or epoxies such as silver impregnated pastes;
graphite; carbon or mixed
composition nanotubes; doped silicons or other semiconductive structures; or
layered/mixed form
structures comprised of inert and conductive materials, such as structures
fabricated using MEMS-
like (MicroElectroMechanical Systems-like) processes or techniques, e.g.
micromachined
constructs having metallic layers or sections upon high resistivity
substrates. In general, a preferred
material to be used for the composition of the electrodes is platinum or
platinum alloys.
The electrodes may be patterned on or affixed to either interior aspects or
exterior aspects
of the device or separated from the device or critical structure. In a one
embodiment of a device
utilizing the apparatus of this invention, the first electrode is built into
the structure of a critical
feature, e.g. a fluid access site, of a device while the second electrode is
located elsewhere on the
device. In another embodiment of the invention, the first electrodes are
located in proximity of one
or more critical locations on a device but do not form a part of the device
structure. That is, one or
more electrodes may be positioned in close proximity to the critical features
of the device (but not
on the device) thereby providing the necessary electrophoretic activity to
mobilizes the
biomolecules/cells associated with clogging or rejection away from these
critical features or
structures of the device.
In yet other alternate embodiments, the first electrode is on the structure of
device while the
second electrode is located upon a second introduced structure or material,
e.g. an introduced
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second electrode or a second device having, as part of its function, the
second electrode. Such
systems require the completion of the circuit between the first and second
electrodes by external or
other form of electrical connection in addition to the electrical pathway
provided by tissue
conductivity. In other embodiments, neither the first nor second electrodes
are part of the structure
of the device but are positioned in close proximity to the device and the
device critical features.
In a preferred embodiment of the invention, the electrode form typically is
primarily planar,
having one surface exposed to the surrounding medium and the other surface
supported by
underlying structures, e.g. the outside wall of the tube or catheter. However,
other embodiments of
electrodes are conceivable. These embodiments include, but are not limited to,
electrode structures
that are either: predominantly conical in shape; brush-like in composition,
e.g. arrayed nanotubes;
transitory (formed from conductive fluid droplets alcin to those used in
dropping mercury electrodes
which provide fresh surfaces periodically); or are formed from wires or otller
conductive materials
extending along edges of fabricated surfaces.
In yet other embodiments of the invention, one or more electrodes may be
located within
lumenal spaces of devices or otherwise separated from direct contact with
surrounding tissue while
still in electrical contact by fluidic means to said tissue. Such means of
separation include but are
not limited to, coating of the electrode surface with permeable gels such as
polyethylene glycol, or
polyurethane, or employing meshes, membranes or other structures, e.g. glass
frits, such that the
electrode surface is not in direct contact with surrounding cells, membranes
or extracellular
structures. Such methods allow the application of the current while distancing
the surrounding
tissue from the destructive electrolysis zone.
Control Circuitry
Activation of electrodes for the purpose of electrophoresis may be done in a
variety of
fashions, including, but not limited to, activation upon command, activation
periodically, or being
activated substantially continuous fashion, e.g. always "on". That is,
circumstances may indicate
that a defined pattern of activation, followed by lesser activity. An example
of this embodiment is
the use of frequent pulses of electrical current for the immediate period post
implantation of the
device, e.g. 24-72 hours, to limit the initial steps of the wound healing
cascade followed by a lower
frequency or periodicity of application for the remainder of the implant's
lifetime to deal with a
lower, more chronic inflammatory activity.
In alternate embodiments of the invention, additional activation, upon demand,
may
facilitate removal of additional debris occluding fluid transport across the
access port. Activation of
the electrodes would then be upon set by therapeutic agent delivery or sensor
needs so that
occlusion was minimized during or just prior to therapeutic administration or
sensor activation.
Thus, a variety of activation schemes and profiles are possible within the
scope of this invention
and this invention is not limited to the embodiments described.
