Patent Publication Number: US-2007100321-A1

Title: Medical device

Description:
TECHNICAL FIELD  
      The invention concerns a medical device for insertion into a bodily vessel to treat an aneurysm having an aneurysm neck.  
     BACKGROUND OF THE INVENTION  
      Intracranial aneurysms are currently treated by engaging neurosurgical clipping or using several minimally invasive techniques. For example, interventional neuroradiology uses minimally invasive methods to treat aneurysms. Other methods include: coiling, stenting and coiling; and using gels, glues, or fibrin sealants.  
      There is a desire to treat aneurysms such that it does not leave any mass (such as solid coils) or foreign body material in a healed aneurysm.  
     SUMMARY OF THE INVENTION  
      In a first preferred aspect, there is provided a medical device for insertion into a bodily vessel to treat an aneurysm having an aneurysm neck, the device comprising: 
          a mechanically expandable device expandable from a first position to a second position, said mechanically expandable device is expanded radially outwardly to the second position such that the exterior surface of said mechanically expandable device engages with the inner surface of the vessel so as to maintain a fluid pathway through said vessel;     a therapeutically effective amount of a chemical compound comprising a biosynthesis accelerator to stimulate cell growth; and     a polymer mixed with the chemical compound to manage the release rate of the chemical compound;     wherein the mechanically expandable device provides a support for the release of the chemical compound within the aneurysm to stimulate cell growth within the aneurysm and close the aneurysm neck.        

      The accelerator may be a threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol compound. Specifically, the accelerator may be L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) and therapeutically acceptable salts thereof.  
      Synthetic ceramide analog, L-PDMP, may stimulate the biosynthesis of glycosphingolipids (GSL) such as Lactosylceramide (LacCer) and glucosylceramide (GIcCer), which in turn stimulates cell growth.  
      The polymer may be biocompatible, biodegradable, hydrophilic, and has a high degree of swelling.  
      The polymer may be in a solid or highly viscous form, or is highly elastic.  
      The polymer may comprise a hydrophilic shell and a hydrophobic core or solely consists of a hydrophilic composition.  
      The polymer may be selected from the group consisting of: synthetic biodegradable polymers such as Poly (glycolic acid) (PGA), Poly (lactic acid) (PLA), Poly (lactic-co-glycolic acid) (PLGA), poly (ecaprolactone), Polyanhydride, poly (orthoesters), polyphosphazane; biodegradable polymers from natural sources such as modified polysaccharides (cellulose, chitin, dextran) and Modified proteins (fibrin, casein); and hydrogels or superabsorbants such as Poly (ethylene oxide) (PEO), Poly (ethylene glycol) PEG, Methylacrylate (MAA), Maleic anhydride (MAH), Polyacrylamide, Poly (hydroxyethyl methacrylate), Poly (N-vinyl pyrrolidone), Poly (vinyl alcohol).  
      The L-PDMP compound may be coated on 2D or 3D platinum coils.  
      The mechanically expandable device may comprise a generally tubular structure having an exterior surface defined by a plurality of interconnected struts having interstitial spaces therebetween.  
      The polymer and chemical compound may be released into the aneurysm by a delivery catheter passing through the mechanically expandable device and between the struts of the mechanically expandable device proximal to the aneurysm.  
      The polymer and chemical compound may be in the form of micro-spheres, spherical, or cylindrical (with coils).  
      The delivery catheter may comprise a distal compartment for securing the chemical compound, and a proximal compartment, the distal and proximal compartments being separated by an elastic membrane, wherein pressure applied to the proximal compartment is translated to the distal compartment causing the polymer and chemical compound to be released from the delivery catheter into the aneurysm.  
      The delivery catheter may further comprise a valve to allow exit of the polymer and chemical compound but prevents blood from entering the delivery catheter.  
      The polymer and the chemical compound may be in the form of a membrane attached to the outer surface of the mechanically expandable device, such that when the mechanically expandable device is expanded, the membrane faces the aneurysm and the chemical compound is released towards the aneurysm.  
      The membrane may be a single layer or comprises multiple layers.  
      The membrane may be biodegradable.  
      The polymer may be solid or porous.  
      The polymer may be amorphous or semi-crystalline.  
      The device may further comprise radiopaque markers incorporated in the polymer to improve the visibility of the polymer and chemical compound during deployment.  
      The device may further comprise radiopacifers such as barium sulphate, zirconium dioxide or iodine.  
      The mechanically expandable device may be biodegradable.  
      The mechanically expandable device and polymer may biodegrade at different rates.  
      In a second aspect, there is provided a method for treating an aneurysm having an aneurysm neck, the method comprising: 
          positioning a mechanically expandable device into a bodily vessel proximate to the aneurysm neck;     releasing a therapeutically effective amount of a chemical compound comprising a biosynthesis accelerator to stimulate cell growth within the aneurysm;     wherein the mechanically expandable device provides a support for the release of the chemical compound within the aneurysm to stimulate cell growth within the aneurysm and close the aneurysm neck.        

