WO2021094702A1

WO2021094702A1 - Ammonia sensor

Info

Publication number: WO2021094702A1
Application number: PCT/GB2019/053224
Authority: WO
Inventors: Mark Waters
Original assignee: MBI (Wales) Ltd
Priority date: 2019-11-14
Filing date: 2019-11-14
Publication date: 2021-05-20
Also published as: CN113133318A; GB202000850D0; GB2594235A; JP2022510519A

Abstract

The present invention relates to an ammonia sensor for use in a catheter drainage system. The present invention also relates to a catheter, drainage bag or connection unit comprising the ammonia sensor of the present invention, methods of using the ammonia sensor and methods of making the ammonia sensor.

Description

Ammonia Sensor

Field of the Invention

Background to the Invention

The care of many of the elderly and disabled patients undergoing long-term bladder catheterisation is complicated by the encrustation and blockage of their catheters. The problem is unpredictable and community nurses are called out at any time of the night or day to patients in discomfort with urinary retention or incontinence of urine owing to sudden blockage of the catheter. Current methods of controlling the encrustation are ineffective, and generally the replacement catheters block recurrently and the patient gains a reputation as a “blocker”.

Encrustation results from infection of the catheterised urinary tract by urease producing organisms, in particular Proteus mirabilis. The bacterial urease generates ammonia from urea and the urine becomes alkaline (pH 8-9). P. mirabilis also colonizes the catheter surfaces and forms a biofilm. In the alkaline conditions calcium and magnesium phosphates crystallize from the urine and crystalline biofilms develop on the catheters. It should be noted that commonly the urine of these patients is infected with organisms such as Escherichia coli which are not urease producers and their metabolism generates slightly acid urine (pH 5-6).

After 2-3 weeks of catheterisation, infection is generally always present within a patient in a benign state. Antibiotics are not used as the infection will reappear when use is stopped. In long-term catheterisation patients, as indicated above, biofilms of bacteria grow on the catheters and in some cases crystalline biofilms form, which block the catheter. This results in bladder expansion, kidney reflux, septic shock and in some cases death. Crystals can break off the biofilms and can cause side effects such as bladder stones. Additionally, in patients with spinal injuries or neurological disorders, stroke can occur. 50% of long-term patients suffer from encrustation. Therefore there are huge costs both financially and in terms of morbidity associated with this problem.

There was a need for a simple sensor that could be incorporated into a catheter drainage system to signal that urease producing bacteria have infected the urine, thus giving an early warning signal of impending catheter encrustation and blockage.

In International Patent Application WO 2006/000764, the present inventor, along with another inventor, devised a pH sensor for use in a catheter drainage system based on a polymer matrix with a chemically bound pH indicator. In a preferred embodiment the polymer matrix was cellulose acetate. However, the sensor proved difficult to make, and has not been commercialised. In addition, as a general pH sensor, the sensor was prone to false positives, as high pH can be produced by raised levels of other alkaline substances, such as hydroxyl ions, which can be present in the urine as a result of dietary changes or other factors. Urine pH is typically 5 as a result of daily net acid excretion. An alkaline pH is often noted after meals, when an “alkaline tide” to balance gastric acid secretion increases urine pH. A high urine pH is also seen in patients who are on a vegetarian diet. Vegetarians generally have more alkaline urine than meat eaters, because meat and dairy produce acidic urine and most vegetables and fruit a more alkaline urine. Urine with a high pH or alkalinity can also be attributed to kidney disease, vomiting, diseases that cause rapid breathing or urinary tract infection. Drugs that can cause alkaline urine include sodium bicarbonate, potassium citrate and acetazolamide, a diuretic used to treat glaucoma, some types of seizures and congestive heart failure.

As an alternative to chemically bonding the pH indicator to the polymer matrix, the possibility of using silicone with an incorporated or physically bound indicator and a hydrophilic filler was suggested in the publication: Malic Sladjana, Waters Mark G. I, Basil L, Stickler DJ, Williams DW. 2012. Development of an “early warning” sensor for encrustation of urinary catheters following Proteus infection. J Biomed Mater Res Part B 2012: 100B: 133-137. However, this publication also relates to a general pH sensor. It is said that tests in buffered solutions showed that the silicone sensors were capable of responding to pH changes from 6 to 8. Accordingly, these sensors are also prone to false positive results.

There is a need for a simple sensor that could be incorporated into a catheter drainage system and which can be specific to ammonia, thereby eliminating the false positive results.

