Abstract:
Devices for imparting vibration to implanted devices to reduce accumulation of biofilm thereon including a vibration tip, the vibration tip being sized and shaped to couple to a vibrator and receive a vibration therefrom, wherein the vibration tip is sized and shaped to conduct the vibration from the vibrator to an implanted device are disclosed. Methods of inhibiting biofilm formation including abutting a vibration source against an implanted device, and activating the vibration source to impart vibration to the implanted device thereby inhibiting a formation of biofilm on the implanted device are also disclosed.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Application Ser. No. 62/055,642, filed on Sep. 25, 2014, the entire disclosure of which is hereby expressly incorporated by reference. 
     
    
     FIELD OF THE DISCLOSURE 
       [0002]    The present disclosure is related to methods and devices to reduce the formation of biofilms. The disclosure is more particularly directed to methods and devices reduce the incidence of biofilm formation on implantable items by imparting vibration thereto. 
       BACKGROUND 
       [0003]    Devices that are implanted in the body are subjected to the body&#39;s processes and subjected to the potential for accumulating biofilms thereon. One such device includes tracheoesophageal prostheses (TEPs). Based on their makeup, TEPs can have a device life of up to two years. However, greater than 90% of TEPs fail to adequately function to their full potential device life due to the formation of biofilm thereon. Indeed, TEPs end up needing to be switched out every 3-4 months on average. The biofilms not only coat TEPs (and other implantable devices) but infiltrate and anchor in the device (such as in the silicone of TEPs). This infiltration is able to produce leakage in a valve of the TEP, which is a failure mode thereof. 
         [0004]    Research has been done with the aim of reducing or eliminating such biofilms from implantables. Such research has included attempts such as administering oral topical antifungals/biocidals, surface and actual material modifications (including impregnation of antibiotics), unique magnetic and multivalve designs, and dietary modifications. These attempts have been only partially successful and are often prohibitively costly and see poor compliance rates. 
         [0005]    Accordingly, what is needed is a method and device that reduces the incidence and/or effects of biofilm formation and that does so in a way that has an ease of implementation that results in high patient compliance. 
       SUMMARY 
       [0006]    Biofilm inhibitors including a vibration tip, the vibration tip being sized and shaped to couple to a vibrator and receive a vibration therefrom, wherein the vibration tip is sized and shaped to conduct the vibration from the vibrator to an implanted device are disclosed. 
         [0007]    Also disclosed are biofilm inhibitors including a vibrator, and a vibration tip, the vibration tip being sized and shaped to couple to the vibrator and receive a vibration therefrom, the vibration tip further being sized and shaped to conduct the vibration from the vibrator to an implanted device. 
         [0008]    Methods of inhibiting biofilm formation including abutting a vibration source against an implanted device, and activating the vibration source to impart vibration to the implanted device thereby inhibiting a formation of biofilm on the implanted device are also disclosed herein. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0009]    The above-mentioned aspects of the present teachings and the manner of obtaining them will become more apparent and the teachings will be better understood by reference to the following description of the embodiments taken in conjunction with the accompanying drawings, wherein: 
           [0010]      FIG. 1  is a perspective view of a first embodiment device of the present disclosure; 
           [0011]      FIG. 2  is a side view of the device of  FIG. 1  with certain internal features shown in phantom; 
           [0012]      FIG. 3  is a bottom perspective view of the embodiment of  FIG. 1 ; 
           [0013]      FIG. 4  is a side view of the device of  FIG. 1  mounted on a base; 
           [0014]      FIG. 5  is a side view of the base of  FIG. 4  without the device of  FIG. 1  mounted thereto; 
           [0015]      FIG. 6  illustrates a method of inhibiting biofilm formation according to various embodiments; 
           [0016]      FIG. 7  illustrates a comparison of paired vibratory and non-vibratory groups with various tracheoesophageal prostheses (TEPs) sizes; and 
           [0017]      FIG. 8  illustrates a comparison of the TEP sizes for samples with vibratory and non-vibratory groups. 
       
