Apparatus for electrical stimulation of blood vessels

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ELECTRICAL STIMULATION OF BLOOD VESSELS

Yossi GROSS C: 64428 WO 2007/013065 PCT/IL2006/000856

ELECTRICAL STIMULATION OF BLOOD VESSELS

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of: (a) US Provisional Application 60/702,491, filed July 25, 2005, entitled, "Electrical stimulation of blood vessels," and (b) 5 US Provisional Application 60/721,728, filed September 28, 2005, entitled, "Electrical stimulation of blood vessels," both of which applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to implantable medical devices, and 10 specifically to methods and apparatus for stimulating and replacing blood vessels.

BACKGROUND OF THE INVENTION US Patents 6,865,416 and .6,347,247 to Dev et al., which are incorporated herein by reference, describe methods for inducing or increasing the vasodilation of a vessel, or the flow of blood therethrough, including applying an electrical impulse to the vessel. 15 According to the inventors in the '416 and 247 applications, the induction or increase of vessel vasodilation by an electrical impulse appears to result either from a direct effect caused by the electrical current applied to the vessel, or an indirect effect resulting from the release or stimulation of factors that promote vasodilation, such as the release of endothelium derived relaxation factors (EDRP) currently identified as nitric oxide (NO) 20 or other vasodilating substances triggered by the electrical pulses applied to the cells of the vessel. In an embodiment, a double-balloon catheter system incorporating electroporation technology is used to apply the electrical impulse endoluminally. US Patent Application Publication 2003/0204206 to Padua et al., which is incorporated herein by reference, describes techniques for regulating delivery of 25 therapeutic proteins and nucleic acids. The' techniques include using a genetically-engineered electrically-responsive promoter operably linked to a therapeutic gene sequence, wherein expression of said sequence is controlled by an electrical pulse generator. In an embodiment, the pulse generator is able to deliver charge balanced electrical pulses at rate of about 10 to 100 Hz, preferably about 30 to 80 Hz, and more 30 preferably about 50 to 60 Hz. In an embodiment, an implantable system uses an RF 1 WO 2007/013065 PCT/IL2006/000856 signal to communicate and generate an electrical current in a coiled stent. In an embodiment, an electric field is applied to engineered cells grown on a scaffolding, using either a conductive matrix having parallel electrodes, or a conductive stent matrix. US Patent 6,845,267 to Harrison et al., which is incoiporated herein by reference, 5 describes an implantable control unit adapted to apply stimulating drugs and/or electrical pulses to predetermined areas affecting circulatory perfusion. In an embodiment, the implantable control unit applies electrical stimulation. directly to smooth muscle to modulate its contractile state. The '267 patent states that relatively low frequency electrical stimulation ([sic] than about 50-100 Hz) tends to excite smooth muscle and lead 10 to contraction, and relatively high frequency electrical stimulation tends to relax smooth muscle and lead to dilation. In an embodiment, electrical and/or drug stimulation is applied to autonomic sites responsible for innervation of the coronary arteries, and/or directly to the . smooth muscle surrounding these arteries, in order to dilate the coronary arteries and provide relief from cardiac ischemia. For some applications, the implantable 15 control unit includes an electrical coil or other means of receiving energy and/or information inside the package, which receives power and/or data by inductive or radiofrequency (RF) coupling to a transmitting coil placed outside the body. For some applications, the control unit communicates with other implanted stimulators, other implanted devices, and/or devices external to a patient's body, e.g., via an RF link, an 20 ultrasonic link, or an optical link. US Patent 6,871,092 to Piccone, which is incoiporated herein by reference, describes apparatus for the treatment of vascular, muscle and/or tendon disorders, for increasing the production of Vascular Endothelial Growth Factor (VEGF), for antiinflammatory treatment, and/or for the activation of microcirculation. The apparatus 25 generates and applies electrical pulses through the epidermis , of a subject. The pulses are described as inducing a biochemical response which not only eliminates inflammation from the part of the body treated and reduces or eliminates pain, but also has a rapid muscle-relaxant effect, and stimulates vasodilatation and VEGF production. US Patent Application Publication 2004/0106954 to Whitehurst et al., which is 30 incoiporated herein by reference, describes techniques for treating congestive heart failure (CHF) by implanting of a discharge portion of a catheter and, optionally, an electrode on a lead, near tissue to be stimulated. Stimulation pulses, such as drug infusion pulses and 2 WO 2007/013065 PCT/1L2006/000856 optional electrical pulses, are supplied by a stimulator implanted remotely, and through the catheter or lead, which is tunneled subcutaneously between the stimulator and stimulation site. Stimulation sites include the coronary arteries, the aorta, the left ventricle, the left atrium, and/or the pulmonary veins, among other locations. For some 5 applications, a stimulator includes electrical circuitry (including, for example, an inductive coil) for receiving data and/or power from outside the body by inductive, radio frequency (RF), or other electromagnetic coupling. For some applications, the stimulator communicates with other implanted stimulators, other implanted devices, and/or devices external to a patient's body via, e.g., an RF link, an ultrasonic link, a thermal link, and/or 10 an optical link. US Patent Application Publication 2006/0074453 to Kieval et al., which is incorporated herein by reference, describes a method for treating heart failure in a patient, including activating a baroreflex system of the patient with at least one baroreflex activation device and resynchronizing the patient's heart with a cardiac resynchronization 15 device. Activating the baroreflex system and resynchronizing the heart may be performed simultaneously or sequentially, in various embodiments. A device for treating heart failure includes a baroreflex activation member coupled with a cardiac resynchronization member. The baroreflex activation member may comprise a wide variety of devices which utilize mechanical, electrical, thermal, chemical, biological, or other means to 20 activate baroreceptors and/or other, tissues. In many embodiments, particularly the mechanical activation embodiments, the baroreflex device indirectly activates one or more baroreceptors by stretching or otherwise deforming the vascular wall surrounding the baroreceptors. US Patent Application Publication 2003/0060858 to Kieval et al., which is 25 incorporated herein by reference, describes techniques for selectively and controllably reducing blood pressure, nervous system activity, and neurohormonal activity by activating baroreceptors. A baroreceptor activation device is positioned near a baroreceptor, for example a baroreceptor in the carotid sinus. A control system may be used to modulate the baroreceptor activation device. In some embodiments, the 30 baroreceptor activation device takes the form of an intravascular deformable structure.

