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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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• • G—PHYSICS
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• • C—CHEMISTRY; METALLURGY
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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/58—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving urea or urease
• • G—PHYSICS
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Definitions

• Figure 3 A is a graphic illustration of measured high urea concentration (95 mg/dL) versus cartridge age of twelve urea biosensors after short sensor shelf-life of two weeks and up to 3 week use-life; Daily urea concentration measurement in high urea sample (95 mg/dL) over 3 -week use life;
• Figure 3B is a graphic illustration of measured high urea concentration (95 mg/dL) versus cartridge age of twelve urea biosensors stored at ambient temperature over 5 months and up to 3 week use-life. Daily urea concentration measurement in high urea sample (95 mg/dL) over 3-week use life.
• the inventions described below are directed to a device and related method for enhancing enzyme stability and extending the shelf-life and use-life of urea biosensors useful in clinical analyzers for in vitro diagnostics, point-of-care applications in particular.
• the outer diffusion layer 165 controls the diffusion of the analyte into the enzyme layer 170 and protects the other components of the urea biosensor 150 from direct contact with the analytical sample in the channel 20.
• the enzyme layer 170 may include at least one enzyme, or a mixture of several enzymes, proteins and stabilizers that react with a particular analyte, i.e., urea in the patient sample. If the analyte diffuses through the outer diffusional membrane 165 into the enzyme layer, it can react with the enzyme in the enzyme layer 170 to produce a chemical byproduct, in the case of urea, ammonium ions. An electrical potential is generated across the composite membrane 160 that depends on the concentration of the chemical byproduct that is proportional to the concentration of urea in the analytical sample.
• PVC may be a constituent of the ammonium selective polymeric membrane 175.
• the steps for making a stable disaccharide- treated urea sensor according to the invention include:
• the steps include;
• a urease enzyme in a polysaccharide solution such as a sucrose solution or alternatively a solution of trehalose, raffmose, or lactitol in concentrations (w/v) ranging from >0% to 2%, 2% to 25%, 2% to 20%, 5% to 15%, 10% to 15%, preferably, 10% solution
• a polysaccharide solution such as a sucrose solution or alternatively a solution of trehalose, raffmose, or lactitol in concentrations (w/v) ranging from >0% to 2%, 2% to 25%, 2% to 20%, 5% to 15%, 10% to 15%, preferably, 10% solution
• the steps include:
• a urease enzyme solution in a polysaccharide solution such as a sucrose solution in water or alternatively a solution of trehalose, raffmose, or lactitol in concentrations (w/v) ranging from >0% 2% to 25%, 2% to 20%, 5% to 15%, 10% to 15%, preferably, 10% solution;
• a solution for an ammonium selective polymer membrane is prepared in THF and contains, for example, 25-35 % PVC, 60-70 % DOS, 1-5 % nonactin, and 0-1 % KTpCIPB by weight.
• Nonactin is an ionophore with specific selectivity towards ammonium.
• Other reagents for example, monactin, dinactin, trinactin, tetranactin, narasin, benzocrown ethers, cyclic depsipeptides, and mixtures of the preceding can also be used for this purpose.
• NPOE is another commonly used plasticizer.
• KTpCIPB Lithyl tetrakis[4-chlorophenyl]borate
• the polymer membrane can also include, for example, polyurethane, poly(tetrafluoroethylene), poly(methyl methacrylate), silicone rubber, and mixtures of above.
• THF tetrahydrofuran
• Cyclohexanone can also be used for this purpose.
• the ammonium sensor is planar and formed by casting the ammonium selective polymer membrane solution made as described above on a Ag/AgCl metal electrode and an inner electrolyte layer to form an internal reference electrode which is embedded in a solid substrate, for example, but not limited to PVC.
• the inner electrolyte layer is formed by casting the inner solution on the Ag/AgCl electrode surface.
• the inner solution contains, for example, a 65% MES buffer, 1% sodium chloride, 1% ammonium chloride, and 33% HEC (percentages by weight) in water.
• the enzymatic layer is formed by casting an enzyme solution on the outer surface of the ammonium-selective PVC membrane.