      The method may further comprise passing a delivery catheter through the mechanically expandable device and between the struts of the mechanically expandable device proximal to the aneurysm, to deliver the chemical compound.  
      The method may further comprise mechanically pushing the chemical compound from the delivery catheter and into the aneurysm.  
      The method may further comprise applying pressure in a proximal compartment of the delivery catheter to cause the chemical compound to be pushed out of a distal compartment of the delivery catheter and into the aneurysm. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      An example of the invention will now be described with reference to the accompanying drawings, in which:  
       FIG. 1  is an illustration of the molecular structure of Poly (glycolic acid);  
       FIG. 2  is an illustration of the molecular structure of Poly (lactic acid);  
       FIG. 3  is an illustration of the molecular structure of Poly (lactic-co-glycolic acid);  
       FIG. 4  is a diagrammatic view of a delivery catheter delivering the polymer and L-PDMP compound;  
       FIG. 5  is a diagrammatic view of the polymer in two forms;  
       FIG. 6  is a diagrammatic view of the polymer in membrane form;  
       FIG. 7  is an illustration of the molecular structure of L-PDMP;  
       FIG. 8  is a diagrammatic view of a stent positioned across an aneurysm;  
       FIG. 9  is a diagrammatic view of the delivery catheter delivering the polymer and L-PDMP compound into the aneurysm;  
       FIG. 10  is a diagrammatic view of the polymer and L-PDMP compound filling the aneurysm and embolising;  
       FIG. 11  is a diagrammatic view of a membrane attached to the stent for releasing the L-PDMP compound into the aneurysm;  
       FIG. 12  is a diagrammatic view of the L-PDMP compound degrading and the aneurysm healing; and  
       FIG. 13  is a diagrammatic view of the membrane biodegrading and the aneurysm healing. 
    
    
     DETAILED DESCRIPTION OF THE DRAWINGS  
      Referring to the drawings, the medical device generally comprises three components: a stent  20 , a polymer  30 ,  41 ,  42  and L-threo-1-Phenyl-2-Decanoylamino-3-Morpholino-1-Propanol (L-PDMP) compound. A first embodiment of the medical device comprises the stent  20  and a biodegradable, hydrophilic polymer  30  mixed with the L-PDMP compound. A second embodiment of the medical device comprises the stent  20  with a biodegradable membrane  41 ,  42  with at least one layer of the hydrophilic polymer  30 .  
      The stent  20  may be made of the following materials utilizing different deployment mechanisms: 
          Balloon expandable stent made from: stainless steel, PtW alloy, or Ti;     Self-expandable stent made from NiTi; or     Biodegradable stent.        

