GB2383333A

GB2383333A - Synthetic membranes comprising a polymer & dispersed liquid crystal, and membrane-based enzyme biosensors comprising such membranes

Info

Publication number: GB2383333A
Application number: GB0130197A
Authority: GB
Inventors: Subrayal Medapati Reddy; Jodie Manini
Original assignee: University of Surrey
Current assignee: University of Surrey
Priority date: 2001-12-18
Filing date: 2001-12-18
Publication date: 2003-06-25
Also published as: GB0130197D0

Abstract

A synthetic membrane is disclosed which comprises a polymer, a liquid crystal dispersed therein and optionally a surfactant. Such a membrane displays selective permeability (thus allowing specific compounds to be screened from a liquid sample) and good biocompatibility (thus reducing the biofouling of the membrane surface) characteristics. A membrane-based amperometric enzyme biosensor is disclosed which comprises such a membrane. The enzyme may be a hydrolytic enzyme such as an arylacylamidase enzyme. These biosensors may be used in the analysis of liquid samples, for example the monitoring of glucose concentration in blood or urine in diabetes treatment, analysis of paracetamol concentration, detection/quantification of compounds (such as ascorbic acid, catechol, hydrogen peroxide, dopamine or 4-aminophenol) and analysis of water samples for environmental applications. The membrane may be used in haemodialysis. The membrane can be produced by: <SL> <LI>a) dissolving a polymer in tetrahydrofuran (THF), <LI>b) dissolving a liquid crystal and optionally surfactant (eg. by ultrasonification) into the polymer solution, <LI>c) pouring the resulting solution onto a surface, eg a petri dish, and <LI>d) covering the surface to effect slow and controlled evaporation of solvent and precipitation of the membrane. </SL>

Description

Membrane The present invention relates to a synthetic membrane which is selectively permeable and biocompatible, methods of production of the membrane and for adjustment of permeability of a membrane, a biosensor comprising the membrane, use of the membrane for example in a biosensor, and a kit comprising the membrane.

Within the context of this specification the word"comprises"is taken to mean "includes, among other things". It is not intended to be construed as"consists of only".

Known biosensors include a membrane-based amperometric enzyme electrode.

Generally, they comprise an analyte-specific oxidase enzyme chemically immobilised between an external (sample-interfacing) membrane and an internal (permselective) membrane. Analytes entering through the external membrane are oxidised to produce hydrogen peroxide and this signal species is then transported through the internal membrane to the underlying amperometric electrode for detection and analyte quantification. See Reddy, S. M. et al. (1997) Anal. Chim. Acta. , 343,59-68 ; Reddy, S. M. and Vadgama, P. M. (1997) Biosensors and Bioelectronics, 12,1003-1012 ; Mutlu, M. et al (1998) Polymers in Sensors, 690,57-65.

The performance of known biosensors suffers due to problems including interference, low sensitivity, signal drift and reduction in signal size due to membrane surface

fouling. Biosensors have wide ranging industrial uses and a need therefore exists for the optimization of their performance.

Detection. of electrochemically active interferents, for example paracetamol, often present in liquid samples such as blood is particularly problematic. In particular, it has been difficult to overcome problems presented by electrochemical interference due to paracetamol in biosensor analysis. One method that has been suggested is a reduction of the polarity or bias potential of an amperometric biosensor. However, interference has not been eliminated. Therefore, the incorporation of one or more selectively permeable membranes in a biosensor that could exclude interferent molecules, yet still allow the selective passage of analyte and signal species, would be greatly advantageous.

As indicated above a means for addressing the problems affecting biosensor performance lies in the modification of membrane properties. Approaches previously adopted include screening out of salts and increasing the hydrophobicity of the external membrane to increase the hydrogen peroxide concentration at the inner membrane, thus increasing sensitivity. However, these approaches have not sufficiently addressed the existing problems.

A range of synthetic membranes with varying properties are currently used in many biological and biochemical applications, including haemodialysis, peritoneal dialysis,

production of implants and biosensors. Many polymer materials have been exploited, including Chitosan [See Suzuki, T. et al (1999) J. Bioscience & Bioengineering, 88 (2), 194-199], polycarbonate, cellulose (Cuprophan), poly (vinylchloride) (PVC), polyurethane (PU) and polyacrylonitrile-based membranes.

