Patent Application
20070281071
Referring to the drawings, which form a part of this disclosure:
a shows a dispensing device for applying a coating to a workpiece that may be employed in accord with the present invention;
b shows the formation of a droplet that has been formed in accord with the present invention;
c is a side-view in partial cross-section of the dispensing device of
d shows a partial cross-section of another dispensing device that may be employed in accord with the present invention;
a is a cross-sectional view of a portion of a coated strut from a medical device that has been coated in accord with the present invention;
b is a cross-sectional view showing the coated strut of
c shows an arterial stent, which is a medical device that may be coated in accord with the present invention;
The present invention regards the selective coating of one or more surfaces of a workpiece with acoustic energy. In some embodiments this may include coating the outside or side surfaces of the workpiece while not coating the inside surfaces of the workpiece. By coating in this fashion the amount of coating resident on the workpiece may be selectively applied, such as in the drop-on-demand fashion. This can be useful when the amount of coating resident on the workpiece is metered or otherwise of interest. For example, if the workpiece is a stent and the coating contains therapeutic, a reduction in coating may allow the therapeutic to be delivered in a more targeted fashion after the stent is implanted at a target site. The limited use of coating can also conserve coating materials, which themselves may be valuable.
The selective coating of a workpiece may be accomplished in various ways in accord with the present invention. A dispensing device, which can generate droplets of therapeutic or other coating by using a focused acoustic wave or acoustic energy, may be used to direct coating at a surface of a workpiece to be treated. The acoustic wave is typically generated by a piezoelectric transducer and may be focused by an acoustic lens. A dispensing device, such as a drop-on-demand dispensing device, may include one or more piezoelectric transducers for generating multiple acoustic waves. This dispensing device may contain a pool of coating, such as a pool of liquid, that is impacted by the focused acoustic waves or acoustic energy generated by the device at a free surface of the liquid. The walls of the pool may be sized and shaped in certain ways such that these droplets may be generated with a desired firing rate, while the pool of coating may be unaffected by the orientation of the dispensing device. The pool of coating may also be sized to retard clogging or build up of the coating. For example, the opening 108 shown below may be greater than 100 microns, and may be preferably about 300 microns. This may be far greater than the 30-50 micron openings in non-acoustic systems, which may be prone to clogging as they are used. A lid with an opening sized to allow droplets of coating created by the acoustic wave or acoustic energy to move from the device toward the target can be added for coating evaporation control. The lid opening may be much larger than the droplets being created such that the droplet may pass through it without contacting the opening.
The dispensing device may be fluidly connected to a fluid reservoir storing or otherwise including coating that can be applied by the device. The device may also be in communication with a controller that also controls or at least receives signals from a calibration sensor that senses the presence and orientation of a workpiece to be coated. The piezoelectric transducers of the dispensing device, which are sources of acoustic waves, may be isolated from one another and may be individually addressable such that only one droplet may be created by the device at a time. Likewise, multiple droplets may also be created and fired at the workpiece depending upon the coating requirements.
a, 1c, and 1d show a dispensing device 100 in accord with the present invention. Evident in
The transducer, which is used and controlled to generate acoustic waves, may be arranged on and in physical communication with the substrate 102. The transducer 104 in this example includes piezoelectric material which is used to generate an acoustic wave 114. The piezoelectric material of the dispensing device may contain many individual addressable regions that may be isolated from one another and may be controlled to allow placement or direction of coating by the dispensing device. A buffer material, which may be made of a suitable material such as metal, may be used between the transducer 104 and the pool 106 to purify the acoustic waves generated from the transducer prior to the waves reaching the coating. Thus, the buffer material can filter noise from the acoustic wave generated by the piezoelectric material.
An external voltage may be applied to the piezoelectric material of the transducer to activate it. When the voltage is applied at a certain frequency, the piezoelectric material may deform such that it produces mechanical vibrations that can emit acoustic waves through the buffer material into the coating. This wave of high and low pressure may carry energy that acts on the coating. Thus, when the wave is focused at a high enough intensity towards the coating, droplets may be created that pass from the dispensing device to the target area of the workpiece. Piezoelectric materials that may be used include quartz, rochelle salt, lead zirconate titanate, ceramics, barium titanate, tungsten-bronze, gallium orthophosphate, berlinite, polymer materials, and polymer films.
