Patent Publication Number: US-2011067703-A1

Title: Medical device with antimicrobial layer

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of prior U.S. application Ser. No. 11/337,995, filed Jan. 24, 2006, which is a continuation of prior U.S. application Ser. No. 10/425,030. filed Apr. 29, 2003, the specifications of which are incorporated by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to medical devices, and more particularly, to a method of adding an antimicrobial function to a medical device, and a system and apparatus thereof. 
     2. Description of the Related Art 
     Ventilator-associated pneumonia may be a cause of morbidity in critically ill patients. Approximately 250,000 cases of Ventilator Associated Pneumonia (VAP) are reported each year. The mortality associated with VAP is approximately 23,000 patients annually. (Engelmann, J. et al.; Ventilator-Associated Pneumonia; Seminars in Infection Control. Vol. 1. No. 2 2001). 
     Prolongation of hospitalization, ventilation, and management of VAP infections may add up to seven days in additional patient care and over $5,000 in incremental treatment costs per patient. The costs associated with VAP may be in excess of $1.5 billion per year. It would be desirable if costs associated with the prevention and intervention of VAP could be reduced. 
     VAP may be associated with the long-term use of invasive positive pressure medical devices such as mechanical ventilators or tracheal tubes. Medical devices may be suction catheters, gastric feeding tubes, esophageal obturators, esophageal balloon catheters, oral and nasal airways, bronchoscopes, breathing circuits, filters, heat and moisture exchanges, or humidifiers. Tracheal tubes may be airway management devices such as endotracheal (ET) tubes, tracheostomy tubes, or transtracheal tubes. 
     Airway management devices such as ET tubes may be associated with VAP because they may provide a substrate upon which bacterial colonization can occur. Bacteria for colonization may come from inhaled aerosols and nasal, oropharyngeal, and gastric secretions. Bacteria for colonization may also result from the formation of microbial adhesions or biolilms on the surfaces of contaminated medical devices. Colonization, in turn, may lead to microaspiration of pulmonary pathogens and related lung infection. 
     As shown in  FIG. 1 , bacteria  18  for colonization may “flow” down an ET tube  10  from the mouth along with oral, nasal or gastric secretions. Such bacteria may flow to the area immediately before the cuff  4  and pool there, eventually becoming sessile on the outer surface of the ET tube. Microorganisms may adhere to an abiotic surface and allow complex biofilms to form. The complex biofilm may protect the microorganisms against antibiotic action. 
     The accretion of antibiotic-resistant biofilms may form a reservoir of infecting microorganisms which may then migrate from the outer surface past the protective cuff and contaminate the trachea and lungs. Lung secretions containing microorganisms, blood, mucous, and cellular debris may colonize on the tip and inner lumen of the ET to form biofilms of antibiotic-resistant microorganisms. Such interluminal biofilms may occlude the breathing tube or migrate back into the lungs to cause further infection. 
     The process of removing these biofilms and secretions with conventional suction catheters may lead to the aspiration of fragments of biofilms or infected aerosols. Contaminated suction catheters, feeding tubes, ventilator tubing and breathing circuits, or filters, heat and moisture exchangers, nebulizers, heated humidifiers, or other related breathing tubes or devices may be sources of microorganism contamination and thus may contribute to biofilm formation. 
     One method of mitigating colonization of the tube surface by bacteria is by suctioning. Suctioning of subglottic secretions that may collect above the ET cuff may reduce the likelihood of aspiration. Routine suctioning of subglottic secretions may be associated with significant reduction of VAP. The Mallinckrodt Hi-Lo Evac™ tracheal tube is an example of an ET tube with an integral subglottic suctioning apparatus. 
     Suctioning, aspirating, or draining subglottic secretions, however, requires the frequent intervention on a clinician in order to be effective. It would be desirable if the incidence of VAP could be reduced without extensive reliance on suctioning. It would be desirable the incidence of VAP could be reduced without requiring additional activities on the part of the clinician in order to be effective. 
     Another method of mitigating colonization of the tube surface by bacteria is by administration of large doses of antibiotics. Administering large doses of antibiotics, however, may promote the development of more disease resistant bacteriotypes and is thus undesirable. 
