Patent Grant
8551096
1. Field of the Invention
The present invention is generally related to medical devices, systems, and methods. In particular, the invention provides methods and systems for delivery of energy and/or bioactive materials (i.e. bioactives) to body tissue, most preferably by selective delivery to body tissues disposed about a lumen using a catheter-based treatment system.
2. Discussion of Related Art
Physicians use catheters to gain access to, and repair interior tissues of the body, particularly within the lumens of the body such as blood vessels. For example, balloon angioplasty and other catheters often are used to open arteries that have been narrowed due to atherosclerotic disease. Balloon angioplasty is often effective at opening an occluded blood vessel, but the trauma associated with balloon dilation can impose significant injury, so that the benefits of balloon dilation may be limited in time.
Stenting procedures, in conjunction with balloon dilation, are often the preferred treatments for atherosclerosis. In stenting, a collapsed metal framework is mounted on a balloon catheter, which is introduced into the body. The stent is manipulated into the site of occlusion and expanded in place by the dilation of the underlying balloon, or in the example of a self-expanding stent, the stent scaffolds open upon release of constraint by the catheter. Stenting has gained widespread acceptance, and produces generally acceptable results in many cases. Along with treatment of blood vessels (particularly the coronary arteries), stents can also be used in treating many other tubular obstructions within the body, such as for treatment of reproductive, gastrointestinal, and pulmonary obstructions. Restenosis or a subsequent narrowing of the body lumen after stenting has occurred in a significant number of cases.
A variety of modified restenosis treatments or restenosis-inhibiting treatment modalities have also been proposed, including intravascular radiation, cryogenic treatments, ultrasound energy, and the like, often in combination with balloon angioplasty and/or stenting. While these and different approaches show varying degrees of promise for decreasing the subsequent degradation in blood flow following angioplasty and stenting, the trauma initially imposed on the tissues by angioplasty remains problematic.
A number of alternatives to stenting and balloon angioplasty have been proposed to open stenosed arteries. For example, a wide variety of atherectomy devices and techniques have been disclosed and attempted. Despite the disadvantages and limitations of angioplasty and stenting, atherectomy has not gained the widespread use and success rates of dilation-based approaches. More recently, still further disadvantages of dilation have come to light. These include the existence of vulnerable plaque, which can rupture and release materials that may cause myocardial infarction or heart attack.
More recently, drug coated stents (such as Johnson and Johnson's Cypher stent, the associated drug comprising Sirolimus) have demonstrated a markedly reduced restenosis rate, and others are developing and commercializing alternative drug eluting stents. While drug-eluting stents appear to offer significant promise for treatment of atherosclerosis in many patients, there remain many cases where stents either cannot be used or present significant disadvantages. Generally, stenting leaves an implant in the body. Such implants can present risks, including mechanical fatigue, corrosion, thrombus formation, and the like, particularly when removal of the implant is difficult and involves invasive surgery. Stenting may have additional disadvantages for treating diffuse artery disease, for treating bifurcations, for treating areas of the body susceptible to crush, and for treating arteries subject to torsion, bending, elongation, and shortening.
Information that may be relevant to proposed treatments of atherosclerotic disease can be found in U.S. Pat. Nos. 5,102,402; 5,304,121; 5,304,171; 5,306,250; 5,380,319; 5,588,962; 5,693,029; 6,389,314; 6,477,426; 6,623,453; 6,695,830; 6,706,011; 6,723,064; 6,788,977; 6,991,617; 6,958,075; 7,008,667; 7,066,904; 7,291,146; and 7,407,671, for example. Further information can be found in U.S. Patent Application Publication Nos. 2003/0069619; 2003/0229384; 2004/0062852; 2004/0243199; 2005/0203498; 2005/0251116; 2005/0283195; 2006/0235286; 2007/0278103; 2008/0125772; 2008/0140002; 2008/0161801; 2008/0188912; 2008/0188913; 2008/0262489 and 2009/0074828 as well as European Patent Application No. EP 1622531 and PCT Patent Publication Nos. WO 2005/007000 and WO 2009/121017. Scheller et al., “Potential Solutions to the Current Problem: Coated Balloon,” EuroIntervention, 2008 Aug.; 4 Suppl C: C63-66 and Tepe et al., “Local Delivery of Paclitaxel to Inhibit Restenosis During Angioplasty of the Leg,” N Engl J Med, 2008 Feb. 14; 358(7): 689-699 may also include relevant information.
Therefore, it would be advantageous to provide new and/or improved methods and systems for delivery of therapeutic treatment to diseased tissue. Ideally, these improved techniques would facilitate selectively targeting tissue for treatment through the introduction of temperature change and/or bioactives to the targeted tissue in such a way that may simplify the procedure, may reduce procedure time, may improve the therapeutic result, or any combination thereof.
The present invention relates to the treatment of targeted tissue by directionally delivering energy and/or bioactive materials in order to achieve a therapeutic effect. In the most preferred embodiment a balloon catheter system having a balloon portion, further comprised of a plurality of electrodes, may be energized to selectively deliver energy, bioactives, or a combination thereof to targeted tissue. Tissue may be targeted by applying energy, making tissue impedance analysis, and further selectively energizing electrodes through the use of an energy source with a controller.
In a preferred embodiment, a system for the treatment of a target tissue by directionally delivering energy and/or bioactive material comprises an elongate catheter having a proximal end and a distal end with an axis therebetween. The catheter has a radially expandable balloon near the distal end and an energy delivery surface on the balloon. A thermally changeable coating with a releasable bioactive material is coupled to the balloon. The thermally changeable coating is oriented to be urged against the target tissue when the balloon expands. An energy source is operatively coupled to the catheter to energize the energy delivery surface to heat the thermally changeable coating and release the bioactive material to the target tissue.
In another embodiment, the energy delivery surface comprises a plurality of spaced electrodes disposed about the expandable balloon. The energy source is operatively coupled to the plurality of electrodes to selectively energize the electrode pairs to heat portions of the thermally changeable coating between the electrode pairs to release the bioactive material to the target tissue.
