U.S. patent application number 12/881302 was filed with the patent office on 2010-12-30 for system for dissociation and removal of proteinaceous tissue.
Invention is credited to John C. Huculak, Steven W. Kovalcheck.
Application Number | 20100331911 12/881302 |
Document ID | / |
Family ID | 38179730 |
Filed Date | 2010-12-30 |
View All Diagrams
United States Patent
Application |
20100331911 |
Kind Code |
A1 |
Kovalcheck; Steven W. ; et
al. |
December 30, 2010 |
System for Dissociation and Removal of Proteinaceous Tissue
Abstract
An apparatus and method for the dissociation of soft
proteinaceous tissue using pulsed rapid variable direction energy
field flow fractionization is disclosed. The pulsed rapid
disruptive energy field is created by the use of a probe which
surrounds the soft proteinaceous tissue to be removed. Once the
adhesive mechanism between tissue constituents has been
compromised, fluidic techniques are used to remove the dissociated
tissue.
Inventors: |
Kovalcheck; Steven W.;
(Aliso Viejo, CA) ; Huculak; John C.; (Mission
Viejo, CA) |
Correspondence
Address: |
ALCON
IP LEGAL, TB4-8, 6201 SOUTH FREEWAY
FORT WORTH
TX
76134
US
|
Family ID: |
38179730 |
Appl. No.: |
12/881302 |
Filed: |
September 14, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11608877 |
Dec 11, 2006 |
7824870 |
|
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12881302 |
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60755839 |
Jan 3, 2006 |
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Current U.S.
Class: |
607/53 ;
606/34 |
Current CPC
Class: |
A61B 18/14 20130101;
A61F 9/00736 20130101 |
Class at
Publication: |
607/53 ;
606/34 |
International
Class: |
A61N 1/00 20060101
A61N001/00; A61B 18/04 20060101 A61B018/04 |
Claims
1. A system for applying high-intensity pulsed electric fields to
ocular tissue in order to change the state and increase the
fluidity of the ocular tissue, the system comprising: a probe for
applying a stressing pulsed electric field to ocular tissue; and an
electric field generator for creating the stressing pulsed electric
field with the probe; wherein the pulsed electric field stresses
and partially liquefies a proteinaceous complex to cause
dissociation and increased fluidity of the ocular tissue and
further wherein the pulsed electric field is insufficient to create
an electron avalanche.
2. The system of claim 1, further comprising an aspiration
system.
3. The system of claim 2, wherein the aspiration system removes
dissociated ocular tissue.
4. The system of claim 1, wherein the probe includes at least two
electrodes.
5. The system of claim 1, wherein the electric field traverses the
ocular tissue to be dissociated.
6. The system of claim 1, wherein the direction of the electric
field is varied.
7. The system of claim 3, wherein the electric field is generated
from a first set of electrodes to a second set of electrodes by
applying a pulsed voltage across the electrodes.
8. The system of claim 7, wherein the pulsed voltage is switchable
between the first set of electrodes and the set of second
electrodes.
9. The system of claim 7, wherein the pulsed voltage is repeatedly
reversed between the first set of electrodes and the second set of
electrodes.
10. The system of claim 7, wherein electrical activity between the
first set of electrodes and the second set of electrodes is
sequentially changed.
11. The system of claim 6, wherein the direction of the electric
field is varied by repeated reversal of electrode potential,
repeated switching of active electrodes or a combination of
both.
12. The system of claim 7, further comprising: a liquid medium in
which the electrodes are immersed.
13. The system of claim 12, wherein the liquid medium has
electrically conductive properties.
14. The system of claim 1, further comprising: an irrigation
system.
15. The system of claim 14, wherein the irrigation system supplies
fluid with electrically conductive properties.
16. The system of claim 1, wherein the electric field has a pulse
shape, pulse pattern, pulse repetition rate, and pulse train length
that is disruptive to the tissue to be dissociated.
17. The system of claim 1, wherein the field strength of the
electric field is larger than 1 kV/cm.
18. A method for dissociative liquefaction and for increasing
fluidity of a macroscopic volume of proteinaceous ocular tissue,
the method comprising the step of: creating a weakened
proteinaceous liquid complex by establishing a confined, localized,
stressing pulsed electric field within the extracellular matrix of
the proteinaceous tissue without creation of an electron
avalanche.
19. The method of claim 18, wherein the creation of a confined,
localized, stressing pulsed electric field within the extracellular
matrix of the proteinaceous tissue causes dissociation of the
proteinaceous complexes and local liquefaction of the macroscopic
volume of proteinaceous tissue.
20. The method of claim 18, wherein the creation of a confined,
localized stressing pulsed electric field within the tissue weakens
the adhesive and structural relations between tissue
components.
21. The method of claim 18, wherein the creation of the electric
field within tissues promotes separation and detachment of tissue
components from adjacent structures.
22. The method of claim 18, wherein the creation of the electric
field within tissues weakens the hydrophobic and hydrostatic bonds
within the tissue.
23. The method of claim 19, wherein the stressing pulsed electric
field is advanced into the volume of tissue.
24. The method of claim 19, further comprising: aspirating
tissue.
25. The method of claim 24, wherein aspirating tissue further
comprises entraining macroscopic volumes of tissue into the
electric field.
26. The method of claim 24, wherein aspirating tissue further
comprises removing a volume of tissue.
27. The method of claim 19, comprising: irrigating tissue.
28. The method of claim 18, wherein the electric field is created
by use of microwaves.
29. The method of claim 18, wherein the electric field is created
by use of a laser.
30. The method of claim 29, wherein the laser operates with pulse
duration in the femtosecond range and at substantially the peak
absorption frequency of water.
31. The method of claim 18, wherein the electric field is created
by use of ultrasound.
32. The method of claim 18, wherein the electric field is created
by the use of pulsed voltage.
33. The method of claim 18, wherein the electric field is created
by the use of pulsed DC voltage.
34. The method of claim 18, wherein the electric field is created
by the use of gated AC voltage.
35. A method of using high-intensity pulsed electric fields to
change the state and increase the fluidity of ocular tissue, the
method comprising: providing a hollow probe for insertion into a
posterior region of an eye; engaging a volume of ocular tissue with
the hollow probe; creating a high-intensity pulsed electric field
with electrodes located within the probe to partially liquefy the
ocular tissue; and removing a volume of the ocular tissue; wherein
the high-intensity pulsed electric field is insufficient to create
an electron avalanche.
36. The method of claim 35, wherein the high-intensity pulsed
electric field is substantially orthogonal to the volume of tissue
to be dissociated.
37. The method of claim 35, wherein the high-intensity pulsed
electric field traverses the volume of tissue to be
dissociated.
38. The method of claim 35, wherein the volume of tissue is removed
by aspiration.
39. The method of claim 35, further comprising: irrigating the
ocular tissue with irrigation fluid.
40. The method of claim 39, wherein the irrigation fluid is
electrically conductive.
41. The method of claim 35, wherein the pulses in the
high-intensity-pulsed electric field are used to dissociated
proteinaceous components of tissue.
42. The method of claim 38, wherein irrigation fluid is used with
aspiration.
43. The method of claim 42, wherein the flow of the aspiration and
the irrigation are matched in order that the volume and pressure
within the eye is maintained within physiological limits.
44. The method of claim 38, wherein the aspiration flow rate is
matched to the fluidity of the ocular tissue.
45. A system for creating a high-intensity pulsed electric field
between electrodes of a surgical probe in order to change the state
and increase the fluidity of ocular tissue, the system comprising:
a surgical probe with at least two electrodes; at least one pulse
generator; a control circuit, the control circuit for controlling a
duration, a repetition, a polarity, and an amplitude of electrical
pulses delivered to the electrodes of the surgical probe; and an
electrical conductor, the electrical conductor connecting the pulse
generator, the control circuit, and the electrodes; wherein a
high-intensity, pulsed, electric field formed at a tip of the
surgical probe is sufficient to create a weakened proteinaceous
liquid complex from the volume of ocular tissue and further wherein
pulse strength of the high-intensity pulsed electric field is
insufficient to create an electron avalanche.
46. The system of claim 45, wherein the pulse generator further
comprises a pulse forming circuit.
47. The system of claim 45, further comprising: a switch
circuit.
48. The system of claim 45, wherein the pulse generator has one or
more output channels.
49. The system of claim 45, wherein the pulse generator delivers
pulsed DC voltage.
50. The system of claim 45, wherein the pulse generator delivers
gated AC voltage.
51. The system of claim 45, wherein the control circuit changes a
parameter selected from the group consisting of: the pulse-shape,
the pulse-repetition-rate, the pulse-duration, the pulse
train-length, the pulse-pattern, the pulse amplitude, and the
number of pulses.
52. The system of claim 45, wherein the control circuit changes the
activation sequence of the electrodes.
53. The system of claim 52, wherein the output sequence of the
pulse generator is selected from the group consisting of: a
sequence of ordered pulses and a sequence of random pulses.
54. The system of claim 47, wherein the control circuit changes the
polarity of the pulsed electric field created between the
electrodes.
55. The system of claim 47, wherein the control circuit changes the
direction of the pulsed electric field created between the
electrodes.
56. The system of claim 45, further comprising: an electrically
conducting medium located between the electrodes.
57. The system of claim 45, further comprising: a fluid located
between the electrodes that maintains a stable electrical
environment.
58. The system of claim 45, wherein the surgical probe has one or
more through lumens.