Synthetic polymer membranes are being used extensively at the interface between biosensor and biological sample in attempts to improve selective solute permeability in complex samples. Membrane permselectivity depends on a number of characteristics of the membrane including surface charge, hydrophilic/lipophilic balance, and polymer fluidity.

It is known from Reddy, S. M. and Vadgama, P. M. (1997) Anal. Chim. Acta, 350, 67-76 that the permeability properties of a PVC membrane can be altered by plasticisation with a surfactant. Membrane plasticisation has been used to impart desired surface and intra-membrane functional properties. Plasticising of a polymer involves introduction of plasticiser molecules to a polymer to occupy space within the polymer phase thereby increasing polymer chain segmental motion. This results in modification of membrane permeability and selectivity. Synthetic polymeric membranes can be modified with surfactants such as Tween 80, Triton X-100 and bis (2-ethylhexyl) hydrogenphosphate (BEP) to mimic conventional dialysis membranes. However, a toxicity problem has arisen with such membranes as a result

of surfactant loss from the membrane matrix due to leaching. This problem has been minimised with the use of BEP, a species with extensive side chain branching.

In addition to interactions due to interfacial properties, intra-membrane interactions within the bulk of a membrane contribute to membrane permselectivity. In a homogeneous (non-porous) membrane phase, a solute would be expected to partition into the membrane phase from a sample solution if there are favourable solute-polymer interactions. In this regard, a solute partition coefficient provides an indication of membrane selectivity.

It is possible to plasticise a membrane by integrating a lipophilic compound within the structure of a membrane. For example, Christie et al (1997) Electroanalysis, 9 (14), 1078-1082 have disclosed a lipophilically plasticised membrane which has been used for an improved detection strategy of phenolic compounds.

In addition to being used in the production of sensors, it has been disclosed by Jacobsen, S. H. (1999) Scand. J. Urol. Nephrol. , 33,83-88 that membranes can be used in cartridge form for haemodialysis. Here, selectivity is limited and is based on molecular size ; cellulose-based membranes selective for specific molecular weights have been extensively used in renal care. Heterogeneous membranes with defined micropores also offer limited pennselectivity where solute mass transport is a function of membrane pore size and solute molecular weight.

Biocompatibility is an important property in a membrane used at the interface between biosensor and biological sample or in any other biochemical or biological application. This property is based on a similar range of characteristics to those that influence jnembrane permselectivity. These characteristics determine the nature of interactions between a membrane and biomaterials.

In certain circumstances it is possible for a surface clot to be formed by the deposition of protein, colloid or one or more cellular components on a membrane surface (biofouling). Biofouling of a membrane component of a biosensor leads to the formation of a barrier over the electrode. This could result in malfunction of the biosensor. Therefore a membrane incorporated in a biosensor should be reusable and minimum membrane fouling should take place on protein exposure.

Biocompatibility of a membrane has been correlated with negatively charged surfaces, interfacial free energy between blood and the membrane surface and mimicry of phospholipid asymmetry of natural biomembranes. PVC membranes modified with nonionic Tween 80, Triton X-100 and anionic BEP surfactants have been shown by Reddy and Vadgama (1997) Anal. Chim. Acta, 350,77-89 to have superior biocompatibility over previously commercially available polycarbonate and Cuprophan haemodialysis membranes. Chitosan and variously modified polyurethane (PU) membranes have also been identified as highly biocompatible materials for use in implants. Zhou and Yi (1999) Biomaterials, 20,2093-2099 suggests that the surface

of polyurethane membranes can be modified using nematic liquid crystals to mimic a lipid bilayer. The membranes produced include a polyurethane phase and a separate liquid crystal phase. The resultant hydrophobic membranes show small amounts of platelet adhesion and deformation.

In view of the above, it will be apparent that synthetic membranes are of use in a variety of applications, in particular in the field of biosensors. Accordingly, it is valuable to this field to identify new synthetic membranes with properties that can be used to overcome the problems that presently exist.

Remarkably the present invention introduces a new class of synthetic membrane with permselectivity that can be incorporated into biosensors to reduce interference and thus increase accuracy in measurment.

