AU671253B2 - Solid state ion sensor with polyurethane membrane - Google Patents

Description

nPI DATE 27/11/91 AOJP DATE 02/01/92 APPLN. ID 80811 91 PCT NUMBER PCT/11S91/03074 PCr INTERNATIONAL Art'LlA11iN ruU 5Ltari u UINULK incr. -AiI _tI i .uurntAnviuiN i r i PCT) (51) International Patent Classification 5 (11) international Publication Number: WO 91/17432 G01N 27/30 A (43) International Publication Date: 14 November 1991 (14.11.91) (21) International Application Number: PCT/US91/03024 (81) Designated States: AT (European patent), AU, BE (European patent), CA, CH (European patent), DE (Euro- (22) International Filing Date: 2 May 1991 (02.05.91) pean patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, LU (Euro- Priority data: pean patent), NL (European patent), SE (European pa- 517,651 2 May 1990 (02.05.90) US tent).

(71)Applicant: THE UNIVERSITY OF MICHIGAN [US/ Published US]; Intellectual Properties Office, 475 East Jefferson, With international search report.

Room 2354, Ann Arbor, MI 48109-1248 Before the expiration of th ne telimit for amending the claims and to be republished in the event of the receipt of (72) Inventors: BROWN, Richard, B. 3910 Windemere Drive, amendments.

Ann Arbor, MI 48105 CHA, Geun-Sig 2151 Hubbard, Ann Arbor, MI 48105 (US).

(74) Agent: ROHM, Benita, Ruden, Barnett, McClosky, Smith, Schuster Russell, 110 East Broward Boulevard, Floor, Fort Lauderdale, FL 33301 (US).

(54)Title: SOLID STATE ION SENSOR WITH POLYURETHANE MEMBRANE -to-NOACI POTENTIM (ZVI -150- -200 -300 I I I -I I 0 10 20 30 40 50 TIME (IH UTES) (57) Abstract A polyurethane matrix is employed to form a substance-sensitive membrane which is particularly suited for installation on a solid state sensor. The ionophore may be a potassium ionophore, an ammonium ionophore, or any other ionophore may be coupled to the molecule of inte,.st through a bioactive agent, such as an enzyme, an immuno-chemical, bacteria, antibody, virus, or antigen. The resulting substance-sensitive membrane has electrochemical properties which compare favorably to those of conventional PVC membranes, and exhibit significantly greater adhesion to glasses and semiconductor substrate materials. The improved adhesion will prolong the life of the sensors and prevent the formation of electrolyte shunts which have been known to render solid state sensors inoperative.

WO 91/17432 PCT/US91/03024 SOLID STATE ION SENSOR WITH POLYURETHANE MF BRANE Background of the Invention This invention relates generally to devices and systems for measuring concentrations of icns, chemicals, biological materials, and reaction products, and more particularly, to a solid state device which employs a polyurethane matrix, having electrochemical properties comparable in quality to conventional PVC membranes, as the substance-sensitive membrane, and wherein the polyurethane membrane exhibits excellent adhesion to the Si 3

N

4 surface of solid state sensors.

As a result of their small size and potentially lower cost, solid state io-. sensors are of interest in industrial and medical applications as replacements for traditional ion-selective electrodes. These sensors make possible new direct-monitoring applications. There is a need, however, for improved membrane adhesion, as such would be beneficial, not only to all users of solid-state chemical sensors, but particularly those interested in long-term monitoring.

Basically, the potential uses of solid-state ion sensors can be divided into industrial and medical applications. Industrial uses include, for example, the monitoring of treated or waste water for hardness or pollutants; on-line analysis of industrial chemicals, foodstuffs, and medicines; and low cost analytical instruments. Medical applications include the monitoring of electrolytes, blood gases, and metabolic substrates, both for biochemical control systems and for patient monitoring or diagnostics.

There is a need for solid state ion sensors which can achieve the :7eeds of industrial and medical monitoring for very long periods of time. Silicon-based chemical sensors often use ionophore-doped polymeric membranes as transducers because of their excellent selectivity toward the ion of interest, the wide range of ions for which ionophores WO 91/17432 PCT/US91/03024 2 are available, and because they can borrow from ongoing developments in ion-selective electrode technology.