      If the stent  20  is deployed by balloon expansion, it is made from stainless steel, platinum tungsten alloy or titanium. If the stent  20  is deployed by self expansion, it is made from Nitinol.  
      Suitable biodegradable materials for the stent  20  include: 
          Poly (glycolic acid) (PGA) as shown in  FIG. 1 ;     Poly (lactic acid) (PLA) as shown in  FIG. 2 ;     Poly (lactic-co-glycolic acid) (PLGA) as shown in  FIG. 3 ;     Poly (ecaprolactone) (PCL);     Polyanhydride (PA); or     Poly (orthoesters) (POE).        

      If the stent  20  is made from a biodegradable material, foreign material in the vessel  6  is reduced or eliminated after the aneurysm  5  is healed. The stent  20  also biodegrades while the aneurysm  5  is healing.  
      Referring to  FIGS. 4, 5  and  6 , the polymer  30 ,  41 ,  42  is a medium for the attaching the L-PDMP compound. The polymer  30 ,  41 ,  42  manages the release rate of the L-PDMP compound and also provides a scaffold for cell growth. The shape of the polymer  30 ,  41 ,  42  may include: micro-spheres  30 , spherical  30 , cylindrical (with coils), or be in the form of a thin membrane  41 ,  42 .  
      The polymer  30  is biocompatible, biodegradable, hydrophilic, has a high degree of swelling. The polymer  30  has a fast swelling rate (from instantaneous to approximately 5 to 6 minutes). The polymer  30  may be in a solid or highly viscous form, or is highly elastic.  
      The polymer  30  is based on any one of the following materials: 
          Synthetic biodegradable polymer such as Poly (glycolic acid) (PGA), Poly (lactic acid) (PLA), Poly (lactic-co-glycolic acid) (PLGA), poly (ecaprolactone), Polyanhydride, poly (orthoesters), polyphosphazane;     Biodegradable polymers from natural sources such as modified polysaccharides (cellulose, chitin, dextran) and Modified proteins (fibrin, casein); and     Hydrogels or superabsorbants such as Poly (ethylene oxide) (PEO), Poly (ethylene glycol) PEG, Methylacrylate (MAA), Maleic anhydride (MAH), Polyacrylamide, Poly (hydroxyethyl methacrylate), Poly (N-vinyl pyrrolidone), Poly (vinyl alcohol).        

      Referring to  FIG. 7 , L-PDMP is a chemical compound which promotes a glycolipid biosynthesis-accelerating effect. This is described in U.S. Pat. No. 5,041,441 and Japanese Patent 254623/1989. L-PDMP or its derivatives are used to enhance healing and facilitate closing of the aneurysm  5 . L-PDMP is used with other types of enzyme GaIT-2 enhancing compounds (including L-PDMP and its derivatives) for the purpose of cell proliferation, including targeting cells such as endothelial, smooth muscle and other types of cells that are available in the intracranial vascular system. Cell proliferation embolizes and effectively obstructs blood circulation to the aneurysm  5 . Also, the aneurysm  5  is naturally healed because the aneurysm  5  is deprived of blood circulation and nutrient supply.  
      The L-PDMP compound is locally released within the aneurysm  5 . The release profile of the L-PDMP compound has an initial burst release within the first few hours, to activate biosynthesis and form an outer sphere of emboli, thus enhancing the process of closing the aneurysm neck  5  with a biological cell based substrate. This is followed by a steady state release lasting for 1 to 2 weeks. The L-PDMP compound is designed to activate biosynthesis after it is released. The L-PDMP compound stimulates the biosynthesis of glycosphingolipids (GSL), specifically Lactosylceramide (LacCer) and glucosylceramide (GIcCer). GSLs exist as constitutional component of cell surface membranes and are closely related to a cellular function. GIcCer is precursors for other complex GSLs and are involved in proliferation of cells. LacCer is present in vascular cells such as smooth muscle cells, endothelial cells, macrophages, neutrophils, platelets and monocytes, all of which are involved in the natural healing process. It also serves as a lipid second messenger that orchestrates a signal transduction pathway, leading to cell proliferation.  
      The acceleration of GSL biosynthesis leads to the following cellular response: 
          fibroblast and endothelial cell growth;     promotion of collagen formation and smooth muscle cell proliferation; and     occlusion of the aneurysm and neointima coverage of the aneurysm neck. The aneurysm is removed from normal blood circulation.        

