Patent Application
20230302180
The present invention relates to methods of sterilising sensor components used in systems for measuring the concentration of analytes in a fluid, in particular for sensor components that determine the concentration of analytes by changes in the optical property of one or more sensing elements.
It is desirable in many areas to be able to determine the concentration of an analyte in a fluid which may contain a mixture of several different substances. For example, in clinical settings it is important to be able to accurately determine the concentration of oxygen in a patient’s blood in real time to detect and prevent hypoxia. Examples of clinical settings where monitoring of blood analytes is important include cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), and continuous renal replacement therapies (CRRT). Continuous monitoring provides continuous patient status information to the clinician that will aid in therapy, eliminating blind intervals and reducing the risk to the patient.
For the types of sensor component considered herein, changes in analyte concentration are detected through changes in the optical property of one or more sensing elements. These are ideal for continuous monitoring, because they can be designed to have low levels of drift in their optical properties over time due to factors other than the analyte concentration. This means they can provide regular, accurate measurements over extended periods of time while reducing the need to take regular blood samples or perform frequent and time-consuming calibration procedures.
In order to measure the concentrations of analytes in the fluid, it is necessary for parts of the sensor component to come into contact with the fluid. However, at least some of the sensing elements and other materials used in this type of sensor component become hydrated in use when exposed to the fluid. If the sensor component is supplied with the sensing elements in a non-hydrated state, it can take several hours for the optical properties of the sensing element to stabilize following exposure to the fluid. This is impractical in real-world contexts, and so the sensor components must be supplied with the sensing elements already in a hydrated state.
In addition, particularly in clinical contexts, it is important that the sensor components are supplied to the end user in a sterile condition. Because the sensor component must come into contact with the fluid in use, sterilisation reduces the risk of contamination of, for example, a patient’s blood by foreign biological matter that could be introduced to the sensor component during manufacture.
A challenge is therefore to supply the sensor component to the user in a sealed, sterile package, while simultaneously keeping the sensing elements in a hydrated state, potentially for extended periods of time during the shelf life of the sensor component.
At present, this is achieved by sealing the sensor component in packaging with a hydrating fluid, and then sterilising the entire sealed package using gamma irradiation with the sensor component in a wet condition. However, ionising radiation generates highly reactive free radicals and reactive oxygen species which can be deleterious to the sensing elements and connector materials. This can cause drift in the optical properties of the sensor component and loss of signal when the sensor component is used.
Sterilisation with a gaseous sterilising agent, such as ethylene oxide, is a much more benign method of sterilisation. However, this must be carried out dry to prevent the gaseous sterilising agent interacting with the fluid, which can create or deposit chemicals inside the sensor component that are themselves damaging to the sensing elements and materials of the sensor component, or which create a risk of contamination of the sensor component that would potentially cause harm to a patient.
It is therefore desirable to provide a method of sterilisation that reduces damage to the sensor component, and which allows the sensor component to be supplied in a sterile, hydrated state.
According to a first aspect of the invention, there is provided a method of sterilising a sensor component for use in a system for measuring the concentration of one or more analytes in fluid in a fluid line, the sensor component comprising one or more sensing elements having an optical property that varies with the concentration of the one or more analytes in the fluid, the sensor component being configured to engage with the fluid line such that the sensing elements are exposed to the fluid in the fluid line, and a connector configured to connect to one or more optical waveguides, the sensor component being configured to transmit light between the one or more optical waveguides and the one or more sensing elements, the method comprising introducing a gaseous sterilising agent into a sealed cavity via one or more ports providing fluid connection to the cavity, wherein the one or more sensing elements are exposed to the cavity, replacing the gaseous sterilising agent with a sterile liquid via the ports, and sealing the ports.
By exposing the sensing elements to a cavity, the environment of the sensing elements can be controlled and kept sterile as the gaseous sterilising agent is replaced by the sterile liquid. In addition, the cavity full of sterile liquid is sealed using the ports, ensuring that the sensing elements remain exposed to the sterile liquid and in a hydrated state until the sensor component is used. This method thereby enables the use of more benign gaseous sterilising agents, improving the accuracy of subsequent measurements using the sensor component.