The deformable structure device includes· a coil, braid or other stent-like structure disposed in the vascular lumen. In other embodiments, the baroreceptor activation device takes the form of an extravascular deformable structure, which is disposed about the 3 WO 2007/013065 PCT/IL2006/000856 vascular wall, and therefore compresses, rather than expands, the vascular wall. The deformable structure device includes a coil, braid or other stent-like structure. US Patent 6,086,527 to Talpade, which is incoiporated herein by reference, describes a system for regulating blood flow to a portion of the vasculature, such as the 5 renal system, in order to treat heart disease. A regulator maintains blood flow so as to control physiological feedback responses in order to relieve overload conditions on the heart. US Patent Application Publication 2002/0103454 to Sackner et al., which is incorporated herein by reference, describes methods of medical treatment and diagnosis -10 using mediators released by endothelial cells stimulated by external addition of pulses to the circulation. The external pulses produce circumferential shear stress in body fluid channels that subsequently stimulates the endothelial cells to produce mediators that become available for therapeutic and diagnostic purposes. The preferred means of adding external pulses is the mechanical inducement of periodic acceleration of the body or parts 15 of the body by a reciprocating motion platform. US Patent Application Publication 2005/0149130 to Libbus et al., which is incorporated herein by reference, describes a baroreflex stimulator including a pulse generator for providing a baroreflex stimulation signal through an electrode, and a modulator to modulate the baroreflex stimulation signal based on a circadian rhythm 20 template, hi some embodiments, the stimulator includes a sensor to sense' automatic nervous system (ANS) activity. Such a sensor can be used to perform feedback in a closed loop control system. For example, various embodiments sense surrogate parameters, such as respiration and blood pressure, indicative of ANS activity.

The following patents and patent application publications, all of which are 25 incorporated herein by reference, may be of interest: US Patent 6,824,561 and US Patent Application Publication 2004/0039417 to Soykan et al. US Patent 6,810,286 to Donovan et al. US Patent 6,463,323 to Conrad-Vlasak et al. 30 US Patent 6,058,331 to King US Patent 6,200,259 to March 4 189,018/2 US Patent Application Publication 2003/0036773 to Whitehurst et al.

European Patent Application Publication EP 0 109 935 Al to Charmillot et al.

Levenberg S et al., in an articled entitled, "Endothelial cells derived from human embryonic stem cells," Proc Natl Acad Sci USA 99(7):4391-6 (2002) Epub 2002 Mar 26, which is incorporated herein by reference, describe the differentiation steps of human embryonic stem cells into endothelial cells forming vascular-like structures.

SUMMARY OF THE INVENTION

There is therefore provided, in accordance with some applications of the present invention, apparatus for applying counterpulsation to an artery of a subject, the apparatus including: one or more electrodes, adapted to be placed in a vicinity of the artery; and a control unit, configured to: drive the electrodes to apply a systolic electrical signal to a wall of the artery during at least a portion of systole, configure the systolic signal to induce an increase in nitric oxide (NO) secretion by the wall, and withhold driving the electrodes to apply the systolic signal to the wall during at least a portion of diastole.

For some applications, the apparatus includes a physiological sensor, which is configured to generate a sensor signal, and the control unit is configured to set at least one parameter of the systolic signal responsively to the sensor signal.

For some applications, the control unit is configured to drive the electrodes to begin application of the systolic signal slightly prior to a commencement of systole.

For some applications, the control unit is configured to drive the electrodes to begin application of the systolic signal less than 50 ms prior to a commencement of systole.

For some applications, the control unit is adapted to configure the systolic signal to have an amplitude of between 1 and 10 mA. 5 189,018/1

For some applications, the control unit is adapted to configure the systolic signal to have a frequency of less than 30 Hz.

For some applications, the control unit is configured drive the electrodes to apply a biphasic systolic signal.

For some applications, the artery includes a coronary artery of the subject and the one or more electrodes are configured to be placed in a vicinity of the coronary artery.

For some applications, the artery includes an aorta of the subject and the one or more electrodes are configured to be inserted in a vicinity of the aorta.

For some applications, at at least one time, the control unit is configured to drive only a portion of the electrodes.

For some applications, the control unit is configured to activate the electrodes in a sequence by time dividing the activation of the electrodes.

For some applications, the control unit is adapted to drive the electrodes to apply a diastolic electrical signal to the wall during at least a portion of diastole, and to configure the diastolic signal to enhance constriction of the artery during diastole.

For some applications, the control unit is configured to drive the electrodes to apply a biphasic diastolic signal.

For some applications, the control unit is adapted to configure a diastolic value of a parameter of the diastolic signal to be between 1.5 and 4 times a systolic value of the parameter of the systolic signal, the parameter selected from the group consisting of: an amplitude, and a frequency.

For some applications, the control unit is adapted to configure the diastolic signal to have an amplitude of between 5 and 20 mA.

For some applications, the control unit is adapted to configure the diastolic signal to have a frequency of between 15 and 100 Hz.

For some applications, the apparatus further includes an element configured to mechanically dilate the artery. 5a 189,018/1

For some applications, the element is configured to be placed at least partially in the artery.

For some applications, the element is configured to be placed at least partially outside the artery.

For some applications, the element is configured to serve as at least one of the one or more electrodes.

For some applications, the element configured to dilate the artery includes a magnet.

For some applications, the element configured to dilate the artery includes a coil.

For some applications, the element configured to dilate the artery includes a piezoelectric element.

For some applications, the element is configured to dilate the artery using electricity.

For some applications, the element is configured to dilate the artery using hydraulic pressure.

For some applications, the element is configured to mechanically dilate the artery during at least a portion of systole.

For some applications, the element is configured to be placed at least partially in the artery.

For some applications, the element is configured to be placed at least partially outside the artery.

For some applications, the element is configured to serve as at least one of the one or more electrodes.