In an exemplary embodiment, the electrodes are coated with an insulating material.
In yet another embodiment, the balloon is encapsulated by a selectively permeable membrane overlaid by a plurality of circumferentially spaced electrodes.
In another embodiment, the balloon is configured to receive inflation media comprising bioactive material.
In some embodiments, a tissue analyzer is configured to characterize the body tissue.
In other embodiments, the electrode delivery portion is energized to heat the thermally changeable coating to release the bioactive material in response to the characterized body tissue.
In another embodiment, the electrode delivery portion is energized to heat the body tissue before, during and/or after the delivery of the bioactive material.
In another embodiment, the thermally changeable coating includes more than one releasable bioactive material. Each material may have a different phase change temperature.
In another embodiment, the bioactive material is selected from at least one of an antiproliferative, an antithrombin, an immunosuppressant, a lipid, an anti-lipid, a liposome, an anti-inflamatory, an antineoplastic, an antiplatelet, an angiogenic agent, an anti-angiogentic agent, a vitamin, an aptamer, an antimitotic, a metalloproteinase inhibitor, a NO donor, an estradiol, an anti-sclerosing agent, a vasoactive, a growth factor, a beta blocker, an AZ blocker, a hormone, a statin, an antioxidant, a membrane stabilizing agent, a calcium antagonist, a retinoid, a peptide, a lipoprotein, a polypeptide, a polynucleotide encoding polypeptides, a protein, a protein drug, an enzyme, a genetic material, a cell, a chemical solvent, an energy-activated agent, an anti-lymphocyte, an anti-macrophage substance or a combination of any of the above.
In yet another embodiment, the bioactive material is attached to a portion of a liposome.
In another embodiment, the thermally changeable coating is selected from at least one of, polylactic acid, polyglycolic acid, polyvinyl acetate, polyvinyl propylene, hydroxypropyl methylcellulose, methacrylate or a combination of any of the above.
In other embodiments, the energy source is a RF energy source and the delivery portion is configured to transmit RF energy to release and/or activate at least one bioactive material.
In other embodiments, the energy source is a light energy source and the delivery portion is configured to transmit light energy to release and/or activate at least one bioactive material.
In an exemplary embodiment, a method for the selective delivery of a releasable bioactive material includes engaging a body tissue disposed about a lumen with a thermally changeable coating by radially expanding a balloon of a catheter. The thermally changeable coating is disposed on the balloon. A surface on the balloon is energized to heat the thermally changeable coating. The bioactive material is released from the thermally changeable coating into the body tissue in response to the heating.
In another embodiment, the delivery portion comprises a plurality of electrodes disposed about the expandable balloon and select electrode pairs are energized to heat and liquefy portions of the thermally changeable coating between the electrode pairs.
In yet another embodiment, the body tissue of the lumen includes a diseased portion. Select electrode pairs are energized to heat the thermally changeable coating proximate the diseased portion.
In another embodiment, tissue is characterized to identify body tissue to be treated. Portions of the thermally changeable coating are selectively heated to release the bioactive material in response to the characterized body tissue to treat the identified body tissue.
In another embodiment, the body tissue is heated before, during and/or after the delivery of the bioactive material. The bioactive material is selected from at least one of a therapeutic fluid, an anesthetic drug, a therapeutic drug, a small molecule, a gene therapeutic compound, an anti-thrombolytic agent, a lubricant to allow higher temperatures without sticking, an electrically conductive compound to lower the impedance at an electrode, an electrically insulating compound to prevent treatment to tissue that does not need treatment, an electrically conductive compound that is intended to migrate through the endothelial layers of tissue to carry energy to the interstitial layers, or a combination of the above.
In another embodiment, the delivery portion is energized with RF energy to release and/or activate at least one bioactive material.
In another embodiment, the delivery portion is energized with laser energy to release and/or activate at least one bioactive material.
In another embodiment, the delivery portion is energized with ultrasound energy to release and/or activate at least one bioactive material.
In another embodiment, the delivery portion is energized with microwave energy to release and/or activate at least one bioactive material.
In a preferred embodiment, a catheter system for bioactive material delivery to a body tissue being disposed about a lumen, the system comprises an elongate catheter having a proximal end and a distal end with an axis therebetween. The catheter has a radially expandable balloon near the distal end and an energy delivery surface proximate the balloon for transmission of energy. A plurality of biomolecules have a thermally releasable drug portion and an inert portion covalently bound to the balloon. An energy source is operatively coupled to a controller to selectively energize the delivery portion so as to heat the biomolecules to release the bioactive material to the body tissue.
In an exemplary embodiment, a method of delivering a bioactive material in a lumen comprises engaging a body tissue disposed about the lumen with a plurality of biomolecules. A thermally releasable drug portion and an inert portion are covalently bound to the balloon near a distal end of a catheter when the expandable balloon expands. An electrode delivery portion of the catheter proximate the balloon is energized to heat the biomolecules and release the drug portion from the biomolecules into the body tissue in response to the heating of the biomolecules.
In a preferred embodiment, a catheter system for selective fluid delivery to a body tissue being disposed about a lumen comprises an elongated flexible catheter body. The body has a proximal end and a distal end. A radially expandable structure os near the distal end of the catheter body. A plurality of fluid delivery channels expandable with the expandable structure, the fluid delivery channels are initially blocked with a thermally changeable material. An energy source is operatively coupled to the fluid delivery channels to heat and liquefy the thermally changeable material to open one or more of the fluid delivery channels for fluid release.
In another embodiment, the plurality of fluid delivery channels protrude from the expandable structure to penetrate the body tissue of the lumen.
In another embodiment, a tissue analyzer is configured to characterize the body tissue.
In yet another embodiment, the fluid delivery channels can be selectively energized to selectively open one or more fluid delivery channels in response to the characterized body tissue.