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Control and power of the electrophoresis process may be accomplished with
devices as
simple as a battery plus microcontroller or as complicated as an external
power circuit plugged into
a wall plug plus controlling software. The needs, cost and lifetime of the
implanted device will
govern the form of power supply and control used. In the case of fully
implanted devices, power
may also be supplied using inductive or other power coupling means in addition
to on-board
batteries or other forms of power storage. Power sources may also include
indirect means, e.g.
utilizing an inductively coupled means to transmit energy to the electrical
circuit or by use of
energy obtained from mechanical or chemical activities.
FIGURE 3 illustrates the components of one such circuit for the controlled
delivery of
pulsatile DC currents to electrodes. One slcilled in the art of electronics
will recognize that
numerous other circuits that accomplish this purpose are conceivable and are
covered within the
scope of this invention. Power is supplied by the Power Supply (120),
typically a battery. The
repetitive pulse is generated within the 555 timer (125) (an industry standard
integrated circuit
available from Texas Instruments, Philips Electronics, National Semiconductor,
etc.). Frequency
and duty cycle are determined by external resistors, Rl (100), R2 (105) and
capacitor, CI (110).
The output of the timer drives a constant current source which in turn,
provides the constant current
source (130) through the circuitry (135) to the anode electrode (140) and
current sink to the cathode
electrode (145).
An example calculation for determining duty cycle employing the circuitry of
FIGURE 3 is
shown in Equation 1:
Equation 1) Duty cycle (Ratio of ON time to OFF time) = R2 /(Rl + 2 R2)
Assuming Rl = 98 Kohm and R2 = 1 Kohm and C = 10 uf, then the duty cycle
equals 1/
(98 + 2*1) or 1% and the pulse frequency equals 1.44 Hz. One skilled in the
art of electronics will
readily appreciate that more complex circuits, involving delays, changes of
pulse amplitudes or
frequencies as well as additional variety of pulse patterns may be readily
conceived and employed
within the scope of this invention.
In one embodiment of the invention, regulation of the control circuitry, i.e.
the
programming of the amplitude and periodicity of the current to be delivered,
is set prior to
installation of the invention into a medical device. In another embodiment of
the invention, a
separate means to adjust or provide control electrical current output post-
installation is provided.
Such means include, but are not limited to, lceypad entry, wireless control,
or by optical or acoustic
means.
Other embodiments of the invention providing for adjustment/activation of the
currents
applied also include the use of input or controls provided within a larger
medical device or system
employing this invention. In yet other embodiments of the invention, feedback
from sensors
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indicating the need to alter the current profile, either associated with the
apparatus of this invention
or as part of other devices, may be sent to a control circuit in an automatic
fashion and thereby
providing a "closed-loop" system of operation of the apparatus of this
invention within the body of
a subject.
Devices
The novel use of apparatus to produce electrical currents to retard or
diminish fibrous
capsule formation is suitable for use with a variety of implanted medical
devices. These devices and
systems include, but are not limited to, catheters, MEMS-based drug delivery
systems and
removable/replaceable diagnostic or drug delivery devices. In addition, the
invention may be useful
for systems such as that described in US patent application 10/032,765
"Gateway Platform for
Biological Monitoring and Delivery of Therapeutic Coinpounds", which describes
devices suitable
for percutaneous drug delivery and sampling of interstitial fluids. The use of
the structure of this
invention may also be applied to other devices and systems which may benefit
from reduction of
the wound healing response or encapsulation control or having use of the
electric fields generated in
the surrounding tissue.
For instance, application of the electric currents in conjunction with a
subdermal
therapeutic delivery means may result in accelerated dispersal of the
therapeutic agent through
surrounding tissues. This is, if the therapeutic agent possesses a net charge,
it will migrate along the
electrophoretic path into the surrounding biofluid, in accordance with its net
charge, mass, effective
field strength, etc.. It should be noted that this process differs from use of
electrophoresis as means
of delivery of charged materials from the interior lumen of devices to the
exterior space with
devices, e.g. the technique of iontophoresis. In these inventions, the
electrophoretic path is
substantially between interior space and the exterior passing through a
semipermeable structure and
electrophoresis is typically employed to mobilize the therapeutic agent from
an interior reservoir or
site through the semipermeable membrane. Thus, this accelerated dispersal of
drugs or agents
through surrounding tissue by electrophoretic means represents a novel aspect
of one embodiment
of this invention.