For some applications, the electrode is configured to be placed inside the artery. STATEMENT IN ACCORDANCE WITH PARAGRAPH 1 OF COMMISSIONER'S CIRCULAR 23 (P) 5b 189,018/1

Inasmuch as the invention is defined in the appended claims, it will be apparent that the portions of the present specification, which fall outside the scope of the claims, do not relate directly to the . claimed invention. This Notice is not meant to disclaim any legitimate rights to which the Patentee is legally entitled, especially any rights in accordance with Section 49 of the Israel Patent Law.

ADDITIONAL ASPECTS OF THE INVENTION

In some embodiments of the present invention, an electrode device is adapted to be inserted into a blood vessel. The electrode device comprises one or more electrodes that are adapted to apply an electrical signal to a wall of the blood vessel, and to configure the signal to induce an increase in nitric oxide (NO) secretion by the wall.

For some applications, stimulation using the electrode device causes healing of the blood vessel. For example, the stimulation may (a) reduce a level of atherosclerosis of the blood vessel, (b) have an anti-inflammatory and/or antithrombotic effect on the blood vessel, (c) increase endothelial cell growth, (d) reduce smooth muscle cell growth (e.g., to reduce blockage of the blood vessel), and/or (e) reduce plaque activity. For applications in which the blood vessel includes a coronary artery, stimulation using the electrode device typically dilates the coronary artery, thereby treating cardiac ischemia.

In some embodiments of the present invention, the electrode device is adapted to apply the signal to an artificial blood vessel graft that has been implanted in the subject. Endothelial cells often grow into the lumen of such grafts. This growth is generally viewed as desirable. However, such growth sometimes causes platelets to accumulate in and thereby block the lumen. The signal applied by the electrode device is configured to induce an increase in NO secretion by the endothelial cells in the lumen, which increased NO secretion de-aggregates the platelets. Alternatively or additionally, the signal applied by the electrode device is configured to stimulate cell growth in the lumen of the artificial graft.

For some applications, the electrode device comprises at least one stent. The electrodes are coupled to the stent, or are integrated into structural elements of the stent. For some applications, the stent comprises a bifurcation stent. The electrode device is configured to induce an increase in NO secretion by a wall of the blood vessel, typically 5c WO 2007/013065 PCT/IL2006/000856 in order to reduce platelet aggregation outside the stent (such as between the stent and the wall) and/or to minimize restenosis.

In some embodiments of the present invention, the electrode device is used to apply electrical stimulation during the process of deriving blood vessels (i.e., veins or 5 arteries) -from stem cells, such as from embryonic stem cells. Alternatively or additionally, the electrode device is used to apply electrical stimulation to blood vessels derived from stem cells after the blood vessels have been implanted in a subject. Further alternatively or additionally, the electrode device is used to apply electrical stimulation to tissue-based blood vessels created by another technique. An increase in NO production 10 caused by such stimulation may be beneficial for the blood vessels, e.g., may aid the process of differentiating the stem cells into the blood vessels.

In some embodiments of the present invention, a counteipulsation device is adapted to be inserted in an ascending aorta and/or a descending aorta of a subject. The counterpulsation device comprises one or more electrodes, and an implantable or external 15 control unit. The control unit is adapted to drive the electrodes to apply an electrical signal to a wall of the aorta during systole, and to configure the signal to induce an increase in NO secretion by the wall. The increased NO secretion dilates the wall such that during systole the wall stores energy, and pressure on the heart is reduced. During diastole, the wall constricts, releasing the stored energy and thereby increasing blood 20 pressure and coronary blood flow. For some applications, the control unit is additionally configured to drive the electrodes to apply, during diastole, stimulation configured to enhance the rapid constriction of the aorta.

In some embodiments of the present invention, an artificial artery is provided that is configured to assume a first cross-sectional shape during a first phase of a cardiac.cycle 25 (e.g., systole or diastole),· and a second cross-sectional shape during a second phase of the cardiac cycle (e.g., diastole or systole). Typically, both of the cross-sectional shapes are elliptical, and have major axes with different lengths. For some applications, one of the cross-sectional shapes is substantially circular (i.e., the major and minor axes are substantially the same). Such shape changing during each cardiac cycle generally reduces 30 the likelihood of the artificial artery becoming blocked over time.

In an embodiment of the present invention, one or more electrodes are placed in or adjacent to an eye of a subject, and are driven to apply a signal that induces NO 6 WO 2007/013065 PCT/IL2006/000856 production adjacent to the electrodes, in order to treat an eye disease. For example, the increased NO production may be used to reduce intraocular pressure, in order to treat glaucoma. Alternatively or additionally, increased blood flow induced by arterial dilation cause by the NO production minimizes optic nerve degeneration, such as is seen in age- 5 related macular degeneration (AMD). Alternatively or additionally, the increased blood flow in one or more retinal arteries treats or prevents diabetic retinopathy.

There is therefore provided, in accordance with an embodiment of the present invention, apparatus including: a bifurcation stent including one or more electrodes, the stent configured to be 10 placed in a primary passage and a secondary passage of a blood vessel; and a control unit, configured to drive the electrodes to apply a signal to a wall of the blood vessel, and to configure the signal to increase nitric oxide (NO) secretion by the wall.

For some applications, the control unit is adapted to configure the signal to reduce 15 platelet aggregation outside the stent between the stent and the wall of the blood vessel.

For some applications, the control unit is configured to drive the electrodes to apply the signal with a frequency of between 3 and 20 Hz, and/or a voltage of less than 5 volts.

There is further provided, in accordance with an embodiment of the present 20 invention, apparatus for applying counteipulsation to an aorta of a subject, the apparatus including: one or more electrodes, adapted to be inserted into the aorta; and a control unit, configured to: drive the electrodes to apply a systolic electrical signal to a wall of the aorta 25 during at least a portion of systole, configure the . systolic signal to induce an increase in nitric oxide (NO) secretion by the wall, and · withhold driving the electrodes to apply the systolic signal to the wall during at least a portion of diastole. 7 WO 2007/013065 PCT/IL2006/000856

In an embodiment, the apparatus includes a physiological sensor, which is configured to generate a sensor signal, and the control unit is configured to set at least one . . parameter of the systolic signal responsively to the sensor signal.