As is the case with ion-selective electrodes, most solid state sensors have used poly(vinylchloride) (PVC) as a membrane matrix. One of the primary causes of failure in conventional microsensors has been poor adhesion of the organic membrane to the chip surface. This leads to the formation of electrolyte shunts around the membrane, rendering the membrane inoperative.

Others in the prior art have endeavored to improve membrane adhesion such as by the use of a polyimide suspended mesh, modification of PVC for binding to hydroxyl-bearing surfaces, and mechanical attachment of the membrane. These methods have tended to improve adhesion of the membrane, but generally have resulted in either inferior electrochemical performance when compared to PVC or added processing complexity. There is, therefore, a need for a permselective membrane which exhibits good electrochemical properties, preferably at least as good as traditional PVC membranes, but which exhibits excellent adhesion to the Si 3

N

4 surface of solid state sensors.

It is, therefore, an object of this invention to provide a substance-sensitive solid state sensor which has an extended lifetime.

It is another object of this invention to provide a substance-sensitive membrane system for a solid state sensor which is possessed of excellent electrnchemical properties.

It is also an object of this invention to provide a substaice-sensitive membrane system for a solid state sensor which is characterized with excellent adherence to solid state sensor materials.

It is a further object of this invention to provide a substance-sensitive membrane system for a solid state sensor which can be applied to a plurality of solid state devices simultaneously using conventional integrated circuit manufacturing techniques.

WO 91/17432 PC'T/US9 1/03024 3 It is additionally an object of this invention to provide a solid state sensor system which is not subject to the generation of disabling electrolyte shunts around the substance-sensitive membrane.

It is yet a further object of this invention to provide a solid state sensor system which is simple and low in cost.

It is also another object of this invention to provide a substance-sensitive polymeric membrane system for a solid state sensor which can be applied to a multiplicity of solid state devices simultaneously using conventional integrated circuit manufacturing techniques and which utilizes ionophoric doping to create the substance sensitivity.

It is yet an additional object of this invention to provide a substance-sensitive membrane for use with a solid state sensor and which does not require a structural layer associated therewith to maintain communication between the membrane and a solid state substrate.

It is still another object of this invention to provide a substance-sensitive solid state sensor which can be manufactured inexpensively in production quantities, and which can be adapted for industrial uses, such as monitoring treated or waste water for hardness or pollutants, online analysis of industrial chemicals, foodstuffs, and medicines, and low cost analytical instruments.

It is a yet further object of this invention to provide a substance-sensitive solid state sensor which can be manufactured inexpensively in production quantities, and which can be adapted for medical uses, such as monitoring of electrolytes, blood gases, and medical substrates.

It is also a further object of this invention to provide a substance-sensitive solid state sensor which can be manufactured inexpensively in production quantities, and which can be adapted for biochemical control systems.

It is additionally another object of this invention to provide a substance-sensitive solid state sensor which can WO 91/17432 PCT/US91/03024 4 be manufactured inexpensively in production quantities, and which can be adapted for patient monitoring and diagnostics.

A still further object of this invention is to provide a substance-sensitive membrane for use in a solid state sensor, wherein the membrane exhibits good adhesion to SiO 2 surfaces.

An additional object of this invention is to provide a substance-sensitive membrane for use in a soiid state sensor, wherein the membrane exhibits good adhesion to Si 3

N

4 surfaces.

Yet another object of this invention is to proVride a substance-sensitive membrane for use in a solid state sensor, wherein the membrane exhibits a reduced electrical resistance characteristic, and thereby yields reduced electrical noise for the sensor.

Another object of this. invention is to provide a substance-sensitive membrane for use in a solid state sensor, wherein the membrane exhibits a reduced tendency to adsorb protein.

A yet further object of this invention is to provide a substance-sensitive membrane for use in a solid state sensor, wherein the membrane exhibits a reduced tendency to cause blood clotting.

Summary of the Invention The foregoing and other objects are achieved by this invention which provides an integrated circuit chemical sensor arrangement. The integrated circuit sensor is provided with an input electrode formed of a conductive material in the vicinity of a region formed of a siliconbased semiconductor material, and a permselective membrane having a predetermined electrochemical property and formed of a polyurethane-based compound. The silicon-based compound is arranged to be in adherence with the polyurethane-based semiconductor material, and in electrical communication with the input electrode. In this manner, a voltage response to the electrochemical property is produced at the input electrode.