As noted, the transducer 104 may generate an acoustic wave that acts on the coating. The reaction of the coating upon encountering the acoustic wave is shown in
A coating 112 may be stored or otherwise included in the pool 106 of the dispensing device shown in
An aerosol mist, or a combination of mist and a droplet 116, may also be generated by the dispensing device. For instance, the dispensing device 100 can generate droplets of volumes from about 1 femtoliter (fL) or 10−15 to 10 nanoliter (nL) or 10−9. At around 1 fl, an aerosol mist may be formed. At around 2 pL, a droplet may form. The characteristics of the droplet 116 may depend, in part, on the firing pulse and firing rate of the dispensing device 100. If operated at a 25 kHz firing rate a 16 pL droplet 116 may form. If operated at a 50 kHz firing rate a 2 pL droplet 116 may form. Further, if operated at 2 kHz firing rate a mist of 1 fL may form. The acoustic wave may range from about 50-300 MHz. In the example, both aqueous and non-aqueous solutions 112 may be used.
a is a side sectional view of a strut 218 of a stent 230 that may be coated in accord with the present invention. The strut 218 in
b shows another example of how a coating may be applied in accord with the invention. In
c is a side view of an implantable aortic stent 230 including a lattice portion 232 that may be coated in accord with the invention. The stent 230 may be porous or have portions thereof that are porous. The struts 218 shown in
The dispensing device 300 may be controlled by, or at least receive signals from, an electronic signal processor 336, which may instruct the dispensing device 300 to selectively coat portions of the medical implant 330. For example, in
The dispensing device 300 may be adjustable to increase or decrease the distance between the opening 308 and the medical implant 330. The distance between the opening 308 and the medical implant 330 may depend on factors such as the diameter of the opening 308 and the viscosity of the fluid 316 being applied to the medical implant 330. As stated, an exemplary range of values for the diameter of the opening 308 may be from about 100 microns to at least 300 microns.
The track may be controlled by a drive mechanism 338. The drive mechanism 338 can be use an electrical, mechanical, or hydraulic drive source, and may use combinations thereof. For example, motors, endless belts, gearing, or hand cranks may be used.
In
Also as seen in
In other arrangements, wherein the medical implant 330 may be orientated differently, such as vertically, the configurations may be different than that described above. As stated herein, in these configurations, the support structure may provide for movement of the medical implant 330 in both the x, y, and z planes or around the diameter of the medical implant 330 such that the dispensing device 300 may move around the entire outside surface of the medical implant 330.
Also shown in
The visual detection member 544 may be used in any one of, or any combination of, the following ways. First, the visual detection member 544 may be used to determine the position and orientation of the stent 530 by scanning an identifiable feature on the stent 530 such as a strut 532 before or during coating. Second, the visual detection member 544 may be used to determine the position and orientation of the opening 508 of the dispensing device 500 by observing the dispensing device 500 directly before or during coating. Third, the visual detection member 500 may be used to monitor the amount coating on the stent 530 as the coating process proceeds. The visual detection member 544 may be any number of systems including optics, laser scanners, video cameras, visible light scanners, and invisible light scanners.
It should be understood that the foregoing descriptions of various examples of the dispensing device, support structure, and workpiece are not intended to be limiting, and any number of modifications, combinations, and alternatives of the examples may be employed to facilitate the effectiveness of the coating of target surfaces of the workpiece.
As described above, the dispensing device may be in fluid communication with a fluid source. The fluid source may contain any one of several possible coatings to be placed on the workpiece.
The coating, in accord with the embodiments of the present invention, may comprise a polymeric and or therapeutic agent formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. A suitable list of drugs and/or polymer combinations is listed below. The term “therapeutic agent” as used herein includes one or more “therapeutic agents” or “drugs”. The terms “therapeutic agents” or “drugs” can be used interchangeably herein and include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), viruses (such as adenovirus, andenoassociated virus, retrovirus, lentivirus and α-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences.
Specific examples of therapeutic agents used in conjunction with the present invention include, for example, pharmaceutically active compounds, proteins, cells, oligonucleotides, ribozymes, anti-sense oligonucleotides, DNA compacting agents, gene/vector systems (i.e., any vehicle that allows for the uptake and expression of nucleic acids), nucleic acids (including, for example, recombinant nucleic acids; naked DNA, cDNA, RNA; genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector and which further may have attached peptide targeting sequences; antisense nucleic acid (RNA or DNA); and DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences (“MTS”) and herpes simplex virus-1 (“VP22”)), and viral, liposomes and cationic and anionic polymers and neutral polymers that are selected from a number of types depending on the desired application. Non-limiting examples of virus vectors or vectors derived from viral sources include adenoviral vectors, herpes simplex vectors, papilloma vectors, adeno-associated vectors, retroviral vectors, and the like. Non-limiting examples of biologically active solutes include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPACK (dextrophenylalanine proline arginine chloromethylketone); antioxidants such as probucol and retinoic acid; angiogenic and anti-angiogenic agents and factors; anti-proliferative agents such as enoxaprin, angiopeptin, rapamycin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylic acid, and mesalamine; calcium entry blockers such as verapamil, diltiazem and nifedipine; antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors; antimicrobials such as triclosan, cephalosporins, aminoglycosides, and nitrofurantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, Warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet factors; vascular cell growth promotors such as growth factors, growth factor receptor antagonists, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; survival genes which protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; and combinations thereof. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogeneic), genetically engineered if desired to deliver proteins of interest at the insertion site. Any modifications are routinely made by one skilled in the art.
