Abstract:
Microbial growth on the surface of a valve of a voice prosthesis and optionally the cartridge or ring supporting the valve, is inhibited by providing antimicrobial activity at a level sufficient to retard growth of a microbial film by dispersing an inorganic antimicrobial agent such as silver oxide or an organic antimicrobial agent such as triclosan or butyl paraben dispersed in a medical grade silicone elastomer. The valve, ring or cartridge is in contact with body fluids containing microorganisms and nutrients therefor. The antimicrobial surface can interfere with or inhibit the growth of a biofilm, bacterial layer or a yeast layer. The body of the prosthesis may also contain an antimicrobial surface as long as it is non-toxic to the tissue it contacts.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of Ser. No. 10/487,614 filed Feb. 19, 2004 (issued Sep. 27, 2005 as U.S. Pat. No. 6,948,526), which is a national phase filing of PCT/US02/41274 filed Dec. 20, 2002, which claims benefit of U.S. provisional application Ser. No. 60/344,444 filed Dec. 28, 2001; and is a continuation in-part of Ser. No. 09/833,961 filed Apr. 11, 2001. 
    
    
     TECHNICAL FIELD 
     The present invention relates to microbial-resistant medical devices and, more particularly, this invention relates to a voice prosthesis having a valve which retards growth of microbial organisms. 
     BACKGROUND OF THE INVENTION 
     Medical devices, particularly synthetic resin prosthetic devices which are used in environments where micro-organisms such as fungi or yeast and/or bacteria are actively growing, can become covered with a biofilm colonized layer to the point where the function of the device is impaired. After growth of the biofilm microbial layer, filaments can grow and descend into the body or wall of the polymeric device and detrimentally affect its physical properties until the device no longer functions. The fouled device must be cleaned or discarded. 
     Whenever a prosthesis is in contact with moisture in a warm, dark environment, the surfaces are subject to microbial growth, usually containing a predominant amount of  Candida  usually mixed with bacteria. The microbial growth can interfere with the functioning of the prosthesis, requiring removal of the prosthesis for disposal or cleaning. The microbial growth is a persistent problem in the management and care of patients who have had their larynx removed and utilize a voice prosthesis since the prosthesis is exposed to a non-sterile, humid, warm, nutrient rich environment. 
     There are several options for restoring speech to patients who have had their larynx removed. One procedure is to surgically create a puncture or fistula between the trachea and the esophagus. A tracheoesophageal voice prosthesis containing a one-way valve such as a BLOM-SINGER® voice prosthesis is inserted into the tracheoesophageal fistula. The one-way valve protects the airway during swallowing but opens under positive pressure from the trachea. The voice prosthesis, thus, permits a patient to divert air from the lungs into the esophagus and out through the mouth. Speech is created during passage of air through the upper part of the esophagus. 
     The prosthesis maintains the fistula open, transfers air from the trachea to the esophagus for voice production and prevents esophageal leakage into the trachea during swallowing. The oral cavity which extends into the throat has a high microbial population. However, the prosthesis being in contact with moisture in a warm, dark, nutrient rich environment is subject to growth of commonly found micro-organisms, typically  Candida  on the valve and the retaining flange. The microbial attack is currently being studied. The microbial attack organisms and sequence of events are quite complex and are still undetermined. The microbial growth on and into the soft silicone resin can interfere with function of the valve and can cause the flange to wrinkle and the valve to leak. The fouled device must be cleaned or discarded and replaced with a new device. 
     One type of current low pressure voice prosthesis can be removed by the patient every few days and can be replaced with a clean prosthesis. The removed prosthesis is soaked in hydrogen peroxide to sterilize and clean the valve and flange. Some patients however, have difficulty managing frequent removal and reinsertion of the prosthesis. Others, who are physically handicapped are not able to remove, sterilize, or reinsert the prosthesis. 
     A longer dwelling, low pressure voice prosthesis has been developed that can remain in place in the tracheoesophageal fistula for many weeks or months, depending on the patient and conditions of use. The patient can confidently use the prosthesis for longer periods. The longer dwelling voice prosthesis is not removable by the patient. Trips to a health care specialist to remove and replace the prosthesis are greatly extended providing increased comfort and lower cost to the patient. 
     Another type of soft voice prosthesis includes a rigid stiffening ring  14  inserted into a groove in the soft body of the prosthesis. Though the ring stiffens the body adjacent the valve it does not prevent distortion of the body by muscular movement or distortion of the valve by growth of yeast. 
     U.S. Pat. No. 5,578,083 issued Nov. 26, 1996, discloses the use of a stiff cartridge to support the soft silicone prosthesis and to provide a seat for the valve which is connected to the cartridge by a tab in slot design. Another cartridge-valve design includes a one piece sleeve-valve which is stretched over and seats in a cylindrical groove in the cartridge as disclosed in U.S. Ser. No. 10/487,614, filed Feb. 19, 2004, the disclosure (051) of which is incorporated herein by reference. However, microbial growth can still proceed to a point at which the valves can not be reliably sealed. 
     Microbial growth on the valve can also cause distortion of the shape of the valve or form wrinkles in the body of the valve which prevents the valve from closing. Leaking also appears to be due to distortion of the valve body adjacent to the seat of the valve and to microbial growth on the seat. Forming the valve with an arcuate dome shape increased resistance to folding or bending of the valve. However, some valves still leaked after extended placement in a fistula. 
     The use of silicone elastomer is limiting because of the open matrix nature of the material. The open nature of silicone allows microorganisms to attach to and sometimes burrow through the material. The attachment of microorganisms at the valve seat interface can interfere with creating a seal. Attachment of microorganisms to the flexible hinge area can reduce the flexibility of the hinge, and can also be a precursor for other microorganisms to burrow into the silicone, effectively changing the shape of the silicone and thereby interfering with the ability for the valve to seal correctly. In extreme cases, microorganisms can attach and burrow into the esophageal side of the valve to the point where the sealing seat of the valve is altered in shape. 
     Historically, microbial ingrowth resistance has come from selection of hard plastics and metals that reduce attachment of microorganisms to certain components. These materials were restricted from use in the hinge area and other areas that required flexibility and resilience. The components requiring this flexibility and resilience have traditionally been molded from silicone elastomer. 
     In other medical devices, antimicrobial coatings have been available for some years. Coatings typically do not last the lifetime of the product on the highly flexible hinge, as the coating tends to flake off. Once this happens, the hinge is left unprotected and is exposed to the effects of microorganisms. 
     Application of antimicrobial substances to silicone articles can also come by way of solvent introduction. In this method, the silicone part is soaked with a solvent containing a dissolved antimicrobial agent. The silicone part is removed from the solvent and the solvent is allowed to evaporate. The dissolved antimicrobial agent is then deposited in the matrix of the silicone elastomer. There are several variations of this method. This method is limited to antimicrobial agents that are soluble in an effective solvent and to the uncertainty of exact load level. This method also requires the additional steps and regulations associated with working with solvents. 
     The use of polymers having antimicrobial properties is disclosed in PCT Publication No. WO98/04463 published March 1998. Through the voice prosthesis device formed of flurosilicone polymer showed same initial success, examination of returned devices from a clinical study showed significant microbial growth on both the posterior aspect and periphery of the valve flap and on the inner surface of the valve hood which interfered with movement of the valve flap. Any further use of the flurosilicone device was abandoned. 
     