General operation of the apparatus of this invention, including first and
second electrodes,
power supply and control circuitry, requires the installation of the apparatus
into the body of a
subject. Such installation is preferably done in coordination with the
installation of a medical
device. Such installation may be concurrent with the implantation of the
medical device, e.g. the
apparatus forms a portion of the device, or the apparatus may be installed at
a time other than that
of the medical device installation, e.g. to permit post-surgical recovery
following installation of the
medical device. Once installed, the apparatus of the invention may be
activated either upon
command, e.g. manually activation of a switch, or by instruction, e.g. remote
wireless instruction.
Upon activation, the electrical current is passed through the tissue from one
or more first electrodes
to one or more second electrodes. The nature of this electrical current,
including the amplitude,
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periodicity, frequency, duty cycle, and polarity may be based upon the
instructions supplied by the
control circuitry or as part of the construction of the apparatus itself, e.g.
the polarity being set by
battery contact orientation. Further control of the apparatus, including the
cessation of activity, may
be accomplished in a variety of fashions, including but not limited to, manual
command, pre-set
progranuning or received instructions.
The following embodiments are representative to the types of devices possibly
employing
the use the apparatus of this invention to minimize encapsulation. One skilled
in the art will readily
recognize that additional devices and systems are conceivable and that the
scope of this invention is
not limited to those embodiments shown below.
Percutaneous Catheter - A typical use for electrophoretic control of the
body's rejection
response is to reduce rejection of implanted catheters which continuously or
intermittently deliver
therapeutics or fluids over an extended period of time, e.g. days or weeks, to
the body. Sites for
these deliveries include but are not limited to, subcutaneous, cerebrospinal,
targeted organ or
intraperitoneal locations.
Such a percutaneous catheter-lilce device is shown diagrammatically in FIGURE
4. In this
figure, the catheter-like device (180) has a fluid reservoir (158) for the
parenteral delivery or
infusion of therapeutics, fluids or drugs. Located on the outer aspect of the
catheter beneath the slcin
(150) are a set of first electrodes (165) and a second electrode (160). In
this embodiment of the
invention, the electrical current supplied by an external power/control unit
(155) passes through
insulated wires 175 and 173, to electrodes (165) and (160). The current passes
from the first
electrodes (165) to the second electrode (160) through the surrounding tissue
(55). In alternate
embodiments of the invention, such power supply/control circuitry are located
within the device
and may be incorporated into sections of systems implanted into the body of
the subject.
Also shown in FIGURE 4 is the lumenal space (183) of the catheter-like device
through
which the fluids/therapeutic agents pass. The agents exit from the lumenal
space by holes (170)
adjacent to the first set of electrodes. The proximity between the holes (170)
and the first electrodes
(165) aids in the efficiency of maintaining patency and reducing fibrous
capsule formation in this
region. Alternatively, a catheter-like device such as that shown in FIGURE 4
may employ a
polymeric mesh through which the therapeutic solution passes into the
surrounding interstitial fluid,
instead of the holes (170) indicated.
Driving the current through the electrodes may be through a circuit such as
previously
illustrated in FIGURE 3 or by an external control unit connected to a power
supply. Suitable power
supplies are readily available off-the-shelf, e.g. from Keithley Instruments.
In one embodiment of
the invention, the first electrodes are biased to serve as anodes. As an
example of one possible
embodiment of applied electric fields which may be transmitted through such a
device, a weak
current (approx. 1 uA) is passed for 10 sec once every 2 minutes from the
first electrodes to the
second electrodes.