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       [0018]    The embodiments disclosed herein are not intended to be exhaustive or limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiments were chosen and described so that others skilled in the art may utilize their teachings. 
         [0019]      FIG. 1  shows an exemplary vibration head  10 . Vibration head  10  is illustratively formed from plastic, more specifically polypropylene. However, it should be appreciated that head  10  can be formed from any material, including plastic generally with one or more elastomers, that has sufficient stiffness to translate received vibration as described herein. Vibration head  10  includes a proximal end  12  and distal end  14 . Proximal end  12  is illustratively wider than distal end  14  to match up with base  100  shown in  FIG. 5 . Base  100  is shown as a base produced by PHILLIPS and marketed under the name SONICARE. While the shown base  100  provides vibration as will be discussed herein, use of the specific base  100  shown in not needed. Indeed, any base  100  that is able to generate vibration and transmit that vibration to head  10  is usable within the teaching of the present disclosure. Still further, embodiments are envisioned where head  10  is integral with base  100 . 
         [0020]    Proximal end  12  of head  10  includes proximal wall  16  and mounting bore  18 . Mounting bore  18  is illustratively circular. However, it should be appreciated that the shape of mounting bore  18  is chosen to mate with base  100  and thus can take on any shape needed to achieve such mounting. As shown in  FIG. 2 , mounting bore  18  is a multi-sectioned bore with each section having a differing diameter. First section  20  provides a friction fit on a corresponding portion of base  100 . Second section  22  of mounting bore is sized to receive and abut a vibration post  110  of base  100  such that vibration of vibration post  110  is translated to head  10 . 
         [0021]    Vibration head  10  further includes an elbow portion  28 . Proximal portion  30  (at proximal end  12 ) tapers as it extends towards elbow portion  28 . Elbow portion  28  provides an angle between a proximal axis  24  of proximal portion  30  and a distal axis  26  of distal portion  32  of head  10 . Elbow portion  28  illustratively provides a 120-degree angle between proximal axis  24  and distal axis  26 . However, it should be appreciated that this angle is exemplary only and other angles are envisioned. The angle is generally chosen to provide desired ergonomics and ease of use during the use described herein. 
         [0022]    Distal end  14  of head  10  includes engagement portion  34 . In the shown embodiment, engagement portion  34  is sized and shaped to engage a TEP. It should be appreciated that the specific shape of engagement portion  34  is chosen based upon the specific implementation. Thus, while the shape and dimensions shown are configured to engage a TEP, other shapes and dimensions would likely be chosen when the item to which vibration is being imparted is other than a TEP. Indeed embodiments are envisioned to impart vibration to any number of devices that are exposed to biofilm-forming environments (pacemakers, cochlear implants, etc.) 
         [0023]    The illustrated example of engagement portion includes a first diametered portion  36 , a second diametered portion  38 , and a shoulder  40  at a common boundary for first diametered portion  36  and second diametered portion  38 . Second diametered portion  38  is distal of first diametered portion  36  and provides the distal-most portion of head  10 . Second diametered portion  38  has a diameter that is smaller than a diameter of the first diametered portion  36 . The diameter of the second diametered portion  38 , in the present case, is chosen to fit within a bore in a TEP. The diameter of the first diametered portion  36 , in the present case, is chosen so that it is too large to fit within the bore of the TEP. The length of the second diametered portion  38  is chosen such that shoulder  40  engages the TEP to arrest further advancement of head  10  into the TEP before the second diametered portion  38  is able to extend an undesired amount. In one embodiment, the second diametered portion  38  has a length equal to the depth of the bore in the TEP engaged by the head such that the second diametered portion  38  is unable to extend into the body beyond the TEP. Embodiments are envisioned having other lengths of second diametered portion  38 . The diameter of the second diametered portion  38  is illustratively chosen to snugly fit within the bore of the TEP. Embodiments are envisioned where second diametered portion  38  is externally textured, grooved, and/or includes bristles. 
         [0024]    In operation, as mentioned above, a user positions distal end of head (the second diametered portion  38 ) within the bore of the TEP and advances the second diametered portion  38  until shoulder  40  abuts the TEP. Button  102  on base  100  is then pressed to activate base  100 . This activation causes vibration post  110  to vibrate. This vibration is transmitted to head  10 . Vibration of head  10  is transmitted to the abutting TEP. 
         [0025]    For example, with reference to  FIG. 6 , method  600  of inhibiting biofilm formation is illustrated. Method  600  comprises abutting a vibration source against an implanted device (step  610 ), such as a medical device (e.g., tracheoesophageal prostheses) and then activating the vibration source to impart vibration to the implanted device (step  620 ). Thus, various systems and methods may cause an implanted device (e.g., an implanted medical device) to vibrate. In various embodiments, the vibration of the device slows, eliminates, and/or at least partially reverses biofilm growth and/or infiltration into the device, such as a TEP. Accordingly, regular vibration of the TEP is expected to prolong the useful life of the TEP. 