For some applications, the control unit is configured to drive the electrodes to 5 begin application of the systolic signal slightly prior to a commencement of systole. For some applications, the control unit is configured to drive the electrodes to begin application of the systolic signal less than 50 ms prior to a commencement of systole.

For some applications, the control unit is adapted to configure the systolic signal to have an amplitude of between 1 and 10 mA, and/or a frequency of less than 30 Hz. 10 In an embodiment, the control unit is adapted to drive the electrodes to apply a diastolic electrical signal to the wall during at least a portion of diastole, and to configure the diastolic signal to enhance constriction of the aorta during diastole. For some applications, the control unit is adapted to configure a diastolic value of a parameter of the diastolic signal to be between 1.5 and 4 times a systolic value of the parameter of the 15 systolic signal, the parameter selected from the group consisting of: an amplitude, and a frequency. For some applications, the control unit is adapted to configure the diastolic signal to have an amplitude of between 5 and 20 mA, and/or a frequency of between 15 and 100 Hz.

In an embodiment, the apparatus includes an element configured to mechanically 20 dilate the aorta during at least a portion of systole. For some applications, the element is configured to be placed at least partially in the aorta. Alternatively or additionally, the element is configured to be placed at least partially outside the aorta. For some applications, the element is configured to serve as at least one of the one or more electrodes. 25 There is still further provided, in accordance with an embodiment of the present invention, apparatus including an artificial artery configured to assume a first cross-sectional shape during a first phase of a cardiac cycle, and a second cross-sectional shape during a second phase of the cardiac cycle.

For some applications, exactly one of the first and second cross-sectional shapes is 30 substantially circular. 8 WO 2007/013065 PCT/IL2006/000856

For some applications, the first and second phases include systole and diastole, respectively, and the artificial artery is configured to assume the first and second cross- sectional shapes during systole and diastole, respectively.

In an embodiment, the first and second cross-sectional shapes are elliptical, having 5 respective major axes having first and second lengths, respectively. For some applications, a ratio of the first length to the second length is at least 1.1, such as at least 1.3.

There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating an eye of a subject, the apparatus including: 10 one or more electrodes, configured to be placed at least partially in the eye; and a control unit, configured to treat the eye by driving the electrodes to apply an electrical signal to the eye that induces production of nitric oxide (NO).

In an embodiment, the control unit is configured to drive the electrodes to apply the signal to induce the NO production sufficiently to induce dilation of a retinal artery of 15 the subject.

In an embodiment, the control unit is configured to drive the electrodes to apply the signal to induce the NO production sufficiently to minimize degeneration of an optic nerve of the subject.

For some applications, the control unit is configured to be placed in the eye, and 20 the apparatus includes a photovoltaic cell that is configured to power the control unit. For some applications, at least one of the electrodes includes a coil that is configured to receive energy inductively from the control unit For some applications, at least one of the electrodes is configured to be placed at a site posterior to a retina of the eye.

In an embodiment, the control unit is configured to drive the electrodes to apply 25 the signal to induce the NO production sufficiently to reduce an intraocular pressure of the eye. For some applications, the electrodes are configured to be placed around a cornea of the eye, and the control unit is configured to drive the electrodes to apply the signal to induce the NO production in a vicinity of a trabecular meshwork of the eye.

There is still additionally provided, in accordance with an embodiment of the 30 present invention, apparatus for application to a blood vessel of a subject, the apparatus including: 9

I WO 2007/013065 PCT/EL2006/000856 one or more electrodes, configured to be placed in or outside the blood vessel in a vicinity of a baroreceptor of the subject, such that the electrodes are in electrical communication with the blood vessel; and a control unit, configured to drive the electrodes to apply an electrical signal to the 5 blood vessel, and to configure the signal to induce an increase in nitric oxide (NO) secretion by a wall of the blood vessel sufficiently to cause dilation of the wall, thereby activating the baroreceptor.

In an embodiment, the apparatus includes aii element configured to mechanically dilate the blood vessel in the vicinity of the baroreceptor. In an embodiment, the 10 electrodes are configured to apply mechanical force to the wall that is sufficient to change a shape of the wall.

In an embodiment, the apparatus includes a sensor configured to sense a feature of a cardiac cycle of the subject and to output a sensor signal responsively thereto, and the control unit is configured to drive the electrodes to apply the signal responsively to the 15 sensor signal. For some applications, the control unit is configured to apply the signal during at least a portion of systole, and to withhold applying the signal during at least a portion of diastole.

In an embodiment, the electrodes are configured to be placed in the blood vessel, and are shaped so as to define springy rib-shaped elements. For some applications, the 20 apparatus includes one or more piezoelectric elements positioned in direct or indirect mechanical contact with the rib-shaped elements, and the apparatus is configured such that pulsing of the blood vessel causes the piezoelectric elements to generate power5 and the control unit is configured to use the power to drive the electrodes to apply the signal.

There is also provided, in accordance with an embodiment of the present 25 invention, a method including: placing a bifurcation stent including one or more electrodes in a primary passage and a secondary passage of a blood vessel; driving the electrodes to apply a signal to a wall of the blood vessel; and configuring the signal to increase nitric oxide (NO) secretion by the wall.

I 10 PCT/IL2006/000856 WO 2007/01?065

There is further provided, in accordance with an embodiment of the present invention, a method for applying counterpulsation to an aorta of a subject, the method including: applying a systolic electrical signal to a wall of the aorta during at least a portion 5 of systole; configuring the systolic signal to induce an increase in nitric oxide (NO) secretion, by the wall; and withholding applying the systolic signal to the wall during at least a portion of diastole. 10 There is still further provided, in accordance with an embodiment of the present invention, a method including: providing an artificial artery configured to assume a first cross-sectional shape during a first phase of a cardiac cycle, and a second cross-sectional shape during a second phase of the cardiac cycle; and 15 grafting the artificial artery to a natural artery of the subject.

In an embodiment, grafting includes grafting during a coronary bypass procedure.

