Patent Application
20250177585
The present disclosure relates to an apparatus and method for removal of biofilm and/or bacteria from a metallic medical device.
Infection, whether acute or chronic, is a common complication following the implantation of a prosthesis or osteosynthesis material in a patient. This complication has a high morbidity rate, as well as a substantial mortality rate and the available treatments have a high economic cost.
Despite the many advances made in recent years in sterility measures and in systemic and local prophylactic antibiotic therapy, the infection rate continues to be between 0.3 and 25% depending on the type of intervention and the size of the implant used. Although the exact pathophysiology of orthopaedic hardware infection is not clear, it is known that any infection of orthopaedic hardware is preceded by: 1) contamination of the surgical site, 2) bacterial adhesion and 3) biofilm formation on the prosthetic material.
It is the presence of this biofilm that makes it necessary, after several weeks of infection, to remove the metal material in order to eliminate the entire bacterial load and thus cure the infection, as the methods currently available cannot destroy all the biofilm present on the surface of the implant.
The antibacterial usefulness of electric fields has been known since the beginning of the last century: a method to sterilise milk using low frequency alternating current (AC) is known. In science fields other than medicine, such as industrial water and food processing, high voltage electric fields are routinely used to “sterilise” or kill various micro-organisms and pathogens.
It has further been demonstrated the ability of electric fields to enhance the bactericidal effect of certain antibiotics. Since then, multiple in-vitro studies have emerged, demonstrating the capacity of low-energy electric fields (alternating and direct current) to inhibit bacterial growth of different strains of S. aureus, P. aeruginosa and S. epidermidis. It has also been demonstrated in rabbits the effectiveness of electric fields for the treatment of osteomyelitis caused by S. epidermidis (U.S. Pat. No. 5,312,813).
However, the application of a DC generates, among other things, the electrolysis of water, which in turn generates changes in the pH of the medium, free radicals and the release of various ions that can be cytotoxic, particularly for prolonged exposure of a DC current. In addition, there is an electro-corrosion effect (on the anode) which makes its direct application on an orthopaedic implant impossible. This is why the applicability of this current on the human body could only be carried out under very controlled conditions, so that the applicability of its studies is very limited.
Various studies have been published that demonstrate their capacity to modify electrostatic forces, altering bacterial adherence to biomaterials or even deconstructing the biofilm already formed and adhered (U.S. Pat. No. 6,663,634 B2).
US 2013/0041238A1), discloses a catheter (urinary or intravascular) resistant to infection thanks to the use of electric fields.
Electric fields can be applied to the surface of the medical device in order to repel biofilms from the surface by ionic forces. However, this method is not able to repel all of the bacteria on the surface of the medical device and the process of removing the biofilm may take several hours or longer. Therefore, the electric fields affect the liquid solution (synovial fluid or blood) where the metallic implant is placed and cause the coagulation of the medium and the formation of bacterial lumps.
Another proposed method involves placing the medical device in an electrolytic solution and applying a direct electric current to the solution, wherein the electrolysis reaction generates pH changes and the formation of antibacterial molecules such as HCl which have antimicrobial properties. This process directly reduces the viability of bacteria in the medium, and kills the bacteria but again, the medical device must be placed in the electrolytic medium for several hours or days to kill the bacteria in biofilms and the potential cytotoxic effect on host cells is not controlled.
There is therefore a need to provide a device for removing biofilm from, or reducing bacteria adhesion to, medical devices more effectively. There is also a need to provide a device for removing biofilm from, or reducing bacteria adhesion to medical devices in which the duration of the removal process is shortened.
According to a first aspect of the invention, there is provided an in vitro method of removing biofilm from, or reducing bacterial adhesion to, a metallic medical device external to the human or animal body, comprising: connecting a first electrode to a surface of the medical device; exposing a target area on the surface of the medical device to an electrolytic fluid; placing a second electrode proximal to the target area; providing electrical power between the first and second electrode such that electrolysis occurs in the electrolytic fluid; wherein the electrical power comprises a plurality of electrical pulses, wherein the potential difference between the first and second electrode is is at least 1V; and wherein the current density applied in each electrical pulse is up to 15A per cm2 of the target area.
In a preferred embodiment, the current density applied is between 0.1 and 15 A per cm2 of the target area, preferably between 0.1 and 5 A per cm2 of the target area. In another preferred embodiment, the current density applied is between 0.2 and 2 A per cm2 of the target area.
According to the first aspect of the invention, there is provided another in vitro method of removing biofilm from, or reducing bacterial adhesion to, a metallic medical device external to the human or animal body, comprising: connecting a first electrode to a surface of the medical device; exposing a target area on the surface of the medical device to an electrolytic fluid; placing a second electrode proximal to the target area; providing electrical power between the first and second electrode such that electrolysis occurs in the electrolytic fluid; wherein the electrical power comprises a plurality of electrical pulses, wherein the potential difference between the first and second electrode is at least 1V; wherein the current applied in each electrical pulse is up to 2A, and wherein each electrical pulse has a duration of less than 1 second.
In a preferred embodiment, the step of providing electrical power between the first and second electrodes comprises providing a potential difference between 1V and 50V, preferably between 10V and 30V, and the step of providing electrical power between the first and second electrodes further comprises providing a current between 0.5A and 1A.
In another preferred embodiment, each electrical pulse has a duration between 0.05 and 0.2 seconds.