59. The system of claim 45, further comprising: an irrigation
system to deliver a fluid between the electrodes.
60. The system of claim 58, wherein a number of the lumens are for
irrigation.
61. The system of claim 45, further comprising: an aspiration
system to remove dissociated tissue.
62. The system of claim 58, wherein the number of the lumens are
for aspiration.
63. The system of claim 45, where the pulse generator delivers one
or more pulses in bursts.
64. The system of claim 63, wherein the control circuit changes the
time between the pulses in a burst.
65. The system of claim 63, wherein the control circuit changes the
pulse train length.
66. The system of claim 63, wherein the control circuit changes the
burst frequency.
67. The system of claim 45, further comprising: irrigation fluid
with pH properties conducive to a pulsed electric field induced
increase of the fluidity of the tissue.
68. The system of claim 45, further comprising: irrigation fluid
combined with ingredients conducive to a pulsed electric field
induced increase of the fluidity of the tissue.
69. The system of claim 68, wherein the ingredients in the
irrigation fluid has enzymatic properties.
70. A method of using high-intensity pulsed electric fields to
change the state and to increase the fluidity of a macroscopic
volume of ocular tissue, the method comprising: applying a
localized pulsed electric field to the tissue without causing an
electron avalanche; wherein the localized pulsed electric field
comprises pulses that have a pulse-shape, a pulse-repetition-rate,
and a pulse-duration; wherein the pulses are grouped into bursts or
pulse-trains; and wherein the pulse-trains have a
pulse-train-length, and a pulse-pattern.
71. The method of claim 70, wherein the pulse-shape is tuned to
structural properties of the ocular tissue and its
surroundings.
72. The method of claim 71, wherein the pulse-repetition rate is
tuned to structural properties of the ocular tissue and its
surroundings.
73. The method of claim 70, wherein the pulse-duration is tuned to
structural properties of the ocular tissue and its
surroundings.
74. The method of claim 70, wherein the pulse-pattern is tuned to
structural properties of the ocular tissue and its
surroundings.
75. The method of claim 70, wherein the pulse-train-length is tuned
to structural properties of the ocular tissue and its
surroundings.
76. A device for distributing a high-intensity pulsed electric
field to ocular tissue for changing the state and increasing the
fluidity of ocular tissue, the device comprising: a probe having a
handle and a shaft for engaging ocular tissue, the probe shaft
having a first number of electrodes; a distal termination of each
electrode being spatially positioned to provide a contained region
wherein a penetrating disruptive electric field is created and
applied to a volume of the ocular tissue; the electrode
terminations being shaped to concentrate a pulsed electric field
within the ocular tissue; and a connection to an electrical system
that generates ultra short high-intensity electric pulses; the
connection delivering the high-intensity electric pulses to the
probe;
77. The device of claim 76, wherein outside diameter of the probe
shaft is less than 0.04 inches.
78. The device of claim 76, wherein the distal termination of one
or more of the electrodes is shaped to concentrate the electric
field to ocular tissue between the electrodes.
79. The device of claim 76, wherein two or more of the electrodes
are axially arranged around the center longitudinal axis of the
probe shaft.
80. The device of claim 76, wherein the electrodes are axially
positioned so that one or more of the electrodes terminates at
different lengths or different axial positions.
81. The device of claim 76, wherein the distal termination of one
or more of the electrodes is pointed.
82. The device of claim 76, wherein the distal termination of one
or more of the electrodes is angled.
83. The device of claim 76, wherein the electrodes are made of
wires, a portion of the wires being round shaped.
84. The device of claim 76, wherein the electrodes are made of
wires, a portion of the wires being ovular shaped.
85. The device of claim 76, wherein the electrode terminations are
not insulated.
86. The device of claim 76, wherein the distance between the
electrode terminations is less the 0.5 millimeters.
87. The device of claim 76, wherein the distal termination of one
or more of the electrodes is shaped to concentrate a pulsed rapid
electric field to ocular tissue in the vicinity of the
electrodes.
88. The device of claim 76, wherein one or more edges of the
electrode terminations are rounded.
89. The device of claim 76, wherein the distal termination of one
or more of the electrodes is triangular.
90. The device of claim 89, wherein the apex of the triangular
distal termination is pointed towards the center of an orifice of
the probe.
91. The device of claim 76, wherein the distal termination of one
or more of the electrodes has one or more sharp edges.
92. The device of claim 91, wherein one or more of the sharp edges
are directed toward a longitudinal axis of the probe.
93. The device of claim 76, wherein a portion of the electrodes are
flat ribbon shaped.
94. The device of claim 93, wherein one or more of the electrodes
are orientated with a wider side tangent to the circumference of
the probe shaft.
95. The device of claim 93, wherein one or more of the electrodes
are orientated with a narrower side tangent to the circumference of
the probe shaft.
96. The device of claim 76, wherein the distal end of the probe
terminates in an atraumatic tip.
97. The device of claim 96, wherein the atraumatic tip comprises a
formed polymer over-sheath on the distal end of the probe
shaft.
98. The device of claim 97, wherein the atraumatic tip encases a
treatment zone within which the electric field is directed and
ocular tissue is engaged.
99. The device of claim 76, wherein the location of the distal
electrode terminations creates a region of ocular tissue
encirclement.
100. The device of claim 76, wherein the electrode termination
shape is selected from the group of shapes consisting of: straight
edges, corners, curvatures and combination thereof.
101. The device of claim 76, wherein the probe is hollow.
102. The device of claim 101, wherein the shaft of the probe
terminates in an axial orifice for engagement of ocular tissue.
103. The device of claim 101, wherein the shaft of the probe
terminates in a lateral orifice for engagement of ocular
tissue.
104. The device of claim 101, wherein the hollow in the shaft
comprises one or more lumens through the probe shaft.
105. The device of claim 104, wherein one or more of the lumens are
for aspiration.
106. The device of claim 104, wherein one or more of the lumens are
for fluid irrigation.
107. The device of claim 104, wherein one or more of the lumens are
for passage of an instrument.
108. The device of claim 104, wherein one or more of the lumens are
for passage of an optical fiber.
109. The device of claim 104, wherein aspiration is provided
through an independent cannula.
110. The device of claim 76, wherein irrigation is provided through
an independent cannula.
Description
RELATED APPLICATIONS
[0001] This Application is a division of U.S. patent application
Ser. No. 11/608,877, filed Dec. 11, 2006, which is a
non-provisional of U.S. Patent Application Ser. No. 60/755,839
filed Jan. 3, 2006.
BACKGROUND OF THE INVENTION
[0002] The present invention pertains to the dissociation and
removal of highly hydrated macroscopic volumes of proteinaceous
tissue; more particularly, the present invention pertains to the
dissociation and removal of highly hydrated macroscopic volumes of
proteinaceous tissue using rapid variable direction energy field
flow fractionization.
[0003] The present invention is described in terms of vitreoretinal
surgery; however, those of ordinary skill in the art will
understand the applicability of this invention to medical
procedures in other areas in the body of humans or animals.
[0004] For decades, prior art procedures for vitreoretinal
posterior surgery have relied on mechanical or traction methods
for: 1) tissue removal with shear cutting probes (utilizing either
a reciprocating or rotary cutter); 2) membrane transection using
scissors, a blade, or vitreous cutters; 3) membrane peeling with
forceps and picks; and 4) membrane separation with forceps and
viscous fluids. While improvements in mechanisms, materials,
quality, manufacturability, system support, and efficacy have
progressed, significant advancements in posterior intraocular
surgical outcomes are primarily attributable to the knowledge,
fortitude, skill, and dexterity of the operating ophthalmic
physicians.
[0005] Traction-free removal of intraocular tissue during
vitreoretinal surgery is nearly impossible with the current arsenal
of mechanical medical instruments. Through the application of
skill, precise movement, experience, and knowledge, operating
physicians have been able to minimize the traction from the use of
mechanical medical instruments during tissue removal but are unable
to eliminate it. Mechanical or traction surgical methods utilize a
shearing action to sever tissue bonds. This shearing action
inherently puts tension on the tissue to be removed, that tension,
in turn, is transferred to the retinal membrane. Because of the use
of mechanical or traction surgical methods, the forces which impart
motion to the cutting element of the mechanical medical devices
being used to sever tissue bonds are superimposed on the retinal
membrane. Despite the skill and the care of the ophthalmic surgeon,
this superimposition of the forces associated with traction
surgical methods onto the retinal membrane gives rise to the
possibility of damage to the retinal membrane.
[0006] A potential traction-free surgical method that has been used
in generating conformational changes in protein components involves
the application of high intensity pulsed electrical fields;
however, the use of a high-intensity pulsed electrical field has
not made its way into delicate surgical procedures such as
vitreoretinal surgery.
[0007] High-intensity pulsed electric fields have found numerous
applications in the medical field, the food industry, and in the
machining of micromechanical devices. Examples of medical field use
include delivery of chemotherapeutic drugs into tumor cells, gene
therapy, transdermal drug delivery, and bacterial decontamination
of water and liquid foods. In the food industry, high-intensity
ultrashort-pulsed electric fields have found commercial use in
sterilization and decontamination. Finally, the machining and
surface modification techniques used for Micro Electric Mechanical
Systems (MEMS) chips employ high-intensity ultrashort-pulsed
electrical fields.