      The healing process begins when the aneurysm neck  5  is filled by the proliferation of cells activated by the L-PDMP compound. The membrane  30 ,  41 ,  42  and stent  20  biodegrade over time.  
     EXAMPLE 1  
      In the first embodiment, the medical device includes a stent  20  with a biodegradable hydrophilic viscous composition  30 , that is, a highly viscous solution of biodegradable, hydrophilic material mixed with the L-PDMP compound. In a specific example, the L-PDMP compound is coated on 2D or 3D platinum coils. Alternatively, one coil is used in parallel with gel spheres used as markers.  
      The stent  20  assists with the delivery of the L-PDMP compound to a selected aneurysm site  5  by supporting or scaffolding the vessel  6  and protecting and securing the L-PDMP composition introduced into the aneurysm  5 . A delivery catheter  40  is provided to deploy the L-PDMP compound in a controlled manner to treat the aneurysm  5 . After the stent  20  is positioned at a selected aneurysm site  5 , the L-PDMP compound is deployed using the delivery catheter  40  to create an embolization environment at the aneurysm site  5 . This eventually causes the aneurysm neck  5  to close as a result of the biological reaction caused by L-PDMP compound and subsequent biological activity.  
      The polymer  30  is delivered as a single particle or as connected smaller particles. The microstructure of the polymer  30  may be solid or porous (micropores (10-100 nm), macropores (100 nm-10 μm) or superpores (˜100 μm). The polymer  30  is either amorphous or semi-crystalline. If radiopaque markers are used, platinum coils are incorporated in the polymer  41 ,  42 . Radiopacifers are added to the polymer  41 ,  42  such as barium sulphate (BaSO 4 ), zirconium dioxide (ZrO 2 ) and iodine.  
      Referring to  FIG. 5   a , the particle(s)  30  facilitate the rate and degree of swelling as well as the rate of degradation. These particles  30  consist entirely of a hydrophilic polymer, for fast release and degradation. Alternatively, referring to  FIG. 5   b , the particle(s)  30  consists of an outer shell of a hydrophilic polymer with a core made of hydrophobic polymer, such as polyanhydride, poly (ortho esters) or poly (L-lactic acid), for greater sustained release and extend degradation time if needed.  
      Referring to  FIG. 8 , the stent  20  is deployed and expanded against the aneurysm neck  5  to create a scaffold or support. The polymer  30  and L-PDMP compound is secured in a distal compartment at the distal tip of the delivery catheter  40 . Next, the delivery catheter  40  with the hydrophilic substrate is introduced to the aneurysm  5 . The hydrophilic substrate is a mixture of hydrophilic viscous biodegradable material with L-PDMP compound.  
      Referring to  FIG. 9 , the distal tip of the delivery catheter  40  is introduced to the aneurysm neck  5  between the stent struts. When the distal tip is positioned in or near the aneurysm neck  5 , the polymer  30  and L-PDMP compound is released from the distal compartment by mechanically pushing the L-PDMP compound with a core wire in the inner lumen of the delivery catheter  40 . The tip of the delivery catheter  40  has a valve to allow the L-PDMP compound to exit but prevents blood from entering to reduce premature swelling of the polymer  30  and activation of the L-PDMP. The L-PDMP compound is pushed out of the inner lumen of the delivery catheter  40  by a core wire. The core wire functions similarly to a piston in a hydraulic cylinder.  
      Another way to deploy the L-PDMP compound is to modify the delivery catheter  40  by providing an inner lumen proximal/mid-shaft compartment and distal compartment within the delivery catheter  40 . The L-PDMP compound is secured within the distal compartment. The proximal and distal compartments of the delivery catheter  40  are separated by a super elastic membrane. When pressure is applied to the proximal compartment, the membrane transfers the pressure from proximal compartment to the distal compartment and thus pushes the L-PDMP compound out of the delivery catheter  40  and into the aneurysm  5 .  