In a first aspect the present invention provides a synthetic membrane comprising a polymer and a liquid crystal dispersed therein. Preferably the membrane is selectively permeable and biocompatible.

Preferably an embodiment of a membrane according to the invention provides a membrane which comprises a polymer selected from the group consisting of poly (vinylchloride), polysulphone, cellulose acetate, nitrocellulose, acrylic polymers

and polyurethane. More preferably an embodiment of this invention provides a membrane comprising PVC.

Preferably an embodiment of a membrane according to the invention comprises a liquid crystal with the general structure: a)

wherein x and y are preferably independently selected from 0,1 or more. More preferably, x and y are independently selected from 0 to 5. Most preferably, x and y are independently selected from 0 to 3. orb)

wherein n is preferably 0,1 or more. More preferably, n is selected from 0 to 5. Most preferably, n is selected from 0 to 3.

More preferably an embodiment of a membrane according to the invention comprises a liquid crystal selected from the group consisting ofN- (4-methoxybenzylidene) - 4-butylaniline) (NMBB), 4'-Pentyl-4-biphenylcarbonitrile (PBCN), Cholesterol oleyl carbonate- (COC), 4-methoxy-4'-n-butylazoxy-benzene (MBAB), p-azoxyanisole (PAA) or a combination of one or more thereof.

Structural formulae of the preferred liquid crystals are as follows:

--Moc/tMc/t-MaMtKnc CATMBJ

'-P--A/caoKMeC)

Cholesteryl oleyl carbonate (COQ

4-methoxy-4'-n-butylazoxy-benzene (MBAB)

p-azoxyanisole (PAA)

More preferably an embodiment of a membrane according to the invention comprises PVC and the liquid crystal N- (4-methoxybenzylidene)-4-butylaniline) (NMBB) which has the structure:

Preferably an embodiment of a membrane according to the invention has a ratio of polymer to liquid crystal which is greater than 15% to provide a polymer dispersed liquid crystal (PDLC). More preferably the ratio of polymer to liquid crystal is greater than 20%. Even more preferably the ratio of polymer to liquid crystal is greater than 25%.

Preferably an alternative embodiment of a membrane according to the invention provides a membrane wherein the ratio of polymer to liquid crystal is less than 15% to

provided a polymer stabilised liquid crystal (PSLC). More preferably the ratio of polymer to liquid crystal is less than 10%. Even more preferably the ratio of polymer to liquid crystal is less than 5%.

Preferably an embodiment of a membrane according to the invention provides a membrane comprising a surfactant. More preferably the surfactant is dispersed within the membrane.

Preferably an embodiment of a membrane according to the invention provides a membrane comprising a non-ionic, a cationic or an anionic surfactant. In some cases, the liquid crystal is a solid at room temperature and pressure. Effective dissolution of the liquid crystal in a membrane phase is achieved by incorporation of a liquid surfactant or lipid. The latter plasticising liquids provide the advantage that they aid solubility of the liquid crystal. Choice of the surfactant or lipid depends on the hydrophylic/lipophylic balance of the liquid crystal (s) present.

Preferably an embodiment of a membrane according to the invention provides a membrane comprising a non-ionic surfactant selected from the group consisting of Tritons and Tweens.

Preferably an embodiment of a membrane according to the invention provides a membrane comprising a non-ionic surfactant selected from the group consisting of :

Triton X-114 (N = 7 or 8)

Triton X-I Oa (N = approx-9. 5)

TritonX-45 structure not shown Tween 80

Tween 20

or a combination of one or more thereof.

Preferably an embodiment of a membrane according to the invention provides a membrane which comprises PVC and additionally comprises NMBB and Tween 80 in a 1: 1 ratio.

In a second aspect the invention provides a method for the production of a membrane according to the invention which comprises the steps of ; a) dissolving a polymer in tetrahydrofuran (THF), b) dissolving liquid crystal and optionally surfactant (eg. by ultrasonification) into the polymer solution, c) pouring the resulting solution onto a surface, eg a petri dish, d) covering the surface to effect slow and controlled evaporation of solvent and precipitation of a membrane.

Preferably an embodiment of a method according to the invention comprises dissolving a ratio of polymer to liquid crystal of greater than 15% and the result is a polymer dispersed liquid crystal (PDLC). More preferably the ratio of polymer to liquid crystal is greater than 20%. Even more preferably the ratio of polymer to liquid crystal is greater than 25%.