[0008] Manipulation of biological structures, such as
macromolecules, cellular membranes, intracellular organelles, and
extracellular entities, has been the focus of recent research by
both biophysics and biochemical engineering groups. Under the
general heading of electrokinetics, the response of biological
tissues to electric fields has been used in research, diagnostic,
and therapeutic applications.
Non-Surgical Electrokinetic Research and Development
[0009] Basic understanding of the invention described herein is
best obtained through an appreciation of some of the prior-art
nonsurgical technologies now in use for biochemical molecular
research, therapeutic pharmaceutical developments, sterilization
techniques, commercial polymerization, plasma research, and MEMS
(lab-on-a-chip) advancements. Key aspects of these prior-art
technologies are described below to demonstrate other systems in
which proteinaceous material has been manipulated and compromised
by the delivery of high-intensity pulsed electrical fields.
Electrorheology
[0010] Electrorheology (ER) is a phenomenon in which the rheology
of fluids, to include biological fluids, is modified by the
imposition of electrical fields (usually low DC fields). The
electrical field imposed on the fluid induces a bulk-phase
transition in the fluid with the strength of the electrical field
being the most important parameter, and the frequency of the
electrical field generally being the least important parameter.
Most colloidal ER fluids demonstrate an increase in viscoelastic
effects with increased field amplitude. Interestingly, a decrease
in viscoelasticity of the fluid appears at the highest field
strengths, but definitive research into the effect of field
strength on viscoelasticity of the fluid is lacking, and the
mechanism of ER remains unknown.
Electrophoresis
[0011] Electrophoresis (or dielectrophoresis) involves the movement
of particles in an electrical field toward one or another electric
pole, anode, or cathode. The electrophoresis process is used to
separate and purify biomolecules (e.g., DNA and RNA separation).
For materials that are on the order of nanometers to micrometers,
the electrophoresis process works well for both highly specific
isolation of materials and determination of material properties.
During electrophoresis, electrical field induced phase transition
in a confined suspension is the subject of a spatially uniform AC
electrical field. This electrical-field-induced phase transition
follows the well-known field-induced formation of a columnar
structure in a suspension. When subjected to an external electrical
field, the particles within the electrical field align themselves
along the field direction, forming chains and columns. The chains
and columns of particles are then stretched by the actions of the
electrical field and fluid flow. The time for separation and
isolation of particles is on the order of minutes to hours and
often involves the application of multiple secondary processes. An
ionic surfactant (e.g., sodium dodecyl sulfate SDS) and sample
dilution are often used to enhance macromolecular separation. Ionic
surfactants have the ability to form a chemical bridge between
hydrophobic and hydrophilic environments, thus disrupting or
diminishing the hydrophobic connecting forces needed to maintain
native protein structure.
Field Flow Fractionation
[0012] Field Flow Fractionation (FFF) is a laboratory solution
separation method comparable in many ways to liquid chromatography.
In general, both the materials and size range of materials
separated in FFF systems are complimentary to those analyzed using
electrophoresis and liquid chromatography. In FFF systems, the
separation protagonist (electrical field) is applied in a direction
perpendicular to the direction of separation and creates spatial
and temporal separation of the sample components at the output of
the FFF channel. Separation in an FFF channel is based on
differences in the retention (time) of the sample components. In
turn, the retention in FFF systems is a function of the differences
in the physiochemical properties of the sample, the strength and
mode of the applied assault, and the fluid velocity profile in the
separation channel. Utilization of FFF has reduced electrophoresis
times from hours to minutes.
Electric Field Flow Fractionation
[0013] Arising from the work being done in machining Micro Electric
Mechanical Systems (MEMS) is Electric Field Flow Fractionation
(EFFF). EFFF is a process for the ex-vivo separation of
nanoparticles, proteins, and macromolecules entrained in
microchannels by applying electrical fields either in the axial or
in the lateral direction. This technique is currently under study
in connection with MEMS microphoresis devices. The method is based
on axial flow of analyte under the action of an electrical
potential (unidirectional lateral electrical field). The separation
performance and the retention time of particulate samples in the
flow channel depend on the interaction of the sample with the
electrical field applied transverse to the flow field in the
channel Dissociation of protein complexes, disruption of protein
connections, and subsequent fractionization has been achieved with
EFFF. An increase in retention, resulting in much better
separation, has also been seen with the application of periodic
(oscillating) electrical fields in EFFF.
[0014] In addition, the application of pulsed potentials with
alternating polarity has been shown to increase the effectiveness
of the electrical field. It has been postulated that shear plays a
significant role in chain scission, since local deformation of
proteinaceous tissue in any electrical field gradient is pure
elongation. Quantified by a strain rate and axes of extension and
compression, careful manipulation of array geometry and flow-field
strength can result in significant extension of the majority of the
macromolecules. Microchips have been designed that can generate
rotational, extensional, and shear electrical field patterns, as
long as the input voltages are changed. Separation time on a 1.25
cm chip has been reduced to approximately 5 seconds.
Electroporation
[0015] Electroporation is another nonsurgical prior-art technology
that has been used to reversibly and transiently increase the
permeabilization of a cell membrane. Introduced in about 1994,
electroporation (EP) to enhance the delivery of drugs and genes
across cell membranes in-vitro has become a standard procedure in
molecular biology laboratories in the last decade. Electroporation
is a technique in which pulses of electrical energy, measured in
kilovolts per centimeter, having a duration in the
microsecond-to-millisecond range, cause a temporary loss of the
semi-permeability of cell membranes. This temporary loss of the
semi-permeability of cell membranes leads to ion leakage, escape of
metabolites, and increased cellular uptake of drugs, molecular
probes, and DNA. Some prior-art applications of electroporation
include introduction of plasmids or foreign DNA into living cells
for transfection, fusion of cells to prepare hybridomas, and
insertion of proteins into cell membranes. Classically, pulse
durations in the order of 0.1 to 10 milliseconds and electrical
field strength of kV/cm, depending on cell type and suspension
media, have been utilized. The mechanism of electroporation (i.e.,
the opening and closing of cellular channels) is not completely
understood.
[0016] Adaptations of the electroporation technology have been used
for drug delivery. U.S. Pat. No. 5,869,326 and Published U.S.
Patent Application 2004/0176716 both describe instruments for
transcutaneous drug delivery. Published U.S. Patent Application
2004/021966 describes a catheter instrument for intravascular
delivery of therapeutic drugs and in-vitro drug delivery using
electrode array arrangements. U.S. Pat. No. 6,653,114 teaches a
means for electrode switching. U.S. Pat. No. 6,773,736 and U.S.
Pat. No. 6,746,613 have adapted electroporation technology to
decontaminate products and fluids by causing cell deactivation and
death. U.S. Pat. No. 6,795,728 uses electroporation-induced cell
death as the basis for an apparatus and method for reducing
subcutaneous fat deposits in-vivo.
Nanosecond Pulsed Electrical Field
[0017] Nanosecond Pulsed Electrical Field (nsPEF) technology is an
extension of electroporation technology described above, to include
in-vivo application, where a square or trapezoidal pulse formed
with significantly shorter duration (1-300 ns), together with
considerably higher electric fields (up to 300 kV/cm), is utilized.
nsPEF evolved from advances in pulse-power technology. The use of
this pulse-power technology has lead to the application of
nanosecond-pulsed electronic fields (nsPEF) with field intensities
several hundred times higher than the pulses of electrical energy
used in electroporation to cells and tissues without causing
biologically significant temperature increases in the samples
tested. Using very few pulses of electrical energy, the effects of
nsPEF are essentially non-thermal. In contrast to classical
electroporation techniques, the effects of nsPEF on mammalian cells
have only recently been explored. Application of nsPEF of
appropriate amplitude and duration creates transient cellular
permeability increases, cellular or subcellular damage, or even
apoptosis. In in-vivo nanosecond electroporation, the goal is to
obtain an even distribution of an efficacious electrical field
within a narrow time window.
[0018] Current research has shown that the application of
nanosecond pulses (kV/cm) to tissues can energize electrons without
heating ions or neutral particles. It has been found that an
ultrashort-pulsed energy field (Electromagnetic EM, Laser, or High
Intensity Focused Ultrasound HIFU) can be used to temporarily and
reversibly increase the permeability of cell membranes or even
compromise intracellular components without affecting the cell
membrane. It has also been found that higher energies will excite
ions and may cause the formation of short-lived radicals (OH and
O.sub.2.sup.+). This finding has lead to the development of
processes for sterilization and decontamination whereby cells are
killed. The use of still higher energies may cause the formation of
super-charged plasma arcs which attack cellular bonds at the
molecular level.
Electro-Osmosis
[0019] Electro-osmosis (EO) is a technique used to transport or mix
fluid for use in micro devices. A key concept is to exploit
different charging mechanisms and polarization strength of the
double layer at the electrode/electrolyte interface, to produce a
unidirectional Maxwell force on the fluid, which force generates
through-flow pumping. In "induced-charge electro-osmosis" (ICEO),
an effect is created which produces microvortices within a fluid to
enhance mixing in microfluidic devices. Mixing can be greatly
enhanced in the laminar flow regime by subjecting the fluid to
chaotic-flow kinematics. By changing the polarity and the applied
voltage, the strength and direction of the radial electro-osmotic
flow can be controlled.
Other Electrokinetic Phenomena
[0020] Electrokinetic phenomena are not limited to that described
above. Recent variants associated with very large voltages and
unique electrical fields in MEMS research have demonstrated
interesting and counter-intuitive effects occurring with variable
applied electrical fields, including the finding that the
electrophoretic mobility of colloids is sensitive to the
distribution of charges, rather than simply the total net
charge.