In some embodiments, the step of introducing a gaseous sterilising agent into the cavity comprises placing the sensor component into a sealed environment and introducing the gaseous sterilising agent into the sealed environment, the step of replacing the gaseous sterilising agent being carried out without removing the sensor component from the sealed environment. The use of a sealed environment, for example a sterilisation bag, means that the exterior surfaces of the sensor component can also be kept sterile during the procedure, thereby further reducing the chance of contamination of the surfaces of the sensor component that will come into contact with the fluid in use.
In some embodiments, the gaseous sterilising agent remains in the cavity for at least 1 hour before carrying out the step of replacing the gaseous sterilising agent. This allows sufficient time to ensure the relevant parts of the sensor component are completely sterilised.
In some embodiments, the method further comprises preconditioning the sensor component prior to introducing the gaseous sterilising agent by exposing the sensor component to a predetermined temperature and/or humidity for a predetermined length of time. This can ensure optimal conditions for the sterilisation using the gaseous sterilising agent to be most effective.
In some embodiments, replacing the gaseous sterilising agent with a sterile liquid via the ports comprises replacing the gaseous sterilising agent with a sterile gas via the ports, and subsequently introducing the sterile liquid via the ports. This reduces the likelihood of any of the gaseous sterilising agent remaining in the cavity and coming into contact with the sterile liquid.
In an embodiment, replacing the gaseous sterilising agent with a sterile gas via the ports comprises removing the gaseous sterilising agent by evacuation via the ports, and subsequently introducing the sterile gas via the ports. Evacuation further improves the removal of the gaseous sterilising agent to prevent any gaseous sterilising agent remaining in the cavity after sterilisation.
In some embodiments, the method is carried out at a temperature in a range from 35° C. to 65° C. This provides optimal conditions for the gaseous sterilising agent to be most effective.
In some embodiments, the gaseous sterilising agent is one of ethylene oxide, ozone, hydrogen peroxide, nitrogen dioxide, and formaldehyde. These gaseous sterilising agents are readily available and suitable for sterilising devices used in clinical contexts.
In some embodiments, the sterile liquid is a calibration solution containing predetermined concentrations of the one or more analytes. This facilitates calibration of the sensor component at the point of use.
In some embodiments, the one or more ports comprise two ports, and the steps of introducing the gaseous sterilising agent and replacing the gaseous sterilising agent are carried by flowing the gaseous sterilising agent and sterile liquid between the two ports. Using a flow of gas and liquid between two ports can ensure that the fluids more effectively penetrate all parts of the cavity.
In some embodiment sealing the ports comprises permanently sealing the ports. This reduces the chance of later contamination of the cavity in embodiments where the ports are used only during the calibration procedure.
In some embodiments, sealing the ports comprises sealing the ports with removable elements. This can reduce the chance of contamination of the cavity where the ports may need to be used again at a later time following sterilisation.
In some embodiments, the method further comprises, prior to the step of introducing a gaseous sterilising agent into the cavity, connecting tubing to the one or more ports, wherein the step of introducing the gaseous sterilising agent comprises flowing the gaseous sterilising agent through the tubing, the step of replacing the gaseous sterilising agent comprises flowing the sterile liquid through the tubing, and the step of sealing the one or more ports comprises sealing the tubing, and cutting the tubing outside the position where the tubing is sealed such that a sealed section of the tubing remains connected to the ports. Using tubing can provide additional flexibility in placing and connecting the necessary parts during sterilisation, and also provides a convenient way to seal the ports.
In some embodiments, the tubing comprises a tubing valve configured to open and close the tubing, the step of introducing the gaseous sterilising agent is performed with the tubing valve open, the step of replacing the gaseous sterilising agent is performed with the tubing valve open, the tubing is cut between the position where the tubing is sealed and the tubing valve, and the method further comprises closing the tubing valve prior to the step of sealing the ports. Inclusion of a tubing valve makes it easier for the user to control the flow of fluids through the tubing during the sterilisation procedure.
In some embodiments, the tubing is sealed using ultrasonic welding or solvent sealing. These are convenient methods for sealing tubes, which may typically be formed of plastic.