In another embodiment, the radially expandable structure comprises a balloon and the fluid delivery channels are mounted on a circumference of the balloon. In yet another embodiment, the radially expandable structure includes an expandable basket and the fluid delivery channels are mounted on a circumference of the basket.
In another embodiment, the body tissue of the lumen includes a diseased portion. Select electrodes are energized to selectively open one or more fluid delivery channels proximate the diseased portion.
In another embodiment, select electrodes are energized to heat the body tissue in conjunction with the release of the fluid in the lumen.
In other embodiments, the fluid is selected from at least one of, ceramide, suramin, rapamycin, paclitaxel, sirolimus, zotarolimus, everolimus, a therapeutic fluid, an anesthetic drug, a therapeutic drug, a small molecule, a gene therapeutic compound, an anti-thrombolytic agent, a lubricant (to allow higher temperatures without sticking), an electrically conductive compound to lower the impedance at an electrode, an electrically insulating compound to prevent treatment to tissue that does not need treatment, an electrically conductive compound that is intended to migrate through the endothelial layers of tissue to carry energy to the interstitial layers, or a combination of the above.
In a preferred embodiment, a catheter system for selective fluid delivery to body tissue is disposed about a lumen. The system includes an elongated flexible catheter body having a proximal end and a distal end. A radially expandable structure is located near the distal end of the catheter body. A plurality of fluid delivery channels are oriented to be urged against the body tissue of the lumen when the expandable structure expands. A plurality of micro-electromechanical systems (MEMS) are coupled to the fluid delivery channels to selectively open one or more fluid delivery channels and release a fluid in the lumen.
In another embodiment, a method for selective fluid delivery in a lumen includes engaging a body tissue disposed about the lumen with a plurality of fluid delivery channels by a radially expanding a structure within the lumen. One or more of the fluid delivery channels are selectively opened and release a fluid from the select fluid delivery channels into the lumen.
In another embodiment, one or more fluid delivery channels include a plurality of micro-electromechanical systems (MEMS) coupled to the fluid delivery channels to selectively open and/or close the fluid delivery channels.
In a preferred embodiment, a catheter assembly for drug delivery to a body tissue disposed about a lumen includes an elongate catheter having a proximal end and a distal end with an axis in between. A radially expandable porous balloon has an inner surface and an outer surface. The balloon is positioned near the distal end of the catheter with an energy delivery surface proximate the balloon for transmission of energy. A selectively porous membrane, having an inner surface and an outer surface, is overlaid on the balloon. An inflation media, including a drug, for inflating the balloon is introduced between the outer surface of the porous balloon and the inner surface of the membrane when the balloon is inflated with the inflation media. An energy source is coupled to the proximal end of the catheter to deliver energy to the energy delivery surface while the balloon is expanded within the lumen to deliver the drug from the outer surface of the balloon through the membrane to the body tissue.
In another embodiment, a catheter system for selective drug delivery to a body tissue being disposed about a lumen includes an elongated flexible catheter body having a proximal end and a distal end. A radially expandable balloon near the distal end of the catheter body has an inner and outer surface. The outer surface is comprised of a biocompatible matrix and a coating of a soluble bioactive material on the matrix. The material is oriented toward a moist surface of the tissue to allow the moisture to solubilize the bioactive material and force it from the matrix when the balloon is expanded against the tissue and a fluid pressure overcomes an osmotic pressure.
In other embodiments, a system for the treatment of a target tissue by directionally delivering energy and/or bioactive material comprising an elongate catheter having a proximal end and a distal end with an axis therebetween. The catheter has a radially expandable balloon near the distal end and an energy delivery surface on the balloon. A changeable coating having a releasable bioactive material is coupled to the balloon. The changeable coating is oriented to be urged against the target tissue when the balloon expands. An energy source operatively coupled to the catheter to energize the energy delivery surface so as to change the changeable coating and release the bioactive material to the target tissue.
In many exemplary embodiments, the balloon portion may further comprise one or more surface coatings or layers containing a bioactive or a plurality of bioactives that are directed to tissue through the application of energy, exposure to the in vivo environment, or a combination thereof.
In some exemplary embodiments, surfaces of the balloon catheter may further comprise lubricant, electrically conductive compound, compound intended to migrate through the layers of tissue to carry energy to the interstitial layers, or any combination thereof.
In other exemplary embodiments, the balloon portion may further comprise insulative portions that preferably avoid the direct transmission of energy to the area most proximate to the electrodes.
In yet other exemplary embodiments, the balloon portion may be comprised of bioactives attached directly to the surface of the balloon.
In yet other exemplary embodiments, the balloon catheter system is further comprised of a means for transmitting light energy that may be used to release bioactives, activate bioactives, or a combination thereof.
In yet other alternate exemplary embodiments, the balloon may be comprised of delivery channels, or porous material, or a matrix, or a combination thereof, that aides in the delivery of bioactives.
Preferred embodiments of the present invention may be used in therapeutic procedures for achieving biologic effects in tissue. Most preferably, the present invention may be used at any point and time before, during, and/or after an angioplasty procedure.
Embodiments of the present invention relate to the treatment of targeted tissue by directionally delivering energy and bioactive materials in order to achieve a therapeutic effect. Preferably, the target tissue is luminal tissue, which may further comprise diseased tissue such as that found in arterial disease. However, any tissue may be targeted for therapy comprising directional delivery of energy and/or delivery of bioactive agents. The directional delivery of energy may be used to treat tissue, aid in the delivery of bioactives, aid tissue uptake of bioactives, or any combination thereof.
Bioactives contemplated by the present invention may be delivered alone or in combination. Examples of bioactives may be large or small molecules, and may include, but are not limited to, antiproliferatives, antithrombins, immunosuppressants, lipids, anti-lipids, liposomes, anti-inflammatories, antineoplastics, antiplatelets, angiogenic agents, anti-angiogentic agents, vitamins, aptamers, antimitotics, metalloproteinase inhibitors, NO donors, estradiols, anti-sclerosing agents, vasoactives, growth factors, beta blockers, AZ blockers, hormones, statins, antioxidants, membrane stabilizing agents, calcium antagonists, retinoids, peptides, lipoproteins, polypeptides, polynucleotides encoding polypeptides, proteins, protein drugs, enzymes, genetic material, cells, energy-activated agents, anti-lymphocytes, and anti-macrophage substances.