In another preferred embodiment of any of the in vitro methods of the first aspect of the invention, the second electrode is an anode comprising a sacrificial metal, preferably comprised of silver, and/or wherein the electrolytic fluid comprises one or more of a disinfecting agent, antibacterial agent or antibiotic agent; or the second electrode is an anode comprising a non-corrodible metal and free from sacrificial metals, wherein the method further comprises isolating bacteria from the electrolytic fluid after the electrical power is provided.
According to a second aspect of the invention, there is provided an apparatus for removal of biofilm from a metallic medical device, comprising: a fluid output connectable to a source of electrolytic fluid, the fluid output for supplying the electrolytic fluid to wash a target area of the medical device; a first electrode for electrically connecting to the medical device; the second electrode configured to be placed proximal to the fluid output; and an electric power source for supplying electrical power between the first and second electrodes; wherein the electrical power source is configured to provide intermittent electrical pulses between the first and second electrode such that electrolysis occurs at the surface of the metallic device, wherein the potential difference between the first and second electrode is at least 1V and wherein the current density applied in each electrical pulse is up to 15 A per cm2 of the target area.
In a preferred embodiment, the electrical power source is configured to provide intermittent electrical pulses with current density applied is between 0.1 and 15 A per cm2 of the target area, preferably between 0.1 and 5 per cm2 of the target area.
In another preferred embodiment, the electrical power source is configured to provide intermittent electrical pulses with current density applied is between 0.2 and 2 A per cm2 of the target area.
According to the second aspect of the invention, there is provided another apparatus for removal of biofilm from a metallic medical device, comprising: a fluid output connectable to a source of electrolytic fluid, the fluid output for supplying the electrolytic fluid to wash a target area of the medical device; a first electrode for electrically connecting to the medical device; the second electrode configured to be placed proximal to the fluid output; and an electric power source for supplying electrical power between the first and second electrodes; wherein the electrical power source is configured to provide intermittent electrical pulses between the first and second electrode such that electrolysis occurs at the surface of the metallic device, wherein the potential difference between the first and second electrode is at least 1V; and wherein the current applied in each electrical pulse is up to 2A, and wherein each electrical pulse has a duration of less than 1 second.
In a preferred embodiment, the electrical power source is configured to provide intermittent electrical pulses with a potential difference between 1V and 50V, and preferably between 10V and 30V, and a current between the first and second electrodes between 0.5A and 1A.
In another preferred embodiment, the electrical power source is configured to provide each electrical pulse with a duration between 0.05 and 0.2 seconds.
In another preferred embodiment of any of the apparatus of the second aspect of the invention, the apparatus further comprises a controller configured to control the supply of electrolytic fluid from the source of fluid to the fluid output.
In another preferred embodiment, the fluid output and/or the first electrode and/or the second electrode are removably connectable to the apparatus via a detachment mechanism.
In another preferred embodiment, the fluid output comprises a tubular body, optionally wherein the tubular body is curved so that the longitudinal axis of the tubular body at a proximal end is offset from the longitudinal axis of the tubular body at a distal end by between greater than 0 and 90 degrees, or wherein the fluid output comprises a porous sponge or a conical cap at its distal end.
In another preferred embodiment, the first or second electrode and the fluid output are provided on a single detachable body connectable to the apparatus, more preferably wherein both the first and second electrode are provided on the single detachable body.
In another preferred embodiment, the power source is configured to supply an intermittent direct current between the first and second electrodes.
In another preferred embodiment, the apparatus further comprises a source of electrolytic fluid connected to the fluid applicator, wherein the fluid is a saline solution; optionally wherein the fluid comprises one or more of a disinfecting agent, antibacterial agent or antibiotic agent.
In another preferred embodiment, the apparatus further comprises a pump configured to provide the electrolytic fluid to the fluid output at a predetermined pressure.
In another preferred embodiment, the fluid output and the first and/or second electrode are configured to be connected to a handheld portion, and the handheld portion comprises a user actuated element for actuating the supply of fluid and/or electrical power.
Embodiments will now be explained in detail, by way of non-limiting example only, with reference to the accompanying figures described below.
The present invention relates to a method and apparatus for removal of biofilm or reducing adhesion of bacteria on a metallic medical device, which is configured to apply electrical pulses between two electrodes when one electrode is electrically connected to the metallic medical device, and when the metallic device is exposed to an electrolytic fluid. The application of the electrical pulses (specifically DC pulses) to the metallic device reduces bacterial attachment to a target area of the medical device by forming bubbles (in the case where the medical device is electrically connected to the cathode and the electrolytic solution is a saline solution, the bubbles are hydrogen bubbles) as a product of electrolysis directly on the surface of the metallic device, which mechanically lifts the bacteria or biofilm from the surface of the metallic device. The apparatus may be configured to rinse or wash the device with an intermittent supply of the electrolytic fluid to a target area of the metallic device. The intermittent supply of fluid to the target area further washes the bacteria which has been detached from the surface by the electrical pulses, and inhibits electrocoagulation and the formation of bacterial clumps.
As disclosed herein, the term “electrolytic fluid” may be considered as any liquid which contains electrolytes such that electrolysis occurs when a DC voltage is applied between a cathode and anode exposed to the electrolytic fluid. Therefore, the electrolytic fluid may be a saline solution or any other type of buffer solution.
As disclosed herein, the term “expose to electrolytic fluid” may be considered as any manner of providing the electrolytic fluid to the exposed element. This may include submerging the element in the electrolytic fluid or providing the electrolytic fluid to the exposed element by a flow of electrolytic fluid, for example by continuous or intermittent flow of the electrolytic fluid onto the element.