     SUMMARY 
     In a first embodiment, a medical device includes a conduit for a fluid which comprises a wall having an outer surface, the wall comprising a hydrophobic polymer, with an outer layer disposed on the outer surface. the outer layer comprising a first quantity of a hydrophilic polymer having an antimicrobial compound substantially dispersed therein, the antimicrobial compound comprising a predetermined amount of phosphorus-based glass having a predetermined quantity of a metal substantially. dispersed therein, and wherein the wall and the outer layer are formed by extrusion. 
     In a second embodiment, a method of making a medical device includes the actions of providing a hydrophobic polymer. extruding the hydrophobic polymer to form a wall, producing an antimicrobial compound comprising a predetermined amount or phosphorus-based glass having a predetermined quantity of a metal substantially dispersed therein, mixing the antimicrobial compound and a hydrophilic polymer, and extruding a layer of the hydrophilic polymer having the antimicrobial compound substantially dispersed therein over an outer surface of the wall. 
     In a third embodiment, a system for making a medical device includes means for providing a hydrophobic polymer, means for extruding the hydrophobic polymer to form a wall, means for producing an antimicrobial compound comprising a predetermined amount of phosphorus-based glass having a predetermined quantity of a metal substantially dispersed therein, means for mixing the antimicrobial compound and a hydrophilic polymer, and means for extruding a layer of the hydrophilic polymer having the antimicrobial compound substantially dispersed therein over an outer surface of the wall. 
     In a fourth embodiment, a medical device includes a conduit for a fluid which comprises a wall having an outer surface. the wall comprising a hydrophobic polymer, with an outer layer disposed on the outer surface. the outer layer comprising a first quantity of a hydrophilic polymer having an antimicrobial compound substantially dispersed therein, the antimicrobial compound comprising a predetermined amount of phosphorus-based glass having a predetermined quantity of a metal substantially dispersed therein, and wherein the wall and the outer layer are formed by molding. 
     In a fifth embodiment, a method of making a medical device includes the actions of providing a hydrophobic polymer, molding the hydrophobic polymer to form a wall, producing an antimicrobial compound comprising a predetermined amount of phosphorus-based glass having a predetermined quantity of a metal substantially dispersed therein, mixing the antimicrobial compound and a hydrophilic polymer, and molding a layer of the hydrophiloc polymer having the antimicrobial compound substantially dispersed therein over an outer surface of the wall. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
         FIG. 1  shows a medical device in situ in a trachea: 
         FIG. 2  shows a plan view of a medical device according to an embodiment of the invention: 
         FIG. 3  shows a schematic of an extruder for use with an embodiment of the invention; and 
         FIG. 4  shows a section of a medical device according to the embodiment of  FIG. 2 . 
     
    
    
     DETAILED DESCRIPTION 
     Medical devices arc devices which may be used around or inserted into a living body. One such medical device may be a tube such as an ET tube. Although an ET tube is used in the following examples, the invention is not limited to ET tubes. The invention may apply in various embodiments to other types of medical devices, such as tubes, catheters, stents, feeding tubes, breathing circuits, intravenous tubes, breathing tubes, circuits, and related airway accessories such as connectors, adapters, filters, humidifiers, nebulizers, and prosthetics as well. 
     Microbes may attach themselves to a surface before beginning colonization of the surface and the formation of biofilms. The colonization of a surface by microbes may require the microbes to become sessile on the surface before attaching themselves to the surface. Preventing the microbes from becoming sessile may thus inhibit the colonization of a surface by microbes. 
     A biofilm may be described, in general, as a colony cooperative. A biofilm may furthermore be of mixed species with a high degree of specialization or order among individual members of the biofilm. Additionally, normally inactive or quiet genes of these organisms may up-regulate, i.e., turn on, while the organisms settle on a surface, but prior to building the biofilm structure. Up-regulated organisms may become more adaptable to the colony way of life and may also become excessively virulent. 