Summary of the Invention

According to a first aspect, the present invention provides an ammonia sensor for incorporation into a catheter drainage system wherein the ammonia sensor is obtained by curing a composition, the composition comprising: a) 70 to 95 % by weight vinyl- terminated polydimethylsiloxanes, comprising vinyl-terminated polydimethylsiloxane having a molecular weight of 100000 to 125000, vinyl-terminated polydimethylsiloxane having a molecular weight of 25000 and 35000 and vinyl- terminated polydimethylsiloxane having a molecular weight of 4000 to 8000; b) 1 to 10 % by weight untreated fumed silica; c) 1 to 5 % by weight a pH indicator; and d) 1 to 4 % by weight a cross linker.

According to a second aspect, the present invention provides an ammonia sensor for incorporation into a catheter drainage system that comprises a polymer matrix comprising: 70 to 95 % by weight cross linked polydimethylsiloxanes, comprising cross linked polydimethylsiloxanes having a molecular weight of 100,000 to 125,000, cross linked polydimethylsiloxanes having a molecular weight of 25,000 and 35,000 and cross linked polydimethylsiloxanes having a molecular weight of 4,000 to 8,000; wherein the polymer matrix encapsulates 1 to 10% by weight untreated fumed silica and 1 to 5% by weight a pH indicator.

The inventors have surprisingly found that by using a mix of three polydimethylsiloxanes with high, medium and low molecular weights, as defined above, in combination with the specific levels of untreated fumed silica, pH indicator and cross linker, a sensor can be made that is selective for ammonia, and won’t react to other alkaline solutions. This is important as it means that the sensor does not indicate a falsely positive result when urine has a raised pH for reasons other than infection by urease producing organisms that generate ammonia such as P. mirabilis.

Without wanting to be bound by theory, we note that ammonia is a weak base and is usually in the form of a neutral molecule which can diffuse into a low polarity disordered medium like silicone, especially if the properties such as the density of the silicone are particularly adapted for this. In contrast, other common high pH solutions such as sodium hydroxide are fully ionised and therefore dynamically unfavourable to diffuse into silicone. Using the selected molecular weights of the starting siloxanes and defined levels of cross linker as in the present invention means that a sensor with particular properties can be obtained that is favourable to ammonia diffusion and unfavourable to diffusion of ions. Further, the use of 1 to 10% untreated fumed silica in the composition further promotes diffusion of ammonia but not of hydroxide ions.

Furthermore, using vinyl-terminated polydimethylsiloxanes makes the manufacturing process straightforward compared with prior art sensors.

According to a third aspect, the present invention provides an article comprising an ammonia sensor according to the first or second aspect of the invention, wherein the article is a catheter, a drainage bag, a drainage unit or a connection unit. The ammonia sensors are preferably designed so that they are located in the drainage system of a catheter so that they are clearly visible to the patient or carer, enabling the sensor to be monitored continuously.

According to a fourth aspect, the present invention provides a use of an ammonia sensor according to the first or second aspect of the invention, for predicting impending catheter encrustation and blockage comprising positioning the ammonia sensor in the flow of urine from a catheter and monitoring for a change in the ammonia sensor indicating the presence of ammonia in the urine. The presence of ammonia signals infection by P. mirabilis or related urease producing organisms and indicates that action should be taken to avoid an acute clinical episode. According to the fifth aspect, the present invention provides a method of making the ammonia sensor according to the first or second aspect of the invention, the method comprising the steps of preparing a composition according to the first aspect of the invention, and curing the composition to form a sensor.

Description

The present invention relates to an ammonia sensor, which is defined both in terms of the composition from which it is made and the material of the sensor itself. The pH indicator in the ammonia sensor reacts to the presence of ammonia by changing colour. The components and levels of components in the composition used to make the sensor are specially adapted so that when the composition is cured, it is possible that a material is formed that allows the diffusion of ammonia into it, but not of other alkaline compounds, so the sensor can be selective for ammonia.

The ammonia sensor is suitable for incorporation into a catheter drainage system. The term “catheter drainage system” refers to a catheter and the drainage unit. The drainage unit is defined as the drainage bag and drainage bag tubing for connection to the catheter.

The composition that is cured to make the sensor of the invention has 70 to 95 % by weight vinyl-terminated polydimethylsiloxanes. The vinyl-terminated polydimethylsiloxanes are cross linked to create a polydimethylsiloxane elastomeric structure, which is called the polymer matrix.