As disclosed herein, the term “metallic medical device” may include any medical device which includes at least a portion made of metal. The metallic device may be entirely or partly made of metal. The term “medical device” may be defined as any device which interfaces with the human or animal body in use. Medical devices may include medical implants, prosthesis or any other device configured to be placed on or in the human or animal body.
As disclosed herein, the term “sacrificial metal” may be considered as any metal whose surface dissolves into an electrolytic fluid when acting as an anode during electrolysis.
As disclosed herein, the term “non-corrodible metal” may be considered as any metal whose surface does not dissolve into an electrolytic fluid when acting as an anode during electrolysis.
The methods disclosed herein may be used to removing biofilm from, or reducing bacteria adhesion to a medical device in vivo or in vitro. In other words, the methods disclosed herein may be used to removing biofilm from, or reducing bacteria adhesion to a medical device whilst it is in or on a human or animal body, or a medical device which is external to the human or animal body.
The fluid output 10 may be connectable to any suitable fluid source 12. For example, the fluid output 10 may be connected via one or more conduits forming a flow path from a fluid reservoir to the fluid output 10. Additional components for regulating the flow of fluid from the fluid source 12 to the fluid output 10 may be provided. For example, one or more pumps or valves may be provided in order to selectively provide fluid 14 to the fluid output 10 at a desired pressure or fluid flow rate. In other embodiments, the fluid source 12 may provide the required pressure without the use of a pump. In a preferred embodiment, fluid may be provided to the fluid output 10 via a peristaltic pump so that the pump parts are not exposed to the fluid. Accordingly, the pump may be re-used between washes. The connection may be a permanent one, i.e. the conduits are integral with the fluid source 12 and the fluid output 10, or it may be detachable. For example, the conduits may be attached to the fluid source 12 and/or the fluid output 10 by a detach mechanism, such as a screw thread connection, frictional fit or stab connection, as known in the art.
The first and second electrodes 50, 20 may be connectable to any suitable power source 22. For example, the electrodes 50, 20 may be connected via electrical wiring forming an electrical connection between the power source 22 and the electrodes 50, 20. Additional electronic components may be situated between the power source 22 and the electrodes 50, 20 to regulate the power supplied by the power source 22 to the electrodes 50, 20. For example, the electrodes 50, 20 may be connected to the power source 22 by a power converter, such as any DC-DC, AC-DC, DC-AC or AC-AC power converter. The power source 22 may comprise a mains power source, one or more batteries, a constant voltage or constant current power source or the like. The electrical connection between the electrodes 50, 20 and the power source 22 be a permanent one, i.e. the electrical wiring forming the connection may be integral with the electrodes 50, 20 and/or the power source 22, or it may be detachable. For example, electrical wiring forming the connection may be attached to the power source 22 and/or the electrode 50, 20 by a detach mechanism, such as a screw thread connection, frictional fit, plug or stab connection, as known in the art.
The electrical power source 22 is configured to provide intermittent electrical pulses between the first and second electrode such that electrolysis occurs at the surface of the metallic device 40, wherein the current applied in each electrical pulse is sufficient to cause bubbles to escape the surface of the metallic device during the electrical pulse. When the potential between the electrodes is greater than the decomposition potential required for electrolysis to occur, and the current applied in each electrical pulse is sufficient to cause bubbles to escape the surface of the metallic device during the electrical pulse, bacteria or biofilms on the surface of the metallic device are lifted away from the surface of the device by the bubbles. It will be appreciated that the current and potential difference required of each electrical pulse so that bubbles escape the surface of the metallic device will depend on the apparatus used, including the surface area of the electrodes, the materials for the electrodes used, the type of electrolytic fluid and so on. For a given apparatus according to the invention, it can be verified by visual confirmation whether the current supplied for each electrical pulse is sufficient to release bubbles. For example, the medical device may be submerged in a container containing the electrolytic fluid, and it can be visually verified if bubbles escape the surface of the medical device for each pulse.
It is noted that the decomposition potential, defined as the minimum voltage between the anode and cathode (first and second electrode) needed for electrolysis to occur, depends on the oxidation and reduction reactions occurring at the electrodes and therefore depends on the electrolyte solution and the electrode metals chosen. For a saline solution, the decomposition potential is between 1V and 2V. Above the decomposition potential, the gas production rate at the electrodes increases proportionally with the current flow, according to Faraday's law. For a saline solution, a current of between greater than 0A and 2A is sufficient for bubbles to escape the surface of the medical device for each pulse. Accordingly, when a saline solution is used, the following voltage and current ranges are preferred:
It is however noted that these preferred values are also feasible for other electrolytic fluids such as buffer solutions. We also note that by saying a current up to 2A it is understood that it is bigger than 0A and up to 2A, i.e. that in any case there shall be some current.
As observed in Examples 1 to 3 described herein, it has been observed that a plurality of pulses of less than 1 second in duration is sufficient to at least partially detach the biofilm. A series of 100 electrical pulses, each 0.1 seconds in duration, reduces the amount of biofilm on the substrate by several orders of magnitude (
The term “proximal” in relation to the second electrode 20 and the fluid output 10 should be understood as meaning the second electrode 20 and fluid output 10 are positioned sufficiently close so that the required bubbles (caused by electrolysis) escape the surface at the target area on the medical device 40 in use. The distance between the second electrode 20 and the fluid output 10 may depend on the parameters of the apparatus 1. For example, apparatus 1 may be configured to output fluid 14 from the fluid output 10 in a jet of fluid, such that the fluid output 10 is located further from the target area than the electrode 20 whilst still applying both the fluid 14 to the target area of the medical device 40 and the electric power causing electrolysis at the target area. Also, the electrical power source may be a constant current source with a maximum voltage, with larger maximum voltages allowing for the second electrode 20 to be held further away from the surface of the medical device 40 whilst still achieving the required level of current for bubbles to be released from the surface of the medical device 40 during each electrical pulse.