     Particles of biolilm may fall into the lungs during treatment. These particles may produce VAP. VAP may also be produced by simple planktonic (free-floating) single cell microbes that may come from leakage around the cuff, or air entering from the tube lumen. Bacterial may become sessile and also resistant to antibiotics by accretion of a protective glycocalyx coating that becomes a biofilm over time. This biofilm may then change its texture, becoming smooth, thus adding further to its defense against antibiotics. Polyvinyl chloride (PVC) may, in some cases, contribute to the formation of such biofilms. 
     Microbes may be more likely to become sessile on hydrophobic surfaces such as e.g., those of polyethylene (PE), polypropylene (PP), silicone rubber such as polydimethylsiloxane (PDMS), polyester, polyurethane, and PVC. Hydrophobic surfaces reject water. Hydrophilic surfaces, in contrast, which are characterized by an affinity for water, may inhibit microbes from attaching themselves to the surface, and consequently inhibit the formation of biofilms as well. 
     Friction between a medical device and surrounding tissue may cause irritation in the surrounding tissues such as vocal cords. Such friction may make it more difficult to insert a medical device in the first place. Such friction may also produce trauma to the surrounding tissues. It would be desirable for the surface of a medical device to have lower surface friction, so that it slid across surrounding tissues more easily. 
     Biofilms may adhere to surfaces of medical devices, resulting in a buildup of dried secretions. It would be desirable for a medical device to have a slippery surface so that biofilms may be less likely to adhere to the surface of the medical device. It would be further desirable for a medical device to have a slippery surface so that biofilms that did build up might be easier to remove by suctioning techniques, so less frequent suctioning might be required. 
     A medical device such as an ET tube may have a cuff. Such a cuff may form a seal around the tube to block secretions that may otherwise be aspirated. It would be desirable for such a cuff to swell in thickness upon absorbing moisture from the surrounding tissues. It would further be desirable if such a swelling resulted in an ability to seal at a lower pressure, such as a lower contact pressure between the cuff and the surrounding tissues. 
     Successive concentrations and rarefactions of moisture may occur across a medical device during intubation. It would be desirable if a surface of a medical device could transport moisture across such concentration gradients by, for example, osmosis. It would further be desirable if a hydrophilic layer on an inner diameter of a tracheal tube could condense and absorb moisture from exhaled gases in a cooler region of the tube and re-evaporate the warmed moisture to drier or cooler inhalation gases. 
     Medical devices, and in particular ET tubes, are often formed of hydrophobic materials such as PVC. Microbes may be inhibited from attaching themselves to a hydrophobic surface by applying a hydrophilic layer over the hydrophobic surface. A medical device may be formed of e.g., a hydrophobic material coated with a hydrophilic material to give it a hydrophilic surface. The hydrophilic coating may be, e.g., a polyurethane (PU), such as medical grade hydrophilic thermoplastic polyurethane. Hydrophilic coatings may be applied by a coating operation. 
     A medical device, such as an ET tube, may promote respiration. It would be desirable if the carbon dioxide (CO.sub.2) content of respiration could be determined, so as to determine whether the intubation is proper. It would further be desirable if a hydrophilic surface of a medical device were injected with a chemical, such as an acid-base color dye, to indicate CO.sub.2 concentration. 
     Destroying the microbes before they have a chance to become sessile and colonize the surface of the medical device could mitigate the conditions promotion colonization. It would further be desirable for the incidence of VAP to he reduced without extensive reliance on large doses of antibiotics. 
     Some elements, such as some metals, may have a deleterious effect on microbes. Some of these metals may be oligodynamic, in that they have an effect in small quantities only. Some metals may kill microbes by destroying their cell walls or by interfering with the metabolic functions of the cells. These metals may thus have antimicrobial or antiseptic properties. Some examples of such metals are copper, silver, or gold. Silver or silver ions (Ag.sup.+), for example, may be adsorbed on the bacterial cell surface as an RSAg complex. The RSAg complex may immobilize the respiratory activity of the cell and eventually kill the cell. 
     The hydrophilic layer may therefore further contain a metal such as copper, silver, or gold in a metal hearing material. In several exemplary embodiments, the metal may be elemental silver. powdered silver, silver ions (Ag.sup.+), or a silver bearing material like silver oxide (AgO). The hydrophilic layer may thus be an antimicrobial (AM) layer. In this way the colonization-inhibiting properties of the hydrophilic surface can be reinforced by antimicrobial properties. 