       
         
               
             
               
               
             
           
               
                   
               
               
                 List of Prior Art 
               
             
          
           
               
                 Patent No. 
                 Patentee 
               
               
                   
               
               
                 3,932,627 
                 Margraf 
               
               
                 4,054,139 
                 Crossley 
               
               
                 4,483,688 
                 Akijama 
               
               
                 4,563,485 
                 Fox, Jr. et al. 
               
               
                 4,581,028 
                 Fox, Jr. et al. 
               
               
                 4,603,152 
                 Laurin, et al. 
               
               
                 4,612,337 
                 Fox, Jr. et al. 
               
               
                 4,615,705 
                 Scales et al. 
               
               
                 5,019,096 
                 Fox, Jr. et al. 
               
               
                 5,567,495 
                 Modak et al. 
               
               
                 5,624,704 
                 Darouiche et al. 
               
               
                 5,772,640 
                 Modak et al. 
               
               
                 5,902,283 
                 Darouiche et al. 
               
               
                 6,083,208 
                 Modak et al. 
               
               
                 6,106,505 
                 Modak et al. 
               
               
                   
               
             
          
         
       
     
     Statement of Prior Art 
     Margraf discloses the use of a silver-heparin-allantoin complex to a form non-thrombogenic, self sterilizing surface on prosthetic valves or arterial grafts. The complex can be coated or impregnated into the surface of the valve or graft. 
     Crossley coats the surface of an urinary tract catheter with Ag or Ag compounds by dispersing silver or its compound in resin. The surface is abraded to expose the silver material. The coating contains 10% by weight of silver (col 4, line 10). The coating can be extremely thin such as those deposited by electroless deposition (col 4, lines 16-18). 
     Fox, Jr. et al., U.S. Pat. No. 4,563,485 discloses use of silver norfloxacin or silver perfloxacin to render muscular graft prosthesis formed from resins such as silicone infection resistant. 
     Fox, Jr. et al., utilizes silver metal salts of sulfonamides or other antimicrobials for the same purpose. 
     Fox, Jr. et al., discloses and claims a method of preparing an infection resistant material by solvent impregnation of the material with a silver salt and another compound and reaction in situ to form a silver salt. 
     Scales et al., provides a bioerodible silver coating on the surface of endoprosthetic orthopaedic implants to render the surface antimicrobial. 
     Fox, Jr. et al., discloses the use of a complex of a silver salt and chlorhexidine to add antimicrobial properties to biomedical polymers such as silicones. 
     Laurin, et al. discloses mixing an oligodynamic material such as a salt of silver, gold, platinum, copper or zinc with a resin to form an antimicrobial coating for catheters. 
     Akijama coats an oligodynamically active silver, gold or copper salt on the periphery of a tubular catheter. 
     Modak et al. and Darouiche et al. discloses the use of triclosan to silicone medical devices such as catheters to inhibit microbial growth. By coating the agent onto the surface of the device or soaking the device in swelling agent and then in a solution containing triclosan to introduce triclosan into the device. 
     When soft prosthesis were compounded with antimicrobial agents such as silver compounds at a level which resists growth of microorganisms, it was discovered that the prosthesis was irritating to and/or toxic to tissue in contact with the prosthesis. 
     Statement of the Invention 
     It has been discovered in accordance with the present invention that antimicrobial agents can be compounded into parts of a prosthetic that are not in contact with tissue. The antimicrobial parts will be free of microbial growth for an extended period which contributes to longer use of the prosthesis in vivo. For example, the valve in most voice prostheses is not in contact with tissue. It is only in intermittent contact with body fluids. The same is true of the inside surface of the tubular prosthesis and/or the facial and inside surfaces of rings or cartridges present to reinforce the soft body of a prosthesis. By adding an amount of microbial agent effective to resist growth onto or into the valve, ring or cartridge it is found that microbial growth is delayed for a significant period without any evidence of irritation or toxicity to the tissue. 
     The isolation of the valve from tissue is enhanced by recessing the valve forward of the rearward edge of the prosthesis and/or forward of a flange which seats the prosthesis in a tracheoesophageal fistula. 
     The body of the prosthesis may have some antimicrobial properties as long as the surface of the body is not toxic to tissue. For example, the body can be formed of a polyurethane polymer which resists attachment of a biofilm or a microbial layer. 
     The antimicrobial agent can also be compounded by dispersion into the raw material. For example, silicone elastomer can contain up to 100 phr of an antimicrobial agent such as silver or silver compounds such as silver oxide suitably about 5 up to less than 50 phr of silver oxide. Other suitable antimicrobial compounds toxic to tissue can be used in the non-tissue contact regions such as gold, platinum, copper, zinc metal powder or oxides and salts thereof. 