It has been found that a sensor having properties that allow ammonia but not other alkaline compounds such as hydroxides to diffuse into it can be obtained by using a combination of a high molecular weight vinyl-terminated polydimethylsiloxane (having a molecular weight of 100000 to 125000), a medium molecular weight vinyl-terminated polydimethylsiloxane (having a molecular weight of 25000 and 35000) and a low molecular weight vinyl-terminated polydimethylsiloxane (having a molecular weight of 4000 to 8000). In a preferred embodiment, the composition comprises 75 to 90% by weight vinyl- terminated polydimethylsiloxanes, preferably 80 to 85% by weight vinyl-terminated polydimethylsiloxanes.

It is also preferred that the composition comprises 30 to50% by weight of the high molecular weight vinyl-terminated polydimethylsiloxane, 25 to 45% by weight of the medium molecular weight vinyl-terminated polydimethylsiloxane and 1 to 5% by weight of the low molecular weight vinyl-terminated polydimethylsiloxane.

It is particularly preferred that the composition comprises vinyl-terminated polydimethylsiloxane with a molecular weight of 117000, vinyl-terminated polydimethylsiloxane with a molecular weight of 28000 and vinyl-terminated polydimethylsiloxane with a molecular weight of 6000.

Once the polydimethylsiloxanes are cross linked, the terminal vinyl groups will be replaced by linkers to other siloxanes.

The use of vinyl-terminated polydimethylsiloxanes is advantageous as no by-products from the polymerisation reaction are produced. Another advantage is that the pH indicator can be physically trapped within the polymer matrix rather than being chemically bound. This reduces the steps in the synthesis of the polymeric material.

The composition that the ammonia sensor is made from also contains 1 to 10% untreated fumed silica. The silica is unchanged during the curing process, so the same silica is present in the sensor itself. This is a very important component as it acts as a filler and aids the diffusion of ammonia into the polymer matrix so that it can interact with the pH indicator. Ammonia is a weak base and as a neutral molecule can diffuse into low polarity media such as a filled polydimethylsiloxane elastomer. The untreated silica is hydrophilic and helps to regulate the diffusion of ammonia into the elastomer. It would be thermodynamically unfavourable for fully ionised solutions such as sodium hydroxide to diffuse into a filled polydimethylsiloxane elastomer, therefore such solutions would not trigger the sensor. By untreated fumed silica we mean a silicone dioxide that has not been treated to alter the predominantly hydroxide surface chemistry.

Preferably the composition and resultant polymer matrix comprises 2 to 5% by weight untreated fumed silica, more preferably about 3% by weight untreated fumed silica.

In a preferred embodiment of the invention the hydrophilic filler is a synthetic, amorphous, colloidal silicon dioxide.

The particle size of the untreated fumed silica can determine how quickly ammonia is able to diffuse into the sensor. The inventors have found that untreated fumed silica with an average particle size in the range 0.1 to 0.5 microns, preferably 0.15 to 0.4 microns gives good results. Particle sizes are determined using an X-ray scattering technique based on ISO 17867:2015 - particle size analysis - Small-angle X-ray scattering.

Similarly, the surface properties of the untreated fumed silica can determine how quickly ammonia diffuses into the sensor. Untreated fumed silica with a BET (Brunauer, Emmett and Teller) surface area in the range 150 to 250 m²/g gives particularly good results. The BET (Brunauer, Emmett and Teller) theory is commonly used to evaluate the gas adsorption data and generate a specific surface area result expressed in units of area per mass of sample (m²/g). The measurement of BET surface area conforms to ISO 9277:2010 - Determination of the specific surface area of solids by gas adsorption - BET method.

Suitable materials are known to the skilled person. A commercially available example is CAB-O-SIL M5 which is available from Cabot. An additional role of the filler is to enhance the physical properties of the cross linked elastomer.

The composition that the ammonia sensor is made from, and the resultant polymer matrix also contain 1 to 5% by weight of a pH indicator. The pH indicator can be any agent that produces a visible signal (e.g. a colour change) in response to a change in pH that is indicative of impending catheter encrustation and blockage. Urine is normally about pH 6, but when this is raised above pH 7.6, there is danger of catheter encrustation and blockage. Suitable pH indicators include neutral red, bromothymol blue, bromothymol blue sodium salt, cresol red, phenol red, 3-(m)-nitrophenol, fluorescein and rosolic acid. When a biofilm of Proteus mirabilis or similar urease producing organisms are formed on the ammonia sensor, a local pH of 8 to 10 is produced indicating there is a danger of catheter encrustation. Details of the range at which colour transition occurs for these preferred indicators as well as other indicators with lower and higher pH ranges that may be used are described in Table 1 below. Table 1 pH Indicator pH Range Colour Transition