Tissue Removal
[0021] All of the processes described above are applicable to
manipulation of macromolecules, but not to the extraction or
removal of macroscopic volumes of proteinaceous tissue by tissue
dissociation. As other systems using pulsed energy with tissues
employ high levels of energy, it has been found that higher
energies delivered through the use of longer pulse durations, pulse
trains, repetition rates, and exposure times will cause thermal
effects or the formation of super-charged plasma. These thermal
effects or the formation of super-charged plasma have been
effectively utilized in several devices to develop surgical
instruments for tissue cutting. In these instruments, a microsize
(thickness or projection) plasma region is created about an
instrument. Within the super-charged plasma are charged electrons,
ions, and molecules with an erratic motion which, when contacted
with tissues or cells, attack bonds at the molecular level--thereby
ablating or obliterating via sublimation the target tissue or
tissue surface. The formation of super-charged plasma relies on
electron avalanche processes--high rate of tunneling by electrons
from the valence band to the continuum to form electron plasma
avalanche ionization. The density of this super-charged plasma
rapidly builds up by virtue of additional tunneling as well as
field-driven collisions between free electrons and molecules. A
major goal of the treatment of tissue with super-charged plasma is
nondestructive surgery; that is, controlled, high-precision removal
of diseased sections with minimum damage to nondiseased tissue. The
size and shape of the active plasma are controlled by probe design,
dimensions, and media. Both gaseous and fluid media have been
employed. Within a liquid, an explosive vapor may be formed.
Pulsed Electron Avalanche Knife
[0022] The Pulsed Electron Avalanche Knife (PEAK) disclosed in
Published U.S. Patent Application 2004/0236321 is described as a
tractionless cold-cutting device. A high electrical field (nsPEF 1
to 8 kV, 150 to 670 uJ) is applied between an exposed
microelectrode and a partially insulated electrode. The application
of this high electrical field leads to a plasma formation
manifested in the form of micrometer-length plasma streamers. It is
the size of the exposed electrode which controls the dimensions of
the plasma streamers. The plasma streamers, in turn, create an
explosive evaporation of water on a micron scale. Pulsed energy is
critical. Precise, safe, and cost-effective tissue cutting has been
demonstrated. Even with the electrode scaled down in size to the
micron level, the plasma discharges must be confined to the probe
tip, because ionization and explosive evaporation of liquid medium
can disrupt the adjacent tissue and result in cavitation bubble
formation. The high pressure achieved during plasma formation, the
fast expansion of vapor bubble (>100 m/sec), and the subsequent
collapse of the cavity that can extend the zone of interaction is
mainly mechanical due to rapid bubble vapor cool down. In
ophthalmic surgery, the volatility and aggressiveness of the effect
caused by the use of a PEAK could be detrimental to retinal
integrity.
Coblation
[0023] Coblation, or "Cold Ablation," uses radio frequency RF in a
bipolar mode with a conductive solution, such as saline, to
generate plasma which, when brought into contact with a target
tissue, sublimates the surface layer of the target tissue. The
range of accelerated charged particles is short and is confined to
the plasma boundary layer about the probe and to the surface of
tissue contact. Coblation energizes the ions in a saline-conductive
solution to form a small plasma field. The plasma has enough energy
to break the tissue's molecular bonds, creating an ablative path.
The thermal effect of this process has been reported to be
approximately 45-85.degree. C. Classically, RF electrosurgical
devices use heat to modify tissue structure. The generation of a
radio frequency induced plasma field, however, is viewed as a
"cold" process, since the influence of the plasma is constrained to
the plasma proper, and the plasma layer maintained is
microscopically thin. The plasma is comprised of highly ionized
particles of sufficient energy to achieve molecular dissociation of
the molecular bonds. The energy needed to break the carbon-carbon
and carbon-nitrogen bonds is on the order of 3-4 eV. It is
estimated that the Coblation technique supplies about 8 eV. Due to
the bipolar configuration of the electrodes and the impedance
differential between the tissue and the saline solution, most of
the current passes through the conductive medium located between
the electrodes, resulting in minimal current penetration into the
tissue and minimal thermal injury to the tissue. If the threshold
of energy required to create plasma is not reached, current flows
through the conductive medium and the tissue. Energy absorbed by
both the tissue and the conductive medium are dissipated as heat.
When the threshold of energy needed to create plasma is reached,
impedance to RF current flow changes from almost purely
resistive-type impedance into a more capacitive-type impedance.
Similar to the drawbacks of the PEAK for ophthalmic surgery, the
use of coblation techniques may be too aggressive for surgical
applications near the retina.
Plasma Needle
[0024] The plasma needle is yet another device that allows specific
cell removal or rearrangement without influencing surrounding
tissue. Use of the plasma needle is a very exacting technique which
utilizes a microsize needle affixed to a hand-operated tool to
create a small plasma discharge. An electrical field is created
between the needle tip and a proximal electrode with an inert gas
(helium) flowing there between. The small plasma discharge contains
electrons, ions, and radicals--with the ions and radicals
controllable by the introduction of a contaminant, such as air,
into the inert gas. It has been postulated that the small size of
the plasma source (plasma needle) creates ROS (reactive oxygen
species) and UV light emissions at such minute levels as to alter
cell function or cell adhesion without damaging the cells
themselves. However, an increase in ROS (i.e., air) in the inert
gas along with an increased irradiation time can lead to cell
death. While shown to exert an influence across thin liquid layers,
use of the plasma needle is not optimal in a total liquid
environment, as often found in ophthalmic surgery.
Spark Erosion
[0025] Spark erosion technology is a cousin to the plasma
technologies discussed above. The spark erosion device utilizes a
pulsed energy field of 250 kHz, 10 ms duration, and up to 1.2 kV to
produce a vapor. As the electric breakdown of vapor occurs, a small
spark (<1 mm) is formed. With up to a 1.7 mm far-field effect,
the cutting performance from spark erosion is similar to
electrosurgery, but, like plasma--only the plasma contacts
tissue.
Lasers
[0026] Lasers represent another traction-free technology that has
been used to break down tissue macro molecules. Lasers have been
utilized in ophthalmic surgery since about 1960. The greatest
success in laser usage has been in the area of non-invasive retinal
coagulation in diseases such as diabetic retinopathy, central vein
occlusion, and choroidal neovascularization in age-related macular
degeneration or ischemic retinal vasculitis. Lasers have also been
used extensively in anterior eye applications for such applications
as corneal sculpting and glaucoma. Attempts to utilize lasers in
posterior ophthalmic surgeries have achieved mixed results.
Non-invasive (trans-corneal/lens or trans-sclera) techniques are
not practical, due to the absorptive properties of these
intervening tissues. The extraordinary precision needed in
intraocular surgery of the retina and vitreous requires the use of
increasingly refined invasive techniques for tissue manipulation
and removal. The tissue/laser interaction regimes include 1)
thermal--conversion of electromagnetic energy into thermal energy;
2) photochemical--intrinsic (endogenous) or injected (exogenous)
photosensitive chemicals (chromophores), activated by absorption of
laser photos; 3) photoablative--direct photodissociation of
intramolecular bonds of absorption of photons; and 4)
electromechanical--thermionic emission or multiphoton production of
free electrons leading to dielectric breakdown and plasma
production. It has been found that lasers are costly and require
the use of shields and backstops on uniquely designed laser probes
to protect fine intraocular tissues from stray laser energy and
far-field thermal effects. However, recent developments in
femtosecond-pulsed lasers have opened new possibilities in fine
surgical applications.
Other Tissue Removal Methods
[0027] Methods currently employed to disrupt intraocular tissues
include morcellation (fragmentation), which is the objective of
mechanically shearing vitrectomy devices; liquefaction as
accomplished by thermal (protein denaturizing) or enzymatic
reactions; and sublimation via laser or plasma treatments.
Sublimation via laser or plasma treatments actually compromises
bonds on a molecular level, whereas morcellation and liquefaction
affect the binding mechanism of lesser strength (i.e., non-covalent
bonds).
[0028] Accordingly, despite many advances in vitreoretinal surgery,
a need still remains for an effective apparatus and method for the
dissociation and removal of highly hydrated macroscopic volumes of
protein tissues, such as vitreous and intraocular tissues, during
vitreoretinal surgery.
SUMMARY
[0029] The present invention describes an apparatus and method for
the dissociation and removal of highly hydrated macroscopic volumes
of proteinaceous tissues, such as vitreous and intraocular tissue,
during vitreoretinal surgery.
[0030] While the disclosed invention is described in terms of an
instrument and method for traction-free removal of vitreous and
intraocular membranes from the posterior region of the eye without
damaging the ultrafine structure and function of the adjacent or
adherent retina, those of ordinary skill in the art will understand
the applicability of the disclosed invention for other medical
procedures on both humans and animals.
[0031] The disclosed invention is described in terms of a new means
of performing vitreoretinal surgery using a high-intensity short
directionally changing electrical field, as opposed to classical
mechanical means to engage, decompose, and remove vitreous and
intraocular tissues. Specifically, the following disclosure affects
the discovery that a transient change in tissue condition caused by
the application of a high-intensity short directionally changing
electrical field is satisfactory for removal of macroscopic volumes
of proteinaceous tissue. The technical success of mechanical and
liquefying means supports the contention that vitreous material
need not be obliterated or disrupted on a molecular level to be
removed--but, rather, an innocuous macroscopic change of state is
all that is needed for tissue removal. Accordingly, the removal of
intraocular tissue enabled by the disclosed invention is entirely
traction-free.