       Comparative Data 
     Overview 
       [0026]    Ex vivo tracheoesophageal prostheses were obtained and prostheses demonstrating physical integrity and an absence of gross biofilm accumulation were utilized. 16 prostheses were cleansed and sterilized prior to random placement by size in two modified Robbins devices arranged in parallel. Each device was seeded with a polymicrobial oral flora on day 1 and received basal artificial salivary flow continuously with three growth medium meals daily. One device was randomly selected for vibratory stimulus and 2 minutes of vibration was applied to each prosthesis before and after meals for 5 days. The prostheses were explanted, sonicated, and the biofilm cultured for enumeration. This process was repeated after study arm crossover. 
         [0027]    Tracheoesophageal prostheses in the dynamic model receiving vibratory stimulus demonstrated reduced gross biofilm accumulation and a significant biofilm colony forming unit per milliliter reduction of 5.56-fold compared to non-vibratory controls (p&lt;0.001). Significant reductions were observed within size subgroups. 
         [0028]    It was found, as explained in further detail below, that application of vibratory stimulus around meal times significantly reduces biofilm accumulation on tracheoesophageal prostheses in a dynamic in vitro model. 
         [0029]    In this experimental comparison, a polymicrobial suspension of oral flora including  Candida albicans, Candida tropicalis, Streptococcus salivarius, Rothia dentocariosa, Staphylococcus aureus , and  Staphylococcus epidermidis  was applied to TEPs partially submerged in growth medium in sterile well culture plates. Vibratory stimulus was applied to the treatment group during a 4 day growth course. Cultures that were made from TEPs after completion of the growth course demonstrated some reduction in colony forming unit (CFU) per milliliter (mL) in those treated with the vibratory stimulus compared to controls. 
       Experimental Methods 
       [0030]    Tracheoesophageal Voice Prostheses Preparation 
         [0031]    Expired and ex vivo Atos Medical® (available from West Allis, Wis.) Provox® 2 low-resistance, indwelling silicone voice prostheses of 22.5 French (F) internal diameter and shaft length sizes 6 millimeter (mm), 8 mm, and 10 mm were utilized for this experiment. The included TEPs were individually scrubbed, sonicated for 15 seconds (s), rinsed with deionized water, disinfected for 30 minutes (min) in 70% ethanol, and dried in aseptic conditions prior to loading into the Robbins devices. TEPs were arranged by size and then equal quantities of the sized groups were randomly assigned to placement in either the vibration arm Robbins device or the control arm Robbins device. 
       Robbins Device Setup 
       [0032]    Robbins devices are common systems used in microbiological studies on biofilm formation. The basic experimental setup involves a closed system of tubing with an influent source of liquid nutrition moved by a peristaltic pump through a unidirectional device chamber which has effluent tubing to waste. A Robbins device that emulated the tracheoesophageal puncture site interface was used for this experimental comparison. 
         [0033]    The experimental setup involved three separate influent sources containing 1) normal saline (representing saliva), 2) a 1:1 mixture growth medium (GM) of Brain Heart Infusion (BHI) and Yeast Extract-Peptone-Dextrose (YPD) broths, and 3) a smaller 1:1 mixture GM of BHI and YPD broths to be inoculated (after autoclaving) with a polymicrobial culture of  C. albicans, C. tropicalis, S. salivarius, R. dentocariosa, S. aureus , and  S. epidermidis . Preliminary testing demonstrated that a 1:1 mixture GM of BHI and YPD broths was appropriate for growth of polymicrobial biofilms on TEPs and that appreciable biofilm accumulation could be observed over the course of 4 to 5 days. Autoclavable tubing from the three fluid sources were Y-connected together before splitting into separate parallel tubing through 2 cassettes in an Ismatec® Reglo Digital 2 channel peristaltic pump (available from IDEX Corp, Wertheim, Germany). From the pump, the parallel tubing connected to the influent spigots of two Robbins devices each with effluent spigot tubing dumping into an effluent beaker. The parallel Robbins devices were utilized in an effort to create a microcosmic dynamic tracheoesophageal puncture site interface while reducing intergroup variability as each Robbins device received the same influent fluids and flow rates from the same source containers. The entire system of flasks, tubing, and Robbins devices was autoclaved to ensure internal sterility prior to starting the experimental run in an aerobic 5% CO 2  incubator set at 37° C. 
       Inoculation, Simulated “Meal” Feeding Cycles, and Biofilm Formation 