Bromocresol purple 5.2 - 6.8 Yellow - purple

Chlorophenol red 5.4 - 6.8 Yellow - red

Neutral red 6.8 - 8.0 Red - yellow

Bromothymol blue 6.2 - 7.6 Yellow - blue

Bromothymol blue sodium salt 6.2 - 7.6 Yellow - blue

( ^'resol red 7.2 - 8.8 Yellow - red m-Cresol purple 7.4 - 9.0 Yellow - purple

Phenol red 6.4 - 8.0 Yellow - red

3-(m)-Nitrophenol 6.6 - 8.6 Colourless - yellow/orange

Thymol blue 8.0 - 9.6 Yellow blue

Cresolphthalein 7.8 - 9.0 Colourless - pink

Fluorescein 7.0 - 9.0 Yellow - orange

Rosolic acid 6.8 - 8.0 Yellow - red a-Naphtholbenzene 9.0 - 11 Yellow - blue

Preferably the pH indicator is bromothymol blue sodium salt. The colour change for bromothymol blue and bromothymol blue sodium salt are the same but the sodium salt is preferable in the silicone elastomer. The pH indicator may change colour in response to an increase in pH of urine due to the presence of ammonia, but not a general pH rise that is not due to ammonia, or of the bacterial biofilm that may develop on the ammonia sensor. This indicates infection by the urease producing bacterium Proteus mirabilis and impending catheter blockage by encrustation.

The pH indicator is present in the composition from which the ammonia sensor is obtained, and also in the sensor itself. When the polydimethylsiloxanes are cured, the pH indicator is unchanged as it does not react, but becomes physically trapped in the siloxane polymer matrix during the curing of the composition.

The composition from which the ammonia sensor is obtained, and the resultant polymer matrix comprises between 1 and 5% pH indicator by weight of the composition, preferably 2 to3% by weight.

The ammonia sensor of the present invention preferably comprises a matrix stabiliser which can be present at a level of 5 to 15% by weight of the composition from which the sensor is made, preferably at 8 to 10 %. The matrix stabiliser does not react during the curing, so is present in the sensor in the same form and proportions as in the composition.

The purpose of the matrix stabiliser is to improve retention of the pH indicator. It is advantageous to retain the pH indicator so that the effectiveness of the pH indicator is maintained during use. Furthermore, leaching of the pH indicator from the ammonia sensor will contaminate the fluid passing over the sensor.

Quaternary ammonium compounds such as cetrimonium bromide can be used as matrix stabilisers. Quaternary ammonium compounds can be used as surface-active agents and are strongly absorbed by many substances. They produce positively charged ions in solution and help retention of pH indicators when deprotonation has occurred (e.g. following the colour change of the pH indicator).

The composition used to make the sensor of the present invention has 1 to 4 % by weight of the composition of a cross linker. The cross linker is critical for polymerising the vinyl-terminated polydimethylsiloxanes during curing. The level of cross linker has been selected to ensure that the properties of the sensor are compatible with diffusion of ammonia into the sensor, but not ions like hydroxide. A cross linked polydimethylsiloxane elastomer is a low polarity disordered medium which is favourable for the diffusion of neutral molecules like ammonia. The level of cross linker has been specifically tailored to optimise, in conjunction with the type and amount of silica filler, this diffusion of ammonia into the elastomeric matrix. Fully ionised hydroxide based molecules are thermodynamically unfavourable to diffuse into this type of cross linked silicone matrix.

The vinyl-terminated polydimethylsiloxanes are joined together by the cross linkers via a polyaddition cross linking reaction. The cross linkers are not present in the sensor itself, because they are used up in the reaction.

The composition preferably contains 1.5 to 3% cross linker, more preferably 2.5% by weight cross linker. These levels have been found to work particularly well.

Any suitable cross linker for the vinyl-terminated polydimethylsiloxanes can be used, and the skilled person will be familiar with such compounds. Preferably the cross linker is a hydride functional siloxane. The hydrosilylation of vinyl functional siloxanes by hydride functional siloxanes is the basis of the addition cure chemistry use in 2-part room temperature and heat curing systems. In a preferred embodiment, the cross linkers are: MethylHydrosiloxane-Dimethylsiloxane Copolymers, Trimethylsiloxy terminated in the molecular weight range 900-65,000; Hydride Terminated PolyDimethylsiloxanes in the molecular weight range 400-65,000; or Poly MethylHydrosiloxane, Trimethylsiloxy terminated in the molecular weight range 1400-2400.