      Referring to  FIG. 10 , upon release, the polymer  30  and L-PDMP compound immediately absorbs the blood within the aneurysm  5  and swells to a size larger than the stent struts, at a fixed rate. The inner space of the aneurysm  5  is filled up after deployment is completed and the L-PDMP compound is released and activated. A biological cell based substrate is formed and swells and expands. It grows in size very quickly size, larger than the distance between stent struts. At this point, the stent struts prevent the substrate from returning towards the vessel. After the substrate occupies the aneurysm dome  5 , it starts releasing the L-compound and activating the cell proliferation and embolization process. The L-PDMP compound is designed to be active only during its release and facilitates the embolization process as long as it needed. The L-PDMP compound ceases activity after its release is seized. After the aneurysm dome  5  is filled by newly developed emboli, blood supply into the aneurysm  5  is reduced and eventually stopped. The biodegradable material gradually biodegrades leaving the healing site with a natural vessel wall.  
     EXAMPLE 2  
      In the second embodiment, the medical device includes a stent  20  with a biodegradable membrane  41 ,  42  made from biodegradable material mixed with the L-PDMP compound. The stent  20  is deployed at the aneurysm site  5  against its neck. The membrane  41 ,  42  obstructs blood circulation through the aneurysm neck to the aneurysm  5 . The L-PDMP compound is encased in layers of the membrane  42 . The L-PDMP compound starts to release and activate cell proliferation towards the aneurysm neck and dome  5 .  
      The membrane  41 ,  42  is made from a mixture of the biodegradable polymer and L-PDMP compound. The direction that the L-PDMP compound is released is controlled and directed outwards towards the vessel wall and aneurysm neck.  
      Referring to  FIG. 6   a  and  6   b , if the polymer is in the form of a membrane  41 ,  42  to cover the aneurysm  5 , the polymer is a single layer of biodegradable polymer  41  or is multi-layered  42 ; consisting of both biodegradable materials. The microstructure of the polymer  41 ,  42  may be solid or porous (micropores (10-100 nm), macropores (100 nm-10 μm) or superpores (˜100 μm). The polymer  41 ,  42  is either amorphous or semi-crystalline. If radiopaque markers are used, platinum coils are incorporated in the polymer  41 ,  42 . Radiopacifers are added to the polymer  41 ,  42  such as barium sulphate (BaSO 4 ), zirconium dioxide (ZrO 2 ) and iodine.  
      Referring to  FIG. 11 , a thin film membrane  41  is made of a biodegradable polymer and the L-PDMP compound. The membrane  41  is attached to stent struts. Alternatively, a non-biodegradable polymer can be used. When the stent  20  is deployed, the membrane  41  obstructs blood circulation through the neck of the aneurysm  5 . The L-PDMP compound is activated and released towards the aneurysm neck and dome  5 .  
      Referring to  FIGS. 12 and 13 , the polymer  30 ,  41 ,  42  slowly degrades after deployment. The degradation/release time varies from  10  to  14  days to  1  to  2  months. The degradation is controllable by mechanisms and structures described. This enables the aneurysm to  5  heal completely, and leaves a natural vessel wall  6 .  
      The medical device is suitable for different aneurysm sizes, including small aneurysms (&lt;15 mm), large aneurysms (15-25 mm), giant aneurysms (25-50 mm) as well as different aneurysm types such as Berry aneurysm or wide neck aneurysm (neck&gt;4 mm and/or dome-to-neck ratio&lt;2).  
      It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the scope or spirit of the invention as broadly described.  
      The present embodiments are, therefore, to be considered in all respects illustrative and not restrictive.