Abstract:
A medical implant that delivers therapeutic via microtubes and a method of making the same is provided. In one embodiment a biologically implantable structure adapted to fit within the body of a patient is provided. This structure may have a plurality of individual microtubes in physical communication with its outer surface, the microtubes containing or carrying a therapeutic. In another embodiment a method of manufacturing an implantable medical appliance is provided. This method includes placing a pliant stratum of microtubes onto a biologically implantable medical structure and then applying a therapeutic to the pliant stratum to cover or fill the microtubes.

Description:
RELATED APPLICATIONS  
       [0001]     This is a continuation of copending U.S. patent application Ser. No. 09/954,179, which was filed on Sep. 18, 2001, and is entitled “Microtubes for Therapeutic Delivery.” This application claims the benefit of and incorporates the &#39;179 application in its entirety. 
     
    
     TECHNICAL FIELD  
       [0002]     The present invention regards the delivery of therapeutic to a target site. More specifically, the present invention regards the use of therapeutic laden microtubes, implanted near or at a target site, to deliver therapeutic to a target site of a patient.  
       BACKGROUND  
       [0003]     The delivery of therapeutic to a target site is an oft-repeated procedure in the practice of contemporary medicine. Therapeutic may be delivered to a target site through direct injection as well as through implants that somehow carry the therapeutic. Implants that are used to deliver therapeutic may serve several purposes including reinforcing fatigued lumens and bridging ruptured vessels. In each of these cases the therapeutic being delivered may not only facilitate the short term healing associated with the introduction of the implant, but may, also, provide long term delivery of therapeutic to the surrounding areas.  
         [0004]     One example of an implant is an expandable stent. Expandable stents are tube-like medical implants designed to support the inner walls of a patient&#39;s lumen. They can be self-expanding or, alternatively, may require external forces to expand them. In either case they are often deployed through the use of a catheter of some kind.  
         [0005]     Because of the direct contact of the stent with the inner walls of the lumen, stents have been coated with various compounds and therapeutics to enhance their effectiveness. When this coating is haphazardly applied or has somehow been removed during the stent&#39;s manufacture or delivery the stent&#39;s effectiveness can be compromised because a uniform dosage of therapeutic from the coating of the stent to its surroundings may not be plausible.  
       SUMMARY OF THE INVENTION  
       [0006]     A medical implant that delivers therapeutic via microtubes and a method of making the same is provided. In one embodiment a biologically implantable structure adapted to fit within the body of a patient is provided. This structure may have a plurality of individual microtubes in physical communication with its outer surface, the microtubes containing or carrying a therapeutic.  
         [0007]     In an alternative embodiment a method of manufacturing an implantable medical appliance is provided. This method includes placing a pliant stratum of microtubes onto a biologically implantable medical structure and then applying a therapeutic to the pliant stratum to cover or fill the microtubes. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]      FIG. 1  is an enlarged cross-sectional view of five microtubes as may be employed in the present invention.  
         [0009]      FIG. 2  is an enlarged perspective view of a pliant stratum of microtubes covered in and containing a therapeutic in accord with an embodiment of the present invention.  
         [0010]      FIG. 3  is a side view of a stent covered with a pliant stratum of microtubes, the Figure having an enlarged portion to highlight the microtubes attached to the stent, all in accord with another embodiment of the present invention.  
         [0011]      FIG. 4  is an enlarged cross-sectional view taken along line II-III of  FIG. 3 .  
         [0012]      FIG. 5  is a view of a system for applying a therapeutic to cover and fill microtubes dispersed over stent in accord with another embodiment of the present invention.  
         [0013]      FIG. 6  is a view of system for applying a therapeutic to cover and fill the microtubes dispersed over a stent in accord with another embodiment of the present invention.  
         [0014]      FIG. 7  is an enlarged view of microtubes dispersed in a polymer matrix as may be used to coat an implantable medical implant in accord with another embodiment of the present invention.  
         [0015]      FIG. 8  is an enlarged view of abraded microtubes dispersed in a polymer matrix as may be used to coat a medical implant in accord with another embodiment of the present invention.  
         [0016]      FIG. 9  is a cross-sectional view of a pliant layer of microtubes used to form a medical implant in accord with another embodiment of the present invention.  
         [0017]      FIG. 10  is a cross-sectional view of a pliant layer of microtubes used as a medical implant in accord with another embodiment of the present invention. 
     
    
     DETAILED DESCRIPTION  
       [0018]      FIG. 1  provides an illustration of an enlarged cross-sectional view of several different microtubes as may be used in various embodiments of the present invention. As can be seen in  FIG. 1 , microtubes may be sized to be smaller than a human hair, being a few tens of microns in diameter, and may be constructed with various cross-sectional configurations, including U-, Y-, star-, and oval-shaped cross-sections. The microtubes may be hollow closed vessels, sleeves having one or more open ends, and solid structures. The microtubes in  FIG. 1  are illustrated as being hollow with at least one open end. The microtubes may be made from a number of materials including metals, ceramics, and hard carbon. One advantage of employing microtubes in accord with the present invention is the increased surface area associated with their use.  