Preferably an alternative embodiment of a method according to the invention comprises dissolving a ratio of polymer to liquid crystal of is less than 15% and the result is a polymer stabilised liquid crystal (PSLC). More preferably the ratio of

polymer to liquid crystal is less than 10%. Even more preferably the ratio of polymer to liquid crystal is less than 5%.

In a third aspect the invention provides a method for adjusting permeability and selectivity properties of a membrane according to the invention which comprises the step of applying an electric field across the membrane.

Remarkably, test results confirm that direct current (DC) fields of about OV to about 30V applied across a membrane facilitates at least the paracetamol selectivity of a membrane.

Preferably, the electric field is provided by a direct current.

Preferably, the magnitude of the electric field is provided by a potential of about 2V to about 50V; more preferably, it is provided by a potential of about 10V to about 40V; most preferably, it is provided by a potential of about 30V.

In an alternative embodiment the invention provides a method for adjusting permeability and selectivity properties of a membrane according to the invention which comprises the step of subjecting the membrane to a temperature within the liquid crystalline range. This range is dependent on the liquid crystal.

For example, liquid crystals have liquid crystal temperature ranges as follows:

Liquid Crystal Liquid Crystal Range NMBB 21-47 C PBCN 10-28 C MBAB 19-76 C PAA 117-137 C Remarkably, data suggests there is a synergistic effect brought about by application of an electric field and temperature together.

In a fourth aspect, the invention provides a membrane-based enzyme biosensor comprising a membrane according to the invention.

Preferably an embodiment a biosensor according to the invention provides a biosensor for use in the detection and/or quantification of glucose, paracetamol, or a compound selected from the group which consists of Paracetamol

Acsorbic acid

Catechol-

H202 H-O-O-H Dopamine

4-aminophenol

Preferably an embodiment of a biosensor according to the invention provides a biosensor for use in the measurement of glucose levels in a liquid sample, for example blood or urine, particularly in the monitoring of diabetes where the presence of paracetamol is a major interferent leading to false positive signals.

Preferably an embodiment of a biosensor according to the invention provides a paracetamol biosensor comprising a specific hydrolytic enzyme wherein; a) the membrane acts as a barrier to paracetamol and; b) the specific hydrolytic enzyme converts paracetamol to 4-aminophenol and; c) the membrane allows relatively free permeation of 4-aminophenol, the presence of which can thus be detected either electrochemically, ie amperometrically or by some other means of detection, to allow quantification of paracetamol in a test sample.

Preferably the hydrolytic enzyme is an arylacylamidase enzyme.

In a fifth aspect the invention provides use of a membrane or biosensor in the pre-concentration or exclusion of a specific compound.

Preferably an embodiment of a use according to the invention provides use of a membrane or biosensor for pre-concentration or exclusion, followed by the detection of an electrochemically active compound eg by using a sensor or an electrochemical set-up.

Preferably an embodiment of a use according to the invention provides use of a membrane or biosensor for specific detection and testing of a compound including, dopamine, a steroid, paracetamol, a phenol, environmental testing eg for a phenol in water waste products from the coke industry.

In a sixth aspect the invention provides a kit comprising a membrane according to the invention. Preferably, an embodiment of a kit according to the invention is suitable for use according to the invention.

In a further aspect the invention provides a membrane according to the invention for use in a medical application, for example haemodialysis.

An advantage of the present invention is that it provides a membrane that has selective permeability and is therefore able to form a barrier to a specific compound (for example paracetamol) or class of compounds and thus screen it or them from a liquid sample.

A further advantage of the present invention is that it provides a synthetic membrane whose permeability and selectivity properties can be modified by changing its surrounding conditions. The modification of membrane properties provides scope for use of the membranes in a number of applications.

Liquid crystals are rod-like molecules. By virtue of their structure they are polarisable and their orientation can be influenced by the application of an external electric field.

This property can have an ensuing effect on the permeability and selectivity of a membrane comprising a liquid crystal.

The orientation, layering and ordering of a thermotropic liquid crystal is affected by temperature. Liquid crystals can switch from a first smectic mesophase to another with changing temperature, for example from A (parrallel) to C (tilted). This property can have a knock-on effect on the permeability and selectivity of a membrane comprising a liquid crystal.