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A commonly considered side product of electrolysis is altered local pH. Based
upon 1 A
6.24 x 10(18) electrons per sec and assuming each electron represents either
the formation of 1
molecule of base or acid, then activation of the electrode for 10 seconds will
generate
approximately lxlO(-10) moles of acid and base. Using a simple model to
predict the migration of
the acid or base and assuming diffusion constant for a small molecule to be
approximately 3 x 10(-
6) cm2/sec, then, during the time delay between electrode activations, 110
seconds, the generated
acid or base will migrate approximately 0.25 mm (in any one direction). The
volume described by
this migration for a single 1 mm electrode band around a 3 mm circumference
catheter is
approximately 0.75 ul leading to an average acid or base concentration within
this volume of 133
uM.
The buffering capacity of the surrounding fluid extracellular fluid varies
upon the
composition of that fluid, i.e. its protein and modified proteins, ions, etc.,
and therefore will vary
between blood, interstitial fluid, or cerebrospinal fluid. If the buffering
capacity of serum is
assumed to be primarily set by bicarbonate / carbonate ions, and the
concentration of this buffer is
approximately 24 mM (at pH 7.4 with a pKa of 7.6). Assuming these small ions
readily equilibrate
between interstitial fluid and serum, then the interstitial fluid has
approximately two orders of
magnitude excess buffering capacity. Thus, based upon this electrode
activation protocol, the local
generation of acid and base will not grossly alter the pH of the surrounding
interstitial fluid, < 0.01
pH unit, and therefore, the generated acid/base should not be detrimental to
the surrounding cells
and tissue using this electrical current protocol. Other electrode designs,
currents, frequencies,
periodicities and protocols may be employed which do not exceed local
buffering capacity and this
invention is not limited to those conditions supplied in the above example, As
noted earlier, if
higher currents which alter pH are employed and these are deterinined to be
detrimental, then other
means, e.g. materials, altexnating currents, may be employed to reduce the
extent of pH change, if
necessary.
Lilcewise, it can be shown that a 1 uA current for 10 seconds generates
approximately 1.6 x
10(-6) mg of oxygen per 10 seconds, leading to a local concentration (within
0.75 ul) of 2.13 mg/1,
with similar levels for hydrogen. At 37 C, oxygen saturation is 7 ppm (mg/1),
therefore, bubble
formation may not be observed using this current and electrode geometry. Local
micronucleation of
bubbles may occur on the surface of the electrodes, however, these should
absorbed into the
surrounding fluid.
Detrimental effects within the electrolysis zone, i.e. the electrode surface,
may necessitate
coating the electrodes with a semipermeable mesh to separate the electrodes
from the surrounding
cells. One means to accomplish this was shown in FIGURE 2 where the electrode
was positioned
within the lumen of catheter-like device. An alternative means to accomplish
this is by coating the
electrode surface with a non-reactive, biocompatible pourous layer, e.g. a
polymer hydrogel, (such
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as a urea/polyethyleneglycol gel or polyacrylamide gel), or by covering the
electrode surface with a
defined, non-conductive structure such as a thin dacron membrane.
One such modification by coating of the electrode surface is shown in the
cross-sectional
view provided by FIGURE 5. In this figure, a first set of electrodes (165) are
shown located on the
outer aspects of a portion of a catheter-like device (180). Fluid access from
the lumen of the
catheter-like device (183) to the surrounding tissue (55) is provided by one
or more holes (170).
Connection of the electrodes to the power supply / control circuit is via
insulated wires (173). In
this embodiment of the invention, the electrodes (165) are directly coated
with a hydrogel-like
material (185) to provide fluid access yet maintain a distance between the
surrounding tissue (55)
and the outer aspects of the electrode surface.
The catheter-like device shown in FIGURE 4 presents one means by which to
employ the
method and apparatus of this invention to reduce encapsulation and thereby
improve patency of a
catheter-like device. Alternate devices, used for therapeutic delivery or for
sampling of biofluids for
analytes, employing a variety of electrode geometries, materials and current
protocols are readily
conceivable and this example is not intended to limit the scope of this
invention.