     However, it has been discovered that metal oxides such as silver oxide accelerate the curing of silicone elastomers used to form the valve leading to uneven dispersions and short pot life. In accordance with the invention, the pot life of silicone valves containing silver oxide can be increased by adding a curing inhibitor to the composition before cure in an amount of at least of 1 mole of inhibitor to 6 moles of Ag 2 O. The pot life is increased to 4-8 hours and the dispersion of the Ag 2 O powder is uniform throughout the valve by adding 2 drops of inhibitor per 100 grams of silicone elastomer such as NuSil. 
     Preferred organic antimicrobial agents that can be added to the valve are organic antimicrobial agents that can be dispersed throughout the silicone raw material preferably a food grade preservative such as an aromatic carboxylic acid or C 1  to C 9  ester thereof such as butyl paraben (butyl p-hydroxy Benzoate) or an alkene carboxylic acid salt such as alkali metal sorbate salt or a halohydroxy aromatic ether such as triclosan (2,4,4′-trichloro-2′-hydroxydiphenyl ether). Organic antimicrobial agents can be selected from the group consisting of unsaturated aliphatic acid salt, halogenated hydroxy aromatic acids, esters thereof, and aromatic ethers. 
     The agents can be dispersed throughout the silicone by milling a dry powder into liquid resin before curing by predissolving in minimum amount of solvent and then mixing or milling the solution into the liquid resin or heating the agent above its melting temperature but below its decomposition temperature and mixing the molten material with the liquid resin before molding. The agents were chosen to be sufficiently robust to survive the molding process. 
     The hard cartridges or rings are suitably formed of a hard engineering plastic such as Kynar. The cartridges can also contain a uniform dispersion of an organic antimicrobial agent as disclosed above. 
     Valves and cartridges for voice prosthesis have been compounded with a dispersion of antimicrobial agents and were subjected to in vitro and in vivo testing. The valves and cartridges are found to exhibit significant inhibition of microbial growth. The presence of the antimicrobial agent throughout the matrix will retard both surface attachment and penetration of microorganisms into the valve. 
     Another aspect of the invention is to prevent unseating of the valve distortion, of the valve and/or cartridge due to muscle action of the stoma and to further isolate the valve from microorganisms carried by saliva. In accordance with the invention a metal sleeve suitably formed of titanium surrounds the portion of the cartridge supporting the valve and its attachment means. 
     These and many other features and attendant advantages of the invention will become apparent as the invention becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic view of a voice prosthesis installed in a tracheoesophageal fistula; 
         FIG. 2  is a view in section of an assembly of the valve, cartridge and body of an embodiment of the voice prosthesis of the invention; 
         FIG. 2   a  is an enlarged sectional view of the valve securing means shown in  FIG. 2  for purposes of clarity; 
         FIG. 3  is a side view in elevation of the valve shown in  FIG. 2 ; 
         FIG. 4  is a front view in elevation of the valve shown in  FIG. 2 ; 
         FIG. 5  is a rear view in elevation of the cartridge shown in  FIG. 2 ; 
         FIG. 6  is a view in section taken along line  6 - 6  of  FIG. 5 ; 
         FIG. 7  is a view in section taken along line  7 - 7  of  FIG. 6 ; 
         FIG. 8  is a bottom view in elevation of the cartridge illustrated in  FIG. 2 . 
         FIG. 9  is a top view in elevation of the prosthesis illustrated in  FIG. 9 ; 
         FIG. 10  is a view in section taken along line  10 - 10  of  FIG. 9 . 
         FIG. 11  is a view in section of a second embodiment of valve with seating band according to the invention; 
         FIG. 12  is a view in section of a hard cartridge with valve seat according to the invention; 
         FIG. 13  is a view in section of a soft body for a voice prosthesis according to the invention; 
         FIG. 14  is a view in section of the assembly of the body, cartridge and valve illustrated in  FIGS. 11-13 ; 
         FIG. 15  is a top view in elevation of an alternate embodiment of a valve; 
         FIG. 16  is a perspective and sectional view of the valve illustrated in  FIG. 15 ; 
         FIG. 17  is a view in section taken along lines  7 - 7  of  FIG. 16 ; 
         FIG. 18  is a perspective view of an alternate embodiment of a cartridge; 
         FIG. 19  is a top view in elevation of the cartridge illustrated in  FIG. 18 ; 
         FIG. 20  is a view in section taken along lines  10 - 10  of  FIG. 19 ; 
         FIG. 21  is a perspective sectional view of the assembly of a valve with the cartridge illustrated in  FIG. 18 ; 
         FIG. 22  is a top view in elevation of the assembly illustrated in  FIG. 21 ; 
         FIG. 23  is a view in sections taken along lines  13 - 13  of  FIG. 22 ; and 
         FIG. 24  is a view in section illustrating the use of a metal sleeve to isolate and support the valve. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention will be illustrated by two embodiments of a long-dwelling voice prostheses with hard cartridge and a soft body voice prosthesis, though it is applicable to any prosthetic or medical device disposed in a body cavity having an environment conducive to growth of micro-organisms such as  Candida Albicans.    
     Referring now to FIGS.  1  and  8 - 9 , a first embodiment of a voice prosthesis  10  is shown inserted into a fistula  62  with the front flange  14  engaging the outer wall  64  of the trachea and the rear flange  16  engaging the wall  66  of the esophagus. The body  12  of the prosthesis  10  prevents the fistula  62  from closing. The body  12  and flanges  14 ,  16  are formed of an elastomer material which is non-toxic to tissue. The prosthesis  10 ,  310  also contains a valve  60 ,  360  as shown in  FIGS. 2-4  and  FIGS. 8 ,  9  which has an antifungal surface  215 ,  315  toxic to tissue. The valve  60 ,  360  is preferably separately molded and has a flap  20  or  2  posts  320  which are attached to the prosthesis  10 ,  310 . In the soft prosthesis  310 , the posts  320  are received in cavities  322  in the body and secured thereto by potting with a biocompatible adhesive such as RTV. The valve could also be mounted in a rigid sleeve attached to the distal end of the cartridge. 