       [0034]    Twelve hours prior to placement of the experimental system in the aerobic incubator, individual broth cultures of  C. albicans, C. tropicalis, S. salivarius, R. dentocariosa, S. aureus , and  S. epidermidis  were inoculated and incubated aerobically with 5% CO 2  at 37° C. On the first morning of the experiment, 1 mL of each of these culture broths were aseptically added to the smaller GM container to provide polymicrobial inoculation of the Robbins devices. During the first day of the experimental run, the inoculated GM was pumped through the system at a rate of 1 mL/min for 30 min on 3 occasions to simulate 3 meals evenly spaced throughout the day. A normal saline flow rate of 0.5 mL/min between meals simulates wakeful unstimulated salivary flow rates whereas a rate of 0.1 mL/min simulates resting salivary flow rates between evening and morning. On experimental days 2 through 5, the sterile GM source was utilized to simulate meals as the system was adequately inoculated. The entire experimental setup was maintained in the aerobic incubator at 37° C. while biofilm formed over 5 days. 
       Mechanical Vibration Application 
       [0035]    One Robbins device was randomly selected to have its TEPs undergo mechanical vibration. Vibration was applied to TEPs mounted in the treatment group Robbins device by a motor oscillating at approximately 260 Hz for 2 min duration before and after each “meal” to simulate when vibration would reasonably be performed by a patient. This vibration frequency and duration has proven safe for long term intraoral use for prevention of dental caries by electric toothbrush manufacturers. 
       Biofilm Culturing and Colony Counting 
       [0036]    At the conclusion of 5 days, the TEPs were aseptically removed individually from the Robbins devices, unbound bacteria were gently rinsed away with sterile normal saline, and the TEPs were placed in individual 50 mL sterile conical centrifugation tubes containing 5 mL of sterile saline. Each explanted TEP was then vortexed for 15s, sonicated for 15s, and again vortexed for 15s to release the biofilm microorganisms into suspension. For each TEP, the 5 mL undiluted biofilm suspensions were diluted 1:200 and 1:1,000 prior to duplicate culturing of each dilution onto 2 blood agar plates with a spiral plating apparatus. The culture plates were left to dry at room temperature for 15 min prior to aerobic incubation with 5% CO 2  for 36 hours. The ProtoCOL® 1 automated colony counting system (SYNBIOSIS, Frederick, Md.) was utilized to determine CFU/mL for each plate. Three measurements each for the 2 blood agar plates for the 1:1,000 dilution were averaged as they demonstrated appropriately countable colony density. The 1:200 plates were not counted because of the high density of the colonies. 
       Experimental Crossover and Duplication 
       [0037]    At the conclusion of the 5 day experimental run and after counting the biofilm colonies, the entire Robbins device system (including the TEPs) was disassembled and decontaminated with 70% ethanol prior to scrubbing, rinsing with deionized water, and reassembly. New GM and normal saline were prepared and the TEPs were replaced in fresh silicon sheets within the Robbins device chambers. The experimental system was again run with the previously described inoculation methods, flow rates, and time frames. However, during the duplication run the TEPs underwent experimental arm crossover and the previously non-vibration group had mechanical vibration applied as described above. Subsequently, the TEPs underwent explantation, culturing, and colony counting with the same methods as the first run. 
       Statistical Considerations 
       [0038]    The coefficient of variation in this comparative experiment was anticipated to be approximately 0.6 based on a prior study. Therefore, with a total sample size of 12 per group, the comparison was anticipated to have 80% power to detect a 2 times difference in CFU/mL between groups, at an alpha of 5% significance level. Because of the plan for subgroup analysis by size, a total of 16 TEPs were utilized in each run (8 per Robbins device). Each Robbins device was populated by four 6 mm length TEPs, three 8 mm TEPs, and a single 10 mm TEP. Grouping of TEPs into the treatment Robbins device or control Robbins device was randomized by size. A paired-samples t-test was utilized for cumulative treatment arm analysis and to compare vibratory versus non-vibratory groups at different TEP sizes. Insufficient blood agar resulted in an inability to culture and measure biofilm formation in the non-vibratory group&#39;s TEP size 10 sample. Consequently, the paired vibratory size 10 sample was excluded from paired analysis. An independent-samples two-tailed t-test was used for intra-run analysis between vibratory and non-vibratory groups and for inter-run analysis (vibratory versus vibratory; non-vibratory versus non-vibratory). A one-way ANOVA was used to compare the effect of TEP size on CFU/mL cultured. A natural log (ln) transformation was performed to allow for parametric analysis. All variance within paired analysis was expressed as standard error of the mean (SEM) of the differences between paired samples. The variance within one-way ANOVA and independent-samples t-tests was expressed as SEM. Statistical analysis was accomplished using SPSS® 22 (available from IBM Corp). 
       Experimental Results 
       [0039]    When comparing all vibratory TEPs to non-vibratory TEPs for both experimental runs, there was a statistically significant 5.56-fold reduction in mean CFU/mL, as shown in  FIG. 7  and Table 1 below. As illustrated in  FIG. 7  and Table 1 (below), the vibratory group&#39;s mean CFU/mL (0.39×10 6 ±0.072×10 6 ) is significantly different than the non-vibratory group (2.2×10 6 ±0.41×10 6 ); t (14), p=0.00025. The error bars in  FIG. 7  represent SEM of the differences between paired samples. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Comparison of mean CFU/mL formed in vibratory and non-vibratory groups based on TEP size 
               