     It may be desirable for the silver to be released over time, while the medical device is in use. In one embodiment, therefore, the silver bearing material may be a phosphorus-based glass material that dissolves in water at a rate that may be a function of its particular formulation. The glass may also contain trace amounts of other elements, such as calcium oxide (CaO). The rate at which silver is released may further be a function of the rate at which the phosphorus-based glass material dissolves in water. The silver, or the phosphorus-based glass material, or both may be powdered. 
     The hydrophilic layer may be wetted with water prior to use. The hydrophilic layer may also attract and absorb water available in the host during use. The absorbed water may then dissolve the silver bearing phosphorus-based glass material and release the silver into the surroundings of the medical device. The rate at which the silver bearing phosphorus-based glass material dissolves in water may in turn be a function of the amount of water available to dissolve it. 
     The release of silver over time, which is defined as the elution rate and is measured in .lamda.-grams/cm.sup.2/day. may thus be tailored to the specific needs of the application by specifying the formulation of the phosphorus-based glass material. In one embodiment, the silver bearing material, may be made up of about 5-10% by weight, e.g. about 7.5% phosphorus-based glass by weight. Such a material is available from Giltech Limited, 12 North Harbour Industrial Estate, Ayr, Scotland, Great Britain KA8 8BN. 
     In one embodiment, the elution rate should be up to about 0.01 .mu.-grams/cm.sup.2/day. In another embodiment, the elution rate should be between about 0.01 and 1.0 .mu.-grams/cm.sup.2/day. In a preferred embodiment, the elution rate should be, e.g. about .mu.-grams/cm.sup.2/day. 
     In other embodiments, bioactive pharmaceutical agents such as a bronchodilator, an anti-inflammatory agent, or a local anesthetic may be substantially dispersed in a phosphorus-based glass material within a hydrophilic layer. Such bioactive pharmaceutical agents may be delivered to and absorbed by adjacent tissues in substantially the same manner as silver. Regulation and control of dosage, elution rate, and thickness in substantially the same manner as silver may also provide a beneficial pharmacologic or therapeutic action. 
     A hydrophilic coating may be applied to the surface of a medical device by, e.g. dipping, spraying, washing, or painting the hydrophilic coating on the surface. Since the volume of a coating is proportional to the thickness of the coating, however, a hydrophilic surface formed in one of these ways may have only a small volume within which silver is retained. Furthermore, dipping, spraying, washing, or painting formed the hydrophilic coating, the silver may be present only on the surface of the coating. 
     Since the volume of a coating is necessarily small, the hydrophilic coating may have a limited capacity to hold silver prior to delivery. Furthermore, since the silver may only reside on the surface of the hydrophilic coating, the silver may wash off prematurely, early in the use of the medical device, leaving less silver to prevent future bacteria from becoming sessile and colonizing the surface of the tube. 
     It would be desirable if a hydrophilic layer were extruded or molded along with the medical device, since controlling the thickness of the extrusion or mold could then optimize the volume of the hydrophilic layer. 
     In one embodiment, a medical device may be formed by extruding a wall of hydrophobic material along with one or more layers of an AM material. In another embodiment, a medical device may be formed by molding a wall a hydrophobic material along with one or more layers of an AM material. Standard PVC material may form the wall of the medical device, along with one or more layers of an AM material. The AM layer may be formed on an inner or an outer surface of the medical device wall. The AM layer may be comprised of, e.g. polyurethane, such as a medical grade hydrophilic thermoplastic polyurethane into which has been substantially dispersed a silver bearing phosphorus-based glass material. 
     In one embodiment, the AM layer may be within a range of about 0.002 mm-2.5 mm in thickness, or about 0.13 mm in thickness. In another embodiment, the AM layer may be within a range of about 0.002 mm-2.5 mm in thickness. In a third embodiment, the AM layer may be up to about 6.35 mm in thickness. In one embodiment, substantially similar materials may form both the inner and outer surfaces of the tube. 