As disclosed herein, a fluid output may be defined as any fluid port which delivers a fluid 14 from a fluid source 12 to a target. The fluid output may for example comprise a nozzle.
The controller 30 may be any suitable controller, analogue or electronic, for controlling the supply of fluid to the fluid output 10 and/or the supply of electric power to the electrode 20. For example, the controller may be configured to control an actuatable valve which is periodically opened and closed to open and close the fluid flow path 13 between the fluid source 12 and the fluid output 10. The controller may, for example, be configured to control a pump to intermittently supply fluid to the fluid output 10 at a desired pressure. The controller 30 may also be configured to control the supply of electrical power to the electrode. For example, the controller 30 may be an electronic controller configured to open and close the electrical connections 54, 24 between the power source 22 and the electrodes 50, 20. The controller 30 may be configured to control one or more electrical components between the power source 22 and the electrodes, such as converters, variable resistors and the like. It will be appreciated that in any of the embodiments disclosed herein the controller 30 may be powered by any power source, and may be powered by the power source 22 or different power sources.
The apparatus 1 may further comprise a negative pressure source 60 configured to remove fluid from the target area. The negative pressure source 60 may be any suitable negative pressure source such as a vacuum pump, a surgical suction device or similar. The negative pressure may be transmitted from the source 60 to the target area via flexible tubing positionable at the target area of the medical device 40 and forming a fluid path 62. The negative pressure source 60 may be powered by any suitable internal or external power source, and may be powered by power source 22. The negative pressure source 60 may be configured to operate intermittently or continuously so that excess electrolytic fluid is removed from the surface of the medical device 40 intermittently or continuously. The negative pressure source 60 may be controlled by controller 30 via any suitable control connection (not shown). The controller 30 may be configured to synchronize the intermittent supply of fluid 14 with the intermittent operation of the negative pressure source 60 so that the intermittent negative pressure source 60 operates a predetermined period of time after fluid output 10 stops supplying fluid 14 to the medical device 40. The negative pressure source 60 may output the received fluid to a storage reservoir (not shown)
It is noted that two mechanical actions are performed by the apparatus 1 described in relation to
The power source 22 is preferably a current source. In preferred embodiments, the power source 22 is configured to provide electrical pulses of a sufficient current such that bubbles are released from the surface of the medical device 40 for each pulse. According to Faraday's first law, the mass of elements deposited at an electrode is directly proportional to the charge. Accordingly, the rate of gas production on the surface of the medical device 40 is proportional to the current provided by the power source 22. It therefore follows that the amount of current required to be supplied for each pulse depends on the area of medical device 40 over which electrolysis occurs during the pulse, which is generally determined by the cross-sectional area of the second electrode 20 facing the surface of the medical device 40. Therefore, both the cross-sectional area and the duration of the pulse will determine whether bubbles are released from the surface of the medical device 40 during each pulse. It has been observed that a current of 500 mA is sufficient to observe bubbles escaping the surface during each electrical pulse for a cross-sectional area of 177 mm2 and a pulse duration of 0.1 seconds in duration (i.e. a current density of about 2.82 mA/mm2 is sufficient to cause bubbles to lift off the surface of the medical device 40). However, lower current densities could be applied for longer durations for each pulse, the pulses having sufficient duration for bubbles to escape the surface of the medical device 40. The current source preferably has a voltage range of 0 to 15V, preferably 0 to 30V and even more preferably 0 to 50V. A higher maximum voltage means that the electrode 20 can be moved further from the surface of the medical device 40 whilst the current is maintained at the required level.
As shown in Example 5, the current density may be, according to a current of 1 A and for a medical device target area of 0.07 cm2, of 14,29A/cm2, and still be safe for a subject. Therefore, although the current density may vary depending on the size of the electrode, a safe range of current density bigger than 0 A/cm2 and up to 15 A/cm2 may be stablished. More preferably, the current density may be comprised between 0.1 A/cm2 and 5 A/cm2 even more preferably between 0.2 A/cm2 and 2 A/cm2. The spatial dimensions are always referred to the area of the medical device over which electrolysis occurs during the pulse also known as the target area of the medical device, although in some embodiments it may be defined as the cross-sectional area of the second electrode (40) when the voltage is not enough to provide the current to all the area of the device.
The memory 34 may comprise one or more volatile or non-volatile memory devices, such as DRAM, SRAM, flash memory, read-only memory, ferroelectric RAM, hard disk drives, floppy disks, magnetic tape, optical discs, or similar. Likewise, the processor 36 may comprise one or more processing units, such as a microprocessor, GPU, CPU, multi-core processor or similar. The controller 30 may further be implemented in software, hardware, or any combination in order to execute the sequences of operation disclosed herein.
The controller 30 may be further connected to a user interface 32 configured to select one or more parameters of the fluid supply control such as pressure, flow rate, pulse frequency and pulse duration of the fluid supply. The user interface 32 may alternatively or additionally be configured to select one or more parameters of the electric supply such as voltage, current and pulse rate and duration. The user interface 32 may comprise buttons, knobs, sliders, levers, wheels, a touchscreen, and so on, that the user can use to select the parameters. The controller 320 may be connected to the same user interface or a separate user interface to select one or more parameters of the power supply such as voltage, current, pulse rate and duration of the cleaning operation.