An advantage of the present invention is that it provides a biosensor with improved performance and accuracy. Remarkably, a biosensor comprising a selectively permeable membrane, which acts as a barrier to an interferent compound (eg. paracetamol), achieves minimal interference and therefore sensitivity is improved.

The selective permeability of a membrane according to the invention can be used to prevent the passage of a specific compound, for example an interferent, across the membrane yet still allow the passage of a signal species.

A further advantage of the present invention is that it provides a membrane able to selectively exclude paracetamol from a liquid sample. Paracetamol is an

electrochemically active interferent that is often present in biological samples.

An advantage of the present invention is that it provides a membrane that can be easily fabricated.

Additional features and advantages of the present invention are described in, and will be apparent from, the description of the presently preferred embodiments which are set out below with reference to the drawings in which: Figures 1 and 2 show the corresponding permeabilities of various electrochemically active species through dialysis and 0. 06um pore size polycarbonate membranes respectively.

Figure 3 shows the permeabilities of various electrochemically active species through a membrane comprising PVC and Tween 80.

Figure 4 shows the permeabilities of various electrochemically active species through a plasticised membrane comprising PVC and Aliquat.

Figure 5 shows the permeabilities of various electrochemically active species through a membrane comprising PVC and a liquid crystal (PVC (NMBB)).

Figure 6 shows the permeabilities of various electrochemically active species through a membrane comprising PVC and additionally a 1: 1 mixture of Tween 80 and NMBB.

For the purposes of clarity and a concise description features are described herein as part of the same or separate embodiments, however it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described.

EXAMPLES Exarnplel-Modification of PVC Membranes Preparation of Solutions.

Phosphate buffered saline (PBS) was prepared by dissolving 1 tablet per 100ml of distilled water to give a 0. IM solution. Standard 10 mM solutions of the electrochemically active signal species (namely, ascorbic acid, catechol, hydrogen peroxide and paracetamol) were prepared in PBS.

Membrane Fabrication.

Plasticised PVC membranes were prepared by dissolving PVC (0.06 g) in THF (5 ml) followed by adding 150ut of either Tween 80 or Aliquat 336s. The resulting solution

was then poured into a Petri dish (9 cm diameter) and the dish covered to effect slow and controlled evaporation of solvent and precipitation of a PVC membrane. Liquid crystal modified PVC membranes were prepared in a similar fashion: NMBB (75111) with (and-without) Tween 80 (75ill) was mixed and dissolved by ultrasonication into the PVC solution and the solutions cast in a Petri dish as previously described.

Selectivity Testing.

The 2-electrode cell was pre-treated with PBS electrolyte and layered with a lom2 portion of polycarbonate membrane as a spacer to maintain electrolyte contact between the electrodes especially in the presence of plasticised membranes that were hydrophobic and insulating. A portion of the test membrane (1 cm2) was then layered onto the spacer membrane. The sample chamber (with'o'ring) was then screwed on tight to complete the cell assembly. Solutions of hydrogen peroxide, catechol, paracetamol and ascorbic acid (100 M) were then sequentially introduced to the sample chamber (with buffer washing in between) and the electrochemical signal recorded on the chart recorder. Results were compared with those obtained for polycarbonate and dialysis membranes.

Protein Fouling Studies.

Following exposure to the electrochemical species, the membranes were treated with a solution of BSA (40 mg/ml) in PBS for a period of 60 minutes. The protein solution was then removed and the sample chamber was washed with buffer (3 times). The

protein-exposed membrane was then re-tested with the electrochemically active species to assess the extent of protein fouling.

Application of Electric Field Across A Pre-cast Membrane Comprising Liquid Crystal Once the membrane comprising liquid crystal had been prepared, a portion of the membrane (lcm) was tested for selectivity as described above. The permselectivity of membrane given in Figures 5 and 6 was made reproducible by first placing the Icm2 portion of membrane of a glass slide and between two metalic electrodes. A potential of 30V de was applied between the electrodes fora period of 5 minutes. The membrane was then tested for permselectivity.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art.

Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications are covered by the appended claims.