     Referring again to  FIGS. 2-4 , a long dwelling prosthesis  210  can further contain an internal, rigid cartridge  212  which reinforces the body  214  of the soft prosthesis as shown in  FIGS. 2-8  and as disclosed in U.S. Pat. No. 5,578,083 the disclosures of which are expressly incorporated herein by reference. 
     Referring particularly now to  FIGS. 2 and 2   a , a preferred voice prosthesis  210  is formed of a tubular body  214 , a hollow, rigid cartridge  212  received in a channel  213  through the body  214  and a flapper valve  215  mounted on the rear face  217  of the cartridge  212 . 
     A front tracheal flange  216  and a rear retention esophageal flange  219  are connected to the ends of the body  214 . A flexible tab  218  can be attached to the front flange  216 . The tab  218  can contain an aperture  221  which can be connected to an insertion tool, not shown. The body  214 , front flange  216  and rear flange  219  are preferably a single molded, unitary structure formed from a biocompatible elastomer such as silicone resin, suitably a 50 durometer, medical grade, silicone elastomer. Since the resin is transparent and the prosthesis structure is small, the prosthesis is difficult to visualize and handle. Therefore, the molding resin generally, but not always, can contain a small amount, from 0.1 to 0.5% of a biocompatible pigment to aid in seeing the device. The pigment can be a heavy metal salt such as barium sulfate. The cartridge  212  can be formed of an inert, self-lubricating thermo plastic polymer, a fluorinated resin such as KYNAR, a semi-crystalline, low molecular weight polymer of vinylidine fluoride, such as TEFLON (polytetrafluoroethylene) or a polyalkylene resin such as polyethylene or polypropylene. 
     The tubular body  214  has a first section  222  having a wall  223  of a first thickness, a central section  224  having a wall  227  of a greater thickness and a third wall section  226  having a wall  229  of reduced thickness. The central wall section  224  forms a cylindrical boss  231  which is received in an annular channel  228  formed in the outer wall of the cartridge  212 . 
     The hollow cartridge  212  has a front flange  240 , a rear flange  244  forming a central channel  242  between the flanges  240 ,  244 . The cartridge  212  is assembled with the body  214  by inserting the front flange  240  of the cartridge  212  into the rear opening  245  of the body  214  and forcing it through the central channel  213  of the body compressing the boss  231  until the front flange  240 , seats against the end wall  248  of the boss  231  and the rear flange  244  seats against the rear wall  250  of the boss  231 . 
     Referring now to  FIGS. 3 and 4 , the rear flange  244  has a horizontal slot  243  for receiving a tab  232  mounted on the front face of the valve  60  which communicates with an enlarged recess  245 . The remaining volume in the recess  245  can be filled with biocompatible adhesive such as a silicone adhesive. Preferably, the tab  232  contains a bulbous end  261  which seats in the recess  245 . The rear face  262  of the rear flange  244  can be angled to the vertical in order to preload the valve  60 . Usually the angle is form 1 to 20 degrees, preferably 3 to 10 degrees. 
     Referring further to  FIGS. 3 and 4 , the flapper valve  60  has a round segment  230  connected to an attachment flap  256 . A live hinge  234  in the form of a score line separates the segment  230  from the flap  256 . A tab  232  is provided on the flap  256  for attaching the valve  60  to the body of the cartridge  212 . 
     The hinge is located adjacent the lower, recessed portion of the rear face of the flange  244  which preloads the valve  60 . The valve  60  is further strengthened by the increased thickness of the dome-shaped rear face  280  of the round segment  230 . Leakage of the valve is further decreased due to the seating of the valve element  60  on the hard, smooth outer surface  217  of the rear flange  244  of the cartridge. 
     In order to assure that the rear flange  219  of the body  214  is fully seated on the esophageal wall surrounding a fistula, a narrow opaque ring  282  can be attached to or molded into the rear flange  219  as disclosed in U.S. Pat. No. 5,480,432 on Jan. 2, 1996, the disclosure of which is expressly incorporated herein by reference. An opaque pattern can also be provided by depositing opaque dots such as tantalum on the flange. The ring  282  has a width at least 10% the diameter of the rear flange usually from 10% to 50% the diameter of the annular rear flange. Usually the rear flange has a diameter of about 0.5 inch and the ring has a width of about 0.05 to 0.10 inch. The ring  282  preferably has an outer perimeter coincident with that of the rear flange  219  so that folds anywhere on the rear flange will be detected by the displayed image of the ring  282 . The ring is preferably formed of the same flexible resin as the rear flange but contains an amount of radiopaque pigment such as barium sulfate sufficient to render the ring opaque to X-rays. Usually the pigment is present in an amount from at least 5% to 35%, generally around 20% by weight. 
     The front flange  240  of the cartridge  212  can have a bevel  241  so that it is easier to move the front flange  240  past the boss  231  on the body  214  of the device. 
     The body  214  can also contain a recess  220  placed forward of the rear flange  219  to further protect the valve from failing by further isolating the valve from contacting tissue. A hood may also be provided rearward of the flange  219 . 
     Referring more particularly now to  FIG. 5-10  the front flange  240  and the rear flange  244  of the hard cartridge  212  may contain key shaped slots  243 ,  245  which cooperate with a key bar  265  on the bottom of the soft tubular body  214 . The rear end  267  of the key bar  265  bears against the bulbous end  261  of the flexible tab  256 . 