[0032] The apparatus and method disclosed herein causes a local
temporary dissociation of the adhesive and structural relations in
components of intraocular proteinaceous tissue using a rapidly
changing electrical field. This localized temporary dissociation of
the adhesive and structural relations between components of
intraocular proteinaceous tissue enables tractionless detachment
between intraocular tissue components and the retinal membrane.
Fluidic techniques (irrigation and aspiration) are utilized during
the tissue dissociation process to enhance the formation of a
high-intensity ultrashort-pulsed electrical field and to remove
disrupted tissue at the moment of dissociation. It is intended that
only the material within the applied high-intensity
ultrashort-pulsed electrical field is assaulted and removed.
Therefore, because only the material assaulted by the applied
ultrashort pulses receives the high-intensity ultrashort-pulsed
electrical field, there is no far-field effect during the tissue
extraction process.
[0033] The design of the probe used to create the pulsed electrical
field coupled with the use of fluidic techniques entrains the
target macroscopic volume of tissue to be dissociated.
Simultaneously, therefore, the entrained target macroscopic volume
of intraocular tissue is subjected to a high-intensity
ultrashort-pulsed electric field assault. This high-intensity
ultrashort-pulsed electrical field assault leads to dissociation of
the entrained macroscopic volume of intraocular proteinaceous
tissue, and then aspiration removes the dissociated entrained
macroscopic volume of tissue.
[0034] According to the disclosed invention, a probe with two or
more electrodes is inserted into the target hydrated tissue,
vitreous or intraocular tissue. The ends of the electrodes are
exposed at the distal end of the probe. An electrical pulse is
transmitted down at least one of the electrodes while the other one
or more electrodes act as the return conductors. A non-plasma
electrical field is created between the delivery electrode(s)
acting as an anode and the return electrode(s) acting as a cathode.
With each electric pulse, the direction of the created electrical
field is changed by reversing polarity, by electrode switching or
by a combination of both. Pulses may be grouped into burst
reoccurring at different frequencies and different amplitudes. Such
pulse groups may be directed at heterogeneous tissue. The
electrical pulse amplitude, duration, duty cycle and repetition
rate along with continual changing of field direction, create the
disruptive electrical field created across the orifice of the
aspiration lumen. Tissue is drawn into the orifice of the
aspiration lumen by fluidic techniques (aspiration). The tissue is
then mixed or diluted with irrigation fluid and disassociated as it
traverses the high-intensity ultrashort-pulsed directionally
changing electric field. At any given instant, disorder is created
in the electrical field by changing the direction of the electrical
field between one or more of the electrodes at the tip of the
probe. The affected medium between the electrode terminations at
the end of the probe consists of a mix of target tissue (e.g.
vitreous) and supplemental fluid (irrigation fluid). The electrical
impedance of this target medium in which the electrical field is
created is maintained by the controlled delivery of supplemental
fluid (irrigation fluid). In the preferred embodiment, the
supplemental fluid providing the electrical impedance is a
conductive saline. The supplemental fluid may be provided by an
irrigation source external to the probe, through one or more lumens
within the probe or a combination of both. When the supplemental
fluid is provided within an constrained to the probe interior, the
supplemental fluid may have properties (e.g. pH) and ingredients
(e.g. surfactants) that may be conducive to protein
dissociation.
[0035] Critical to the operation of the disclosed invention are the
properties of the generated electrical energy field within the
target medium. Herein, high-intensity, ultrashort pulses
(sub-microseconds) of electrical energy are used. Tissue impedance,
conductivity and dilution are maintained in the target medium by
supplemental fluid irrigation. The pulse shape, the pulse
repetition rate, and the pulse train length are tuned to the
properties of the intraocular tissues. Multiple pulse patterns may
be employed to address the heterogeneity of intraocular tissue. In
addition, the spatial termination and the activation sequence of
the electrodes at the tip of the probe, along with the generated
field profile, play a significant role in tissue decomposition. The
fluid aspiration rate is matched to the tissue dissociation rate.
The pulsed rapid disruptive electric field effect in the target
medium is of such high intensity, but such short duration (i.e.,
low energy), that the actual dissociation of the targeted tissue
from surrounding tissue is a transient effect (microseconds to
milliseconds), which is non-thermal, and devoid of explosive
cavitation.
[0036] The energies delivered by the ultrashort duration,
high-intensity electrical pulses do not cause plasma formation;
thus, there is no aggressive far-field effect. The ultrashort
duration, high-intensity electrical pulses are used to create a
non-contact disruptive electrical force within the tissue, not by
an electron avalanche but, rather, by a continual change in field
direction. Specifically, a non-plasma, non-contact energized region
of disorder is created in the proteinaceous tissue to be
dissociated. Any charged material entering into the electric field
will be affected by that field, and intraocular tissues (e.g.,
proteins) will be changed. By creating a disruptive electric field
about proteinaceous tissues without creating an electron avalanche,
the attachment mechanisms between the tissue components experience
a transient compromise. This transient compromise leads to a
dissociation of tissue components--free of far-field perturbations.
This transient compromise of tissue attachment mechanisms between
the tissue complexes leads to the unfolding of protein complexes
and the uncoiling of helices, thereby allowing for disruption of
collagen segments and adhesive bonds (fragmentation of staggered
fibrils).
[0037] The intended purpose of the work leading to the discovery of
the disclosed invention described herein has been the tractionless
extraction of vitreous and intraocular membranous tissues from the
posterior intraocular region of the eye. The disclosed apparatus
and method engage and disrupt a hydrated proteinaceous gel matrix
causing a transient compromise or dissociation of the adhesive
mechanisms between tissue components. During this transient
compromise or dissociation of the adhesive mechanisms between
tissue components, fluidic techniques are employed to dilute and
aspirate the dissociated tissue complex from the surrounding
tissue.
[0038] The purpose of the system disclosed herein is also to alter
the state of vitreous proteinaceous tissue for safe removal. This
alteration of the state of vitreous proteinaceous tissue entails
the disruption of proteinaceous tissue component interactions, the
promotion of separation and detachment of proteinaceous tissue
components from adjacent structures, and, while proteinaceous
tissue components are separated and detached--their removal.
[0039] Accordingly, it is an object of this disclosure to present a
new surgical device modality and device that addresses the needs of
the modern vitreoretinal surgeon--namely, a device for improved and
more precise extraction of vitreous and intraocular membranes while
preserving retinal integrity. Though this disclosed system is
focused on a new device for altering the state of and removal of
the corpus vitreous and associated intraocular membranes, it will
become obvious to one skilled in the art that the information
presented herein is applicable to other surgical arenas besides
ophthalmology.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0040] A better understanding of the disclosed system for
dissociation and removal of proteinaceous tissue may be had by
reference to the drawing figures wherein:
[0041] FIG. 1 is a perspective view of a probe used for intraocular
posterior surgery on which the system of the disclosed invention is
used;
[0042] FIG. 2 is an enlarged perspective view of the tip of the
probe shown in FIG. 1;
[0043] FIG. 3 is a schematic diagram of a preferred embodiment of
the disclosed system;
[0044] FIGS. 4A, 4B, 4C, 4D, and 4E are front views of alternative
placements of electrodes on the tip of the probe;
[0045] Tables 5A, 5B, 5C, 5D, and 5E are activation schemes
associated with the probe arrays shown in FIGS. 4A, 4B, 4C, 4D, and
4E, respectively;
[0046] FIG. 6 is a perspective view of three electrode embodiment
of the probe used for intraocular posterior surgery employing the
system of the disclosed invention;
[0047] FIG. 7 is an enlarged perspective view of the tip of the
probe shown in FIG. 6 including a transparent cover to reveal the
interior features;
[0048] FIG. 8 is an end view of probe shown in FIG. 7;
[0049] FIG. 9 is an expanded perspective view of the probe similar
to that shown in FIG. 7;
[0050] FIG. 10 is a schematic diagram of an alternate embodiment of
the disclosed system with a supplemental irrigation means included
in the probe;
[0051] FIG. 11A is an end view of the probe tip showing the
placement of three electrodes as in the embodiment shown in FIGS.