It will be appreciated that in any of the embodiments described with reference to
In some embodiments, the apparatus 1 may be suitable for minimally invasive, percutaneous treatment when the medical device 40 is situated in the body. In particular, electrodes 50 and 20 may comprise metallic needles configured to be injected into the body so that the first electrode 50 forms an electrical connection to the medical device 40 and the second electrode 20 is locatable proximal the target area of the medical device 40. The fluid output 10 may also comprise a needle for penetrating into the body and for injecting the electrolytic fluid at the site of the medical device. Finally, the negative pressure source 60 may also comprise a needle for penetrating into the body and extracting fluid from the site, of the negative pressure source 60 may use the fluid path of the fluid output 10 when the negative pressure source 60 and fluid output 10 operate alternately. Once the needles are correctly placed, electrolytic fluid may be injected to the site of the medical device 40 and the electrical pulses may be applied to the electrolytic fluid to remove bacteria from the surface of the medical device 40. The negative pressure source 60 may then be operated to extract the electrolytic fluid containing the removed bacteria, thereby removing bacteria from the body and treating the infection site.
In the embodiments shown in
The apparatus 100 further comprises a pump 104 connectable between the fluid source 12 and the fluid output 10. The pump 104 may be any suitable pump such as a positive-displacement pump, impulse pump or rotodynamic pump. In preferred embodiments the pump is a peristaltic pump. In the illustrated embodiment, the pump 104 forms part of the removable element 102, and when the removable element 102 is connected to the body 110 via the detachment mechanism, the pump 104 forms a mechanical connection with an electric motor 106 for actuating the pump 104. In other embodiments, the pump 104 is hydraulically actuated and the apparatus comprises a source of hydraulic pressure for actuating the pump. The pump 104 is also configured to be connected to the fluid source 12 in order to receive the fluid 14 as an input to the pump. The pump 104 may be connected to the fluid source 12 independently of the body 110, as illustrated in
In the embodiment shown in
As shown in
The apparatus 100 may further comprise a negative pressure source 60 configured to remove fluid from the target area. The negative pressure source 60 may be any suitable negative pressure source such as a vacuum pump or similar and may be provided with the main body 110 or separately to the main body 110. The negative pressure may be transmitted from the source 62 to the target area via flexible tubing positionable at the target area of the medical device 40 and forming a fluid path 62. The negative pressure source 60 may be powered by any suitable internal or external power source, and may be powered by power source 22. The negative pressure source 60 may be configured to operate intermittently so that excess electrolytic fluid is removed from the surface of the medical device 40 intermittently. The negative pressure source 60 may be controlled by controller 30 via any suitable control connection (not shown). The controller 30 may be configured to synchronize the intermittent supply of fluid 14 with the intermittent operation of the negative pressure source 60 so that the intermittent negative pressure source 60 operates a predetermined period of time after fluid output 10 stops supplying fluid 14 to the medical device 40. The negative pressure source 60 may output the received fluid to a storage reservoir (not shown). The negative pressure source 60 may be comprised in the main body 110 and powered by a motor in the main body 110 controlled by controller 30, as in the case of pump 104. The removable element 102 may comprise a second fluid conduit (not shown) extending through the removable element 102 from the fluid output 10 to the negative pressure source 60, when the removable element 102 is attached to the main body 110.
For the apparatus 100, the surface area of the electrode 20 for determining the current density at the electrode 20 is the longitudinal cross-sectional area of the electrode 20 at the distal end of the removable element 102.
In any of the embodiments disclosed herein, the fluid 14 may be any electrolyte solution (for example a saline solution such as physiological saline) and the apparatus is configured to apply DC electrical pulses between the electrodes 50, 20. The second electrode 20 may be selected as the cathode or the anode and the first electrode 50 is connectable to the medical device. Preferably, the first electrode 50 is the cathode so that oxidation or electro-corrosion of the medical device 40 does not occur. The DC electrical power applied between the electrodes 50, 20 causes electrolysis to occur at the target area. The bubbles formed at the target area of the medical device lift up bacteria from the surface of the medical device, reducing adhesion of the bacteria to the medical device and removing biofilms from its surface. In some embodiments, the fluid output is configured to provide the fluid intermittently, which provides intermittent washing to the medical device 40 to prevent the build-up of bacteria in the electrolytic fluid at the surface. That is to say, the fluid output 10 provides the electrolyte solution for allowing the electrolysis at the target area, and may further wash away the detached bacteria by the intermittently supplied fluid at the target area.
The electrolyte solution fluid is comprised of a solvent and electrolytes. The solvent may comprise, for example, water. The electrolytes may comprise, for example, salt ions and/or silver ions. When the electrolyte solution contains silver ions, an antibacterial effect is observed without the need to us a sacrificial electrode such as a silver electrode. The electrolyte solution may further comprise one or more of a disinfecting agent (such as hypochlorous acid), an antibacterial agent (such as dissolved silver, gold or copper ions), or an antibiotic therapeutic composition (the antibiotic therapeutic composition may comprise any suitable antibiotic composition known in the art, including but not limited to one or more of vancomycin, gentamicin and clindamycin). Saline solution is advantageously biocompatible. It is noted that the cleaning effect from the electrolysis and periodic washing at the target area arises from the removal of bacteria from the surface by the bubbles formed during electrolysis, and the washing away of the removed bacteria by the periodic washing. It has been observed that this process greatly shortens the cleaning time of the medical device when compared to the process of indirectly killing bacteria using the toxic chemicals produced by the process of electrolysis.