A bioactive may be incorporated into a coating on a balloon catheter that may be released through the directed application of energy once inside the lumen to selectively treat targeted tissue. Some embodiments of the present invention use heating to release the bioactive coating. Other embodiments combine bioactive delivery with heating of the target tissue before, during, and/or after delivery to the tissue. Devices for heating tissue using RF (i.e. radio frequency), ultrasound, microwave and laser energies have been disclosed in U.S. patent application Ser. Nos. 11/975,474, 11/975,383, 11/122,263 and U.S. Provisional Application No. 61/099,155, the full disclosures of which are incorporated herein by reference. Schematics of balloon catheter based energy delivery systems are shown in
Drug Delivery Coatings
Housing 29 also accommodates an electrical connector 38. Connector 38 includes a plurality of electrical connections, each electrically coupled to electrodes 34 via conductors 36. This allows electrodes 34 to be easily energized, the electrodes often being energized by a controller 40 and power source 42, such as RF energy. In one embodiment, electrical connector 38 is coupled to an RF generator via a controller 40, with controller 40 allowing energy to be selectively directed to electrodes 34. While RF energy is disclosed, other suitable energy sources may be used, such as microwave energy, ultrasound energy, or laser energy, each having energy delivery surfaces configured to deliver the desired energy. See co-pending U.S. Provisional Application No. 61/099,155 filed Sep. 22, 2008 the full disclosures of which are incorporated herein by reference.
In some embodiments, controller 40 may include a processor or be coupled to a processor to control or record treatment. The processor will typically comprise computer hardware and/or software, often including one or more programmable processor unit running machine readable program instructions or code for implementing some or all of one or more of the methods described herein. The code will often be embodied in a tangible media such as a memory (optionally a read only memory, a random access memory, a non-volatile memory, or the like) and/or a recording media (such as a floppy disk, a hard drive, a CD, a DVD, a non-volatile solid-state memory card, or the like). The code and/or associated data and signals may also be transmitted to or from the processor via a network connection (such as a wireless network, an Ethernet, an internet, an intranet, or the like), and some or all of the code may also be transmitted between components of catheter system 10 and within processor via one or more bus, and appropriate standard or proprietary communications cards, connectors, cables, and the like will often be included in the processor. Processor will often be configured to perform the calculations and signal transmission steps described herein at least in part by programming the processor with the software code, which may be written as a single program, a series of separate subroutines or related programs, or the like. The processor may comprise standard or proprietary digital and/or analog signal processing hardware, software, and/or firmware, and will typically have sufficient processing power to perform the calculations described herein during treatment of the patient, the processor optionally comprising a personal computer, a notebook computer, a tablet computer, a proprietary processing unit, or a combination thereof. Standard or proprietary input devices (such as a mouse, keyboard, touch screen, joystick, etc.) and output devices (such as a printer, speakers, display, etc.) associated with modern computer systems may also be included, and processors having a plurality of processing units (or even separate computers) may be employed in a wide range of centralized or distributed data processing architectures.
Balloon 20 is illustrated in more detail in
Electrodes 34 are mounted on a surface of balloon 20, with associated conductors 36 extending proximally from the electrodes. Electrodes 34 may be arranged in many different patterns or arrays on balloon 20. The system may be used for monopolar or bipolar application of energy. For delivery of bipolar energy, adjacent electrodes are axially offset to allow bipolar energy to be directed between adjacent circumferential (axially offset) electrodes. In other embodiments, electrodes may be arranged in bands around the balloon to allow bipolar energy to be directed between adjacent distal and proximal electrodes.
A coating 35 is coupled to the balloon 20 and positioned between electrodes 34, such as shown in
In some embodiments, the layer of coating 35b on the balloon 20 may incorporate more than one bioactive, fluid, or coating layer (
In some embodiments, a second coating 35A may be used to cover electrodes 34, such as shown in
To illustrate, as shown in
Many types of drugs may be included in the coatings. For example, the coating may include drugs currently used in drug eluting stents, such as sirolimus (used in the Cypher™ stent), paclitaxel (used in the Taxus™ stent), zotarolimus (used in the Endeavour™ stent) and everolimus (used in the Xience V™ stent).
Some embodiments of the present invention may include aptamers 52 coated to the balloon 20 using a substrate that breaks down readily when heated, such as when the RF energy source is activated. Aptamers are oligonucleic acid or peptide molecules that bind to a specific target molecule. They can be engineered to bind very specifically to various molecular targets such as small molecules, proteins, nucleic acids, and even cells, tissues and organisms. The aptamers 52 could be synthesized to bind 54 with desired tissue 48 to be treated, such as plaque, within the lumen or artery.
While the catheter system 10 is not powered and the balloon 20 deflated, the coating 35 with aptamers 52 would remain on the balloon 20. Once the balloon 20 is inflated and the energy unit turned on, the coating is released and the aptamers 52 bind to the desired tissue, such as shown in
Aptamers are nucleic acids that bind to the surface of molecules in much the same way as antibodies. One importance difference between aptamers and antibodies is that aptamers can be produced by chemical synthesis whereas antibodies are produced biologically, first animals, then in culture or an expression system. Another important difference is that aptamers are very stable and not sensitive to their surrounding environment, including temperature.
In some embodiments, coating 35 may include a chemical solvent that has plaque softening properties. Ether, chloroform, benzene, and acetone are known to be lipid solvents. Furthermore, amino acids, proteins, carbohydrates, and nucleic acids are largely insoluble in these solvents. If the solvent is used in conjunction with tissue heating, the tissue treatment may require less energy over a shorter time period, lessening the chance of damage to healthy tissue. If the tissue includes calcium deposits, the same process used to deliver lipid solvents to plaque could be used to deliver calcium solvents to calcification sites. Calcium is highly soluble in a variety of organic solvents. In both cases, the solvent would be coupled to the surface of the balloon with a coating that would break down either with the application of heat or RF energy, or as the balloon is inflated.