The most preferred cross linker is MethylHydrosiloxane - Dimethylsiloxane copolymers, trimethylsiloxy terminated, preferably wherein the cross linker has a molecular weight of 900 to 65000, more preferably wherein the cross linker has a molecular weight of 900 to 2000. These cross linkers are preferential because they have more readily controlled reactivity and result in tougher elastomers with lower cross link densities. In a preferred embodiment, the composition that makes the sensor of the invention, additionally comprises an accelerator. The accelerator can catalyse the polymerisation reaction between the cross linker and the vinyl terminated polydimethylsiloxanes to speed up the reaction, and/or cause it to take place at a lower temperature, such as room temperature. The accelerator is not usually used up in the reaction process, so will also be in the sensor itself, incorporated into the siloxane polymer matrix. In a preferred embodiment, the platinum catalyst is present in the composition and the resultant polymer matrix at a level of 0.1 to 0.2 % by weight.

The accelerator is usually a platinum catalyst. It is preferably platinum carbonyl cyclovinylmethylsiloxane complex, platinum-divinyltetramethyldisiloxane complex, platinum-cyclovinylmethylsiloxane complex, or platinum-octanaldehyde/octanol complex. In a preferred embodiment, the accelerator is platinum- divinyltetramethyldisiloxane complex. This has proved to work particularly well, as it allows the composition to cure at room temperature, in around an hour.

In one embodiment, the present invention relates to an ammonia sensor for incorporation into a catheter drainage system wherein the ammonia sensor is obtained by curing a composition, the composition comprising: a) 70 to 95 % by weight vinyl- terminated polydimethylsiloxanes, comprising vinyl-terminated polydimethylsiloxane having a molecular weight of 100,000 to 125,000, vinyl-terminated polydimethylsiloxane having a molecular weight of 25,000 and 35,000 and vinyl- terminated polydimethylsiloxane having a molecular weight of 4,000 to 8,000; b) 1 to 10 % by weight untreated fumed silica; c) 1 to 5 % by weight a pH indicator; and d) 1 to 4 % by weight a cross linker.

The unique combination of polymers, coupled with the hydrophilic filler and pH indicator provides a silicone elastomer polymer matrix which allows diffusion of high ammonia urine which triggers the sensor.

An alternative way to characterise the sensor is a silicone-based sensor that can reliably detect the increase of ammonia in urine caused by infection with urease producing bacteria (predominantly P. mirabilis). This invaluable information allows early intervention to reduce the likelihood of catheter blockage and more serious ascending infections. The highly versatile sensor can be placed anywhere from the end of the catheter to the drainage bag and can be manufactured in any shape of form required.

The present invention also relates to an article comprising an ammonia sensor, wherein the article is a catheter, a drainage bag, a drainage unit or a connection unit. The advantage of the sensor being in a catheter drainage system is that it is clearly visible to the patient or carer, enabling the sensor to be monitored continuously.

When the article is a catheter, the ammonia sensor is positioned so that it can be seen by the patient or carer when the catheter is in use. It is preferred that the ammonia sensor is positioned close to the end of the catheter to be inserted but will still be visible to the patient or carer once the catheter has been inserted. In a preferred embodiment, the ammonia sensor is positioned at the end of the catheter that in use is connected to the drainage bag tubing.

When the article is a drainage unit, the ammonia sensor is positioned so that it can be seen by the patient or carer when the drainage unit is in use. In a preferred embodiment, the ammonia sensor is positioned at the end of the drainage bag tubing that in use is connected to the catheter.

When the article is a connection unit the connection unit can be inserted between the drainage unit and the catheter. The connection unit has the advantage that it can be used with existing catheters and drainage units, is easier and cheaper to manufacture and can easily be replaced without having to replace the catheter or drainage unit.

The present invention also provides the use of the ammonia sensor of the present invention for predicting impending catheter encrustation and blockage comprising positioning the ammonia sensor in the flow of urine from a catheter and monitoring for a change in the ammonia sensor indicating the presence of ammonia in the urine. The composition from which the sensor is made is such that the sensor will only react to a sustained increase in the ammonia level of the urine, as the ammonia diffuses slowly into the sensor. The term “sustained ammonia level” as used herein means that an increased ammonia level is maintained for more than 6 hours, preferably more than 9 hours and most preferably for more than 12 hours. If an increased ammonia level is maintained for more than 6, 9 or 12 hours, it is more than likely that the change in ammonia is due to urease- producing bacteria causing encrustation of the catheter rather than any other factor (e.g. diet).