             
          
           
               
                   
                 Vibratory group 
                 Non-vibratory group 
                   
                   
                   
               
               
                 TEP size 
                 (CFU/mL) 
                 (CFU/mL) 
                 (n) 
                 t-value 
                 Sig. 
               
               
                   
               
             
          
           
               
                 6 
                 0.30 × 10 6  ± 0.11 × 10 6   
                 1.5 × 10 6  ± 0.11 × 10 6   
                 16 
                 t(7) = −5.64 
                 0.00078* 
               
               
                 8 
                 0.44 × 10 6  ± 0.33 × 10 6   
                 2.5 × 10 6  ± 0.33 × 10 6   
                 12 
                 t(5) = −3.10 a   
                 0.027* a   
               
               
                 10 
                 0.79 × 10 6  (n = 1) 
                 5.7 × 10 6  (n = 1) 
                 2 
               
               
                 Combined 
                 0.39 × 10 6  ± 0.18 × 10 6   
                 2.2 × 10 6  ± 0.18 × 10 6   
                 30 
                 t(14) = −4.86 
                 0.00025* 
               
               
                   
               
               
                 Note. 
               
               
                 The combined group represents cumulative data including all TEP sizes 
               
               
                 Note. 
               
               
                 TEP = tracheoesophageal voice prosthesis; 
               
               
                 CFU = colony forming unit 
               
               
                 Note. 
               
               
                 P-values (Sig.) are derived from paired samples t-tests comparing vibratory and non-vibratory groups within each row. 
               
               
                 SEM of the differences between paired samples is used to express variability. 
               