In some embodiments, the coating may incorporate more than one drug, agent, or fluid listed herein within the coating, each having different phase change temperatures. For example, an anesthetic could be administered at a lower melting temperature prior to a specific treatment of higher temperature where there may be a nerve in the general location. Is some embodiments, two coatings of differing material may be used, such as by layering. For example, a first layer may include a first drug that attaches to the target tissue and act as a receptor to a second drug in a second layer. In some embodiments the coating is non-conductive to reduce or eliminate electrical shorts between electrodes.
In some embodiments, tissue signature could be used to identify treatment regions with the use of impedance measurements. Impedance measurements utilizing the radially spaced electrodes 34 within a lumen can be used to analyze tissue. Impedance measurements between pairs of adjacent electrodes (and/or between pairs of separated electrodes), may differ when the current path passes through diseased tissue, and when it passes through healthy tissues of the luminal wall. Hence, impedance measurements between the electrodes on either side of diseased tissue may indicate a lesion, while measurements between other pairs of adjacent electrodes indicate healthy tissue. Other characterization, such as intravascular ultrasound, optical coherence tomography, or the like may be used to identify regions to be treated.
Some embodiments described herein may be used to treat atherosclerotic disease by selective drug delivery in combination with “gentle heating” utilizing the “Q10 Rule” to further enhance the fluid or drug treatment. Under the Q10 Rule, it is well known that rates of biochemical reactions usually double when temperature is increased by 10° C.
As shown in
The controller 40 may energize the electrodes with about 0.25 to 5 Watts average power for 1 to 180 seconds, or with about 4 to 45 Joules. Higher energy treatments are done at lower powers and longer durations, such as 0.5 Watts for 90 seconds or 0.25 Watts for 180 seconds. Most treatments in the 2 to 4 Watt range are performed in 1 to 4 seconds. Using a wider electrode spacing, it would be appropriate to scale up the power and duration of the treatment, in which case the average power could be higher than 5 Watts, and the total energy could exceed 45 Joules. Likewise, using a shorter or smaller electrode pair would require scaling the average power down, and the total energy could be less than 4 Joules. The power and duration are calibrated to be less than enough to cause severe damage, and particularly less than enough to ablate diseased tissue 48 within a blood vessel.
In some embodiments the delivery of the drug and gentle heat may be accompanied by balloon angioplasty using gentle dilation to remodel the artery with dilation pressures which are at or significantly lower than standard, unheated angioplasty dilation pressures. Where balloon inflation pressures of 10-16 atmospheres may, for example, be appropriate for standard angioplasty dilation of a particular lesion, modified dilation treatments combined with appropriate electrical potentials (through flexible circuit electrodes on the balloon, electrodes deposited directly on the balloon structure, or the like) described herein may employ from 10-16 atmospheres or may be effected with pressures of 6 atmospheres or less, and possibly as low as 1 to 2 atmospheres. Such moderate dilations pressures may (or may not) be combined with one or more aspects of the tissue characterization, tuned energy, eccentric treatments, and other treatment aspects described herein for treatment of diseases of the peripheral vasculature.
Covalently Bound BioMolecules
Current endovascular therapies for preventing or permanently removing hyperplastic neointima are not completely efficacious. While removal of such tissue is achieved by multiple such therapies, regrowth of the tissue is a frequent occurrence, leading to restenosis and dysfunctional blood flow. Drug-eluting stents are able to inhibit the frequency of restenosis, but fall short of completely restoring vascular function, owing to the presence of a persistent implant; the stent.
More recently, drug clotting balloons have shown an even greater reduction in the frequency of restenosis than drug eluting stents and are removed after treatment, however, high pressure inflation is required to optimally deliver the anti-proliferation/anti-inflammatory biomolecules. The molecules may function to prevent restenosis by preventing inflammatory cell influx (chemo taxis), cell proliferation. The molecules may also function to stabilize the IEL matrix by providing structural support, thus “setting” the lumen diameter.
Moving now to
The molecule's bioactive portion 235b is released from the intact biomolecule 235 by delivery of energy (such as from electrodes 34) that induces a local hyperthermia environment. The molecule is stable under the hyperthermia conditions. The molecule can prevent one or all of the following functions: 1) cell proliferation; 2) cell function; 3) receptor-ligand binding; 4) chemotaxis of inflammatory cells to the target tissue; and 5) migration of cells in the native artery strata to the diseased tissue.
The influx of the molecule 235b into the diseased tissue 48 is facilitated and/or hastened by the energy mediated hypothermia, i.e., cleavage from the intact biomolecule, migration into the diseased tissue, and residence in the diseased tissue by virtue of increased porosity are all accelerated by the hyperthermia. This invention uniquely delivers a bioactive molecule into diseased tissue with: 1) greater speed by hypothermal acceleration; 2) more completeness by rendering the diseased tissue more receptive/porous to the molecule; and/or 3) no inactive segments of the biomolecule (i.e., no polymer, inactive protein sequence/segment, or co-factors required for activation left at the treatment site since the inactive segments stay on the balloon).
Clinical application and uses are designed to reduce plaque, inhibit restenosis in stented or not-stented site, and may be used as an adjunctive treatment to aggressive non-implantable endovascular procedures and stent implants.
Fluid Delivery Channels
Housing 129 also accommodates an electrical connector 138. Connector 138 includes a plurality of electrical connections, each electrically coupled to electrodes 134 via conductors 136. This allows electrodes 134 to be easily energized, the electrodes often being energized by a controller 140 and power source 142, such as RF energy, microwave energy, ultrasound energy, or other suitable energy sources. In one embodiment, electrical connector 138 is coupled to an RF generator via a controller 140, with controller 140 allowing energy to be selectively directed to electrodes 134 or electrode pairs. Controller 140 may include a processor or be coupled to a processor to control or record treatment.