In some embodiments, the sensor component further comprises a component valve in respect of the or each port configured to open and close the port the step of introducing the gaseous sterilising agent is performed with the component valve open, the step of replacing the gaseous sterilising agent is performed with the component valve open, and the step of sealing the one or more ports comprises closing the component valve. Inclusion of a component valve allows the sensor component to be supplied with a valve permitting access to the cavity via the ports. This can be particularly advantageous if the sensor component is designed to be engaged with the fluid line in a shunt or bypass configuration.
In some embodiments, the sensor component defines the sealed cavity and comprises the one or more ports. This may be advantageous depending on the application of the sensor component.
In some embodiments, the sensor component is configured to engage with a wall of the fluid line. In some embodiments, the sensing elements are covered by a removable seal, the cavity being defined between the sensing elements and the removable seal. This is advantageous where the sensor component engages with the wall of the fluid line, because the removable seal can be removed immediately prior to engagement of the sensor component with the fluid line, thereby exposing the cavity and sensor elements to the fluid in the fluid line.
In some embodiments, the cavity is a conduit that is configured to be inserted into the fluid line for engagement of the sensor component with the fluid line. Inserting the cavity into the fluid line ensures the sensing elements are exposed to the fluid.
In some embodiments, the conduit is configured to be inserted into the fluid line in an in-line configuration. In-line configurations may be appropriate depending on the particular application of the sensor component and provide direct exposure to fluid in the main fluid line.
In some embodiments, the conduit is configured to be inserted into the fluid line in a shunt configuration. A shunt configuration may allow the sensor component to be changes without halting flow of fluid in the fluid line.
In some embodiments, a container defines the cavity and the sensor component is removably inserted into the cavity prior to introducing the gaseous sterilising agent. This may be advantageous depending on the type and configuration of the sensor component. The sensor component can then be removed from the cavity immediately prior to use.
According to a second aspect of the invention, there is provided a sensor component for use in a system for measuring the concentration of one or more analytes in fluid in a fluid line, the sensor component comprising one or more sensing elements having an optical property that varies with the concentration of the one or more analytes in the fluid, a connector configured to connect to one or more optical waveguides, the sensor component being configured to transmit light between the one or more optical waveguides and the one or more sensing elements, a removable seal covering the sensing elements, a sealed cavity between the sensing elements and the removable seal, the one or more sensing elements being exposed to the cavity, and one or more sealed ports in the cavity, wherein the sensor component is configured to engage with a wall of the fluid line following removal of the removable seal such that the sensing elements are exposed to the fluid in the fluid line.
A sensor component comprising a cavity with sealed ports and a removable seal on the cavity is particularly suited to use with embodiments of the method of sterilisation of the first aspect of the invention. The cavity enables the sensing elements to be kept exposed to a sterile liquid, and thereby keeping the sensing elements in a hydrated state, until immediately prior to use. The removable seal provides a quick and straightforward way to open the cavity to allow the sensing elements to be exposed to fluid in the fluid line.
In some embodiments, the sensor component comprises at least two sealed ports. This enables gas or liquid to be flowed through the cavity during sterilisation.
In some embodiments, the removable seal is configured such that the sensor component cannot engage with the wall of the fluid line prior to removal of the removable seal. This ensures the sensing elements will be properly exposed to fluid in the fluid line following engagement of the sensor component with the fluid line.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Embodiments of the present invention will now be described by way of non-limitative example with reference to the accompanying drawings, in which:
The sensor component 1 comprises one or more sensing elements 5. The sensor component 1 comprises four sensing elements, but this is not essential, and other embodiments may comprise one, two, three, or more than four sensing elements 5. The sensing elements 5 each comprise a luminescent compound, preferably a fluorescent compound, more preferably a fluorescent organic dye. The luminescent compound may be different for different sensing elements 5, and will depend on the analytes to be measured. Examples of suitable luminescent compounds include seminaphtharhodafluor (SNARF), mag-fluo-4, and derivatives thereof. The sensing element 5 may comprise the luminescent compound suspended in, dissolved in, or molecularly bonded to a matrix. The matrix may comprise a polymer, for example PMMA or polystyrene. Alternatively, the matrix may comprise a sol-gel or hydrogel.