               
                   a Statistical analysis could not be performed due to insufficient sample size in TEP size 10 group 
               
               
                 *Denotes statistical significance at 95% confidence interval (p &lt; 0.05) 
               
             
          
         
       
     
         [0040]    When comparing the treatment arm to the control arm for each run individually, significant reductions in CFU/mL were also observed. The first run showed a statistically significant 3.6-fold reduction between the mean CFU/mL (2.0×106±0.21×106 CFU/mL (non-vibratory group) versus 0.55×106±0.10×106 CFU/mL (vibratory group); t(13)=−6.39, p=0.000024). Within the second run there was a significant 9.4-fold reduction between the non-vibratory and vibratory mean CFU/mL with analysis following a natural log transformation: 14.4±0.28 ln(CFU/mL) versus 12.2±0.25 ln(CFU/mL); (t(14)=5.70, p=0.000055). 
         [0041]    Since there was a wide range in reduction of biofilm between the first and second runs (3.6-fold versus 9.4-fold, respectively), post-hoc subgroup analyses were performed. The first run&#39;s non-vibratory group mean CFU/mL was compared to the second run&#39;s non-vibratory group, and no significant difference was observed following a natural log transformation (14.4±0.12 ln(CFU/mL) versus 14.4±0.28 ln(CFU/mL); t(13)=0.26, p=0.80). The vibratory group mean CFU/mL between the first and second runs were similarly analyzed, and in this case a significant difference was observed (0.55×106±0.010×106 CFU/mL versus 0.25×106±0.062×106 CFU/mL; t(14)=2.60, p=0.021). 
         [0042]    For all TEP size subgroups analyzed, significant reductions in mean CFU/mL were observed after vibratory treatment with a trend toward higher CFU/mL reduction in larger TEP sizes as illustrated in Table 1 and  FIG. 8 . As illustrated in  FIG. 8 , there were statistically significant differences between vibratory and non-vibratory groups with TEP sizes 6 and 8, where *=p&lt;0.05; **=p&lt;0.001 comparing vibratory and non-vibratory groups at each TEP size. Error bars represent SEM of the differences between paired samples. 
         [0043]    One-way ANOVA comparing mean CFU/mL demonstrated no significant difference between sizes 6 mm, 8 mm, or 10 mm groups in both the vibratory treatment group (F2,13=1.55, p=0.25) and non-vibratory group (F2,12=3.84, p=0.052). 
         [0044]    The experimental results of the in vitro model of the tracheoesophageal puncture site interface demonstrated that the application of mechanical vibration to TEPs resulted in an overall statistically significant 5.56-fold reduction in biofilm accumulation. Moreover, the statistically significant reduction in CFU/mL was observed in TEP size 6 and 8 subgroup analyses as well (as shown in Table 1 above). As TEP size increased, the proportional reduction in CFU/mL also increased; a 5.0 fold reduction for size 6 mm TEPs and a 5.6 fold reduction for size 8 mm TEPs. This may be related to the potential stasis of growth medium and bacteria within the longer TEP shaft by capillary forces. Prolonged stasis of sonicated biofilm elements may allow more rapid re-accumulation of biofilm in these larger TEPs. Analysis revealed that within both the vibratory and non-vibratory groups, size did not significantly affect CFU/mL cultured. Therefore, mechanical vibration appears to have the strongest effect among the potential variables influencing biofilm formation in this study. 
         [0045]    Moreover, the parallel arrangement of Robbins devices within a run and the crossover of treatment arms between runs confirmed that the reduction in CFU/mL was not likely related to local growing condition variability nor intrinsic susceptibility for biofilm formation by a subset of TEPs included in the study. Despite endeavoring to reduce variability, it should be noted that between the first and second run, there existed a significant difference in CFU/mL between each run&#39;s vibratory group while finding no difference between each run&#39;s non-vibratory group. One explanation for this is found in the intrinsically stochastic nature of polymicrobial cultures. There is a possibility that different bacterial species&#39; success was variable in early TEP adherence, and that some of these species are more resistant to the biofilm reducing effect of vibration. All culture plates demonstrated polymorphic colony types consistent with polymicrobial growth, but speciation techniques were not utilized. Despite the difference between the two runs&#39; vibratory groups, however, each vibratory group was significantly different compared to its non-vibratory counterpart within their respective runs. 
         [0046]    The above detailed description and the examples described therein have been presented for the purposes of illustration and description only and not for limitation. For example, the operations described may be done in any suitable manner. The method may be done in any suitable order still providing the described operation and results. It is therefore contemplated that the present embodiments cover any and all modifications, variations or equivalents that fall within the spirit and scope of the basic underlying principles disclosed above and claimed herein.