The electric DC power is applied intermittently. When the fluid is output intermittently, at least one cycle of DC current may be provided to the electrode for each cycle of fluid provided to the fluid output. The provision of at least one cycle of DC current for each cycle of fluid output ensures that bacteria is lifted from the surface of the medical device before the next fluid wash occurs. Preferably, the DC current and the fluid are provided intermittently so that the electrolysis occurs in between washes of the medical device by the fluid.
In a preferred embodiment, the second electrode 20 is a sacrificial anode comprising a sacrificial metal. As disclosed herein, a sacrificial electrode may be defined as an electrode that disintegrates over time when a current is applied to the electrode in an electrolytic solution. The sacrificial electrode may be selected to release particular ions into the electrolytic solution which have antibacterial properties. Examples of suitable materials include silver and copper.
In a further preferred embodiment, the sacrificial anode comprises silver (Ag) so that the oxidation process at the anode from the electrolysis releases silver ions to the target area of the device 40. The silver ions increase the antimicrobial properties of the fluid exposed to the medical device. Thus, the potency of the biofilm or bacterial removal process is increased.
In other embodiments, the second electrode 20 is free from sacrificial metals and comprises a non-corrodible metal, so that little to no metal ions are released into the electrolytic solution during electrolysis. This allows the electrolytic solution to be retrieved after electrolysis which contains bacteria from the biofilm. The bacteria may be isolated from the electrolytic solution and cultured so that the bacteria can be identified in order to guide treatment of the infection, such as the effective course of antibiotics to administer to the patient. Examples of suitable materials include platinum.
In any of the embodiments disclosed herein, the first electrode 50 may comprise one or more non-corrodible metals such as cobalt-chromium and titanium.
In any of the embodiments disclosed herein, the apparatus may be configured to provide a fluid flow of electrolytic fluid to the fluid output of between 0.5 and 2 litres per minute. The flow may be continuous or intermittent with a pulse rate of between 0-100 Hz, and more preferably 0-10 Hz.
In any of the embodiments disclosed herein, the apparatus may be configured to provide DC pulses having a duration between 0.05 and 0.2 seconds, at a frequency of between 0-100 Hz, and more preferably 0-10 Hz. The apparatus may be configured to provide a current of between 0 and 1.5A.
In any of the embodiments disclosed herein, the fluid output 10 may be removably connectable to the controller 30 via a detachment mechanism as disclosed in other embodiments. The fluid output 10 and electrode 20 may be provided on the same detachable body.
Any of the embodiments disclosed herein may comprise a pump situated between the fluid source 12 and the fluid output 10, wherein the controller is configured to control the pump to provide fluid to the fluid output 10 as a predetermined pressure.
Any of the embodiments disclosed herein may comprise one or more user interfaces to select the operating parameters of the fluid supply and the electric supply.
In any of the embodiments disclosed herein, the fluid output 10 and first and/or second electrode 50, 20 may be connectable to a handheld portion, wherein the handheld portion comprises a user actuated element for actuating the supply of fluid and/or electrical power.
Any of the apparatuses disclosed herein may be used to implement the following method of removing biofilm from, or reducing bacterial adhesion to, a metallic medical device internal or external to the human or animal body:
It is noted that the method is not limited to being applied by the above-disclosed devices. For example, the method could be implemented by submerging the medical device in a reservoir or container of the electrolytic fluid, connecting a first electrode to a surface of the submerged medical device, placing a second electrode proximal to the target area of the medical device, and providing the required electrical pulses between the electrodes such that the electrolysis occurs on the surface of the medical device. It is noted that in embodiments where the medical device is submerged in a reservoir of the electrolytic fluid in this manner, there may further comprise the step of washing the medical device with the electrolytic fluid, for example by using a fluid output as disclosed herein for washing the device with fluid.
The fluid may be any electrolyte solution disclosed herein.
Exposing the target area to an electrolytic fluid may comprise washing the metallic device intermittently with the electrolytic fluid. The washing and electrical pulses may be applied alternately (e.g. as shown in
The second electrode may be any sacrificial anode disclosed herein, and preferably the anode is comprised of silver.
In some embodiments, the second electrode is free from sacrificial metals and comprises a non-corrodible metal, so that little to no metal ions are released into the electrolytic solution during electrolysis. This allows the electrolytic solution to be retrieved after electrolysis which contains bacteria from the biofilm. The method may then comprise isolating bacteria from the electrolytic fluid after the electrical power is provided. The bacteria may be isolated from the electrolytic solution and cultured so that the bacteria can be identified in order to guide treatment of the infection, such as the effective course of antibiotics to administer to the patient.
The above methods may also be applied to a medical device in vitro. Furthermore, the above methods may also be applied to a target area on or in the human or animal body directly.