Polynucleotide sequences useful in practice of the invention include DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides can also code for therapeutic proteins or polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic proteins and polypeptides include as a primary example, those proteins or polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body. In addition, the polypeptides or proteins that can be injected, or whose DNA can be incorporated, include without limitation, angiogenic factors and other molecules competent to induce angiogenesis, including acidic and basic fibroblast growth factors, vascular endothelial growth factor, hif-1, epidermal growth factor, transforming growth factor ∀ and ∃, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor ∀, hepatocyte growth factor and insulin like growth factor; growth factors; cell cycle inhibitors including CDK inhibitors; anti-restenosis agents, including p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation, including agents for treating malignancies; and combinations thereof. Still other useful factors, which can be provided as polypeptides or as DNA encoding these polypeptides, include monocyte chemoattractant protein (“MCP-1”), and the family of bone morphogenic proteins (“BMP's”). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively or, in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedgehog” proteins, or the DNA's encoding them.
As stated above, coatings used with the exemplary embodiments of the present invention may comprise a polymeric material/drug agent matrix formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. Curing of the mixture typically occurs in-situ. To facilitate curing, a cross-linking or curing agent may be added to the mixture prior to application thereof. Addition of the cross-linking or curing agent to the polymer/drug agent liquid mixture must not occur too far in advance of the application of the mixture in order to avoid over-curing of the mixture prior to application thereof. Curing may also occur in-situ by exposing the polymer/drug agent mixture, after application to the luminal surface, to radiation such as ultraviolet radiation or laser light, heat, or by contact with metabolic fluids such as water at the site where the mixture has been applied to the luminal surface. In coating systems employed in conjunction with the present invention, the polymeric material may be either bioabsorbable or biostable. Any of the polymers described herein that may be formulated as a liquid may be used to form the polymer/drug agent mixture.
In accord with the embodiments, the polymer used to coat the medical device is provided in the form of a coating on an expandable portion of a medical device. After applying the drug solution to the polymer and evaporating the volatile solvent from the polymer, the medical device is inserted into a body lumen where it is positioned to a target location. In the case of a balloon catheter, the expandable portion of the catheter is subsequently expanded to bring the drug-impregnated polymer coating into contact with the lumen wall. The drug is released from the polymer as it slowly dissolves into the aqueous bodily fluids and diffuses out of the polymer. This enables administration of the drug to be site-specific, limiting the exposure of the rest of the body to the drug.
The polymer used in the exemplary embodiments of the present invention is preferably capable of absorbing a substantial amount of drug solution. When applied as a coating on a medical device in accordance with the present invention, the dry polymer is typically on the order of from about 1 to about 50 microns thick. In the case of a balloon catheter, the thickness is preferably about 1 to 10 microns thick, and more preferably about 2 to 5 microns. Very thin polymer coatings, e.g., of about 0.2-0.3 microns and much thicker coatings, e.g., more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coating onto a medical device. Such multiple layers are of the same or different polymer materials.
The polymer of the present invention may be hydrophilic or hydrophobic, and may be selected from the group consisting of polycarboxylic acids, cellulosic polymers, including cellulose acetate and cellulose nitrate, gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydrides including maleic anhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinyl aromatics, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters including polyethylene terephthalate, polyacrylamides, polyethers, polyether sulfone, polycarbonate, polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene, halogenated polyalkylenes including polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins, polypeptides, silicones, siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate and blends and copolymers thereof as well as other biodegradable, bioabsorbable and biostable polymers and copolymers. Coatings from polymer dispersions such as polyurethane dispersions (BAYHDROL®, etc.) and acrylic latex dispersions are also within the scope of the present invention. The polymer may be a protein polymer, fibrin, collagen and derivatives thereof, polysaccharides such as celluloses, starches, dextrans, alginates and derivatives of these polysaccharides, an extracellular matrix component, hyaluronic acid, or another biologic agent or a suitable mixture of any of these, for example. In one embodiment of the invention, the preferred polymer is polyacrylic acid, available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205, the disclosure of which is hereby incorporated herein by reference. U.S. Pat. No. 5,091,205 describes medical devices coated with one or more polyisocyanates such that the devices become instantly lubricious when exposed to body fluids. In another preferred embodiment of the invention, the polymer is a copolymer of polylactic acid and polycaprolactone.
The examples described herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the exemplary embodiments of the present invention. Moreover, while certain features of the invention may be shown on only certain embodiments or configurations, these features may be exchanged, added, and removed from and between the various embodiments or configurations while remaining within the scope of the invention. Likewise, methods described and disclosed may also be performed in various sequences, with some or all of the disclosed steps being performed in a different order than described while still remaining within the spirit and scope of the present invention.