There is additionally provided, in accordance with an embodiment of the present invention, a method for treating a subject, including: identifying that the subject suffers from a condition of an eye; and 20 treating the eye condition by inducing production of nitric oxide (NO) in the eye by applying an electrical signal to the eye.

In an embodiment, identifying includes identifying that the subject suffers from glaucoma, and applying the signal includes configuring the signal to induce the NO production sufficiently to reduce an intraocular pressure of the eye. For some 25 applications, applying the signal includes applying the signal around a cornea of the eye to induce the NO production in a vicinity of a trabecular meshwork of the eye.

There is also provided, in accordance with an embodiment of the present invention, a method including: applying an electrical signal to a blood vessel of a subject in a vicinity of a 30 baroreceptor of the subject; and 11 WO 2007/013065 PCT/IL2006/000856 activating the baroreceptor by configuring the signal to induce an increase in nitric oxide (NO) secretion by a wall of the blood vessel sufficiently to cause dilation of the wall.

There is further provided, in accordance with an embodiment of the present 5 invention, a method including: implanting an artificial blood vessel in a subject; applying an electrical signal to the artificial blood vessel; and configuring the signal to induce an increase in nitric oxide (NO) secretion by endothelial cells that grow in a lumen of the artificial blood vessel. 10 In an embodiment, configuring the signal includes configuring the signal to induce the NO secretion to de-aggregate platelets accumulated as a result of growth of the endothelial cells. In an embodiment, configuring the signal includes configuring the signal to induce growth of the endothelial cells in the lumen. In an embodiment, configuring the signal includes configuring the signal to have a frequency of between 3 15 and 20 Hz.

For some applications, configuring the signal includes configuring the signal to have a voltage of less than 5 volts.

There is still further provided, in accordance with an embodiment of the present invention, a method for deriving a blood vessel from stem cells, including:· 20 inducing the stem cells to differentiate into the blood vessel; applying an electrical signal to at least one cell selected from the group consisting of: one of the stem cells, a cell of the blood vessel as the blood vessel is being derived, and a cell of the blood vessel after the blood vessel has been derived; and configuring the signal to induce an increase in nitric oxide (NO) secretion by the 25 selected at least one cell.

In an embodiment, the at least one cell· includes at the one of the stem cells, and applying the signal includes applying the signal to the one of the stem cells. In an embodiment, the at least one cell includes the cell of the blood vessel as the blood vessel is being derived, and applying the signal includes applying the signal to the cell of the 30 blood vessel as the blood vessel is being derived. In an embodiment, the at least one cell includes the cell of the blood vessel after the blood vessel has been derived, and applying 12 WO 2007/013065 PCT/IL2006/000856 the signal includes applying the signal to the cell of the blood vessel after the blood vessel has been derived.

There is additionally provided, in accordance with an embodiment of the present invention, a method including: 5 identifying buildup of plaque on a wall of a blood vessel of a subject as.being in a vicinity of a baroreceptor of the subject; and increasing flexibility of the artery in the vicinity by removing the plaque from the artery.

In an embodiment, the blood vessel is selected from the group consisting of: a 10 carotid artery, and an aorta in a vicinity of an aortic arch.

The present invention will be more fully understood from the following detailed description of embodiments thereof, taken together with the drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic illustration of an electrode device adapted to be inserted into 15 a blood vessel of a subject, in accordance with an embodiment of the present invention;

Fig. 2 is a schematic illustration of the electrode device of Fig. 1 comprising a bifurcation stent, in accordance with an embodiment of the present invention;

Fig. 3 is a schematic illustration of another configuration of the electrode device of Fig. 1, in accordance with an embodiment of the present invention; 20 Fig. 4 is a schematic illustration of yet another configuration of the electrode device of Fig. 1, in accordance with an embodiment of the present invention;

Fig. 5 is a schematic illustration of a counteipulsation device inserted in an ascending aorta of a subject, in accordance with an embodiment of the present invention; and 25 Fig. 6 is a schematic cross-sectional illustration of an artificial artery, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS . . Fig. 1 is a schematic illustration of an electrode device 20 adapted to be inserted into a blood vessel 30 of a subject, in accordance with an embodiment of the present 13 WO 2007/013065 PCT/IL2006/000856 invention. Electrode device 20 comprises one or more electrodes 32, and an implantable or external control unit 34. Control unit 34 is adapted to drive electrodes 32 to apply an .. electrical signal to a wall 36.of blood vessel 30, and to configure the signal to induce an increase in nitric oxide (NO) secretion by wall 36. For some applications, wall 36 5 secretes the NO into the lumen of blood vessel 30. Alternatively or additionally, wall 36 secretes the NO into tissue of the blood vessel. For some applications, blood vessel 30 includes an atherosclerotic blood vessel. For some applications, blood vessel 30 includes a coronary artery, a bypass graft (such as a coronary artery bypass graft (CABG)), a retinal artery, a pancreatic artery, or a penile artery (e.g., to treat erectile dysfunction). 10 The applied signal treats erectile dysfunction by functioning as a pump to enhance blood flow (e.g., for adiabetic patient), and/or by generating NO as a signaling molecule which enhances erection.

For some applications, stimulation using, electrode device 20 causes healing of blood vessel 30. For example, the stimulation may (a) reduce a level of atherosclerosis of 15 the blood vessel, (b) have an anti-inflammatory and/or antithrombotic effect on the blood vessel, (c) increase endothelial cell growth, (d) reduce smooth muscle cell growth (e.g., to reduce blockage of blood vessel 30), and/or (e) reduce plaque activity. For some applications, electrode device 20 is configured to drive electrodes 32 to apply the signal for a period of at least one week, such as at least one month, or at least several months. 20 Such long-term stimulation may contribute to healing of the blood vessel. For applications in which blood vessel 30 includes a coronary artery, stimulation using electrode device 20 typically dilates the coronary artery, thereby treating cardiac ischemia.