The delivery channels 160 may protrude from the balloon surface such that they are capable of penetrating the body tissue of the lumen. In some embodiments, the electrodes may penetrate the body tissue.
The catheter system 100 may also include a tissue analyzer configured to characterize the body tissue. In some embodiments, electrodes 134 may be sensing electrodes, as discussed above, that could help characterize the tissue to identify regions the be treated or not using electrical impedance tomography. Other characterization, such as intravascular ultrasound, optical coherence tomography, or the like may be used to identify regions to be treated. Electrodes 134 may be energized in response to the characterized body tissue
Some embodiments described herein may be used to treat atherosclerotic disease by selective fluid delivery in combination with “gentle heating” to further enhance the fluid delivery or treatment, as discussed above.
Electrodes 134 may be selectively energized to open or close fluid delivery channels 160 to treat tissue. One method includes opening the fluid delivery channels 160 by selectively heating the electrodes (by Joule heating or other means, including inducing a heightened temperature in the adjacent region, whereby hear transfer could heat the electrode(s)), such that a material 164, that would otherwise block the channel, is phase changed from solid to liquid. Another possible method may include the use of MEMS (micro-elector-mechanical-systems) to open and/or close channels 160 selectively.
In some embodiments, the fluid delivery channels may be vias through the electrodes (perfused electrodes). The vias or small holes may be used to deliver a fluid to the artery tissue proximate the electrode. The holes may be less than 1 μm in diameter and may be made with a laser or ion beam. The holes may be made in the electrodes and balloon. In one example, electrode pads on a flexible circuit are designed with vias that are plated. The flexible circuit is mounted on a balloon and a laser or ion beam is used to create the holes in the flexible substrate and balloon. There may be several holes in the flexible/balloon for every electrode pad. The balloon may then be perfused with standard perfusion balloon equipment or specialized equipment. This perfusion approach may also provide additional advantages beyond fluid delivery, such as eliminating sticking, carry away heat or regulate the impedance of the load.
In some embodiments, a porous balloon may be used having fluid delivery channels on a micro-level, allowing select molecules through with the addition of heat. The porous balloon may have an inner layer, a porous outer layer or membrane, drug or fluid molecules positioned between the layers (i.e., a reservoir) and electrodes coupled to the outer layer. At low pressures, the molecules stay within the reservoir. As heat is applied, the molecules may go through the porous layer, which may be done in different ways. For example, as the heat is applied, the drug molecules may become exited, providing enough force to go through the porous outer layer. In another example, as heat is applied to the balloon, the pores expand, allowing the drug molecules to go through the porous outer layer. The molecules may also pass through the porous outer layer or membrane by osmotic pressure along with the heat.
In some embodiments, the treatments may include a drug, and/or thermal, and/or small or large molecules injection, and/or RF, and/or balloon dilatation, and/or hyperthermia.
In other embodiments, electromechanical or mechanical means known in the art may be employed to release the fluid, which by way of example may include flaps or microfluidic-type devices 165 powered by the controller. As shown in
While the devices, systems, and methods disclosed herein discuss a balloon as the radially expandable structure, other expandable structures may also be used, such as described in U.S. patent application Ser. No. 11/975,651 filed Oct. 18, 2007; the full disclosure of which is incorporated herein by reference.
Thermally Excited Osmolarity
In some embodiments, a porous balloon may be used having fluid delivery channels on a micro-level in a membrane, allowing molecules through with the addition of pressure and heat. The concept delivers a fluid or drug to a specific site by passing it through the membrane, much like reverse osmosis. In reverse osmosis, a pressure is used to drive a liquid, such as water, through a membrane with passages so small that only the appropriate molecules can pass through. In this embodiment, the membrane barrier retains a drug, like paclitaxel. At low pressures, the drug molecules are not able to pass through the membrane. To release the drug through the membrane, pressure is applied to the drug molecules using a balloon the release of the drug is the accelerated by applying energy locally by an electrode pair or monopolar electrode.
In many embodiments, an energy delivery surface comprises a plurality of spaced electrodes, such as that shown in
In many embodiments, the energy delivery surface comprises a plurality of electrodes disposed about an expandable balloon so as to define a plurality of remodeling zones in the target tissue when the balloon is expanded within the lumen. As shown in
In some embodiments, tissue signature may be used to identify tissue treatment regions with the use of impedance measurements. Impedance measurements utilizing circumferentially spaced electrodes within a lumen, such as those shown in
Some embodiments described herein may be used to treat atherosclerotic disease by selective delivery of bioactives in combination with “gentle heating” utilizing the “Q10 Rule” to further enhance the bioactive treatment. Under the Q10 Rule, rates of biochemical reactions usually double when temperature is increased by 10 degrees Celsius.
In some embodiments electrodes are separated circumferentially around the balloon and RF energy may be directed to selected electrodes or any selected combination of electrodes. By selecting electrodes to receive energy, a controller such as that shown in
In some embodiments, coatings on the balloon or other catheter system surfaces may also be comprised of polymer or polymers (
In embodiments comprising a balloon, the balloon may be further comprised of compliant or non-compliant materials, including combinations thereof, as is well-known in the art.
Tissue Sensing and Selective Direction of Energy
In selectively directing energy, a tissue signature may be used to identify tissue treatment regions with the use of impedance measurements, which may be made by utilizing spaced electrodes, for example, circumferentially spaced electrodes within a lumen as shown in
In some embodiments, a controller such as that shown in
The controller may be employed to selectively energize the electrodes with about 0.25 to 5 Watts average power for 1 to 180 seconds, or with about 4 to 45 Joules. Higher energy treatments are done at lower powers and longer durations, such as 0.5 Watts for 90 seconds or 0.25 Watts for 180 seconds. Most treatments in the 2 to 4 Watt range are performed in 1 to 4 seconds. Using a wider electrode spacing, it would be appropriate to scale up the power and duration of the treatment, in which case the average power could be higher than 5 Watts, and the total energy could exceed 45 Joules. Likewise, using a shorter or smaller electrode pair would benefit from scaling the average power down, and the total energy could be less than 4 Joules. The power and duration are calibrated to be less than enough to cause severe damage, and particularly less than enough to ablate diseased tissue within a blood vessel.