In particular, the ammonia sensor can be used to detect the presence of ammonia in a fluid (i.e. urine) coming into contact with the sensor or within a bacterial film formed on the sensor, and thereby provide an indication of impending catheter encrustation and blockage. Any transitory increases in ammonia will not be detected and false positives will be avoided. Importantly a rise in pH for any other reason that is not caused by ammonia will also not be detected. By predicting impending catheter encrustation and blockage, remedial action can be taken, such as replacing the catheter to ensure that the catheter does not become blocked.

The present invention also relates to a method of making an ammonia sensor, the method comprising the steps of: preparing a composition as outlined above, and curing the composition to form a sensor.

The composition can be prepared in any way that is suitable, as would be apparent to the skilled person. Preferably the composition is made by first preparing a silicone base with the vinyl-terminated polydimethylsiloxanes and untreated fumed silica. These can be mixed together using a standard silicone mixing technique, preferably adding the silica last.

In order to be able to store the composition until it is ready to be cured, in a preferred embodiment the silicone base is split into first and second parts. The matrix stabiliser, pH indicator and accelerator is added to the first part. The matrix stabiliser, pH indicator and cross linker is added to the second part. In this way the first and second parts are not, themselves, readily reactive at room temperature since neither contains both the accelerator and the cross linker, but do react with each other when mixed. When ready to form the sensor, the first and second parts are mixed together to form the composition, which is then cured. They are usually mixed together in or near to a mould, and left to cure in the mould, which is the size and shape of the sensor desired.

The conditions needed to cure the sensor depends on the accelerator used. In a preferred embodiment, the curing takes place at room temperature over about an hour.

Embodiments of the present invention are now described by way of example, with reference to the accompanying Figures in which:

Figure 1(a) shows a FloSense Cartridge and Figure 1(b) shows a FloSense cartridge placed on glass bottle containing solution; Figure 2 shows the colour change of the immersed silicone sensors in vials of the various solutions after 8 hours; and

Figure 3 shows visually the results for the silicone sensor within the FloSense cartridge in the various solutions at 8 hours.

Example 1 - Sensor Silicone Production Protocol List of Ingredients

• V46 - Vinyl terminated polydimethylsiloxane (MW = 117,000) - (Polymer A)

• V31 - Vinyl terminated polydimethylsiloxane (MW = 28,000) - (Polymer B)

• V21 - Vinyl terminated polydimethylsiloxane (MW = 6,000) - (Polymer C)

• Cabosil M5 Untreated Fumed Silica (colloidal silicone dioxide) (BET surface area 200 m²g, particle size 0.2-0.3 microns)Platinum- divinyltetramethyldisiloxane complex (Platinum RTV)

• Cetrimonium bromide (CTAB)

• Bromothymol blue sodium salt standard F (BTB)

• MethylHydrosiloxane-Dimethylsiloxane copolymers, trimethylsiloxy terminated (Xlinker) Formulations and Techniques

Silicone Base

Create base using standard silicone mixing technique. All ingredients slowly introduced into an industrial planetary mixer, with Cabosil filler being introduced last.

Creating Bromothymol Blue Solution (BTB- Solution)

Standard weight to volume solution made: To 10 mL distilled water add 1 g bromothymol blue sodium salt in sealed glass bijou. Warm gently while stirring (magnetic stirrer) until all BTB has dissolved. Creating sub-base part A and sub-base part B

• Use dedicated spatulas for each ingredient in the formulation.

• Weigh out the base and carefully fold in the platinum complex by hand.

• Carefully add in the CTAB and fold in by hand until incorporated as much as possible.

• Add in the BTB-solution and mix by hand until incorporated.

• Use dedicated spatulas for each ingredient in the formulation.

• Weigh out the base and carefully fold in the Xlinker by hand.

• Add in the BTB-solution and mix by hand until incorporated.

Cartridging Sub-base A and Sub-base B

• Use two new 10 mL syringes for each sensor silicone batch.

• Carefully cut the bottom off each syringe with a fresh scalpel.

• Label one syringe A and the other B.

• Insert duel cartridges into holder and tape up one side so only one chamber is accessible.

• Draw up sub-base A using syringe A and inject into one chamber of the duel cartridge.

• Once all part A is used up repeat the process for part B.