• the enzyme solution includes an enzyme urease, enzyme stabilizer glutathione, inert proteins bovine serum albumin, cross-linking agent glutaraldehyde and solvents. Glutathione is used together with one or more inert proteins, e.g., bovine serum albumin, to stabilize the urease in the enzyme layer.
• Cross-linking also secures the enzymatic layer to the underlying ion-selective polymeric layer.
• the enzyme stabilizers are generally added to the solution containing the enzyme prior to the addition of the cross-linking agent to ensure the stabilizers are cross-linked together with the enzyme.
• a typical enzyme solution was prepared containing 50 mg/mL urease, 20 mg/mL glutathione, 10 mg/mL bovine serum albumin, and 0.12% glutaraldehyde in 0.1 M phosphate buffer at a pH of 7.2, and the solution was applied to the top of the ammonium ion- selective PVC membrane.
• Polyurethane (PU) is one of the polymers that has superior
• hydrophilic medical grade polyurethane families selected to be optimized for this application are TecophlicTM and TecoflexTM from Lubrizol (Wickliffe, Ohio). These
• the outer diffusional membrane of the urea biosensor in contact with the patient sample in various embodiments includes one or more distinct layers of identical or different polymers and/or identical or different co-polymers.
• a typical outer diffusional membrane solution was prepared containing 0.12 g/ml polyurethane (Lubrizol, Wickliffe, Ohio) in THF. The outer diffusional membrane solution was applied over the enzyme layer to form the outer diffusional membrane.
• NAFION® the following polymers can also be candidates for the outer diffusional membrane
• poly(tetrafluoroethylene) ionomers) poly(tetrafluoroethylene) ionomers), poly-(2-hydroxymethyl methacrylate), polyvinyl chloride, polycarbonate, and cellulose acetate.
• the urea sensor with composite membrane of inner layer - PVC layer - Enzyme layer - polyurethane layer is then immersed in a disaccharide solution, for example, a sucrose solution, in (w/v) concentrations ranging from ranging from >0% to 2%, 2% to 25%, 2% to 20%, 5% to 15%, 10% to 15%, preferably, 10% solution for at least 30 minutes to 24 hours, at least 30 minutes to 240 minutes, at least 30 minutes to 120 minutes, at least 30 minutes to 60 minutes, preferably at least 30 minutes.
• the sucrose solution is buffered at biological pH of 7.4.
• the sensor is dried at room temperature for 0.5 hours to 3 hours.
• sucrose treatment is repeated multiple times followed by air drying each time.
• the sensor is then stored at ambient temperature until use.
• Figure 2A the use-life stability of each of the tested urea sensors at various applied experimental conditions when the drying time is fixed at 3 hours is provided.
• Figure 2B illustrates the effect of the experimental conditions on urea measurement.
• FIG. 2A The results shown in Figure 2A are readily summarized.
• the condition applied with shorter delay time (2 days) and longer soak time (16 hours) in 10% sucrose solution provided the most stable performance over the use-life of the sensor and most consistent sensor- to-sensor performance.
• the other two conditions provided better performance compared to the poorest performance of 7 day delay time/2 hour soak time but also exhibited inconsistency from sensor-to-sensor (7 days, 16 hours), or performance deterioration over the-use-life (2 days, 2 hours).
• Figure 2B illustrates urea measurement and the favorable direction for all three sucrose treatment condition factors: shorter delay time, longer soak time and longer drying time.
• Example 3 provides stability data at ambient temperature for urea sensors obtained from multiple production batches made according to the invention in a three week use- life stability and 5-month shelf life stability studies.
• Figure 3 A graphically illustrates urea measured in twelve urea sensors selected from three batches of sucrose treated sensors and short shelf-life storage at ambient temperature of two weeks. Daily measurement of the high urea concentration (95 mg/dL) sample over the three week use-life at short sensor shelf-life showed stable use-life performance with consistent measured urea concentration of about 95 mg/dl.
• Figure 3B graphically illustrates the results from another twelve urea sensors from three different batches of sucrose treated urea sensors.

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