Moreover, the Q10 Rule provides for the possibility of combining the release and tissue uptake of bioactives with the directional delivery of energy toward diseased tissue.
Selective Delivery of Energy and Bioactives to Target Tissue
In a preferred embodiment, the balloon portion (
By way of example, the release shown in
By way of another example, the release may at least in part be caused by the liquefying of the coating as it is locally heated above approximately 37 degrees Celsius, wherein the coating may be solid or gel-like at temperatures below approximately 37 degrees Celsius. In yet another example, the coating may break down due to a change in pH such as when the balloon outer surface is placed in contact with a body fluid such as blood. Hydroxypropyl Methylcellulose and Methacrylate polymers are known to rapidly release useful bioactive compounds depending on a change in pH. Galvanic activity triggered by a change in voltage in a localized area may be used to release these compounds in the immediate vicinity of energized electrodes. PEGylated compounds, pNIPA hydrogels, chitosan hydrogels, comb-type graft hydrogels composed of chitosan and poly(N-isopropylacrylamide), and poly(N-isopropylacrylamide) poly(vinyl alcohol) hydrogels, are examples of known hydrogels that may be used as a means for containing and releasing bioactives through a change in temperature, pH, or both.
Most preferably, energy is selectively directed to certain of the electrodes as shown in
Shown in
The balloon coating (such as any of those shown in
As shown in
Liposomes, and their related reverse micelles, may contain a core of aqueous solution 72 (
In nature, phospholipids are found in stable membranes composed of two layers (i.e. phospholipid bilayer 71) as shown in
When membrane phospholipids are disrupted, they can reassemble themselves into tiny spheres, smaller than a normal cell, either as bilayers or monolayers. The bilayer structures are liposomes 70. The monolayer structures are called micelles.
The lipids in the plasma membrane are chiefly phospholipids like phosphatidylethanolamine and phosphatidylcholine. Phospholipids are amphiphilic with the hydrocarbon tail of the molecule being hydrophobic, its polar head hydrophilic. As the plasma membrane faces watery solutions on both sides, its phospholipids accommodate this by forming a phospholipid bilayer with the hydrophobic tails facing each other.
Additionally, some embodiments comprising liposomes may use a plurality of electrodes to apply energy to the target tissue such that the uptake of the bioactive into the target tissue is determined using and/or optimized in accordance with the Q10 Rule and within the total energy limits set by the system controller. Some embodiments may further comprise coatings such as polymers, gels, lubricant, electrically conductive or non-conductive materials, and the like on other surfaces of the catheter system.
In some embodiments, the balloon coating may include a chemical solvent that has plaque softening properties as shown in
In some embodiments, the balloon catheter system (
In another preferred embodiment of a balloon catheter system, the balloon portion (
The housing may also accommodate an electrical connector, which may preferably include a plurality of electrical connections, each electrically coupled to electrodes (
As shown in
In some embodiments, the fluid delivery channels may be coupled to a fluid reservoir or lumen holding the fluid comprised of bioactive material. In some embodiments, the inflation medium may contain the fluid to be delivered (
As shown in
The catheter system may also include a tissue analyzer configured to characterize the body tissue. In some embodiments, electrodes may be sensing electrodes, as those described and disclosed herein, that may aide in the characterization of tissue to identify regions, which may be treated or not, using electrical impedance tomography (
Some embodiments described herein may be used to treat atherosclerotic disease by selective fluid delivery in combination with the “gentle heating” to further enhance the fluid treatment, as described herein.
In some embodiments, as shown in
Some embodiments may further comprise coatings such as polymers, gels, lubricant, electrically conductive or non-conductive materials, and the like on surfaces such as the balloon or other surfaces of the catheter system.
Another embodiment for energy induced bioactive material release in a mechanical device is by compaction of the active material with an inert biodegradable. This binary mixture is broken up by exposure to mechanical vibration such as ultrasonic energy when and where needed. The semi solid compaction allows fluid ingress when the vibration breaks surface tension and then is rapidly mixed and dissolved. This liquefaction process may occur over an extended period of time without the energy application, but is greatly enhanced by it.
In yet another preferred embodiment of the present invention shown in
Most preferably, energy is selectively directed to certain of the electrodes by the controller based on the analysis and selection of diseased tissue targeted for treatment (
In some alternate embodiments the balloon may be configured such that the inflation media of the balloon is the fluid comprised of bioactive material 50, as shown in
In U.S. Pat. No. 5,383,873, the full disclosure of which is incorporated herein by reference, Hoey, et al. have described the use of osmotic pumping as a means to deliver drugs in vivo. In yet another embodiment shown in
In yet another preferred embodiment of the present invention shown in
The most preferable embodiments utilize bioactive molecules that are stable under the hyperthermic conditions. Bioactive molecules may be selected to prevent cell proliferation, cell function, receptor-ligand binding, chemotaxis of inflammatory cells to the target tissue, migration of cells in the native artery strata to the diseased tissue, or any combination thereof. The active portion of the bioactive molecule functions to treat the diseased tissue. By way of example, in an arterial atheroma, bioactives may prevent production of hyperplastic tissue by any means, including, but not limited to, cytostasis (prevention of mitosis), receptor maturation for those receptors at or on cells in the targeted tissue that promote hyperplastic tissue formation.
The influx of the bioactive molecule into the diseased tissue is facilitated and/or hastened by the energy-mediated hyperthermia, i.e., cleavage from the intact bioactive molecule (
Additionally, some embodiments may apply energy to the target tissue such that the uptake of the bioactive into the target tissue is optimized in accordance with the Q10 Rule and within the total energy limits set by the controller. Some embodiments may further comprise coatings such as polymers, gels, lubricant, electrically conductive or non-conductive materials, and the like on surfaces such as the balloon or other surfaces of the catheter system.