In an embodiment of the present invention, electrode device 20 is adapted to apply 25 the signal to an artificial blood vessel graft that has been implanted in the subject. Endothelial cells often grow into the lumen of such grafts. This growth is generally viewed as desirable. However, such growth sometimes causes platelets to accumulate in and thereby block the lumen. The signal applied by electrode device 20 is configured to induce an increase in NO secretion by the endothelial cells in the lumen, which increased 30 NO secretion de-aggregates the platelets. Alternatively or additionally, the signal applied by electrode device 20 is configured to stimulate cell growth in the lumen of the artificial graft. These stimulation techniques may be used, for example, with synthetic vascular grafts manufactured by W. L. Gore & Associates (Newark, DE, USA). 14 WO 2007/013065 PCT/EL2006/000856

In an embodiment of the present invention, electrode device 20 comprises at least one stent 40. For some applications, electrodes 32 are coupled to stent 40, as shown in Fig. 1. Alternatively or additionally, structural elements of stent 40 additionally serve as one or more of electrodes 32. For some applications, electrodes 32 comprise ring 5 electrodes,^as shown in Fig. 1. For some applications, electrodes 32 comprise elongated cylinders, through which blood can flow (configuration not shown). In an embodiment, electrodes 32 are not hollow, and blood does not pass through them. Instead, for example, the electrodes may effectively be point electrodes, or be shaped as needle electrodes that slightly penetrate tissue adjacent thereto. It is thus to be seen that various shapes may be 10 appropriate for electrodes 32, depending on each particular application.

Reference is made to Fig. 2, in which stent 40 is shown comprising a bifurcation . stent 50, in accordance with an embodiment of the present invention. Control unit 34 is adapted to induce an increase in NO secretion by wall 36 of blood vessel 30, typically in order to reduce platelet aggregation outside the stent, such as between the stent and wall 15 36. For some applications, electrode device 20 comprises two or more stents 40, at least a first one of which is adapted to be placed in a primary passage 52 of blood vessel 30, and at least a second one of which is adapted to be placed in a secondary passage 54 of blood vessel 30 in a vicinity of a bifurcation 56.

The particular lattice configuration of stent 40 shown in Figs. 1 and 2 is for 20 illustrative purposes only. Stent 40 may comprise other configurations known in the art. For some applications, stent 40 comprises two elements arranged in a double helix (configuration not shown). Typically, one of the elements serves as an anode and the other as a cathode of electrodes 32.

Fig. 3 is a schematic illustration of another configuration of electrode device 20, in 25 accordance with an embodiment of the present invention. In this embodiment, electrodes 32 are springy, and are configured to expand into contact with wall 36 of blood vessel 30. For example, the electrodes may be shaped so as define springy rib-shaped elements. For some applications, electrodes 32 are configured to apply a sufficient mechanical force to wall 36 to change a shape of the wall. For some applications, electrode device 20 is 30 configured to be placed in a vicinity of a baroreceptor, and to both apply an electrical signal to the baroreceptor and change the shape of wall 36 in the vicinity of the baroreceptor. For some applications, the springiness of ribs of the electrodes is 15 WO 2007/013065 PCT/EL2006/000856 adjustable, such as by mechanical, electrical, or thermal means (e.g., at least a portion of the electrodes may comprises nitinol). The springiness may be mechanically adjusted by sliding a portion of the ribs into a chamber such that such portion is no longer springy.

For some applications, electrode device 20 comprises one or more piezoelectric 5 elements positioned in direct or indirect mechanical contact with the ribs of the electrodes.

Pulsing of blood vessel 30 causes the piezoelectric elements to generate sufficient power for applying the electrical signal.

Fig. 4 is a schematic illustration of yet another configuration of electrode device 20, in accordance with an embodiment of the present invention. In this embodiment, 10 electrodes 32 are configured to expand into contact with wall 36 of blood vessel 30. Electrodes 32 are inserted into blood vessel 30 using a catheter 60. The electrodes are stored in the catheter in a contracted position. After the catheter has been advanced to a desired location in the blood vessel, the catheter is withdrawn from the blood vessel, exposing the electrodes and allowing them to expand against the wall of the blood vessel. 15 For some applications, catheter 60 is additionally used to remove electrodes 32 from blood vessel 30 after treatment. The catheter is advanced over the electrodes, causing the electrodes to contract and be stored in the catheter. The catheter, holding the electrodes, is then withdrawn from the blood vessel. Alternatively, the electrodes are withdrawn without using the catheter, because their orientation within the blood vessel allows them 20 to be freed from their contact points with the blood vessel by pulling the lead connecting the electrodes.

In an embodiment of the present invention, control unit 34 is adapted to drive only a portion of electrodes 32 at any given time. For some applications, control unit 34 drives only a portion of the electrodes by sending a multiplexed signal to all of the electrodes 25 over a set of wires. For example, control unit 34 may use time-division, frequency-division, or digital multiplexing. To enable such multiplexing, each electrode typically comprises a microchip that interprets whether the signal generated by control unit 20 is intended to cause the electrode to apply a current to tissue in its vicinity. The use of these multiplexing techniques typically allows the use of only a few (e.g., 3-4) wires to control 30 all of the electrodes.

Reference is now made to Figs. 1-4. For some applications, control unit 34 is adapted to configure the signal applied by electrodes 32 to have one or both of the 16 WO 2007/013065 PCT/IL2006/000856 following parameters: a frequency of between about 3 and about 20 Hz (e.g., between about 5 and about 10 Hz), and/or a voltage less than about 5 V. For some applications, the signal is monophasic, while for other applications the signal is biphasic. For some applications, the control unit applies the signal having a duty cycle (e.g., about 1-15%, or 5 about 15-50%).

In an embodiment of the present invention, all or a portion of electrode device 20 is biodegradable, and is adapted to degrade after remaining in blood vessel 30 for a certain period of time. For some applications, only the portions of electrode device 20 that are placed in blood vessel 30 are biodegradable, while control unit 34 is not biodegradable. 10 In an embodiment, the portions of electrode device 20 in blood vessel 30 comprise a biodegradable carboii polymer or a biodegradable sugar polymer. As appropriate, one or both of these polymers has metal particles dispersed therein in order to provide suitable electrode properties.