In the first example, nine cathodic bases (three grouped “CH1”, three grouped “CH2”, three grouped “CH3”) comprising plates made of cobalt-chrome (CoCr) and nine corresponding anodic plates also made of cobalt-chrome (CoCr) were used. The plates were discs having a surface area of 1.54 cm2. Before use, the plates were sterilised with UV light for 30 minutes. The cathodic bases were submerged in respective wells of 3 mL. The wells were filled with a culture medium of TSB (Trypticase soy broth) supplemented with 0.25% concentration glucose. A 1/100 dilution of a Staphylococcus epidermidis strain was used in the culture medium. The plates were incubated for 24 hours at 37° C. After 24 hours of incubation, the culture medium was removed from the wells and each well was washed three times with sterile phosphate-buffered saline (PBS 1X). Each well was then filled with 3 mL of saline solution such that the saline electrically connected the respective anodes and cathodes. A plurality of control plates were also incubated in the same manner. The following series of electrical pulses were applied between the respective anodes and cathodes so that electrolysis occurred in the wells and bubbles escaped the surface of the cathodes (the control plates were not exposed to electrical current):
Following the series of electrical pulses, the saline solution was removed from the wells (this removed saline solution was used to measure the number of bacteria in the planktonic state after the pulses as explained below), and each well was washed again three times with sterile PBS 1X (including the control wells). The biofilm adhering to the cathode was removed with a sterile spatula and then homogenised in 900 μL saline solution. One hundred microlitres of the different serial dilutions were seeded on Müller Hinton (MH) agar plates for CFU/mL counting. Data were transformed to CFU/cm2 according to the formula:
Furthermore, and following the previous methodology of dilutions, the number of bacteria in the planktonic state (i.e. not adhered to the surface of the cathode) following the series of electrical pulses was also measured by measuring the amount of bacteria contained in the saline solution removed from the wells directly after the electrical pulses (or at the corresponding time for the control experiment). The data was transformed to CFU/cm2 according to the formula above.
In the second example, nine cathodic bases (three grouped “CH1”, three grouped “CH2”, three grouped “CH3”) comprising plates made of cobalt-chrome (CoCr) and nine corresponding anodic plates made of silver (Ag) were used. The plates were discs having a surface area of 1.54 cm2. Before use, the plates were sterilised with UV light for 30 minutes. The cathodic bases were submerged in respective wells of 3 mL. The wells were filled with a culture medium of TSB (Trypticase soy broth) supplemented with 0.25% concentration glucose. A 1/100 dilution of a Staphylococcus epidermidis strain was used in the culture medium. The plates were incubated for 24 hours at 37° C. After 24 hours of incubation, the culture medium was removed from the wells and each well was washed three times with sterile phosphate-buffered saline (PBS 1X). Each well was then filled with 3 mL of saline solution such that the saline electrically connected the respective anodes and cathodes. A plurality of control plates were also incubated in the same manner. The following series of electrical pulses were applied between the respective anodes and cathodes so that electrolysis occurred in the wells and bubbles escaped the surface of the cathodes (the control plates were not exposed to electrical current):
Following the series of electrical pulses, the saline solution was removed from the wells (this removed saline solution was used to measure the number of bacteria in the planktonic state after the pulses as explained below), and each well was washed again three times with sterile PBS 1X (including the control wells). The biofilm adhering to the cathode was removed with a sterile spatula and then homogenised in 900 μL saline solution. One hundred microlitres of the different serial dilutions were seeded on Müller Hinton (MH) agar plates for CFU/mL counting. Data were transformed to CFU/cm2 according to the formula:
Furthermore, and following the previous methodology of dilutions, the number of bacteria in the planktonic state (i.e. not adhered to the surface of the cathode) following the series of electrical pulses was also measured by measuring the amount of bacteria contained in the saline solution removed from the wells directly after the electrical pulses (or at the corresponding time for the control experiment). The data was transformed to CFU/cm2 according to the formula above.
It is noted that the high capacity of the electrical pulses to detach the biofilm is observed with only 25 electrical pulses of 0.1 seconds duration every 0.5 second, achieving a reduction by eight orders of magnitude with respect to the control over a very short time of less than 30 seconds.
In the third example, nine cathodic bases (three grouped “CH1”, three grouped “CH2”, three grouped “CH3”) comprising plates made of cobalt-chrome (CoCr) and nine corresponding anodic plates made of silver (Ag) were used. The plates were discs having a surface area of 1.54 cm2. Before use, the plates were sterilised with UV light for 30 minutes. The cathodic bases were submerged in respective wells of 3 mL. The wells were filled with a culture medium of TSB (Trypticase soy broth) supplemented with 0.25% concentration glucose. A 1/100 dilution of a Staphylococcus epidermidis strain was used in the culture medium. The plates were incubated for 24 hours at 37° C. After 24 hours of incubation, the culture medium was removed from the wells and each well was washed three times with sterile phosphate-buffered saline (PBS 1X). Each well was then filled with 3 mL of saline solution such that the saline electrically connected the respective anodes and cathodes. A plurality of control plates were also incubated in the same manner. Electrical pulses were applied between the respective anodes and cathodes of groups CH1 and CH3 so that electrolysis occurred in the wells and bubbles escaped the surface of the cathodes. Following the electrical pulses, the saline solution was removed from the wells in group CH1 and each well in group CH1 was washed again three times with sterile PBS 1X (including the control wells). The biofilm adhering to the cathodes of CH1 were each removed with a sterile spatula and then homogenised in 900 μL saline solution. One hundred microlitres of the different serial dilutions were seeded on Müller Hinton (MH) agar plates for CFU/mL counting. Data were transformed to CFU/cm2 according to the formula:
The cathodic plates in groups CH2 and CH3 were removed from the wells and washed with a pressured jet of saline solution, making sure to avoid cross-contamination of the plates by splashes. Once the pressured washing was finished the biofilm adhering to the cathodes of CH2 and CH3 were each removed with a sterile spatula and then homogenised in 900 μL saline solution. One hundred microlitres of the different serial dilutions were seeded on Müller Hinton (MH) agar plates for CFU/mL counting. Data were transformed to CFU/cm2 according to the formula above.