In a highly advantageous embodiment of the invention, the permselective membrane is formed of a hydroxylated copolymer poly(vinylchloride/vinyl acetate/hydroxy propyl acrylate) (PVC/Ac/Hpa) (80/5/15 with polyurethane, dissolved in THF, to form a polyurethane mixture. An ionophore, which may be responsive to ammonium, potassium or any of several other chemicals or biological substances, is also mixed in with the polyurethane mixture. In some embodiments, the sensors may be made responsive to other molecules through addition of bioactive agents, such as an enzyme, an immunochemical, a bacteria, and a virus. A plasticizer is also added.

In accordance with a process aspect of the invention, a substance-sensitive membrane is formed by the process of: first mixing an ionophore into a hydroxylated copolymer poly(vinylchloride/vinyl acetate/hydroxy propyl acrylate) (PVC/Ac/Hpa) (80/5/15 with polyurethane, dissolved in THF, to form a polyurethane mixture; second mixing into said polyurethane mixture an ionophore; and third mixing into said polyurethane mixture a plasticizer.

In one embodiment of this process aspect of the invention, there is provided the further step of depositing the mixture onto a substrate. In other embodiments, the mixture may be solvent cast.

As previously noted, the ionophore may be, for example, an ammonium ionophore or a potassium ionophore.

Illustratively, the ionophore is present in a'proportion of 1 wt.% of the mixture. The plasticizer is present in the mixture in an amount of approximately 66 wt.%.

(5.6/ WO 91/17432 PCr~/US91/03024 6 Brief Description of the Drawing Comprehension of the invention is facilitated by reading the following detailed description, in conjunction with the annexed drawing, in which: Fig. 1 is a graphical representation which illustrates the response of the ammonium-selective membranes.

Fig. 2 shows the response of the potassium-selective membranes, including a measurement in blood serum; Fig. 3 is a graphical representation which illustrates the result of blood clot tests; Fig. 4 is a graphical representation of typical nitrophenylate calibration curves; Fig. 5 is a graphical representation of a nitrophenol phosphate substrate response; and Fig. 6 is a substrate calibration curve for p-Nitrophenyl phosphate.

Detailed Description The present invention has been made by the inventors herein in the form of polyurethane-matrix membranes selective to potassium and ammonium. Such membranes exhibit good electrochemical properties and superb adhesion to silicon nitride. The highly beneficial adhesion characteristic was accomplished by using 20 wt. hydroxylated PVC, which can be processed in the solvent tetrahydrofuran (THF). This polyurethane material exhibits extremely high bond strength to a wide range of substrates, including Si 3

N

4 In addition, the resulting polyurethane membrane exhibits reduced protein adsorption and blood clotting.

The following table compares the electrochemical properties of four different membrane types toward potassium and ammonium. The polyurethane membrane is seen to have a comparable performance to PVC membranes, with even better slopes and detection limits. In addition, these polyurethane hydroxylated PVC membranes have strong adhesion to glass and Si 3

N

4 even without silanizing agents.

TABLE 1 Composition of Matrix (wt%) PVC (33%) Slope Detection (mV/decade) Limit (pM) K* NH 4 KV NH, 4 57.1 55.8 0.5 0.98 pSe Selectivity LogK W i=K j=Na 4 i=NH,+ j=K -4.28 -2.82 -0.85 R A 1.0 P 0.8 G 0.9 E PVC (20%) PVC/Ac/Hpa PU (26.4%) PVC/Ac/Hpa 57.3 56.0 0.52 0.91 -4.22 -2.77 -0.82 57.2 56.8 0.59 0.99 -4.21 -2.89 -0.89 PVC polyvinyl chloride R PVC/Ac/Hpa 80% vinyl chloride vinyl acetate A hydroxy propyl acrylate PU polyurethane G P-SS polydimethylsiloxane E Si-CN 10-12% (cyanopropyl)methyl S Normalized Resistance Qualitative Adhesion p Poor Good Excellent Superb IPotassium and ammonium selective membranes are doped with 1% valinomycin and nonactin, respectively. The balance of the membrane is DOA (bis(2-ethylhexyl)adipate plasticizer.

The following tables illustrate the improvement in electrochemical performance if PVC (PVC/Ac/Hpa) is added.