7, 8, and 9;
[0052] FIG. 11B is an end view of a probe tip having four
electrodes;
[0053] FIG. 12A is an activation scheme associated with the
electrode array shown in FIG. 11A;
[0054] FIG. 12B is an activation scheme associated with the
electrode array shown in FIG. 11B;
[0055] FIG. 13A is an illustration of exemplary field lines
resulting from placement of a charge on one or more of the
electrodes displayed in FIG. 11A;
[0056] FIG. 13B is an illustration of exemplary field lines
resulting from placement of a charge on one or more of the
electrodes displayed in FIG. 11B;
[0057] FIG. 14 is a schematic diagram of an exemplary three-channel
pulse generator used with a three-electrode probe;
[0058] FIG. 15 is a schematic diagram of the channel states during
a single cycle of pulsing of the generators shown in FIG. 14;
[0059] FIG. 16 is an enlarged perspective view of another
embodiment of the tip of the probe shown in FIG. 6 including a
transparent cover to reveal the interior features;
[0060] FIG. 17 is an enlarged perspective view of the probe shown
in FIG. 16 including a jacket that covers the interior
features;
[0061] FIG. 18 is an end view of probe shown in FIG. 16;
[0062] FIG. 19 is an end view of probe shown in FIG. 17;
[0063] FIG. 20 is an enlarged perspective view of another
embodiment of the tip of the probe shown in FIG. 6 including a
transparent cover to reveal the interior features;
[0064] FIG. 21 is an enlarged perspective view of the probe shown
in FIG. 20 including a jacket that covers the interior
features;
[0065] FIG. 22 is an end view of probe shown in FIG. 20; and
[0066] FIG. 23 is an end view of probe shown in FIG. 21.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0067] Liquefaction (synchysis) is manifested in vitreous portion
of the eye as a natural consequence of aging. As an individual
reaches 70 to 90 years, roughly 50% of the vitreous gel structure
has gone through a change of state or become liquefied. The results
of synchysis are realized in the posterior vitreous as a
destabilization of the vitreous matrix, dissolution of HA-collagen
coupling, unwinding of collagen helices, molecular rearrangements,
increases in the volume of liquefied spaces, loosening of entangled
tethers, increases in vitreous detachment from the retina, collagen
fiber fragmentation and aggregation, and loss of proteoglycans,
non-covalent bound macromolecules and adhesive collagen (type IX).
At the cellular level, many of the activities leading to
liquefaction in the vitreous portion of the eye may be emulated by
the present invention.
[0068] The apparatus and method of the disclosed invention deliver
a variable direction, pulsed high-intensity and ultrashort duration
disruptive electric field (low energy) at a pulse duration,
repetition rate, pulse pattern, and pulse train length tuned to the
properties of the components of the intraocular extracellular
matrix (ECM) to create a short period of tissue dissociation. The
recommended modality of ultrashort-pulsed disruptive electric field
application relies on the delivery of high powers of low
energy.
[0069] As shown in FIG. 1, the disclosed apparatus for implementing
the current invention includes a probe assembly 110 which delivers,
channels, and distributes the energy applied to the soft tissue in
such a fashion as to create a confined, localized, non-thermal
dynamic region of electrical forces within a macroscopic volume of
the extracellular matrix ECM (e.g., vitreous and intraocular
membranes) leading to momentary dissociation of proteinaceous
complexes and local liquefaction of the entrained macroscopic
volume of tissue. The tip 112 of the hollow probe 114 is positioned
to encircle the entrained macroscopic volume of proteinaceous
tissue. Fluidic techniques (irrigation) are used first to provide a
region of stable impedance and dilution between the electrodes 116
at the tip 112 of the hollow probe 114 and then draw in and remove
(aspiration) the affected macroscopic volume of proteinaceous
tissue before the reassembly of non-covalent proteinaceous
relationships can occur. The fluidic techniques used with the probe
assembly 110 may include both saline irrigation and effluent
aspiration.
[0070] The directionally changing electrical field created at the
tip 112 of the hollow probe 114 is presented substantially
perpendicular or orthogonal to the direction of carrier fluid
movement (i.e., proteinaceous material in a water solution). The
direction of the electrical field is changed with every or nearly
every pulse. Pulse duration (nanoseconds) is short, relative to the
dielectric relaxation time of protein complexes (.about.1 ms).
Multiple pulse direction changes may occur within the dielectric
relaxation time interval. Pulse duration, pulse repetition rate,
pulse pattern, and pulse train length are chosen to avoid the
development of thermal effects ("cold" process). The disclosed
system generates and delivers square-shaped pulses of variable
direction with fast (<5 nanoseconds) rise time and fall time.
The shorter the rise and fall times of the pulse, the higher the
frequency components in the Fourier spectrum of the pulse and,
consequently, the smaller the structures that can be affected by
the pulse. In the system for dissociation and removal of
proteinaceous tissue disclosed herein, pulse durations are in the
nanosecond range, and the electric field strength would be greater
than 1 kV/cm, preferably in the range of hundreds (100s) of
kV/cm.
[0071] The apparatus and method which effect the system of the
disclosed invention utilize ultrashort chaotic high-intensity
pulsed electric field flow fractionation (CHIP EFFF) to engage,
dissociate, and remove vitreous and intraocular membranous
material. A stepwise continual change in direction of the field (by
use of an array of electrodes 116) created by reversing polarity,
switching active electrodes or a combination of both is
incorporated into the tip 112 of the hollow probe 114 to create a
disruptive effect on charges involved in the non-covalent bonds
holding the vitreous complexes (groups of proteins) together. By
making the macroscopic volume of intraocular electrically unstable
tissue, it is possible to further weaken the hydrophobic and
hydrostatic bonds within the captured proteinaceous tissue,
membranes, and multi-component enzymes, thereby increasing the
fluidity or liquefaction of the tissue. The resulting assault on
the hydrophobic and hydrostatic bonds of the proteinaceous tissue
is sufficient for a momentary compromise of the binding mechanisms
of the adhesive macromolecules of the vitreous and associated
intraocular tissue, thereby temporarily reducing a minute portion
of the bulk vitreous material to a manageable free proteinaceous
liquid complex.
[0072] Paramount to the efficacy of the disclosed invention is the
choice of energy. The object of the assault on the bonds which hold
proteinaceous tissue together is to create disorder among electrons
in the outer shell of the macromolecules associated with
non-covalent bonds. The preferable form of energy is
electricity--energizing electrons by the direct creation of an
electric field. Other sources of energy, such as microwaves, and
ultrasound which utilize photons and phonons to energize electrons,
may also be used to create a disruptive field. It is appreciated
herein that lasers, particularly those operating with pulse
durations in the femtosecond range and at frequencies substantially
at the peak absorption frequency of water, may also be utilized as
an alternative energy source.
[0073] In the preferred embodiment of the apparatus and method
disclosed herein, a rapid variable direction electric field flow
fractionation is used to engage, to dissociate, and to remove
vitreous and intraocular membranous material. Specifically, the
disclosed system utilizes high-intensity ultrashort-pulsed
disruptive electrical field characterized by continuous changes of
field direction coupled with fluidic techniques both to facilitate
creation of the electrical field and then to remove the
proteinaceous dissociated tissue. The high-intensity
ultrashort-pulsed disruptive electric field is generated using
field strengths on the order of kV/cm with pulse widths on the
order of nanoseconds. The high-intensity ultrashort-pulsed
disruptive electrical field is kept substantially orthogonal to the
direction of aspirating carrier fluid flow. A stepwise continual
change in the direction of the high-intensity ultrashort-pulsed
disruptive electrical field (created by reversing polarity or
switching between an array of electrodes) is adopted to create
disorder among the electrons involved in the non-covalent bonds
holding the tissue complexes (groups of proteins) together. Using
pulse durations and pulse trains that are short with respect to the
time required for thermal effects, the assault on the
tissue-binding mechanisms is essentially a "cold" process and
sufficient for momentary tissue matrix dissociation. The assault on
the tissue-binding mechanisms will compromise the binding
mechanisms of the adhesive macromolecules of the vitreous and
associated intraocular tissue, thereby temporarily reducing a
minute portion of the bulk vitreous material to a manageable
proteinaceous liquid complex. The strength of the electrical field
causing the disassociation obeys the inverse square law. As such,
the strength of the field is highest in region between electrodes.
In the preferred embodiment, this distance is less than 0.5
millimeters. The affected proteinaceous liquid complex is localized
within the region of applied pulsed rapid variable direction
electrical field between probe electrodes and is removed using
fluidic techniques (aspiration) before the transient effects of the
assault on the tissue-binding mechanism expire (relax). Once the
volume of proteinaceous tissue is in the extraction channel (i.e.,
within the fluidic aspiration stream), the state of the altered
proteinaceous complex may return to a quasi pre-assault state.
[0074] The disclosed exemplary application of the system described
herein is for the treatment of pathologic retinal conditions
whereby, as shown in FIG. 1, a hollow probe 114, as described
herein, using a handle 120 is inserted by a surgeon into the
posterior region of the eye 100 via a pars plana approach 101, as
shown in FIG. 3. Using standard visualization process, vitreous
and/or intraocular membranes and tissues would be engaged by the
tip 112 of the hollow probe 114, irrigation 130 and aspiration 140
mechanisms would be activated, and ultrashort high-intensity pulsed
electric power from a high voltage pulse generator 150 would be
delivered through a pulse-forming network 160, switching circuit
170, and cable 124, creating a disruptive high-intensity
ultrashort-pulsed electrical field within the entrained volume of
tissue. The adhesive mechanisms of the entrained constituents of
the tissue that are drawn toward the probe tip 112 via aspiration
through an aspiration line 118 connected to an aspiration lumen,
122 in the hollow probe 114 would be dissociated, and the fluidic
techniques employed would remove the disrupted tissue. Engagement
may be axial to or lateral to the tip 112 of the hollow probe 114.
Extracted tissue would be removed through the aspiration lumen 122
via a saline aspiration carrier to a distally located collection
module.
[0075] All of the posterior vitreous tissue could be removed, or
just specific detachments of vitreous tissue from the retina or
other intraocular tissues or membranes could be realized.
[0076] Engagement disruption and removal of vitreous tissue,
vitreoretinal membranes, and fibrovascular membranes from the
posterior cavity of the eye and surfaces of the retina are the
critical processes pursued by vitreoretinal specialists, in order
to surgically treat sight-threatening conditions, such as diabetic
retinopathy, retinal detachment, proliferative vitreoretinopathy,
traction of modalities, penetrating trauma, epi-macular membranes,
and other retinopathologies.