Claims

Claims 1. A synthetic membrane comprising a polymer and a liquid crystal dispersed therein.
2. A membrane according to claim 1 which comprises a polymer selected from the group consisting of poly (vinylchloride), polysulphone, cellulose acetate, nitrocellulose, acrylic polymers and polyurethane.
3. A membrane according to claim 1 or 2 which comprises a liquid crystal with the general structure:

a) wherein x and y are independently selected from 0,1 or more. orb)

wherein n is preferably 0,1 or more.

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4. A membrane according to any preceding claim which comprises a liquid crystal selected from the group consisting ofN- (4-methoxybenzylidene)-4-butylaniline) (NMBB), 4'-Pentyl-4-biphenylcarbonitrile (PBCN), Cholesterol oleyl carbonate (COC), 4-methoxy-4'-n-butylazoxy-benzene (MBAB), p-azoxyanisole (PAA) or a combination of one or more thereof.
5. A membrane according to any preceding claim which comprises PVC and N- (4-methoxybenzylidene)-4-butylaniline) (NMBB).
6. A membrane according to any preceding claim which has a ratio of polymer to liquid crystal which is greater than 15% to provide a polymer dispersed liquid crystal (PDLC) or a ratio of polymer to liquid crystal which is less than 15% to provide a polymer stabilised liquid crystal (PSLC).
7. A membrane according to any preceding claim comprising a surfactant.
8. A membrane according to claim 7 wherein the surfactant is a non-ionic, a cationic or an anionic surfactant.
9. A membrane according to claim 7 or 8 wherein the surfactant is selected from the group consisting of Tritons and Tweens.

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10. A membrane according to any one of claims 7 to 9 wherein the surfactatn is selected from the group consisting of : Triton X-114 (N = 7 or 8)

Triton X-100 V = appro. e. P. J

Triton X-45 structure not shown Tween 80

Tween 20

or a combination of one or more thereof.

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11. A membrane according to any one of claims 7 to 10 which comprises PVC and additionally comprises NMBB and Tween 80 in a 1: 1 ratio.
12. A method for the production of a membrane according to any preceding claim which comprises the steps of ; a) dissolving a polymer in tetrahydrofuran (THF), b) dissolving liquid crystal and optionally surfactant (eg. by ultrasonification) into the polymer solution, c) pouring the resulting solution onto a surface, eg a petri dish, d) covering the surface to effect slow and controlled evaporation of solvent and precipitation of a membrane.
13. A method for adjusting permeability and selectivity properties of a membrane according to any one of claims 1 to 11 which comprises the step of applying an electric field across the membrane.
14. A method for adjusting permeability and selectivity properties of a membrane according to any one of claims 1 to 11 which comprises the step of subjecting the membrane to a temperature within the liquid crystalline range.
15. A method according to claim 13 or 14 which comprises subjecting the membrane to an electric field and a temperature within the liquid crystalline range.

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16. A membrane-based enzyme biosensor comprising a membrane according to any one of claims 1 to 11.
17. A biosensor according to claim 16 for use in the detection and/or quantification of glucose, paracetamol, or a compound selected from the group which consists of ascorbic acid, catechol H202, Dopamine, 4-aminophenol or a combination or two or more thereof.
18. A biosensor according to claim 16 or 17 for use in the measurement of glucose levels in a liquid sample, for example blood or urine, particularly in the monitoring of diabetes where the presence of paracetamol is a major interferent leading to false positive signals.
19. A biosensor according to any one of claims 16 to 18 comprising a specific hydrolytic enzyme wherein; a) the membrane acts as a barrier to paracetamol and; b) the specific hydrolytic enzyme converts paracetamol to 4-aminophenol and; c) the membrane allows relatively free permeation of 4-aminophenol, the presence of which can thus be detected to allow quantification of paracetamol in a test sample.

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20. A biosensor according to claim 19 wherein the hydrolytic enzyme is an arylacylamidase enzyme.
21. Use of a membrane or biosensor in the pre-concentration or exclusion of a specific compound.
22. Use according to claim 21 for pre-concentration or exclusion, followed by the detection of an electrochemically active compound eg by using a sensor or an electrochemical set-up.
23. A kit comprising a membrane according to any one of claims 1 to 11
24. A membrane according to any one of claims 1 to 11 for use in a medical application, for example haemodialysis.