The sensing element 5 has an optical property that varies with the concentration of the one or more analytes in the fluid. The optical property may be emission or absorption of light. In the case where the sensing element 5 comprises a luminescent compound, the optical property may be a luminescence lifetime. The optical property may be the same for all of the sensing elements 5, or may differ between sensing elements 5. Various measurement modalities may be used to minimize drift in sensors. Fluorescent lifetime and ratiometric modalities are commonly used when available, as these are less vulnerable to common sources of error that can cause drift. Ratiometric modalities take two measurements of light from the luminescent compound, for example at different wavelengths, and calculate a ratio. However, often straight intensity measurements methods are the only modalities available, and therefore it is important that aspects of the design of the sensor component 1 are chosen to minimize drift and inaccuracies.
The sensor component 1 is configured to engage with the fluid line 3 such that the sensing elements 5 are exposed to the fluid in the fluid line 3. As shown in
The sensor component 1 comprises a connector 7 configured to connect to one or more optical waveguides. In the embodiments shown in
The optical waveguides allow light to be transmitted to and from one or more light sources elsewhere in the system in which the sensor component 1 is used. Suitable light sources include LEDs or laser diodes. The optical waveguides may comprise optical fibres or optical fibre bundles to transmit the excitation light to the sensing elements 5. Light emitted from (or transmitted through) the sensing elements 5 is also returned via the optical waveguides to detectors in the system that detect the intensity of light from the sensing elements 5. In some embodiments, the sensor component 1 may comprise the one or more optical waveguides and/or the one or more light sources and detectors. The sensor component 1 is configured to transmit light between the one or more optical waveguides and the one or more sensing elements 5, such that the optical property of the sensing elements 5 can be measured.
Medical devices are typically terminally sterilized either by γ-irradiation, e-beam, or gaseous agents such as ethylene oxide. Both γ-irradiation and e-beam are ionizing radiations generating highly reactive free radicals via polymer degradation. This can cause ongoing plastic embrittlement of parts of the medical devices, leading to reduced lifespan. Free radical generation during irradiation also generates colour centres in the plastic and glass materials that are often used for optical components such as optical waveguides, hence causing a decrease in light transmission. This decrease in light transmission can be usually accommodated during calibration of the sensor component 1, unless light transmission is decreased to the point where the optical excitation used to measure the optical property of the sensing elements 5 is hindered. However, the transmission of the materials can be recovered by passing visible light through the optical components. This is exactly what happens during continuous monitoring, and leads to drift in the properties of the optical components during use (effectively causing a gradual, continuous change in the incident intensity of light into the sensing elements 5).
In addition, in the presence of small amounts of oxygen and water, peroxy and hydroxyl free radicals are generated during irradiation. These are extremely reactive, and are likely to react with the sensing elements 5, changing their optical property (for example by causing an effective change in the concentration of luminescent compound in the sensing element, or even the ability of the luminescent compound to luminesce by changing its quantum efficiency). In an attempt to minimize this, sensor components 1 may be γ-irradiated anhydrous and under nitrogen. However, this has the effect of stabilizing the organic free radicals, and when the sensor component is eventually introduced to oxygen and water (usually during use) then the peroxy and hydroxyl free radicals are generated again, leading to in-use drift in the properties of the sensing elements 5.
To avoid these disadvantages of sterilising sensor components 1 using irradiation, it is preferable to use more benign gaseous sterilising agents such as ethylene oxide. Gaseous sterilisation must typically be performed with the sensor component 1 in a dry state to avoid reaction of the gaseous sterilising agent with water. For example, if the sensor component 1 is wet with water, ethylene oxide will react with the water to form ethylene glycol.
However, the properties of the sensing elements 5 may change with the level of hydration. For example, the luminescent compound of the sensing elements 5 may be suspended in a hydrogel, which is up to 90% water. A change in the hydration can cause a change in the intensity of light reaching the luminescent compound, and an effective change in the concentration of the luminescent compound. Even hydrophobic components may take up water slowly. Therefore, the sensor component 1 has to be presented to the user with the sensing elements 5 in a fully hydrated state. This ensures stability of measurements and low hydration drift as soon as required by the user. Otherwise, if the hydration of the sensing elements 5 changes at the point of use, either in calibration or during continuous monitoring, the optical property of the sensing elements 5 will slowly change as the sensing elements 5 become hydrated. This results in significant drift, typically over a timescale of hours. To stabilize the hydration at the point of use would require the user to put the sensor component 1 through a stabilization phase that could last several hours before the sensor component 1 could be used. This would be impractical for use in real-world settings.