     Referring now to  FIGS. 11-14 ,  FIG. 11  illustrates an elastomer flapper valve  10  formed of a valve element  211  spaced from and connected to a surrounding, continuous mounting band  212  by a tab  214  extending from the outer surface  216  of the valve element to inner surface  18  of the band  212 . The rigid cartridge  220  shown in  FIG. 12  has a groove  222  formed in the outer surface  224  and a slot  226  formed in the distal surface  228  extending from the distal surface  228  to the groove  222 . The width of the slot  226  is coextensive with the width of the tab  214 . The outer edges of the distal surface  228  is rounded at  230  to prevent tearing of the mounting band  212  as it is assembled with the cartridge  220 . The outer edge  232  of the proximal surface of the cartridge  220  can also be chamfered or rounded to prevent tearing of the soft body  234  of the voice prosthesis  236 . 
     The cartridge  220  contains a boss  236  extending into the channel  238  through the cartridge forming on its distal surface a seat  240  for the valve element  211 . The seats  240  can be disposed normal to the axis of the channel or can be slanted at an angle of 5-10 degrees as illustrated in  FIG. 19 . The proximal face  242  of the boss  236  can be utilized to engage the distal end of a cleaning brush or insertion tool. The edge  244  of the proximal face  242  can be chamfered. 
     Referring again to  FIGS. 11 to 14  the voice prosthesis  236  is assembled by stretching the band  212  while aligning the tab  214  with the slot  226 . The stretched band  212  is then placed over the groove  222  while the tab  214  is seated in the slot  226  against the seat  240  and released into the groove  222 . The proximal face  246  of the valve element  211  is reliably seated against the valve seat  240 . The valve element  211  may have a dome shape  248  to strengthen the element and prevent wrinkling of the element. 
     The cartridge-valve assembly  250  is then pushed through the distal end  252  of the soft body  234  until it seats in the annular recess  254  within the soft body  234 . The soft body  234  can also contain a conventional distal flange  258  and proximal flange  260  for engaging the surfaces of wall between a trachea and esophagus. The distal flange  260  can contain a radioplaque ring  261  in order to assure that the flange  60  is correctly seated as disclosed in Ser. No. 08/282,277 filed Jul. 27, 1994 now issued as U.S. Pat. No. 5,480,432, the disclosure of which is expressly incorporated herein by reference. The soft body  234  can contain a distal hood  263  to further protect the valve element from being fouled. 
     Referring now to  FIGS. 15-17 , an alternate embodiment of a valve  310  can be preloaded by forming the tab  314  at an angle from 5 to 20% to a plane normal to the axis of the mounting band  312 . The valve element  311  will preload when assembled with a cartridge, not shown. 
     Referring now to  FIGS. 18-20 , another way to preload a valve element, not shown, is to form the seating face  340  of a cartridge  320  at an angle of 5-20 degrees by disposing the face  340  at the slot  326  forward of the opposed face  328 . The cartridge  320  illustrated in  FIGS. 18-20  contains three flanges, a proximal flange  370 , a central flange  372  and a distal flange  374  forming a first groove  322  between flanges  372  and  374  for receiving a mounting band of a valve, not shown and a second groove  376  for receiving a cylindrical boss on the body of a prosthesis, not shown, for better securing the assembly of the soft body and the cartridge  320 . 
     Referring now to  FIGS. 21-23  a valve  410  is illustrated assembled with the cartridge  420 . The edge portion  480  of the valve element  411  opposite the tab  414  is preloaded by being faced rearwardly by the slanted seating surface  440 . 
     Providing a microbial resistant valve according to the invention may eliminate or reduce the need to utilize a thick domed valve and a thicker, stiffer rear flange. Since the growth of a thick biofilm layer will be inhibited, warping of the valve is reduced or eliminated. The microbial resistant valve is formed by dispersing a microbial agent such as metal, metal oxide or salt or organic antimicrobial agent into the biocompatible resin. 
     The preferred manner of providing a surface resistant to microbial growth is to disperse the agent in the resin forming the portion of the device not in direct contact with body tissue. The agent can be inorganic such as a salt or oxide of silver, gold, platinum, zinc or copper, preferably silver oxide or organic materials soluble or dispersible in the resin forming the valve or the cartridge such as hydroxy aromatic carboxylic acids, esters thereof or halogenated phenols. The agent is present in the resin or at least in a surface layer in an amount effective to deter microbial growth and at a concentration that can be toxic to tissue. The portions of the device in contact with tissue can contain a much lower concentration of the microbial agent at a level non-toxic and non-irritating to tissue. 
     For example, in the case of silver oxide, the concentration of silver oxide effective to deter growth of microbial biofilm is from 1 to 50 phr, preferably 8 to 25 phr. The body of the device which is in direct contact with tissue can be compounded to include from 0.1 to 2 phr, preferably 0.5 to 1.0 phr of silver oxide. 
     The following experiments were conducted to determine the biocompatibility requirements of compounding silver oxide into bodies and valves of voice prosthesis at different concentrations and of coating the outside surfaces of a voice silicone elastomer prosthesis and valve with vaporized metal coatings by the SPIRE® process. The silver oxide was dispersed in the resin, molded to form a soft voice prosthesis body valve or disc and then cured. The silicone parts were tested in solution proportional to their size. 
     Cytotoxicity testing was performed on various concentrations of silver oxide and silicone elastomer, and on various combinations of bodies and valves. MEM (Minimum Essential Medium) Elution and Agarose Overlay tests were done. It was decided that the most applicable test, given the use of the voice prosthesis, is the MEM test, as it tends to be more sensitive. The Agarose overlay test is useful to help determine comparative degrees of toxicity for the different percentages of silver oxide. 
     