Accordingly, the CH1 plates were exposed only to electrolysis, the CH2 plates were exposed to only washing using a pressured jet of fluid, and the CH3 plates were exposed to both electrolysis and washing using the pressured jet. The parameters of the electrolysis and washing were as follows:
In the fourth example, a biofilm of E. Coli was grown and developed in 1.4 cm wide plates of Ti, Ti sintered and Cr—Co for 72h to form a mature biofilm, that was dyed with violet crystal such that the biofilm can be easily identified as shown in stage I of
Once this was done, it was tried to detach with physiological serum, this being impossible.
Subsequently, a pulse of 1A (2 pulses per second, 0.25s duration each pulse) was applied (see stage II of
This in vitro experiment shows that the in vitro method of removing biofilm according to the present invention can effectively remove the biofilm on a medical implant in a short period of time.
In the fifth example an in vivo test was performed. Two New Zealand White rabbits were implanted with a specially designed Cr—Co prosthesis (40) in both knees as shown in
In the first animal (control) the joint was closed directly after washing with saline solution. In the second animal (case) treatment was administered on both prostheses with pulses of electric current (1A, 2 pulses per second) with a time gap of 30% for 40 seconds, washing with saline and closure of the joint as shown in
After 72 hours both animals were reoperated to take samples of tissues, bone and explant of the prostheses to perform cultures. In all samples quantitative cultures were previously vortexed and sonicated in one millilitre of BHI. Absence of contamination by identification by MALDI-TOF MS (VITEK-MS) and automated antibiogram of isolated colonies (VITEK-2) was confirmed.
In the control animal, treated with a dose of cefazolin isolates S. aureus in all samples studied, the bacterial count expressed as log 10 (ufc/cm2) in the right leg prosthesis was 9.38 and in the left leg 8.86. The bacterial count expressed as log 10 (ufc/mL) in bone and periprosthetic tissue biopsies was 2.70 and 2.72 in the right leg and 3.24 and 3.87 in the left leg respectively. In the animal in which an electric field was applied to the implant after its placement in addition to a dose of cefazolin, all samples (prosthesis, bone and periprosthetic tissue biopsies) were negative, not being able to isolate the strain of S aureus inoculated after incubation of the sonicated broth for 14 days. The results can be observed in the following table:
This in vivo model suggests the potential efficacy of the application of an electric field on a prosthetic implant in combination with cefazolin in preventing the development of IPA after exposure of the implant to an inoculum of S. aureus ATCC 25923.
In the sixth example another in vivo test was performed. Two New Zealand White rabbits were implanted with a specially designed Cr—Co prosthesis, under standard asepsis measures and antibiotic prophylaxis with cefazolin 10 mg/kg in a single dose.
Then, 0,5-1 mL of serum comprising an inoculum of S. aureus ATCC (105 ufc/ml) was provided and the rabbits were stalled for 4 days to let the infection progress.
Once the infection had progressed for 4 days, the first rabbit (control) and the second rabbit (case) were treated differently. The control rabbit had an extensive surgical cleaning and washing with abundant physiological serum for 1 minute, representing a debridement, antibiotics and implant retention (DAIR) typical intervention. The case rabbit had an extensive surgical cleaning and washing with abundant physiological serum and electrical current pulses (1A, 2 pulses per second with a duty cycle of 30%) for 1 minute.
After the cleaning procedures, both control and case rabbits were monitored for 4 days, keeping the cefazolin doses to prevent sepsis and the progression of the infection to soft tissues.
Finally, the prosthesis were explanted in sterile conditions, further taking samples of the joint fluid, periarticular tissues, bone, and blood cultures.
Results show that in the control animal the bacterial count expressed as log 10 (ufc/mL) in a 1/10 dilution of each prosthesis (data without accounting for the prosthesis surface) was significantly greater than in the case animal, as shown in the following table:
Results shown that electric fields applied according to one or more embodiments of the present invention are very effective for the treatment of articulation prosthetic infections improving results compared to when only DAIR (debridement, antibiotics and implant retention) is performed. The bacterial count on the right knee of the case rabbit can be explained by the recolonization from the bacteria present in the periarticular soft tissues. However, the count was much lower than in prostheses of the control rabbit treated only with DAIR (without electric fields).
In the seventh example another in vitro test was performed.
A biofilm of E. Coli was grown and developed in plates of Ti, Ti sintered and Cr—Co for 72h to form a mature biofilm, that was dyed with violet crystal such that the biofilm can be easily identified as shown in stage I of
First, three implants (of Ti, Ti sintered and Cr—Co) were treated using an electrolytic fluid in a pulsed manner according to the state of the art (
Then, another three implants (of Ti, Ti sintered and Cr—Co) were treated using the apparatus according to one or more embodiments of the present invention of
As shown in stage II of
All of the above are fully within the scope of the present disclosure, and are considered to form the basis for alternative embodiments in which one or more combinations of the above described features are applied, without limitation to the specific combination disclosed above.
In light of this, there will be many alternatives which implement the teaching of the present disclosure. It is expected that one skilled in the art will be able to modify and adapt the above disclosure to suit its own circumstances and requirements within the scope of the present disclosure, while retaining some or all technical effects of the same, either disclosed or derivable from the above, in light of his common general knowledge in this art. All such equivalents, modifications or adaptations fall within the scope of the present disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 22382204.0 | Mar 2022 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2023/055513 | 3/3/2023 | WO |