[0077] Though intended for posterior intraocular surgery involving
the vitreous and retina, it can be appreciated that the device and
modality described herein is applicable to anterior ophthalmic
treatments as well, including traction reduction (partial
vitrectomy); micelle adhesion reduction; trabecular meshwork
disruption, manipulation, reorganization, and/or stimulation;
trabeculoplasty to treat chronic glaucoma; Schlemm's Canal
manipulation, removal of residual lens epithelium, and removal of
tissue trailers. Applicability of the disclosed apparatus and
method to other medical treatments will become obvious to one
skilled in the art.
Parts of System:
[0078] Control Unit (180) [0079] Pulse Power Generator (150) [0080]
Pulse-Forming Network (160) [0081] Switching Circuit (170) [0082]
Transmission Line (124) [0083] Multi-Electrode Surgical Probe
Assembly (110) [0084] Fluidics System (130, 140)
[0085] The apparatus and method of the disclosed invention deliver
pulsed high-intensity and ultrashort duration electrical field (low
energy) at a pulse duration, repetition rate, pulse pattern, and
pulse train length tuned to the properties of the components of the
intraocular extracellular matrix (ECM). The pulse power generator
150 for the system 190 delivers pulsed DC or gated AC against a low
impedance of vitreous and the irrigating solution. Included in the
system 190 are energy storage, pulse shaping, transmission, and
load-matching components. The peak output voltage of the high
voltage generator 150 is sufficient to deliver up to a 300 kV/cm
field strength using the electrodes 116 at the distal end 112 of
the hollow surgical probe 114. Pulse duration would be short
relative to the dielectric relaxation time of protein complexes.
Also, pulse duration, repetition rate, and pulse train length
(i.e., duty cycle) are chosen to avoid the development of thermal
effects ("cold" process). The system 190 generates and delivers
square-shaped pulses with a fast (<5 nanoseconds) rise time and
fall time. In the apparatus and method disclosed herein, pulse
durations would be in the nanosecond range, and the voltage would
be greater than one (1) kV and preferably in the range of tens
(10s) of kV.
[0086] A switching circuit 170 is incorporated to control pulse
duration, repetition rate, and generate a stepwise continual change
in the direction of the electrical field by switching between
electrodes, reversing polarity between electrodes or a combination
of both in an array of electrodes at the tip 112 of the hollow
probe 114, thus creating disorder in the electric field without
causing dielectric breakdown of the carrier fluid between the
electrodes or thermal effects.
[0087] Paramount to the effectiveness of the disclosed invention is
the choice of energy. The object is to create disorder among
electrons in the outer shell of macromolecules associated with
non-covalent bonds binding proteinaceous complexes together. The
preferable form of energy is electricity--energizing electrons by
the direct creation of an electrical field. Sources of energy, such
as microwaves, laser, and ultrasound, which utilize photons and
phonons to energize electrons may also be used to create the
desired disorder among the electrons in the outer shell of
macromolecules.
[0088] The disclosed apparatus includes a transmission line 124 and
a hollow surgical probe 114 which delivers, channels, and
distributes the applied energy in such a fashion as to create a
confined, localized region of electrical force within a macroscopic
volume of the extracellular matrix ECM (e.g., vitreous and
intraocular membranes). The electrical field is presented
essentially perpendicularly or orthogonally to the direction of
carrier fluid movement (i.e., proteinaceous material in a water
solution). FIGS. 4A, 4B, 4C, 4D, and 4E illustrate several possible
electrode array embodiments at the distal end 112 of the surgical
probe 114.
[0089] For example, reference number 1 is used in FIGS. 4A, 4B, 4C,
4D, and 4E to refer to a polymer extrusion with one or more through
lumens. Reference number 2 designates the lumen for aspirated fluid
flow. Reference numbers 3, 4, 5, 6, 7, 8, 9, and 10 refer to the
electrode wires embedded in extrusion 1. In FIGS. 4A, 4C, and 4D, a
centrally located electrode wire 11 is used. In FIG. 4E, a
centrally located tubular electrode 12 is used. Also in FIG. 4E, a
centrally located lumen 13 is used for fiberoptic equipment or some
other form of instrumentation. Those of ordinary skill in the art
will understand that numerous other configurations are possible to
generate the desired pulsed rapid strong electrical field pattern.
Though shown in a substantially planar fashion, the distal face of
each electrode 116 may be axially staggered or aligned and may be
either inset or protruding, or a combination of both, from the
distal end 112 of the hollow probe 114. Though shown terminating in
a plane perpendicular to the axial direction of the probe shaft,
the electrodes 116 may terminate axially about a lateral window
(not shown).
[0090] In the preferred embodiment, the outside diameter of the
extrusion 1 is less than 0.040 inches. It is envisioned that
vitreous or intraocular tissue material would be drawn toward and
into the aspiration channel(s), and, as the material approached the
region orthogonal to the electrodes 116, the electrodes would be
activated, creating an ultrashort, high-intensity disruptive
electric field between electrodes 116.
[0091] Variable field projections with constantly changing
direction would result from the placement and sequential activation
of arrays of electrodes. Tables 5A, 5B, 5C, 5D, and 5E illustrate a
plan of electrode activation for the embodiments shown in FIGS. 4A,
4B, 4C, 4D, and 4E, respectively. In Table 5A, there are 12 pulses
that are illustrative of a pulse sequence used on the embodiment of
the end of the probe 114 shown in FIG. 4A. The first pulse utilizes
the electrode 116, given reference number 11, as an anode, and the
cathodes are 3, 4, 5. The second pulse is just the opposite. The
remaining pulses are illustrative of a pulse arrangement to
establish a variable direction electrical filed.
[0092] In Table 5B, there are 11 pulses that are illustrative of a
pulse sequence used on the embodiment of the probe 114 shown in
FIG. 4B.
[0093] In Table 5C, a 12-pulse sequence is shown as in FIG. 5A for
use on the probe shown in FIG. 4C.
[0094] In Tables 5D and 5E, a 10-pulse sequence is shown for the
probes shown in FIGS. 4D and 4E, respectively. Numerous other field
patterns are envisioned, depending on the embodiment and the
sequence of electrode activation. The object of the electrode
activation is to utilize the polar properties of water and protein,
create disorder with rapidly changing high-intensity electric field
direction, and thus induce conformal changes of both water and
protein, leading to momentary tissue dissociation. The dissociated
tissue complex localized within the region of applied electrical
field is then removed using concurrent fluidic techniques before
the transient effects of the assault expire (relax).
[0095] In the case of embodiment 4E, the central electrode 12 may
be a tubular conductive electrode with a center region 13. The
central region 13 could be a through lumen for an irrigation or
instrument channel, or the central region could be a fiber-optic
device for delivery of light.
[0096] As previously stated, the position of electrodes in the
arrays and the number of electrodes may be configured to present
the most efficacious disruptive electric fields. The electrodes may
also be axially positioned so that one or more of the electrodes
does not terminate at the same length or same axial position. The
terminal end of the electrodes may be shaped in such a fashion as
to optimize spatial field strength between the electrodes. Shapes
of the terminal end of the electrodes may include straight edges,
corners, sharps, curvatures (constant and variable) or combinations
thereof chosen to project and optimize electric field strength
distribution between the electrodes.
[0097] Fluidic techniques (aspiration) are included to draw in and
remove the dissociated tissue volume before reassembly of
non-covalent proteinaceous relationships can occur. The fluidic
techniques used in the preferred embodiment include both saline
irrigation and effluent aspiration. In the preferred embodiment,
the fluidics system includes irrigation and aspiration features
which are uniquely matched such that the volume and pressure within
the eye are maintained within physiological limits. The posterior
vitreous contains more than 97% water, and an important function of
the fluidics system is to ensure dilution, hydration and stable
impedance of engaged material. In the preferred embodiment, the
aspiration channel is incorporated into the hollow surgical probe
114 such that intraocular tissues are drawn into the aspiration
lumen 122 or channels while being subjected to the disruptive
electric field described above. The volume flow rate of the
aspirated effluent is matched to the dissociation rate of the
hydrated proteinaceous material under the influence of the
disruptive electric field. It is anticipated that irrigation with
BSS.RTM. irrigating solution or BSS PLUS.RTM. irrigating solution,
both available from Alcon Laboratories, Inc., will be utilized.
Innocuous properties and ingredients may be incorporated into the
irrigation fluid to enhance dissociation. The irrigation
route/channel may be incorporated into the surgical probe, as
illustrated in FIG. 4E, it may be provided in an independent
cannula, or it may be provided by a combination of both means.
[0098] FIG. 6 is a perspective of an alternate embodiment of a
probe assembly 210 including three electrodes. As in the preferred
embodiment 110, the probe assembly 210 includes a hollow probe 214
and a handle 220. Tissue would be engaged by the tip 212 of the
hollow probe 214. A better understanding of probe assembly 210 may
be had by reference to FIGS. 6, 7, and 8. The three electrodes 216
are positioned at substantially equal angular intervals around a
central spine 217 within the probe 214. Between the electrodes 216
are the irrigation channels 215. In the center of the central spine
217 is located an aspiration lumen 222. Covering the central spine
217, the irrigation channels 215, and the electrodes is an external
jacket 219 which terminates in an atraumatic tip 221. The probe
assembly 210 is positioned so that the tissue to be removed is
located just inside the atraumatic tip 221.