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 TESTS PERFORMED 
               
             
          
           
               
                   
                   
                 AGAROSE 
                   
               
               
                   
                 MATERIAL 
                 OVERLAY 
                 MEM 
               
               
                   
                   
               
               
                   
                 14% Ag 2 O 
                   
                   
               
               
                   
                 Q7-4750 w/14% Ag 2 O (valves) 
                   
                 Nontoxic 
               
               
                   
                 10% Ag 2 O 
               
               
                   
                 10% Ag 2 O sample discs 
                 Toxic 
               
               
                   
                 10% Silver sample discs 
                 Nontoxic 
               
               
                   
                 Q7-4750 w/10% Ag 2 O (10 units) 
                   
                 Nontoxic 
               
               
                   
                 Q7-4750 w/10% silver (10 units) 
                   
                 Nontoxic 
               
               
                   
                 Q7-4750 w/10% Ag 2 O (valves) 
                   
                 Nontoxic 
               
               
                   
                 Q7-4750 w/10% Ag 2 O (bodies) 
                 Toxic 
                 Toxic 
               
               
                   
                 Q7-4750 body w/10% Ag 2 O valve 
                   
                 Nontoxic 
               
               
                   
                 1.0% Ag 2 O bodies/10.0% valves 
                   
                 Intermediate 
               
               
                   
                 0.5% Ag 2 O bodies/10.0% valves 
                   
                 Nontoxic 
               
               
                   
                 8% Ag 2 O 
               
               
                   
                 0.5% Ag 2 O bodies/8.0% valves 
                   
                 Nontoxic 
               
               
                   
                 5% Ag 2 O 
               
               
                   
                 Q7-4750 body w/5% Ag 2 O valve 
                   
                 Nontoxic 
               
               
                   
                 Q7-4750 w/5% Ag 2 O (bodies) 
                 Toxic 
                 Toxic 
               
               
                   
                 2% Ag 2 O 
               
               
                   
                 Q7-4750 w/2% Ag 2 O (bodies) 
                 Toxic 
                 Intermediate 
               
               
                   
                 0.5% Ag 2 O 
               
               
                   
                 Q7-4750 w/0.5% Ag 2 O (bodies) 
                 Nontoxic 
                 Nontoxic 
               
               
                   
                 2% Gentian Violet 
               
               
                   
                 Q7-4750 w/2% Gentian 
                 Toxic 
               
               
                   
                 violet (discs) 
               
               
                   
                 2% Copper Oxide 
               
               
                   
                 Q7-4750 bodies w/2% 
                 Nontoxic 
                 Nontoxic 
               
               
                   
                 Copper Oxide valves 
               
               
                   
                 Q7-4750 control 
               
               
                   
                 Q7-4750 bodies w/2% Copper 
                   
                 Nontoxic 
               
               
                   
                 Oxide valves 
               
               
                   
                   
               
             
          
         
       
     
     The tests showed that 10% silver oxide could be used in the valves if the bodies were straight silicone elastomer, or contain a very low percentage of silver oxide. However, the 10% silver oxide valves seems to be the upper end of toxicity. 
     The bodies and valves at 10% showed different results. They were tested in solution proportional to their size (theoretically), yet the bodies consistently showed a more toxic response than the valves. A theory is that the bodies simply had a greater mass even when this was compensated for in choosing the solution size, so more silver oxide was able to leach out into the test medium. 
     Based on these tests, in-vitro test discs were prepared using 5% and 10% silver oxide concentrations, and the clinical voice prosthesis units were prepared using 10% silver oxide valves. 
     Eight tests were performed using valves of different materials to test for measurable zones of inhibition. Sample discs were prepared of the various materials in the concentrations to be tested. The silver oxide, silver, copper, copper oxide, metallic copper, and gentian violet materials were mixed with silicone elastomer, in the concentrations listed. The SPIRE silver (SPIRE A and B), SPIRE Titanium, SPIRE copper were coatings on the valve using SPIRE&#39;s coating method. The novatran is a parylene coating and the BSI is a polyacrylamide coating, both done on the valves. 
     Cultures of  Candida albicans  were grown up for each test date. The  Candida  cultures were swabbed onto media plates and the sample discs were placed on the plates. The plates were incubated at the specified controlled temperature for 15-24 hours and the plates read for inhibition zones. The plates were then returned to the incubator until overgrown. 
     All tests were performed under the Class 100 laminar flow bench. Particle counting was performed on the clean bench prior to initiation of the testing. 
     Summary: Measurable zones of inhibition were demonstrated only on silver oxide, in both the 5% and the 10% concentrations, and on the 2% gentian violet. The zones of inhibition were consistently in the range of 5-7 mm around the test disc. 
     
       
         
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
             
               
               
               
             
               
             
               
             
               
               
               
             
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                 TESTING PERFORMED 
               
               
                   
               
             
             
               
                 1. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 10% Ag 2 O 
                 Yes 
               
               
                   
                 5% Ag 2 O 
                 Yes 
               
               
                   
                 10% silver 
               
               
                   
                 5% silver 
               
               
                   
                 Novatran 
               
               
                   
                 BSI 
               
               
                   
                 Q7-4750 (control) 
               
               
                   
                   
               
             
          
           
               
                 2. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 New 10% Ag 2 O 
                 Yes 
               
               
                   
                 Old 10% Ag 2 O 
                 Yes 
               
               
                   
                 New 6% silver 
               
               
                   
                 Q7-4750 (control) 
               
               
                   
                 Old 10% silver xx 
               
               
                   
                   
               
             
          
           
               
                 xx Old Ag 2 O was taken from a bottle past the expiration date 
               
             
          
           
               
                 3. 
               
             
          
           
               
                   
                 Test Samples* 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 Ag 2 O soaked 
               
               
                   
                 in saline 1 week 
                 Yes 
               
               
                   
                 SPIRE A 
               
               
                   
                 SPIRE B 
               
               
                   
                   
               
             
          
           
               
                 *Candida successfully rinsed off Ag 2 O sample, but not off SPIRE samples 
               
             
          
           
               
                 4. 
               
             
          
           
               
                   
                 Test Samples* 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 0.5% Ag 2 O 
               
               
                   
                 1.0% Ag 2 O 
               
               
                   
                 5% Ag 2 O 
               
               
                   
                 Q7-4750 (control) 
               
               
                   
                 10% Ag 2 O 
               
               
                   
                   
               
             
          
           
               
                 *No Inhibition; dilutions done incorrectly. 
               