Moulding and Cutting Sensor

• Attach nozzle to prepared cartridge and inject into mould.

• Quickly attach top of mould and screw bolts into place.

• Allow material to cure at room temperature for 1 hour.

• Unscrew bolts and carefully de-mould material.

• Carefully trim excess material of moulded sheets.

• Cut material using new scalpel to created squares 13 mm x 13 mm. Example 2 - Investigation of Sensor Specific Reactivity to Ammonia Solutions

The reaction of the sensor in ammonia solution was compared to the reaction of the sensor in sodium hydroxide solution and high pH buffers.

Method

• Sensor silicone was formulated according to example 1 and made into 13mm x 13mm strips.

• Solutions of ammonia (30% in distilled water, pH 9.25), sodium hydroxide (30% in distilled water, pH 9.5) and a pre-made buffer solution (pH 9) were used in the study.

• 5 mL of each solution was put in glass bottles and sensor strips were placed inside and then sealed carefully.

• FloSense cartridges were placed on the top of the glass bottles so that the tip of the cartridge was just above the solution (see Figure 1(b)).

• The FloSense cartridge is a specially designed chamber which houses two strips of the ammonia sensor silicone and is designed to fit between the catheter and the drainage bag.

Observations of any colour change was carried out after 1 hour, 3 hours, 8 hours, 24 hours and thereafter daily for 11 weeks to simulate the maximum time a catheter could be in- situ. Results

Table 1 and 2 summarises the results for the study. The silicone sensor was yellow in colour at the start of the study. No colour change at all was observed in the sodium hydroxide solution or the pH 9 buffer. In contrast when the sensor was exposed to the ammonia solution a very distinct colour change from yellow to dark blue was seen after 8 hours (See Figure 2). Table 1: Colour change of sensor strips

Table 2: Colour change of Silicone Sensor in FloSense Cartridges

Figure 2 shows the colour change of the immersed silicone sensors in vials of the various solutions after 8 hours. The vial on the left contains a silicone sensor in pH 9 buffer that is yellow in colour. The vial in the middle contains a silicone sensor in sodium hydroxide solution that is yellow in colour. The vial on the right contains a silicone sensor in ammonia solution that is dark blue in colour. The colours remained the same from 8 hours until end of the test at 12 weeks.

Figure 3 shows visually the results for the silicone sensor within the FloSense cartridge in the various solutions at 8 hours. On the left is a glass bottle with a FloSense cartridge attached containing pH 9 buffer. The sensor is yellow in colour. In the middle is a glass bottle with a FloSense cartridge attached containing sodium hydroxide solution. The sensor is yellow in colour. On the right is a glass bottle with a FloSense cartridge attached containing ammonia solution. The sensor is dark blue in colour. Again, the colours remained the same from 8 hours until end of the test at 12 weeks.

Conclusions The silicone sensor shows clear specificity to ammonia solutions (even vapour as seen with FloSense cartridge) and shows no colour change in just high pH solutions. This selectivity makes it particularly useful for picking up the specific high ammonia conditions prevalent in the urine when high level of urease producing bacteria are present. This in turn makes the sensor a powerful tool in predicting the potential blockage of urinary catheters.

Claims

1. An ammonia sensor for incorporation into a catheter drainage system wherein the ammonia sensor is obtained by curing a composition, the composition comprising: a) 70 to 95 % by weight vinyl-terminated polydimethylsiloxanes, comprising vinyl-terminated polydimethylsiloxane having a molecular weight of 100000 to 125000, vinyl-terminated polydimethylsiloxane having a molecular weight of 25000 and 35000 and vinyl-terminated polydimethylsiloxane having a molecular weight of 4000 to 8000; b) 1 to 10 % by weight untreated fumed silica; c) 1 to 5 % by weight a pH indicator; and d) 1 to 4 % by weight a cross linker.

2. The ammonia sensor according to claim 1, wherein the composition comprises 75 to 90% by weight vinyl-terminated polydimethylsiloxanes, preferably 80 to 85% by weight vinyl-terminated polydimethylsiloxanes.

3. The ammonia sensor according to claim 1 or 2, wherein the composition comprises 30-50% by weight vinyl-terminated polydimethylsiloxane having a molecular weight of 100000 to 125000, 25 to 45% by weight vinyl-terminated polydimethylsiloxane having a molecular weight of 25000 to 35000 and 1 to 5% by weight vinyl-terminated polydimethylsiloxane having a molecular weight of 4000 to 8000.