Percutaneous Catlaeter Having Separate Second Electrode - An example of a
system
employing a removable/replaceable electrode is shown diagrammatically in
FIGURE 6. In this
example, a catheter system similar to FIGURE 4 is utilized, with modification.
That is, electrical
connections (217 and 220) enable control and electrical currents to be
supplied to the electrodes
(205 and 215). The percutaneous catheter-like device (200) traverses through
the slcin (150) and
into the underlying tissue (55). This device may serve as a means of infusing
fluid or therapeutic
agents through the holes located near the end of the device (210). However,
only the first
electrodes (205) are located on the outer aspects of the catheter-like device.
The second electrode
(215) is removed from the structure of the catheter and is connected via a
flexible insulated wire
(217) to the power supply/control unit. This second electrode may be
constructed from a variety of
materials. In one example of this embodiment of the invention, the electrode
may be constructed of
platinum approximately 1 mm long connected to polyurethane coated copper wire
(approximately
26 gauge). This electrode may inserted subcutaneously using a trocar-like
device and the electrode
positioned to be near, e.g. within several centimeters, of the first
electrodes.
In one embodiment of the invention, as shown in FIGURE 6, the currents
employed and
times of activation may be the same as those utilized in the apparatus
presented in FIGURE 4,
dependent upon factors including, but not limited to, the geometry of
insertion, device geometry,
tissue characteristics and apparatus structure and materials. One difference
to this system as
opposed to that presented in FIGURE 4 is that any fouling, degradation of
performance or
accumulation of rejection response products observed at the second (counter)
electrode is resolved
by removal of this electrode and replacement with a new electrode. Thus, long
term
rejection/diminished performance of the second electrode may be resolved by
replacing this
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electrode periodically. Extensions of this embodiment of the invention include
the use of a plurality
of counter electrodes simultaneously to provide more equivalent
electrophoretic fields than a single
electrode would provide.
Fully Iinplanted Systena - An entirely subcutaneous implanted device designed
to deliver
therapeutics and/or sampling of biofluids for analytes is shown in FIGURE 7.
This device differs
from the percutaneous devices presented in FIGURES 4 & 6 in that the entire
device is fully located
beneath the slcin and therefore does not directly utilize an external power
supply or control circuitry
to activate the electrodes.
As shown in the cross sectional view provided by FIGURE 7, a means for drug
delivery is
shown schematically within the body of the device (235). That is, the device
contains a reservoir
(240), pump unit (243) and conduit (245) through which the therapeutic agents
may dispensed into
the surrounding tissue (55) through one or more holes (275). Control and power
for the delivery
activity is provided by a battery (260), an integrated circuit (263),
additional circuitry (265) and
wiring/circuitry (270). One skilled in the art of electronics will readily
appreciate that such
integrated circuitry (263) plus power (260) may be also utilized to drive an
electrical current from
one or more first electrodes (250) to one or more second electrodes (255). In
adapting this device
for sampling, the function of the pump plus reservoir is replaced by
appropriate sensors and signal
amplifiers, however, the use of integrated circuitry plus power remains.
In the diagrammatic example shown in FIGURE 7, a battery supplies the
necessary power.
In alternate embodiments, inductive power or other sources of power may be
employed. Assuming
1 uA pulsatile current (10 sec "on" during every 2 minutes), the device is
active approximately 8%
of the time. A typical small coin cell battery 1 cm x 0.3 cm in size has
approximately 20 mA hours
lifetime at 3 V. At a constant (not pulsatile) 1 uA level of drain, this
battery would last for over
20,000 hours (or approximately 2 years). Therefore, a variety of fully
implanted systems and
devices employing electrophoresis as a means of limiting rejection are
feasible, based upon device
needs and apparatus requirements.
One will readily recognize that other devices, current protocols, electrode
geometries,
power sources, and control circuitry, etc. are readily conceivable and this
methods and apparatus of
this invention are not limited to the embodiments shown herein.
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