The method of sterilisation described herein addresses this conflict in the requirements to perform dry sterilisation, but still present the sensor component 1 sterile and in a hydrated state to minimise drift.
To facilitate this method, the sensor component 1 comprises a removable seal 47 covering the sensing elements 5, and a sealed cavity 45 is defined between the sensing elements 5 and the removable seal 47. The one or more sensing elements 5 are exposed to the cavity 45. The removable seal 47 in
The sensor component 1 of
As shown in
The sensor component 1 comprises two sealed ports 41 providing fluid connection to the cavity 45. The ports 41 are sealed when the sensor component 1 is provided to the end user, but may be unsealed to allow fluid connection to the cavity 45 from the exterior of the sensor component 1 during the sterilisation method. Two ports 41 is preferable, as they allow fluids such as the gaseous sterilising agent to be flowed in a continuous fashion from one port 41 to the other. However, it is not essential that the sensor component 1 comprise two ports 41, and in some embodiments, the sensor component 1 may comprise one port 41, or more than two ports 41.
As shown in
As will be discussed further below, it is not in general essential to the method that sensor components sterilised using the method define the sealed cavity 45 and comprise the one or more ports 45. However, the sensor component 1 shown in
A method of sterilising a sensor component 1 for use in a system for measuring the concentration of one or more analytes in fluid in a fluid line is shown in
The method comprises preconditioning S1 the sensor component 1 prior to introducing the gaseous sterilising agent by exposing the sensor component 1 to a predetermined temperature and/or humidity for a predetermined length of time. The predetermined length of time may be at least 4 hours, optionally at least 8 hours, optionally at least 1 day, optionally at least 2 days-1. Pre-conditioning S1 the sensor component 1 by pre-humidification and/or pre-heating places the sensor component 1 in a condition where the gaseous sterilising agent will have optimal effect and be most effective in sterilising the sensor component 1. The preconditioning S1 is preferred, but not essential and may be omitted in some embodiments, depending for example on the choice of gaseous sterilising agent. Preferably, the method is carried out at a temperature in a range from 35° C. to 65° C. Where preconditioning S1 comprises exposing the sensor component 1 to a predetermined temperature, the predetermined temperature may be in the range from 35° C. to 65° C.
The method further comprises introducing S3 a gaseous sterilising agent into a sealed cavity 45 via one or more ports 41 providing fluid connection to the cavity 45, wherein the one or more sensing elements 5 are exposed to the cavity 45. The gaseous sterilising agent is preferably one of ethylene oxide, ozone, hydrogen peroxide, nitrogen dioxide, and formaldehyde. Most preferably, the gaseous sterilising agent is ethylene oxide.
As discussed above in relation to the sensor component of
The sensor component 1 comprises two ports 41, and introducing S3 the gaseous sterilising agent comprises flowing the gaseous sterilising agent between the two ports 41. This is in general not necessary, and in embodiments with only a single port 41, the gaseous sterilising agent may be introduced through the single port 41. In some embodiments, the flow of gaseous sterilising agent may be actively promoted, e.g. using a pressure gradient between the ports 41. In other embodiments, the gaseous sterilising agent may flow between the ports 41 passively, e.g. by diffusion.
The step S3 of introducing the gaseous sterilising agent then comprises flowing the gaseous sterilising agent through the tubing 51, with the tubing valve 53 open. The gaseous sterilising agent is thereby able to flow through the tubing 51 and tubing valve 53 into the cavity 45. This will sterilise the interior of the cavity 45, including the sensing elements 5 and other parts of the sensor component 1 that will be in contact with fluid in the fluid line 3 during use of the sensor component 1. The gaseous sterilising agent preferably remains in the cavity 45 for at least 1 hour, optionally 2 hours, optionally 4 hours, optionally 6 hours, before carrying out the step of replacing the gaseous sterilising agent. This ensures that the interior of the cavity 45 is fully sterilised.