Selective Delivery of Bioactives to Target Tissue
In some embodiments, an insulating coating such as that shown in
Directionally Delivered Energy and Bioactives During an Angioplasty Procedure
Some embodiments of the present invention provide systems and methods for delivery of bioactives in a lumen in combination with heating during an angioplasty procedure. Angioplasty is a well-established clinical method for crossing and opening a stenotic lesion (
Pressure—due to the balloon in order to open the lumen. The pressure, such as pressure “P” shown in
Heating—due to applied energy (
Bioactives—a plurality of which may be released during the procedure (
Some preferred embodiments include any molecule which will enable prevention or reduction of smooth muscle cell (SMC) proliferation and/or migration from the media to the intima, for example: ceramide, suramin, rapamycin and paclitaxel. The heating of the tissue may have a key role in helping deliver the drug into the lesion or tissue, and deeper into the media.
Other preferred embodiments include proteins such as anti-inflammatory proteins, antibodies and other kinds of proteins which will enable the reduction and healing of the inflammation inside the lesion, or enable prevention or reduction of SMC proliferation and migration. Some embodiments may include proteins that will induce cell apoptosis or oncosis. The heating may have a key role in activating these proteins during the treatment, and if heated quickly during the procedure, enabling the maximum time exposure of the tissue to the proteins. In order to make sure that the proteins will be activated during the procedure, one should take into account the half-life of a protein. The half-life of a protein is the time it takes before any half of the protein pool for that particular protein is still present and functional. The half-life for human proteins depends on many factors but especially environmental factors including temperature. Half-life at very high temperatures (greater than about 50 degrees Celsius) can be in seconds whereas modestly high temperatures (about 42 degrees Celsius to about 45 degrees Celsius) could result in half-life times in the hours range. For a protein-eluting balloon, the proteins are preferably maintained in a storage environment that extends the half-life time. Most preferably, the proteins on the surface of the balloon are stable at temperatures between about 0 degrees Celsius and about 37 degrees Celsius to preserve their bioactive potency until exposed to the in vivo environment and the application of energy. Several of the proteins may be combined to a molecule named Adenosine-5′-triphosphate (ATP). ATP is a multifunctional nucleotide that is important as a “molecular currency” of intracellular energy transfer. In one example, the balloon is covered with the protein and the electrodes are covered with ATP (or the opposite) and the protein will be released with the balloon inflation, and the ATP will be released when the energy will be emitted from the electrodes (or the opposite).
Yet other embodiments may comprise a balloon with cells such as endothelium, or any other type of cell, which may migrate to proximate tissue during the procedure, such as lesion tissue, where the cells may release proteins or antibodies to aide in the healing of inflammation or prevent SMC proliferation and migration. Applied heat may also be used to aide in activating the cells during the procedure.
Yet other embodiments include molecules or proteins that may be attached or become activated when attached to heat shock proteins (HSP). HSP are a group of proteins whose expression is increased when the cells are exposed to elevated temperatures or other stress. For example, HSP27 functions in smooth muscle cells (SMC) migration. The application of RF energy and heating may result in elevation of HSP27 inside the SMC, thereby permitting use of any bioactive, such as a protein, to pass directly to the SMC by using anti-HSP27 antibody. The heat and the outcomes of the heat may facilitate or enhance the use of other molecules or proteins to bind, degrade, inhibit or activate other proteins or cells in the lesion and in the media, in order to prevent restenosis.
In many embodiments, diseased tissue is approached and interrogated using evaluation methods such as tissue impedance measurement (
In many embodiments, energy is directed to a plurality of energized electrodes (
In some embodiments, the energizing of a plurality of electrodes may be used to release bioactives for the treatment of diseased tissue, which for example, may be from a balloon catheter system used for the treatment of vascular disease where such release of bioactives may be from a location in the system comprising the balloon (
In some embodiments, a plurality of electrodes is insulated to prevent the transmission of energy from the balloon catheter system to tissue or conductive objects proximate the balloon portion of the system (
The coatings or layers applied to the balloon (such as any of those shown in
The devices, systems, and methods disclosed herein may be used to selectively deliver energy and/or bioactives in any artery or location in the vasculature, for example, the femoral, popliteal, coronary and/or carotid arteries. While the disclosure focuses on the use of the technology in the vasculature, the technology would also be useful for any luminal obstruction. Other anatomical structures in which the present invention may be used are the esophagus, the oral cavity, the nasopharyngeal cavity, the auditory tube and tympanic cavity, the sinus of the brain, the arterial system, the venous system, the heart, the larynx, the trachea, the bronchus, the stomach, the duodenum, the ileum, the colon, the rectum, the bladder, the ureter, the ejaculatory duct, the vas deferens, the urethra, the uterine cavity, the vaginal canal, and the cervical canal. Furthermore, other tissues may be treated by the present invention where less invasive catheter or endoscopic techniques are preferred.
Where reference numbers appear both in the attached figures and in the corresponding figures of Provisional Application No. 61/114,958 and U.S. patent application Ser. No. 12/616,720, those reference numbers generally identify corresponding structures. However, the reference numbers in Table 1 below identify the listed elements.
While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modifications, adaptations, and changes may be employed. Hence the scope of the present invention should not be limited solely by the appending claims.
The present application claims the benefit under 35 USC 119(e) of U.S. Provisional Application No. 61/177,744 filed May 13, 2009; the full disclosure of which is incorporated herein by reference in its entirety. The subject matter of the subject application is related to that of Provisional Application Ser. No. 61/114,958 filed Nov. 14, 2008 and U.S. patent application Ser. No. 12/616,720 filed Nov. 11, 2009; the full disclosure of which is also incorporated herein by reference.
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| Number | Date | Country | |
|---|---|---|---|
| 20110130708 A1 | Jun 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61177744 | May 2009 | US |