Electrochemical performance is excellent in either case, but adhesion is much better when (PVC/Ac/Hpa) is used.

PU/PVC Membrane Optimization Polymer Composition (wt%) PVC PU Slope Detection Selectivity Fluka Tecoflex (mV/decade) Limit (yM) log kI, K+,Na+ 100 0 57.1 0.58 -4.27 0 100 53.6 6.18 -3.46 75 57.7 0.58 -4.32 50 57.9 0.56 -4.33 rdi: PU/PVC/Ac/Hpa Membrane Optimization Polymer Composition (wt%) PVC (Fluka) PU PVC/Ac/Hpe Slope Detection Selectivity wt.% wt.% wt.% (mV/decade) Limit (pM) log k,, K+,Na+ 100 0 0 57.1 0.58 -4.27 0 75 25 53.6 6.18 -3.46 0 80 20 57.7 0.58 -4.32 0 85 15 57.9 0.56 -4.33 0 95 5 55.9 1.57 -3.72 0 100 0 53.6 6.18 -3.46 Fig. 1 is a graphical representation which illustrates the response of the ammonium- selective membranes. Fig. 2 shows the response of the potassium-selective membrane, including a measurement in blood serum. It is evident from these figures that the polyurethane membranes are usable in a wide variety of monitoring situations.

Polyurethane has excellent biocompatibility, an important feature for many solid-state sensors. Blood tests were performed using glass tubes coated with various membrane types. Fresh human blood was brought into contact with the membranes by tilting the tubes every 60 seconds until clots formed. As shown in Fig. 3, the polymer coated tubes had longer clotting times than the glass tubes.

Membrane adhesion is significant because it is one of the properties which determines the lifetime of solid state chemical sensors. In order to determine the adhesion characteristic during testing of the membranes of the present invention, and others, the well-known "Scotch tape test" was employed. The results of this testing process is shown below in tabular form in Table 2.

TABLE 2 ADHESION TESTS Number of Membranes Removed Scotch-Tape Peel Test Soak Test Matrix Type 30 Spots on Si 3 N, 24 Glass Tubes No SiCl4 With SiC14 6-hour Soak PVC 30 30 19 PVC/ (PVC/Ac/Hpa) 30 30 none PU/ (PVC/Ac/Hpa) none none none Silicone none none As set forth in Table 2, thirty membranes, each of four different matrices, were cast on silicon wafers upon which a Si 3

N

4 film had been deposited. After the membranes were cured, the tape was pressed onto the membranes and then removed. None of the polyurethane or silicone rubber membranes came off, while all of the PVC and hydroxylated PVC membranes were removed.

In another experiment, wet adhesion was tested by coating glass tubes with each composition and soaking the tubes in water for six hours. When the tubes were rinsed with flowing water, many of the PVC coatings washed away from the glass tubes, but such was not the case for the polyurethane or silicone-based membranes.

In view of the fact that the foregoing tests are only semi-quantitative, a new adhesion test was designed. The membranes were cast on a Si 3

N

4 surface of a wafer which had been scribed on the backside. The wafer was then cleaved, and mounted on a pull tester with one half attached to a load cell, and the other half to a stationary grip. The wafer halves were pulled apart, peeling the membrane from the surfaces, while the membrane peeling force was monitored by the load cell. With this test, the maximum pulling force required to peel each membrane from the Si 3

N

4 surfaces was compared. These results are set forth below in Table 3.

Table 3 ADHESION TEST RESULTS

D

I

Normalized Pulling Force Matrix Type Dry Wet no SiCl, with SiCl 4 with SiCl 4 PVC 1.00 1.49 1.01 PVC/(PVC/Ac/Hpa) 0.54 1.04 1.01 PU/(PVC/Ac/Hpa) 5.29 54.99 30.84 Silicone 57.87 As is evident from Table 3, the polyurethane rubber membrane had extremely strong bond strength.

The nitrophenolate-sensitive base membrane was prepared by incorporating tetraheptylammonium bromide as the ionophore. Typical nitrophenolate calibration curves for the base membrane, before and after enzyme immobilization, are shown in Fig. 4. Upon addition of the substrate, nitrophenyl phosphate, the alkaline phosphatase-immobilized sensor responded to enzymatically-produced nitrophenylate on the surface of the base sensing membrane, as shown in Fig. 5. Fig. 5 is a graphical representation of a nitrophenol phosphate substrate response. Fig. 6 is a substrate calibration curve for p-Nitrophenyl Phosphate.