The step S3 of introducing a gaseous sterilising agent into the cavity 45 as illustrated in
As illustrated in
Replacing the gaseous sterilising agent with a sterile liquid via the ports 41 comprises replacing the gaseous sterilising agent with a sterile gas via the ports 41, and subsequently introducing S9 the sterile liquid via the ports 41. When introducing S9 the sterile liquid, the sterile liquid will replace the sterile gas. This reduces the chance that any liquid will come into contact with the gaseous sterilising agent, which may be undesirable depending on the choice of gaseous sterilising agent. The use of the syringe 54 to introduce the sterile liquid in
Replacing the gaseous sterilising agent with a sterile gas via the ports 41 comprises removing S5 the gaseous sterilising agent by evacuation via the ports 41, and subsequently introducing S7 the sterile gas via the ports 41. This ventilation/aeration ensures that the gaseous sterilising agent is completely removed from the sensor component 1 and cavity 45. This may be necessary, for example because ethylene oxide and other gaseous sterilising agents are toxic, and it is a regulatory requirement that all the gaseous sterilising agent is removed as part of the sterilisation process to ensure that no residuals are left that could be harmful to a patient.
Where introducing S3 the gaseous sterilising agent into the cavity 45 comprises placing the sensor component 1 into a sealed environment, replacing the gaseous sterilising agent with the sterile liquid is carried out without removing the sensor component 1 from the sealed environment. The syringe 54 may be sterilised in the same sealed environment as the sensor component 1, tubing 51, and tubing valves 53 in order that no contamination is introduced when the syringe 54 is connected to the tubing 51.
Following the replacement of the gaseous sterilising agent with a sterile liquid via the ports 41, the method comprises sealing the ports 41, as illustrated in
As illustrated in
Not all of the steps of the method may be performed in the same location. For example, the introduction S3 of a gaseous sterilising agent, and replacement of the gaseous sterilising agent with a sterile gas may be carried out in one location. The sterile sensor component 1 may then be transported to another location in a sterile container (for example a sterilisation bag that constitutes the sealed environment discussed above). The replacement of the sterile gas with the sterile liquid and sealing of the ports may then be carried out in the other location. This may be facilitated by sterilising the syringe 54 containing the sterile liquid together with the sensor component 1 in the sealed environment, as mentioned above. The replacement of the sterile gas with the sterile liquid and closing S11 of the tubing valves 53 can then be carried out without removing the sensor component 1 from the sealed environment.
The method has so far been discussed in the context of the sensor component 1 of
In some embodiments, the conduit 29 is configured to be inserted into the fluid line 3 in an in-line configuration. In such cases, the conduit 29 becomes a part of the main fluid line 3. It may be preferable in such situations that the ports 41 are sealed using removable elements 43 as described above, so the ports 41 can be unsealed immediately prior to inserting the conduit 29 into the fluid line 3.
The step S1 of preconditioning the sensor component 100 is as described above for the sensor component 100.
The method may also be applied to other types of sensor component, including a sensor component which does not itself define a cavity and does not comprise the ports 41. In all of the embodiments discussed so far, a cavity is defined by the sensor component, for example via a removable seal 47 or by the conduit 29. However, this is in general not necessary for the sterilisation method discussed herein to be applicable.
The step S1 of preconditioning the sensor component 200 is still performed as described above.
Prior to the step S3 of introducing the gaseous sterilising agent, the intravascular sensor component 200 is removably inserted into the cavity 245. The container 60 is configured such that the sensor component 200 forms a seal with the container when it is inserted into the cavity 245. This prevents fluid (for example, the gaseous sterilising agent, sterile gas, or sterile liquid) flowing in or out of the cavity 245 except via the ports 41 during the sterilisation method. It also ensures that the sterile liquid will remain in contact with the sensing element 5 after the completion of the sterilisation method so that the intravascular sensor component 200 is delivered to the end user in a hydrated state.
Tubing 51 and tubing valves 53 may be connected to the component valves 55 as described for the sensor component 100 in
The steps of replacing the gaseous sterilising agent with a sterile liquid, and sealing the one or more ports 41 would also be performed as described for the sensor component 100 above. In the case of the sensor component 200 of