         [0019]      FIG. 2  provides an enlarged view of a pliant stratum  20  of microtubes  21  having a therapeutic  25  coating both the inner  26  and outer  22  surfaces of microtubes  21 . In this embodiment, the microtubes  21  have a circular cross-section although they may also have any other desired cross-section, including those shown in  FIG. 1 . The microtubes  21  are enmeshed with each other so that they form a pliant stratum  20 . This pliant stratum  20  may behave as a felt-like mat being pliable and moldable. The microtubes  21  may be positioned randomly with respect to each other in this embodiment as illustrated  FIG. 2 . Alternatively, they may be arranged in some sort of pattern to create the pliant stratum  20 . In either situation, it is preferable that the microtubes be enmeshed such that they interact with and support one another so as to substantially behave as a single structure or unit.  
         [0020]     The therapeutic  25  may be applied to the microtubes  21  by soaking the microtubes until the therapeutic  25  coats or infiltrates the microtubes  21 . The microtubes  21  may be positioned next to each other in a such a manner as to create voids or spaces between them. These voids or spaces may be filled with therapeutic by dipping the stratum of microtubes  21  in a therapeutic and allowing the therapeutic to wick up into and around the microtubes  21 .  
         [0021]      FIG. 3  is a side view of a stent  30  covered with microtubes  33  as may be employed in an alternative embodiment of the present invention. The enlarged portion  31  of  FIG. 3  illustrates the junction point of two struts  35  of the stent  30  that have been covered with microtubes  33 . As can be seen in  FIG. 3  the microtubes  33  may completely cover the struts  35  of the stent  30  and may also extend out past the struts  33  as indicated by numeral  34 . By completely covering the struts  35  therapeutic carried by the microtubes  33  may be more uniformly released to a target site in the body.  
         [0022]     When the implant is expandable or otherwise reconfigurable, it is preferable to secure the pliant stratum to points on the implant that will deflect or move the least during the implant&#39;s reconfiguration. By securing the stratum to these minimal deflection points the magnitude of the forces that will be placed on the stratum during the implants reconfiguration may be reduced. By reducing the forces during reconfiguration the likelihood that the stratum will be dislodged, impaired or otherwise destroyed during reconfiguration may be reduced. In the embodiment of  FIG. 3  the stratum may be secured to the struts  35  near the joints  32  to reduce the forces that may be placed on the stratum by the stent during the expansion of the stent  30 .  
         [0023]      FIG. 4  is an enlarged cross-sectional view taken along line III-III of  FIG. 3 . In  FIG. 3  the strut  35  has been completely coated with a stratum of pliant microtubes  33 . Although the microtubes  33  are cylindrical in shape in this figure they could have numerous other shapes including those illustrated in  FIG. 1 . The microtubes  33  do not create a smooth external surface in this embodiment but, rather, create a rough profile dictated by the random orientation of the microtubes  33  on the strut  35 .  
         [0024]     The microtubes  33  in this embodiment may be attached to stents or other appliances using various attachment methods. One of these methods would include heating the microtubes and the stent&#39;s struts while they were in contact with each other. Here, the molecules or atoms of the struts and the microtubes may intermingled due to thermal agitation, thereby diffusion bonding the microtubes to the struts. Metallic microtubes may also be attached to the stent by brazing with a biocompatible brazing material such as gold. Alternatively, the microtubes may be mixed into an electrolytic plating material, such as gold, that may then be used to surface plate the stent. Laser or resistance welding may also be used to affix the pliant stratum to the implant. One advantage of laser welding is that it may allow for pinpoint securement of the stratum to the implant. Microtubes may also be attached to the implant using a pressurized thermal bonding process or polymer adhesive.  
         [0025]     In another embodiment, rather than creating a pliant stratum and then applying it to an implant, the microtubes may simply be sprayed directly onto the implant or the implant may be dipped into a vat of polymer or other coating that contains the microtubes.  
         [0026]      FIG. 5  shows a system  50  that may be used to coat a stent  51  with therapeutic laden microtubes  53  in accord with alternative embodiment of the present invention. This system  50  may employ a reservoir  55 , a line  54 , and a nozzle  52  in fluid communication with the reservoir  55  via the line  54 . In this embodiment a therapeutic  53 , or a mixture of microtubes and polymer adhesive, may be held in the reservoir  55 , and may be sprayed at the workpiece  51  in order to coat the workpiece  51 . Polymer adhesives suitable for such coatings include silicones, (e.g. polysiloxanes and substitutes polysiloxanes), polyurethanes (including polycarbonate urethanes), thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers, ethylene-propylene terpolymer rubbers, polyamide elastomers, polyolefin elastomers, and combinations thereof. If the workpiece had been previously coated with microtubes, a therapeutic based mixture may be stored and sprayed at the workpiece  51 . Conversely, if the workpiece had not been previously treated, a mixture of microtubes and therapeutic may be sprayed at the workpiece  51 .  