               
                 (SPIRE A is a very hydrophilic surface with moderately smooth 
               
               
                 surface; SPIRE B is a moderate improvement in surface energy with 
               
               
                 a very smooth surface) 
               
             
          
           
               
                 5. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 5% Cu 
               
               
                   
                 2% Cu 
               
               
                   
                 1% Cu 
               
               
                   
                 10% Ag 2 O 
                 Yes 
               
               
                   
                 Q7-4750 (control) 
               
               
                   
                 5% Ag 2 O, soaked 
               
               
                   
                 in saline for 
               
               
                   
                 18 weeks 
               
               
                   
                 0.5% Ag 2 O 
               
               
                   
                   
               
             
          
           
               
                 6. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
             
          
           
               
                 No data recorded (when lab accident occurred) 
               
               
                   
               
               
                 7. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 10% Ag 2 O 
                 Yes 
               
               
                   
                 2% copper oxide 
               
               
                   
                 SPIRE Ti 
               
               
                   
                 SPIRE Cu 
               
               
                   
                 5% Metallic Cu 
               
               
                   
                 Domed valve, 
               
               
                   
                 Q7-4750 
               
               
                   
                   
               
             
          
           
               
                 8. 
               
             
          
           
               
                   
                 Test Samples 
                 Inhibition 
               
               
                   
                   
               
               
                   
                 2% Gentian violet 
                 Yes 
               
               
                   
                 SPIRE gold 
               
               
                   
                 SPIRE Titanium 
               
               
                   
                 Q7-4750 (control) 
               
               
                   
                   
               
             
          
         
       
     
     Based on the cytoxicity information and the results of the in-vitro tests, it was decided that the clinical units of the silicone elastomer bodies and 10% silver oxide valves, and SPIRE-coated bodies with 10% silver oxide valves would be clinically tested. 
     Ten patients were given the clinical units under supervision. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 STUDY RESULTS 
               
             
          
           
               
                 Patient 
                 Control 
                 Clinical Unit 
                   
                   
               
               
                 Number 
                 Time 
                 Time 
                 Increase 
                 Device 
               
               
                   
               
             
          
           
               
                 1 
                  8 days 
                 49 days 
                 41 days 
                 10% Ag 2 O 
               
               
                   
                 27 days 
                 36 days 
                  9 days 
                 SPIRE-coated 
               
               
                   
                   
                   
                   
                 Ag 2 O 
               
               
                 2 
                 59 days 
                 127 days  
                 68 days 
                 10% Ag 2 O 
               
               
                   
                 36 days 
               
               
                 3 
                 28 days 
                 69 days 
                 41 days 
                 10% Ag 2 O 
               
               
                   
                   
                 215+ days    
                 187 days  
                 10% Ag 2 O 
               
               
                 4 
                 22 days 
                 258+ days    
                 236 days  
                 SPIRE-coated 
               
               
                 5 
                 35 days 
                 42 days 
                  7 days 
                 10% Ag 2 O 
               
               
                   
                   
                 61 days 
                 26 days 
               
               
                 6 
                 42 days 
                 13 days 
                 −29 days   
                 10% Ag 2 O 
               
               
                   
                 42 days 
                 33 days 
                 −9 days 
                 10% Ag 2 O 
               
               
                   
                   
                 38 days 
                 −4 days 
                 10% Ag 2 O 
               
               
                 7 
                   
                 26 days 
                   
                 10% Ag 2 O 
               
               
                   
                   
                  4 days 
                   
                 Ag 2 O valve/ 
               
               
                   
                   
                   
                   
                 SPIRE 
               
               
                   
                   
                 10 days 
                   
                 SPIRE-coated 
               
               
                 8 
                   
                 222 days  
                   
                 10% Ag 2 O 
               
               
                 9 
                   
                 296 days  
                   
                 10% Ag 2 O 
               
               
                 10 
                   
                 98 days 
                   
                 10% Ag 2 O 
               
               
                   
                   
                 287+ days    
                   
                 10% Ag 2 O 
               
               
                   
               
             
          
         
       
     
     The 27 day sample used by patient #1 had the body SPI-Silicone coated to change its surface characteristics and the valve was silver oxide. Patient #4 used a voice prosthesis which had the body SPI-Silicone coated. Patients #8, #9 and #10 used voice prosthesis with standard silicone bodies and 10% concentration silver oxide valves. 
     Organic antimircobial are readily and evenly dispersed in resin in amounts usually from 0.2 to 5 percent by weight. 
     Preferred Percentages of Additives: 
                                                           Preferred                                        Triclosan   0.25 to 5.0%   0.50 to 3.0%           Butyl paraben   0.25 to 3.0%   0.50 to 2.0%                        
Methods of Introduction:
 
     There are three main methods of introduction of organic additives into the silicone elastomer material. The first method is simply mixing or milling the additives as a powder into silicone elastomer. This is done to either part of a two-part silicone elastomer system or to both parts together prior to molding. The problem with this method is the complete dispersion of the additive in the silicone. 
     The second method of introduction of the additive into silicone is to pre-dissolve the additive in a minimal amount of isopropanol or other appropriate solvent. This liquid mixture is then mixed or milled into the silicone as described above. The advantage to this method is that there is better dispersion of the additive within the silicone. One disadvantage is that it has been found that the addition of isopropanol negatively affects the physical properties of the finished, cured silicone. These effects are proportional to the amount of isopropanol added and can be minimized to negligible by the addition of only the minimal required isopropanol. 
     The third method is preferred as it allows dispersion of the additive throughout the silicone without the use of a solvent. This method is simply heating the additive above its melting temperature, but not past the decomposition temperature. It is then mixed into half of the two part silicone at this temperature. The silicone is allowed to cool prior to mixing both parts together and molding. This method provides a uniform distribution of additive throughout the silicone matrix. Additional curing inhibitor such as 2-methyl, 3-butyne-ol. 
     The following voice prosthesis devices were constructed containing the indicated percent of antimicrobial agent according to the invention. None of the following examples contain any antimicrobial agent in the silicone body. 
                                                                           Valve   %   Cartridge Valve Seat   %                                    1.   Ag 2 O   2       0       2.   Ag 2 O   2   Triclosan   2       3.   Triclosan   4   Triclosan   4       4.   Butyl Paraben   2   Triclosen   4       5.   Ag 2 O   2   Triclosan   4       6.   Triclosan   4   Triclosan   4       7.   Butyl Paraben   2   Triclosan   4                    
Toxicity Testing:
 