     In one embodiment, an inner or an outer AM layer may be simultaneously extruded with the medical device wall in a process commonly known as “co-extrusion.” In another embodiment, both an inner and an outer AM layer maybe extruded simultaneously with the medical device wall in a process sometimes referred to as “tri-extrusion.” 
     Applying an AM layer to the surface of a medical device may reduce the incidence of VAP. There may also be a production cost savings to be gained by extruding an AM layer on a medical device over a conventional coating process. 
     In one embodiment, an AM layer is also applied to the cuff portion of the medical device. In a preferred embodiment only the outer surface of the cuff will have an AM layer since only the outer surface of the cuff is exposed to the patient. An AM layer may be applied to the outer surface of the cuff portion of the medical device by, e.g., co-extruding the AM layer with the wall of the cuff. 
     The cuff wall may subsequently be expanded to form a thin-walled cuff device. The cuff wall may be expanded by, e.g., a process such as extrusion blow molding. In this process, a core or mandrel of the extruder has apertures to admit a gas such as pressurized air or an inert gas like nitrogen. into the medical device in the neighborhood of the cuff. After a length of medical device, or prison, has been extruded, a mold clamps the medical device around the mandrel. As gas is admitted to the cuff area through the mandrel the cuff expands against the mold. In the alternative, the cuff wall may he expanded in a second discrete expansion process following an extrusion or molding process, such as with a shuttle blowmolding process. 
     In  FIG. 2  is shown a medical device  100  according to a first embodiment of the invention. Medical device  100  may be a catheter, a stent, a feeding tube, an intravenous tube, an ET tube, a circuit, an airway accessory, a connector, an adapter, a filter, a humidifier, a nebulizer, or a prosthetic, in various embodiments. 
     Medical device  100  may have a conduit  102  for a fluid and an inflatable cuff  104  disposed at a first end  114  of conduit  102 . The fluid may be a gas, an aerosol, a suspension, a vapor, or droplets of liquid dispersed in a gas. A lumen  116  may be disposed alongside conduit  102  to inflate cuff  104 . In one embodiment, a wall  112  of conduit  102  is made of a hydrophobic polymer, a hydrophilic polymer and an antimicrobial compound. 
     As shown in section  4 - 4  shown in  FIG. 4 , a wall  412  of conduit  102  is made of a hydrophobic polymer with an outer layer  406  composed of a hydrophilic polymer and an antimicrobial compound disposed on an outer surface  408  of wall  412 . An inner layer  404  composed of a hydrophilic polymer and an antimicrobial compound may further be disposed on an inner surface  410  of wall  412 . Outer surface  408  may also be an outer surface of cull  104 . 
     In one embodiment, wall  412  is a hydrophobic compound containing a hydrophilic polymer and an antimicrobial compound. In one embodiment, a hydrophilic polymer and an antimicrobial compound arc substantially dispersed, i.e., mixed with a hydrophobic compound forming wall  412  of conduit  102 . In another embodiment, hydrophilic polymer and antimicrobial compound are substantially dispersed within cuff  104 , with e.g. a hydrophobic compound forming cuff  104 . 
     In a second embodiment, a method of making a medical device  100  comprises the actions of providing a hydrophobic polymer, a hydrophilic polymer and an antimicrobial compound, combining the hydrophilic polymer and the antimicrobial compound, forming the hydrophobic polymer into a wall  412  of a conduit  102 , and substantially simultaneously extruding the hydrophilic polymer and the antimicrobial compound as an outer layer  406  on a outer surface  408  of conduit  102 . 
     In another embodiment, the method Further includes Forming the hydrophobic polymer into a cuff  104  on an end of conduit  102 , and substantially simultaneously extruding the hydrophilic polymer and the antimicrobial compound on a surface of cuff  104 . 
     In another embodiment, the method Further includes substantially simultaneously extruding the hydrophilic polymer and the antimicrobial compound as an inner layer  404  on an inner surface  410  of conduit  102  while wall  412  and outer layer  406  are being extruded. 