Reference is again made to Fig. 1. For some applications, control unit 34 is 15 coupled to electrode device 20 over wires 38. Control unit 34 is implanted in the body of the subject outside blood vessel 30, or is positioned external to the body of the subject. For other applications control unit 34 is wirelessly coupled to electrode device 20, for wireless transmission of energy and/or data. For example, the control unit may be inductively coupled to the electrode device, or the control unit may comprise an ultrasonic 20 transducer that transmits energy to the electrode device, which receives the energy using an ultrasonic transducer, such as a piezoelectric transducer. For some applications, stent 40 itself serves as an antenna for receiving inductive energy and/or a wireless data signal from control unit 34. Control unit 34 comprises a power source, such as a batteiy, or a galvanic power source (in which case, separate ones of electrodes 32 may function as the 25 anode and cathode of a galvanic cell).

In an embodiment of the present invention, electrode device 20 is configured to release a local or systemic drug into blood vessel 30, such as an anticoagulation agent (e.g., heparin), an immunosuppressive agent (e.g., sirolimus), a chemotherapy agent (e.g., taxol), a hormone (e.g., estradiol), or anNO-releasing compound. 30 In an embodiment of the present invention, electrode device 20 is adapted to be placed in direct contact with cardiac muscle of the subject, so as to induce an increase in NO secretion by the cardiac muscle. 17 WO 2007/013065 PCT/IL2006/000856

In an embodiment of the present invention, electrode device 20 is adapted to be placed in contact with non-vascular smooth muscle (e.g., smooth muscle of the gastrointestinal tract).

In an embodiment of the present invention, electrode device 20 is adapted to be 5 placed in an eye of a subject, and to induce dilation of a retinal artery, for example to treat diabetic retinopathy. For some applications, electrode device 20 comprises a small coil, which receives energy inductively in order to drive current into the tissue in contact therewith or adjacent thereto. The energy may be released by inductively driving current flow in the tissue, or via an electrode coupled to the coil. As appropriate based on 10 surgical constraints or the particular pathology to be treated, the coil may be placed in an anterior or posterior position within the globe of the eye, or, alternatively, posterior to the retina.

In an embodiment of the present invention, one or more electrodes are placed in or adjacent to the subject's eye, and are driven to apply a signal that induces NO production 15 adjacent to the electrodes, in order to treat an eye disease. For example, the increased NO production may be used to reduce intraocular pressure, in order to treat glaucoma. Alternatively or additionally, increased blood flow induced by the NO production minimizes optic nerve degeneration, such as is seen in age-related macular degeneration (AMD). Alternatively or additionally, as noted hereinabove, the increased blood flow in 20 one or more retinal arteries treats or prevents diabetic retinopathy.

In an embodiment of the present invention, a system for treating glaucoma comprises one or more electrodes (e.g., exactly two electrodes) which are adapted to placed around a cornea of the eye, and a control unit which drives the electrodes to apply a signal that induces NO production in a vicinity of the trabecular meshwork of the eye. 25 Such NO production enhances the flow of aqueous humour through the trabecular meshwork to Schlemm's canal, thereby reducing intraocular pressure to treat glaucoma.

For some applications, the control unit is configured (including being sufficiently small) to be placed in the eye, and the system comprises a photovoltaic cell that is configured to power the control unit. 30 In an embodiment of the present invention, electrode device 20 is used to apply electrical stimulation during the process of deriving blood vessels (i.e., veins or arteries) from stem cells, such as from embryonic stem cells. Alternatively or additionally, 18 WO 2007/013065 PCT/DL2006/000856 electrode device 20 is used to apply electrical stimulation to blood vessels derived from stem cells after the blood vessels have been implanted in a subject. An increase in NO production caused by such stimulation may be beneficial for the blood vessels, e.g., may aid the process of differentiating the stem cells into the blood vessels. These stimulation 5 techniques may be used, for example, in conjunction with techniques for differentiating stem cells into blood vessels described in the above-mentioned article by Levenberg S et al.

Reference is made to Fig. 5, which is a schematic illustration of a counterpulsation device 70 inserted in an ascending aorta 72 of a subject, in accordance with an 10 embodiment of the present invention. Fig. 5 shows insertion into ascending aorta 72 by way of illustration and not limitation, and the scope of the present invention includes, alternatively or additionally, inserting device 70 into the descending aorta. Additionally, it is noted that the size of device 70 may be considerably longer than as shown in Fig. 5 (e.g., 5-15 cm, or 15-30 cm), depending on the extent of the counterpulsation effect that is 15 desired.

Counterpulsation device 70 comprises one or more electrodes 74, and an implantable or external control unit 76. Control unit 76 is adapted to drive electrodes 74 to apply an electrical signal to a wall of ascending aorta 72 during systole, and to configure the signal to induce an increase in NO secretion by the wall. The increased NO 20 secretion dilates the wall such that during systole the wall stores energy, and pressure on the heart is reduced. During diastole, the wall constricts, releasing the stored energy and thereby increasing blood pressure and coronaiy blood flow. For some applications, control unit 76 is additionally configured to drive electrodes 74 to apply, during diastole, stimulation configured to enhance the rapid constriction of aorta 72. 25 In an embodiment, electrodes 74 are driven to apply a signal during systole that is about 1-10 mA (e.g., about 1-7 mA, or about 4-10 mA, typically about 4-5 mA) at about 1-30 Hz (e.g., about 1-20 Hz, or about 10-30 Hz, typically about 10 Hz). For some applications, the signal applied during diastole has an amplitude and/or a signal frequency that is between about 1.5 and 4 times the corresponding value during systole. In an 30 embodiment, electrodes 74 are driven to apply a signal during diastole that is about 5-20 mA (e.g., about 10 mA) at a frequency that is between about 15 and 100 Hz, e.g., about 50 Hz. 19 WO 2007/013065 PCT/IL2006/000856

For some applications, counteipulsation device 70 is about 25 cm long, and induces a 10% dilation of aorta 72 and, in turn, an approximately 40 cc increase in volume along 25 cm of the aorta. For some applications, counterpulsation device 70 is used to treat a subject suffering from congestive heart failure (CHF), while for other applications, 5 the device is used to treat non-CHF subjects, such as subjects suffering from high systolic blood pressure.