                                                                 Test   Results                                Triclosan:            Cytotoxicity (MEM Elution) on the valve material alone   Toxic       Cytotoxicity (MEM Elution) on the device with   Nontoxic       valve material       Acute Oral Toxicity (7 day observation in the mouse)   Nontoxic            Butyl Paraben            Cytotoxicity (MEM Elution) on the device with   Nontoxic       valve material       Acute Oral Toxicity (7 day observation in the mouse)   Nontoxic                    
Zone of Inhibition Data
 
Preface:
 
     In each of these cases, unless noted, a sample of silicone with respective additive was punched from a slab. The final dimensions of the sample pieces were roughly 5 mm in diameter by 2 mm thick. Each variation of these samples were placed separately in 0.45 saline solution and incubated at 37° C. At the specified time, a sample was taken out of the solution and evaluated for zone of inhibition. 
     In each of the cases below, the testing organisms was  Candida albicans , ATCC 10231. The medium used was Sabouraud Dextrose agar. Incubation time was 18 to 24 hours at 37° C. The zone of inhibition test was performed per internal testing standards of Helix Medical, Inc. The base material was Nusil MED 4940 silicone. 
     The zone of inhibition test technically measures leachability of an antimicrobial from a test article. The samples are placed on a lawn of microbial organisms of choice. As the substance leaches from the test sample, there is a concentration gradient set up as a function diffusion through the sample and diffusion away from the sample. At a certain concentration, a critical concentration, the growth of microorganisms will be greatly reduced. This is manifest as no growth or greatly reduced growth in a radius around the sample. With the purpose of the invention in mind, the size of the zone of inhibition is relatively unimportant, as long as the longevity of the substance with some microbial activity is maintained over time in a soaking condition. The result chosen to signify acceptable antimicrobial activity is inhibition of microbial growth underneath the sample. This signifies that the concentration at the surface of the sample has retained at least the critical concentration of antimicrobial substance. If the surface concentration can be maintained at or above the critical concentration, then little to no growth will colonize on the surface of this material. 
     Note: For inhibition underneath sample, it is measured either as Inhibition (I), Partial Inhibition (PI), or No Inhibition (NI). 
     Triclosan 0.5%: 
                                             Inhibition       Time Soaked   Zone of   Underneath Sample       (weeks)   Inhibition (mm)   (I, PI, NI)                      1 day   0   I       1   0   I       2   0   I       3   0   I       4   0   I       12    0   I       16    0   I                    
Triclosan 1.0%:
 
                                                           Inhibition       Time Soaked   Zone of   Underneath Sample       (weeks)   Inhibition (mm)   (I, PI, NI)                                   1 day   1   I       1   1   I       2   1   I       3   1   I       4   1   I       8   1   I       12    1   I       16    0.5   I                    
Triclosan 2.0%:
 
                                             Inhibition       Time Soaked   Zone of   Underneath Sample       (weeks)   Inhibition (mm)   (I, PI, NI)                      1 Day   1   I        1   1   I        2   1   I        3   1   I       11   1   I       12   1   I       16   1   I       20   1   I       24   1   I                    
Triclosan 2.0% molded valves:
 
                                             Inhibition       Time Soaked   Zone of   Underneath Sample       (weeks)   Inhibition (mm)   (I, PI, NI)                      1 day   1   I       1   1   I       2   1   I       3   1   I       4   1   I       8   1   I                    
Butyl paraben 1%:
 
                                                           Inhibition       Time Soaked   Zone of   Underneath Sample       (weeks)   Inhibition (mm)   (I, PI, NI)                                  1 Day   1.5   I       1   1.5   I       2   1.5   I       3   2   I       4   2   I       8   2   I       12    1   I       16    1   I                    
Butyl Paraben 1% molded valves:
 
     
       
         
               
               
               
             
           
               
                   
               
               
                   
                   
                 Inhibition 
               
               
                 Time Soaked 
                 Zone of 
                 Underneath Sample 
               
               
                 (weeks) 
                 Inhibition (mm) 
                 (I, PI, NI) 
               
               
                   
               
             
             
               
                   1 Day 
                 0 
                 I 
               
               
                 1 
                 0 
                 I 
               
               
                 2 
                 0 
                 I 
               
               
                 3 
                 0 
                 I 
               
               
                 4 
                 0 
                 I 
               
               
                 8 
                 0 
                 PI 
               
               
                   
               
             
          
         
       
     
     Voice prosthesis formed with microbial resistant valves will be able to be used for much longer periods without the need to remove the prosthesis for cleaning. The prosthesis can be made with thinner valves, body and flanges since there is no need to be as stiff and rigid to avoid bending and wrinkling due to growth of  Candida Albicans . The body of the voice prosthesis can also be compounded with antimicrobial agents at a level acceptable to the FDA. 
     The Indwelling Low Pressure Voice Prosthesis of the invention is designed for those persons who are unable or resistant to changing the voice prosthesis every two or three days as was recommended for the non-indwelling, patient-removable Low Pressure Voice Prosthesis. The Indwelling Low Pressure Voice Prosthesis has been specifically designed to maintain the placement of the prosthesis in the tracheoesophageal puncture so that routine changing of the device is not necessary. 
     It is to be realized that only preferred embodiments of the invention have been described and that numerous substitutions, modifications and alterations are permissible without departing from the spirit and scope of the invention as defined in the following claims.