Urinary catheter capable of repeated on-demand removal of infectious biofilms via active deformation
Introduction
Infection associated with the use of urinary catheters is a pervasive and challenging issue in healthcare [1], [2], [3], [4], [5], [6]. There are over 30 million urinary catheters used annually in the USA and catheter-associated urinary tract infections (CAUTIs) are the most common type of nosocomial infections, which account for 30–40% of all hospital infections and lead to over 50,000 deaths each year [7], [8]. Microbes such as bacteria colonize the surface of urinary catheters very quickly and often form biofilms in the drainage lumen of catheters [9], [10], [11], [12], [13], [14], [15]. The formation of asymptomatic biofilms in urinary catheters promotes development of symptomatic CAUTIs [8], and nearly all patients that undergo catheterization for longer than 28 days will suffer some form of infection [8]. In addition, CAUTIs also contribute to the alarming general increase in antibiotic resistance due to horizontal gene transfer between bacteria within biofilms, and the frequent use of antibiotics in their treatment [7], [16], [17], [18].
Current commericially marketed strategies, such as killing bacteria or delaying bacterial attachment [10], [19], [20], to reduce infection induced by urinary catheters have been unsuccessful in the long-term prevention of biofilm formation which ultimately leads to CAUTIs [7], [8]. Although recent research on techniques to prevent catheter infection such as bacterial interference [21] and phage delivery [22] show some promise, they are effective only against specific bacterial strains which prohibitively increases the difficulty of their implementation. Identification of the infecting strain(s) is not a typical clinical approach, and even more challenging is the huge variety of infectious microbes, both bacterial and fungal [10]. Indeed, even the most recently discovered new antibiotic is only effective on Gram positive bacteria [23]. Microtopography [4], [24], [25], permanently attached silicone oils [26], [27], hydrogels [8], [28], [29], polymer brushes [30], [31], and ultrasound [32] are other promising non-strain-specific strategies, but again they only delay biofilm formation for a short period and eventually a biofilm still forms. Moreover, the possible large cost to implement them are a hindrance to their routine implementation in clinical settings. Urinary catheters are commodity devices that cost approximately $10 US; any additional technology that costs more than pennies to implement would face a high barrier to enter the urinary catheter market. Therefore, it is both practically important and fundamentally interesting to propose a new kind of antifouling or fouling release method to maintain catheters free of infection-promoting biofilms at minimal additional manufacturing cost.
With these considerations, we recently proposed an active control approach, adapted from our work on marine biofilms, which uses inflation-generated strain of the elastomeric substrate to debond overlying biofilms [33], [34]. We found that increasing the strain in the substrate increases the energy release rate and thereby increases the driving force for debonding of the biofilm. We then used 3D printing to fabricate proof-of-concept (POC) urinary catheter prototypes that generate enough strain to successfully debond and remove mature Proteus mirabilis biofilm from their interiors [34]. However, the POC prototypes left multiple questions of practical significance unresolved. The POC prototypes were less than 7 cm long and over 1.4 cm diameter, which is much shorter and stouter than the standard urinary catheter (25–42 cm long and 5–10 mm in diameter). Additionally, the POC prototypes had only one intra-wall inflation lumen, resulting in straining and debonding of the biofilm from only part of the surface (about 35% of the intra-luminal perimeter). These limitations raised the following questions: does the active control approach work well for the length scales of a standard urinary catheter, in particular, with a small diameter catheter, e.g., around 6 mm? Is it possible to remove biofilm from the full intra-luminal perimeter of the catheter? Although our pilot study demonstrated that strain applied on the substrate debonded a range of biofilms [33], [34], would the technique work with a mixed community biofilm? Finally, we did not know whether the substrate strain would repeatedly debond biofilms (or if the approach would select from resilient biofilms) to allow long term use.
Here we present the design and a prototype of a urinary catheter capable of repeated on-demand biofilm removal. We hypothesized that adjusting the number and position of intra-wall inflation lumens would allow inflation to generate sufficient tensile strain to debond biofilms over the majority of the internal lumen perimeter. We used successive rounds of finite element modeling to optimize the predicted strain of catheter cross sectional profiles to ensure the design fell within the fabrication capability of an industrial catheter manufacturer. We then constructed prototypes with clinically relevant dimensions using a combination of extrusion and 3D printed reversed-mold fabrication techniques. Different materials for the prototype catheter shaft were compared to determine the ideal operational parameters for clinicians to manually inflate our prototype. We further characterized the protoypes and compared their inflation performance against our finite element models. The prototype catheter, less than 7 mm in diameter (well within the range of sizes available for clinical use) with four intra-wall inflation lumens, was able to achieve substrate strain over most of the perimeter of the main drainage lumen, as well as along the full length of the device. We hypothesized that prototypes would debond a mixed community biofilm of Escherichia coli and P. mirabilis, two of the most common bacteria found in CAUTIs, and we developed an artificial bladder flow system to grow mature biofilms inside the main drainage lumen of prototype catheters. Upon on-demand, inflation-generated actuation, the prototypes dramatically removed the vast majority of the biofilm along the full length of the catheter. After that first successful biofilm removal, we then regrew biofilm within the catheter and demonstrated that inflation-induced strain would indeed repeatedly remove biofilm in the catheter. Interestingly, upon dissection of the catheters, we observed that areas that underwent compressive strain, as predicted by the finite element models, debonded biofilm similarly to areas that underwent tensile strain. In total, using currently available manufacturing techniques from a catheter manufacturer, we developed a urinary catheter that allows the repeated and thorough removal of infectious biofilms from its interior; we are thus poised to impact the long-stagnant urinary catheter technology market.
Section snippets
Finite element modeling
Since catheters are relatively long compared to their cross-section dimensions, we simplified our design analysis to a plane-strain problem. In our analysis, the proposed catheter designs were modeled with the hybrid quadratic elements (CPE8MH) under plane-strain deformation using the software package, ABAQUS 6.12. Pressure was applied along the inner surfaces of the inflation lumens while a free boundary condition was used along the outer surface of the catheter to predict its radial
Shaft design
As depicted in Fig. 1, we have proposed a simple but new concept for a urinary catheter prototype capable of releasing biofilms by means of active actuation of elastomers [34]. The design is based on equipping the catheter with inflation lumens between the inner main lumen and outer catheter wall (Fig. 1a). After infectious biofilms form on the surface of the main drainage lumen (Fig. 1b), we pneumatically or hydraulically actuate the inflation lumens to a controlled level of strain for
Conclusion
Active surface deformation is an efficient but simple method for detaching biofilm from a silicone substrate. We demonstrated a prototype of a multi-inflation-lumen urinary catheter with the ability to debond biofilms from the previously-inaccessible main drainage lumen to keep its functionality. With the guidance of finite element analysis and experimental testing, we developed a design of an extrudable catheter shaft with four intra-wall inflation lumens that apply sufficient strains to
Acknowledgments
This work was financially supported by the NSF's Research Triangle Materials Research Science and Engineering Center (DMR-1121107), the Office of Naval Research (N0014-13-1-0828), and the Duke-Coulter Translational Partnership Grant Program. Catheter image from Fig. 1 licensed from Shutterstock Inc.
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These two authors contributed equally to this work.