For some applications, counterpulsation device 70 comprises at least one physiological sensor 78, such as an electrocardiogram (ECG) monitor, or a pressure sensor. Control unit 76 determines the one or more parameters of the signal application 10 (such as a timing parameter) responsively to a sensor signal generated by sensor 78. For some applications, control unit 76 is adapted to drive electrodes 74 to apply the signal every heart beat, while for other applications the signal is applied less than every heartbeat, such as once every several heartbeats. For some applications, the control unit is configured to drive the electrodes to begin application of the systolic signal slightly prior 15 to the beginning of systole (e.g., less than 50 ms prior to the beginning of systole), which generally enhances the induced dilation of the aorta.

For some applications, counterpulsation device 70 alternatively or additionally comprises an element configured to mechanically dilate ascending aorta 72 (or the descending aorta) during at least a portion of systole, by causing the aorta to assume a 20 more elliptical shape. For some applications, the element is placed within the aorta, while for other applications the element is placed outside the aorta. For example, the element may comprise one or more magnets and/or coils, which are driven to change the shape of the element using electricity, piezoelectric elements, and/or hydraulic pressure. For some applications, the element both applies the mechanical force and functions as one or more 25 of electrodes 74. For applications in which both the electrical signal and mechanical force is applied during systole, the counteipulsation effect is intensified by the combination of the electrically-induced dilation, the mechanically-induced change in cross-sectional shape, and the natural expansion of the aorta during systole.

For some applications, counteipulsation device 70 is applied to an arteiy other 30 than an aorta.

Reference is made to Fig. 6, which is a schematic cross-sectional illustration of an artificial arteiy 100, in accordance with an embodiment of the present invention. 20 WO 2007/013065 PCT/IL2006/000856

Artificial arteiy 100 is typically used as a graft for a coronary bypass procedure. For some applications, artificial artery 100 has a diameter of less than 7 mm, such as less than 5 mm or less than 3 mm. Artificial artery 100 is configured to assume a first cross-sectional shape 102 during a first phase of a cardiac cycle (e.g., systole or diastole), and a 5 second cross-sectional shape 104 during a second phase of the cardiac cycle (e.g., diastole or systole). Typically, one or both of the cross-sectional shapes are elliptical, and have major axes with different lengths LI and L2, respectively. For some applications, one of the cross-sectional shapes is substantially circular. For some applications, a ratio of LI to L2 is greater than 1.1, 1.2, 1.3, 1.4, or' 1.5. Such shape changing during each cardiac 10 cycle generally reduces the likelihood of artificial artery 100 becoming blocked over time. Without wishing to be bound by any particular theory, the inventor hypothesizes that the frequent shape changes of arteries in skeletal muscle, caused by movement of the muscle, may help prevent blockage of these arteries. The shape changes of artificial artery 100 may have the same general beneficial effect. 15 In an embodiment of the present invention, an electrode device comprises one or more electrodes. The electrode device is configured to be placed outside of a blood vessel, such as an artery, in a vicinity of the blood vessel, such that the electrodes remain outside the blood vessel in electrical communication with the blood vessel. An implantable or external control unit is configured to drive the electrodes to apply an 20 electrical signal to the blood vessel, and to configure the signal to induce an increase in nitric oxide (NO) secretion by a wall of the blood vessel. For some applications, the electrode device comprises a plurality of electrodes, and the control unit is configured to randomly or quasi-randomly activate a subset of the electrodes, and repeatedly change which electrodes are in the subset. For some applications, the electrode device is shaped 25 as a tube having an inner surface to which the electrodes are coupled. For some applications, the electrode device comprises at least one elongated lead, which is configured to be placed in the blood vessel, and to serve as an electrode having a polarity opposite that of the electrodes outside the blood vessel.

In an embodiment of the present invention, a system comprises an electrode 30 device and an implantable or external control unit. The electrode device comprises one or more electrodes configured to be placed in or outside a blood· vessel in a vicinity of a baroreceptor. The control unit drives the electrodes to apply to the blood vessel an electrical signal that induces NO secretion by a wall of the artery. Such NO secretion 21 WO 2007/013065 PCT/IL2006/000856 causes dilation of the wall of the blood vessel, thereby activating the baroreceptor. For some applications, the system comprises a sensor for sensing a feature of a cardiac cycle, and the control unit is configured to synchronize the signal application with the feature. For example, the control unit may be configured to apply the signal once per heart beat, or 5 every nth heart beat, such as every second or third heart beat. For some applications, the control unit applies the signal only during systole. For some applications, the system comprises a blood pressure sensor, and the control unit drives the electrode device to apply the signal responsively to a sensed blood pressure. For example, the blood vessel may be the carotid artery or the aorta in a vicinity of the aortic arch. 10 Alternatively or additionally, the system comprises an element configured to mechanically dilate the blood vessel in the vicinity of the baroreceptor, such as during systole, as described above. For some applications, the element is placed within the blood vessel, while for other applications the element is placed outside the blood vessel. For example, the element may comprise one or more magnets and/or coils, which are driven 15 to change the shape of the element using electricity, piezoelectric elements, and/or hydraulic pressure. For some applications, the element is configured to store energy during one phase of the cardiac cycle, and use the stored energy to change the shape of the element during another phase of the cardiac cycle. For some applications, the element for applying the mechanical force also serves as one or more of the electrodes. 20 For some applications, the element is configured to cause the cross-sectional shape of the blood vessel to be more elliptical during diastole than the shape would otherwise be (it being noted that rigid blood vessels generally have a substantially circular cross-sectional shape). As a result, the baroreceptor typically detects more shape change during systole that it otherwise would. For example, the element may be configured to function 25 as a weak spring in order to change the cross-sectional shape.

In an embodiment of the present invention, a treatment method comprises removing plaque from an artery in a vicinity of a baroreceptor, in order to increase flexibility of the artery and thus sensitivity of the baroreceptor. For example, the SilverHawk^M Plaque Excision System (FoxHollow Technologies, Inc., Redwood City, 30 CA) may be used to remove the plaque. . . It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope 22 WO 2007/013065 PCT/BL2006/000856 of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are . not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.

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