         [0027]      FIG. 6  shows a process of soaking a stent  63  previously coated with microtubes in accord with another alternative embodiment of the present invention. The coating process in this embodiment may be performed in a vacuum chamber  64  to facilitate the process and improve the wicking of the therapeutic into and around the microtubes already present on the stent  63 . The vacuum force in this embodiment may be generated by using a vacuum pump  65  attached to the vacuum chamber  64  via a line  67  having a valve  66 .  
         [0028]      FIG. 7  provides an enlarged view of microtubes  72  surrounding or covering a surface of a workpiece  79 . Here the microtubes  72  are dispersed in a polymer matrix  74 , such as an epoxy, having a viscosity that prevents the matrix  74  from filling the microtubes. The polymer matrix  74  may also include poly methyl methacrylate, poly methyl pentane, poly ether ether ketone, liquid crystal polymers, polysulfones, polyimides and other suitable “hard” polymers with similar properties. The polymer matrix may be made from a single polymer or a composite of polymers. The microtubes  72  in this embodiment may provide additional structural support to the polymer matrix due to their interaction. In this embodiment the polymer matrix may harden to a substantially smooth surface  70  with some microtubes being exposed at the surface  70  after the matrix  74  has cured.  
         [0029]      FIG. 8  provides an enlarged side view of abraded microtubes  82  dispersed in a high viscosity polymer matrix  84  in accord with another alternative embodiment of the present invention. The microtubes  82 , is this embodiment, may be placed in a polymer before it is hardened. The surface  80  of the polymer may be abraded (as shown in  FIG. 8 ) to uncover the open ends of the microtubes exposed at the surface  80  of the polymer matrix. Uncovering the ends of the microtubes through an abrasion process enables the microtubes to more effectively draw therapeutic into their internal lumens. In this embodiment, the microtubes provide additional structural support to the polymer matrix as well as facilitate the delivery of the therapeutic to a target site. Generally longer microtubes are desired in this embodiment.  
         [0030]      FIG. 9  provides a cross-sectional cutaway view of microtubes  92  dispersed in a high viscosity polymer matrix  93 . Here the polymer matrix has been formed like a medical implant  94  such as a graft. In this embodiment, the microtubes  92 , have a circular cross-section and are formed in the shape of a medical implant rather than being sprayed, dipped or otherwise applied to an implant as described above.  
         [0031]      FIG. 10  provides a side view of a pliant stratum  104  of microtubes  102  in accord with another embodiment of the present invention. In this embodiment, the pliant stratum  104  may be formed like a medical implant, such as an embolic agent  100  which fills an aneurism in an artery  101 , and may be placed at the target site to deliver therapeutic to the target site. In other words, rather than providing the structural support of the stents described above, the present implant  104  simply delivers therapeutic to the target site without providing any additional structural benefits.  
         [0032]     The microtubes  102  in this embodiment may be enmeshed with each other and sintered together to form a structural member such as a pliant stratum  104 . The therapeutic  105  may be applied to the microtubes  102  by soaking or any other effective method. Once prepared, this implant may be inserted into the artery or other target site of the body for the short or long term delivery of therapeutic to the target site.  
         [0033]     The medical implant described above may be any one of numerous medical implants including expandable stents, stent grafts, peripherally-inserted central catheters, (PICCs), arterioventricular shunts (a-v shunts), angio-catheters, embolic agents, vena cava filters, aneurism coils, implantable prostheses, and implantable fasteners. These implants, as well as others, may be carried to a target site within the body by a medical device and then deployed in order to provide medical relief or repair to the targeted site. They may also be deployed through more invasive procedures.  
         [0034]     The implant in each of the above embodiments may also contain a tracer chemical to assist the practitioner positioning or otherwise deploying the implant. For example, when a tracer is employed an imaging system may be used to track the progress and position of a stent as it is snaked through a lumen in the body en route to reaching the target site.  
         [0035]     The therapeutic can include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus (such as adenovirus, andenoassociated virus, retrovirus, lentivirus and a-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences.  
         [0036]     Examples of therapeutics used in conjunction with the present invention include, 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; agents blocking smooth muscle cell proliferation such as rapamycin, angiopeptin, and monoclonal antibodies capable of blocking smooth muscle cell proliferation; 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 endogeneus 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 injection site. The delivery medium is formulated as needed to maintain cell function and viability. Any modifications are routinely made by one skilled in the art.  
         [0037]     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 of the invention 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 ÿ and ÿ, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor ÿ, 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 (“BMPs”). 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 BMPs 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 DNAs encoding them.  
         [0038]     A medical implant that delivers therapeutic via microtubes and a method of making the same is provided. The above-described embodiments are illustrative examples of the present invention. As will be evident to one of skill in the art, modifications to these embodiments as well as entirely new embodiments are plausible without departing from the spirit and scope of the present invention.