[0099] The support system 290 for probe assembly 210, shown in FIG.
10, is similar to that of the preferred embodiment shown in FIG. 3
but for the inclusion of a probe tip irrigation system 235.
Included is a global irrigation system 230, an aspiration system
240 connected to an aspiration line 218, a control unit 280, one or
more high-voltage pulse generators 250, a switching circuit 270
connected to a transmission line 224, and a probe tip diluting
irrigation system 235 connected to a probe tip irrigation tube
237.
[0100] As in FIGS. 4A, 4B, 4C, 4D, and 4E which display the
electrodes at the probe tip, FIGS. 11A and 11B illustrate alternate
arrangements of electrodes 1, 2, 3, and 4 in the probe assembly
210. FIGS. 12A and 12B correspond to FIGS. 11A and 11B showing
exemplary sequences of electrode activation to create the
non-plasma, non-contact energized disruptive region around the
proteinaceous tissue. To better understand the creation of this
non-plasma, non-contact energized disruptive region, FIGS. 13A and
13B illustrate the field lines for the sequence of pulses
illustrated in FIGS. 12A and 12B, respectively, where the polarity
of the electrodes is not reversed.
[0101] FIG. 14 is a schematic diagram of the three-channel pulse
generator 250 which controls the duration of individual pulses, the
repetition rate of the individual pulses, and the pulse length of
the pulse train.
[0102] FIG. 15 is a table illustrating the channel states of an
exemplary single cycle of pulsing of the three-channel pulse
generator 250 shown in FIG. 14.
[0103] A still better understanding of the system 290, shown in
FIG. 10, may be had by understanding that the probe assembly 210
includes a plurality of through lumens 215 for supplemental
irrigation, as shown in FIGS. 6, 7, 8, and 9, respectively. The
flow rate of irrigation is less than the aspiration rate through
the central lumen 222, such that the escape velocity of the
supplemental irrigation fluid is less than the entrance velocity of
diluted hydrated intraocular tissue. Additional irrigation fluid is
presented by probe tip diluting irrigation mechanism 235 which is
external to the probe (FIG. 10). The irrigation fluid is used both
to dilute intraocular tissue and to maintain a stable or near
constant impedance between the electrodes 216, thereby avoiding
significant shifts in realized energy delivery and field strength.
Properties of the irrigation fluid such as pH and ingredients may
be chosen to enhance vitreous dissociation.
[0104] A third conduit for irrigation 237 connects the probe
assembly 210 to the supplemental irrigation source 235. Also to be
noted, in FIG. 10, the pulse forming network is incorporated into
the high voltage pulse generator 250.
[0105] By reference to FIGS. 11A and 12A, it may be seen that, in
lieu of reversing polarity of the electrodes 216 between pulses,
the active anodes and cathodes are switched between the electrodes.
The field lines created are shown in FIG. 13A to illustrate an
example of an electric field for each pulse. For the three
electrode 1, 2, and 3 configuration, shown in FIG. 11A, a single
cycle includes three pulses emanating from different directions. In
the table at FIG. 12A, sequencing examples are shown for cases
involving electrode switching and not actual polarity (reversal).
The table at FIG. 12B and the field lines shown in FIG. 13B
illustrate the possible four-electrode embodiment 1, 2, 3, and 4,
shown in FIG. 11B, where the electrodes act in pairs as anodes and
cathodes.
[0106] The three-channel pulse generator, whose schematic is
illustrated in FIG. 14, shows that the triggering of one channel
sends a pulse to an electrode, then triggers a second channel
which, in turn, sends a pulse to a different electrode, then
triggers the third channel which, in turn, sends a pulse to a
different electrode and triggers the first channel to start the
sequence over again. As one channel fires a pulse, the other two
channels offer zero resistance and act as return circuits for the
fired pulse. The sequencing of channels may be ordered, or it may
be random.
[0107] FIG. 15 illustrates the polarity condition of each channel
during a pulse firing. The polarity condition of each channel
results from electrode switching as opposed to actual polarity
switching on any single channel.
[0108] A further embodiment of probe assembly 210 is pictured in
FIGS. 16-23. FIGS. 16-19 depict an embodiment with electrodes 216
that are flattened and axially elongated. These electrodes 216 are
flattened with the large flat portion aligned radially with respect
to the aspiration channel 222. The sharp corners of electrodes 216
allow for a more intensely focused electric field to be produced at
the aspiration channel 222. These electrodes 216 terminate at the
orifice of jacket 219.
[0109] FIGS. 20-23 depict an embodiment with electrodes 216 that
have pointed tips. These electrodes 216 are flattened with the
large flat portion aligned radially with respect to the aspiration
channel 222. These electrodes 216 terminate in a folded pointed tip
with the pints directed radially inward toward the aspiration
channel 222. The sharp corners of electrodes 216 allow for a more
intensely focused electric field to be produced at the aspiration
channel 222.
[0110] In the two embodiments depicted in FIGS. 16-23, the three
electrodes 216 are positioned at substantially equal angular
intervals around a central spine 217 within the probe 214. Between
the electrodes 216 are the irrigation channels 215. In the center
of the central spine 217 is located an aspiration lumen 222.
Covering the central spine 217, the irrigation channels 215, and
the electrodes is an external jacket 219 which terminates in an
atraumatic tip 221. The probe assembly 210 is positioned so that
the tissue to be removed is located just inside the atraumatic tip
221. In FIGS. 17, 19, 21, and 23, an opening 227 between the jacket
219 and the aspiration channel 222 allows irrigation fluid to pass
in a waterfall effect near the electrodes 216.
[0111] The operation of the probe assembly of FIGS. 16-23 is
similar to that depicted in FIGS. 11A, 12A, and 13A. Other modes of
operation previously described are also appropriate with the
assembly of FIGS. 16-23.
[0112] The disclosed system provides the following advantages:
[0113] a) Traction-free removal of intraocular tissues from the
posterior segment of the eye.
[0114] b) Manageable dissociation of small volumes of tissue with
no far-field effect.
[0115] Specifically, there is no far-field migration, leakage, or
scattering of the electrical field. Unlike enzymatic processes
which affect the entire posterior of the eye, including the retina,
the effect of the disclosed CHIP EFFF is localized.
[0116] c) Partial vitrectomy or traction release without total
vitrectomy.
[0117] Most vitreoretinal surgical applications required extraction
of all the vitreous in the posterior of the eye. Using the
disclosed system, it is possible to selectively detach
proteinaceous tissue and collagen from the retinal membrane without
removing all the vitreous. Accordingly, the need for post-surgical
artificial vitreous is eliminated.
[0118] d) No reactive oxygen species is created.
[0119] As opposed to ablative technologies, such as lasers,
plasmas, and thermal-generating modalities, the disclosed system
affects only the non-covalent adhesion aspects of the vitreous and
intraocular membranes; therefore, no toxic chemicals or ROS are
induced or released. Insufficient energy is delivered to cause
thermal events.
[0120] e) Safety.
[0121] Discontinuation of energy delivery results in reassembly of
proteinaceous tissue. Thus, the disclosed method can be
discontinued almost instantaneously at any time without permanent
damage to target tissue.
[0122] f) Multimodal (extract, coagulate, cut, stimulate).
[0123] Since the probe has a plurality of electrodes, it is
possible to change power settings to achieve different functional
results. In the CHIP EFFF mode, the probe would be utilized to
extract vitreous and intraocular membranes. In the coagulator mode,
RF energy could be applied in order to stop vascular hemorrhage. In
a cut mode, RF energy at the appropriate power and frequency could
be applied as to actually create a plasma or spark erosion to
effect cutting of tissue. In the stimulate mode, an electrical
pulse of lower power could be delivered for therapeutic
purposes.
[0124] g) Reduction in instrument exchange.
[0125] In posterior ocular surgery, an abundant number of custom
and specialized instruments are required to engage, tease,
separate, and remove vitreous and intraocular membranous material.
Instrument exchange during surgery is a major factor in
post-operation complications. Use of this disclosed invention
renders many prior-art instruments obsolete and minimizes
instrument exchange.
[0126] h) No moving parts.
[0127] Reduction in cost and labor for probe fabrication is
realized. Fabrication of mechanical vitrectomy probes is
labor-intensive. The disposable hollow probe perceived herein
consists of a small handle with an attached multi-lumen
co-extrusion or assemblies with wires in the lumens or crevices.
Skill in assembly compared to current mechanical assemblies is
reduced.
[0128] i) Posterior and anterior applications.
[0129] While designed for tractionless removal of vitreous and
intraocular tissues, the disclosed apparatus may be utilized for
certain anterior segment surgeries, such as trabecular meshwork
stimulation, removal of residual lens epithelium, and removal of
tissue trailers, anterior vitrectomy, among others.
[0130] j) Hybrid-friendly.
[0131] The simplicity of design in the disclosed probe assembly
makes it useful as stand-alone or an adjunct to other tissue
disruption and extraction means, such as mechanical vitrectomy,
AquaLase.RTM. surgical instruments, available from Alcon
Laboratories, Inc., and chemical vitrectomy (enzymatic action).
[0132] While the disclosed invention has been described in terms of
its preferred and alternate embodiments, those of ordinary skill in
the art will realize that still other embodiments have been enabled
by the foregoing disclosure.
* * * * *