4. The ammonia sensor according to any preceding claim, wherein the composition comprises vinyl-terminated polydimethylsiloxane with a molecular weight of 117000, vinyl-terminated polydimethylsiloxane with a molecular weight of 28000 and vinyl-terminated polydimethylsiloxane with a molecular weight of 6000.

5. The ammonia sensor according to any preceding claim, wherein the untreated fumed silica has an average particle size in the range 0.1 to 0.5 microns, preferably 0.15 to 0.4 microns.

6. The ammonia sensor according to any preceding claim, wherein the untreated fumed silica has a BET surface area in the range 150 to 250 m²/g.

7. The ammonia sensor according to any preceding claim, wherein the composition comprises 2 to 5% by weight untreated fumed silica, preferably wherein the composition comprises about 3% by weight untreated fumed silica.

8. The ammonia sensor according to any preceding claim, wherein the cross linker is methylhydrosiloxane - dimethylsiloxane copolymers, trimethylsiloxy terminated, preferably wherein the cross linker has a molecular weight of 900 to 65000, more preferably wherein the cross linker has a molecular weight of 900 to 2000.

9. The ammonia sensor according to any preceding claim, wherein the composition comprises 1.5 to 3.5% by weight cross linker, preferably wherein the composition comprises about 2.5% by weight cross linker.

10. The ammonia sensor according to any one of the preceding claims, wherein the pH indicator is selected from neutral red, bromothymol blue, bromothymol blue sodium salt, cresol red, phenol red, 3-(m)-nitrophenol, fluorescein and rosolic acid, preferably wherein the pH indicator is bromothymol blue sodium salt.

11. The ammonia sensor according to any one of the preceding claims, wherein the composition comprises 2 to 3% by weight pH indicator.

12. The ammonia sensor according to any preceding claim, wherein the composition additionally comprises a matrix stabiliser, preferably wherein the composition comprises 5 to 15 % by weight of a matrix stabiliser, more preferably 8 to 10% by weight of a matrix stabiliser.

13. The ammonia sensor according to claim 12, wherein the matrix stabiliser is a quaternary ammonium compound, preferably wherein the matrix stabiliser is cetrimonium bromide.

14. The ammonia sensor according to any preceding claim, wherein the composition additionally comprises an accelerator, preferably where the accelerator is a platinum catalyst, more preferably wherein the accelerator is Pt- divinyltetramethyldisiloxane complex.

15. The ammonia sensor according to claim 14, wherein the platinum catalyst is present in the composition at a level of 0.1 to 0.2 % by weight.

16. An ammonia sensor for incorporation into a catheter drainage system that comprises a polymer matrix comprising: 70 to 95 % by weight cross linked polydimethylsiloxanes, comprising cross linked polydimethylsiloxanes having a molecular weight of 100,000 to 125,000, cross linked polydimethylsiloxanes having a molecular weight of 25,000 and 35,000 and cross linked polydimethylsiloxanes having a molecular weight of 4,000 to 8,000; wherein the polymer matrix encapsulates 1 to 10% by weight untreated fumed silica and 1 to 5% by weight a pH indicator.

17. An article comprising an ammonia sensor according to any one of the preceding claims, wherein the article is a catheter, a drainage bag, a drainage unit or a connection unit.

18. Use of the ammonia sensor according to any one of claims 1 to 16 for predicting impending catheter encrustation and blockage, comprising positioning the ammonia sensor in the flow of urine from a catheter and monitoring for a change in the ammonia sensor indicating the presence of ammonia in the urine.

19. A method of making an ammonia sensor according to any of claims 1 to 16, the method comprising the steps of: preparing a composition comprising: a) 70 to 95 % by weight vinyl-terminated polydimethylsiloxanes, comprising vinyl-terminated polydimethylsiloxane having a molecular weight of 100000 to 125000, vinyl-terminated polydimethylsiloxane having a molecular weight of 25000 and 35000 and vinyl-terminated polydimethylsiloxane having a molecular weight of 4000 to 8000; b) 1 to 10 % by weight untreated fumed silica; c) 1 to 5 % by weight a pH indicator; and d) 1 to 4 % by weight a cross linker; and curing the composition to form a sensor.

20. The method of claim 18, wherein the composition is made by: preparing a silicone base with the vinyl-terminated polydimethylsiloxanes and untreated fumed silica; splitting the silicone base into first and second parts; adding a matrix stabiliser, pH indicator and accelerator to the first part; adding a matrix stabiliser, pH indicator and cross linker to the second part; and mixing the first and second parts together to form the composition.