     In one embodiment, a resulting thickness of the hydrophilic polymer and the antimicrobial compound layer  404  is controlled by the extruder. In an alternative embodiment. extruding the hydrophobic polymer, the hydrophilic polymer and the antimicrobial compound together forms a wall  412  of conduit  102 . 
     In one embodiment, a wall  412  of conduit  102  may be extruded from a hydrophobic compound while an inner layer  404  is extruded in a first predetermined formulation of a hydrophilic polymer and an antimicrobial compound on an inner surface  410  of conduit  102 . In another embodiment, a wall  412  of conduit  102  may be extruded from a hydrophobic compound while an outer layer  406  is extruded in a second predetermined formulation of a hydrophilic polymer and an antimicrobial compound on an outer surface  408  of conduit. In an alternative embodiment, an outer layer  406  composed of a hydrophilic polymer and the antimicrobial compound in a second predetermined formulation may be, e.g., molded on outer surface  408  of conduit  102 . In an alternative embodiment. the hydrophobic polymer, hydrophilic polymer and the antimicrobial compound may be e.g., compounded together and extruded to form a wall  412  of conduit  102 . 
     In one embodiment, the hydrophobic polymer, hydrophilic polymer-and the antimicrobial compound may be, e.g., compounded together and extruded to form a wall  114  of cuff  104 . In an alternative embodiment. the hydrophilic polymer and the antimicrobial compound may be, e.g., molded on an outer surface of cuff  104 . In an alternative embodiment, the hydrophilic polymer and the antimicrobial compound may be, e.g., extruded on an outer surface of cuff  104 . In an alternative embodiment, cuff  104  may be, e.g., formed by extruding the hydrophobic polymer, hydrophilic polymer and antimicrobial compound into a cuff  104 , and expanding cull  104 . 
     In a third embodiment, a system for making a medical device  100  includes means for providing a hydrophobic polymer, means for extruding the hydrophobic polymer to form a wall  412 , means For producing an antimicrobial compound comprising a predetermined amount of phosphorus-based glass having a quantity of silver substantially dispersed therein, means for mixing the antimicrobial compound and a hydrophilic polymer, and means for extruding an outer layer  406  of the hydrophilic polymer having the antimicrobial compound substantially dispersed therein over an outer surface  408  of the wall  412 . 
     In one embodiment, conduit  102  is formed by molding the hydrophobic polymer, the hydrophilic polymer and the antimicrobial compound in a mold. Either the inner or the outer layers  404 ,  406 , or both, may be molded in a mold with the wall  412 . The molding process may be overmolding, insert molding, blow-molding, laminate blow-molding, gas assisted molding, thermoplastic molding, injection molding, or compression molding. 
     A wall  412  may be formed into a tube covered by either an inner or the outer layers  404 ,  406  and inserted in a mold. The tube maybe be heated in order to promote conformance to the shape of the mold. A fluid such as pressurized air may be pumped into the tube so that the tube is forced or expanded against an inner surface of the mold. A thickness of layers  404  or  406  may be controlled by a clearance between wall  412  and an inner surface of the mold. 
     In one embodiment, a wall  412  and either an inner or outer antimicrobial compound layers  404  and  406  may be forced into a mold cavity to form the medical device. In another embodiment, a wall  412  made of hydrophobic polymer is placed in a mold and the hydrophilic polymer and the antimicrobial compound layers  404  and  406  are molded around it. 
     In  FIG. 3  is shown an extruder  300  for use with an embodiment of the invention.  FIG. 3  may include a main extruder  302  to extrude hydrophobic polymer for the wall  412 , a satellite extruder  304  For the AM material, and a satellite extruder  306  for a radio-opaque material. Satellite extruder  304  may feed matching gear pumps  308  to split the AM material into separate layers, one of which may be an inner layer  404  and the other an outer layer  406 . A head  310  collects the material streams From the individual satellite extruders, combines them with the flow of material for wall  412  and extrudes them into a medical device  100 . 
     While the invention has been described in detail above, the invention is not intended to be limited to the specific embodiments as described. It is evident that those skilled in the art may now make numerous uses and modifications of and departures from the specific embodiments described herein without departing from the inventive concepts.