There are many ways by which the membrane could be applied, including dipping, casting, spin-coating, screen printing, etc. Moreover, innumerable slight variations in the formulas could result in useful membranes. The simplest membranes are those containing ionophore to a specific ion. Such membranes should also be used in conjunction with, or incorporate in the membrane matrix, a bioactive agent, such as an enzyme, an immunochemical, a bacteria, etc. Thus, the membranes can be made specific to more complex chemicals.

*r WO 91/17432 PCT/ US9 1/03024 Although the invention has been described in terms of specific embodiments and applications, persons skilled in the art can, in light of this teaching, generate additional embodiments without exceeding the scope or departing from the spirit of the claimed invention. Accordingly, it is to be understood that the drawing and description in this disclosure are proffered to facilitate comprehension of the invention, and should not be construed to limit the scope thereof.

Claims (16)

1. In an integrated circuit chemical sensor arrangement having an input electrode formed of a conductive material in the vicinity of a region formed of a silicon-based semiconductor material, a permselective membrane having a predetermined electrochemical property and formed of a polyurethane-based compound, having an effective portion of a hydroxylated poly(vinylchloride) copolymer therein, arranged to be in adherence with said silicon-based semiconductor material and in electrical communication with said input electroda, for producing at said input electrode a volto'ge responsive to said electrochemical property.

2. The integrated circuit chemical sensor arrangement of claim 1 wherein an ionophore is mixed into said polyurethane- based compound whereby the integrated circuit chemical sensor is responsive to an ion.

3. The integrated circuit chemical sensor arrangement of claim 2 wherein said ionophore is a potassium ionophore. 2 0

4. The integrated circuit chemical sensor arrangement of claim 2 wherein said ionophore is an ammonium ionophore.

The integrated circuit chemical sensor arrangement of claim 4 wherein said permselective membrane further comprises a plasticizer.

6. The integrated circuit chemical sensor arrangement of claim 5 wherein said plasticizer is Dioctyl Adipate.

7. The integrated circuit chemical sensor arrangement of claim 1 wherein said electrochemical property is responsive to a molecule of interest by coupling thereto via a bioactive anent.

8. The integrated circuit chemical sensor arrangement of claim 7 wherein said bioactive agent is an enzyme, an immunochemical, a bacteria, or a virus.

9. A process for forming a substance-sensitive membrane for a solid state sensor arrangement, the process comprising the steps of: first mixing a hydroxylated copolymer poly(vinylchloride/vinyl acetate/hydroxy propyl acrylate) (PVC/Ac/Hpa) (80/5/15 with polyurethane, dissolved in THF, to form a polyurethane mixture; second mixing into said polyurethane mixture an ionophore; third mixing into said polyurethane mixture a plasticizer; and depositing said polyurethane mixture onto a silicon- based substrate.

The process of claim 9 wherein said step of depositing comprises a step of casting said mixture onto said silicon- based substrate.

11. The process of claim 9 wherein said ionophore in said step of second mixing is an ammonium ionophore.

12. The process of claim 9 wherein said ionophore in said step of second mixing is a potassium ionophore.

13. The process of claim 9 wherein said ionophore is present in a proportion of 1 wt.% of the mixture.

14. A process for forming a substance-sensitive membrane for a solid state sensor arrangement, the process comprising the steps of: v first mixing a hydroxylated copolymer poly(vinylchloride/vinyl acetate/hydroxy propyl acrylate) (PVC/Ac/Hpa) (80/5/15 with polyurethane, dissolved in THF, to form a polyurethane mixture; second mixing into said polyurethane mixture an ionophore in an amount of approximately 1 wt.% of said polyurethane mixture; third mixing into said polyurethane mixture a plasticizer in an amount of approximately 66 wt.% of the polyurethane mixture; and depositing said polyurethane mixture onto a silicon- based substrate.

The integrated circuit chemical sensor arrangement of 1 any one of claims 1 to 8, substantially as herein described.

16. The process of any one of claims 9 to 14, substantially as herein described. DATED this 7th day of June 1996 THE UNIVERSITY OF MICHIGAN By their Patent Attorneys MADDERNS