From: Subject: United States Patent: 4216065 Date: Tue, 15 Jan 2008 14:58:06 -0600 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C85787.08E13EC0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C85787.08E13EC0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4216065.PN.&OS=PN/4216065&RS=PN/4216065 United States Patent: 4216065

3D"[Boolean 3D[Help]=20
  (=20 1 of 1 )
United States Patent 4,216,065
Rechnitz ,   et al. August 5, 1980 =
Bio-selective electrode probes using tissue slices =

Abstract

A bio-selective potentiometric electrode probe for the determination = of amino=20 acid concentrations in aqueous liquids comprising an ammonia gas = analytical=20 electrode provided at its tip with a closely adjacent thin layer of a = fresh=20 animal tissue containing, as a natural constituent thereof, an enzyme = effective=20 to catalyze degradation of the specific amino acid in analysis to either = ammonia=20 or to an intermediate compound subject to further degradation to ammonia = by an=20 additional enzyme, which ammonia is a function of the amino acid = concentration=20 in the liquid.

Inventors: Rechnitz; Garry A. (Newark, = DE),=20 Arnold; Mark A. (Newark, DE), Meyerhoff; Mark E. = (Newark, DE)=20
Assignee: University of Delaware = (Newark, DE)=20
Appl. No.: 06/049,092
Filed: June 18, = 1979

Current U.S. = Class: 205/778 ; = 204/403.1;=20 204/415
Current International = Class:=20 C12Q = 1/00 (20060101); G01N=20 33/68 (20060101); G01N 27/30 (20060101); G01N=20 027/46 ()
Field of Search: = 204/1T,195B,195M,195P,296 23/23B=20 424/12 195/13.5R,13.5C 428/213 156/230 210/490,5M =

References Cited [Referenced=20 By]
U.S. Patent Documents
3098813 July 1963 Beebe et al.
3575836 April 1971 Sternberg
3776819 December 1973 Williams
3966580 June 1976 Janata et al.
3979274 September 1976 Newman
Primary Examiner: = Prescott;=20 Arthur C.
Government Interests


GENERAL

The research culminating in this invention was = conducted=20 under National Science Foundation Grant No. CHE-7728158 and National = Institutes=20 of Health Grant No. GM-25312, pursuant to which the Government possesses = certain=20 property rights.=20
Claims


What is claimed is:

1. A bio-selective potentiometric = electrode=20 probe equipped with a gas-permeable membrane for the determination of = the=20 concentration of a preselected amino acid in an aqueous liquid = comprising an=20 ammonia gas analytical electrode provided at its tips with a closely = adjacent=20 thin layer of a fresh animal tissue containing, as a natural constituent = thereof, a preselected enzyme effective to catalyze degradation of said = amino=20 acid in analysis to either ammonia or to an intermediate compound = subject to=20 further degradation to ammonia in the presence of an additional = preselected=20 enzyme, which ammonia is a function of said preselected amino acid = concentration=20 in said aqueous liquid, and a dialytic membrane interposed between said=20 gas-permeable membrane and said animal tissue layer.

2. A = bio-selective=20 potentiometric electrode probe for the determination of the = concentration of a=20 preselected amino acid in an aqueous liquid according to claim 1 wherein = said=20 thin layer of said fresh animal tissue and said additional preselected = enzyme=20 are both retained closely adjacent said ammonia gas electrode tip by a = second=20 dialysis membrane interfacing with said amino acid-containing aqueous = liquid.=20

3. A bio-slective potentiometric electrode probe for the = determination=20 of the concentration of glutamine in an aqueous liquid according to = claim 1=20 wherein said fresh animal tissue is a thin slice of pork kidney excised = from the=20 cortex region.

4. A bio-selective potentiometric electrode probe = for the=20 determination of the concentration of arginine in an aqueous liquid = medium=20 according to claim 2 wherein said fresh animal tissue is a thin slice of = beef=20 liver and said additional preselected enzyme is urease.

5. In = the=20 potentiometric determination of the concentration of a preselected amino = acid in=20 an aqueous liquid utilizing an ammonia gas analytical electrode fitted = with a=20 gas-permeable membrane having its tip immersed in said aqueous liquid, = the=20 improvement comprising maintaining closely adjacent said electrode tip = but=20 separated therefrom and from said gas-permeable membrane by a dialytic = membrane,=20 a thin layer of a fresh animal tissue containing, as a natural = constituent=20 thereof, a preselected enzyme effective to catalyze degradation of said = amino=20 acid in analysis to either ammonia or to an intermediate compound = subject to=20 further degradation to ammonia in the presence of an additional = preselected=20 enzyme, which ammonia is a function of said preselected amino acid = concentration=20 in said aqueous liquid.

6. The method of potentiometric = determination of=20 the concentration of a preselected amino acid in an aqueous liquid = according to=20 claim 5 wherein said thin layer of said fresh animal tissue and said = additional=20 preselected enzyme are both retained adjacent said electrode tip by a = second=20 dialysis membrane interfacing with said amino acid-containing aqueous = liquid.
=20
Description


BACKGROUND OF THE INVENTION

It is frequently necessary = to=20 measure the concentrations of individual amino acids in either clear or = turbid=20 solutions in aqueous liquids, including physiological fluids such as = blood=20 serums and spinal fluids. This has proved difficult or even impossible = to=20 achieve with existing technology. However, two of the present inventors = have=20 achieved success in this regard by the use of membrane electrodes = utilizing=20 living bacterial cells, as described in their publication Science, vol. = 199, pp.=20 440-41 (1978), authors Rechnitz, Riechel, Kobos and Meyerhoff. =

SUMMARY=20 OF THE INVENTION

This invention comprises a bio-selective = potentiometric=20 electrode probe for determination of the concentrations of preselected=20 individual amino acids in aqueous liquids comprising an ammonia gas = analytical=20 electrode equipped with a gas-permeable membrane provided at its tip = with a=20 closely adjacent thin layer of a fresh animal tissue containing, as a = natural=20 constituent thereof, a preselected enzyme effective to catalyze = degradation of=20 the amino acid in analysis to either ammonia or to an intermediate = compound=20 subject to further degradation to ammonia in the presence of an = additional=20 preselected enzyme, which ammonia is a function of the amino acid = concentration=20 in the aqueous liquid.

DRAWINGS

The following drawings=20 constitute part of this disclosure, in which:

FIG. 1A is a = schematic=20 longitudinal cross-sectional view of the electrode tip region of a = preferred=20 embodiment of this invention;

FIG. 1B is an exploded view of the = several=20 components of the embodiment of FIG. 1A which illustrates the analytical = operation thereof; and

FIG. 2 is a typical calibration curve for = an=20 electrode constructed according to this invention for the analysis of=20 L-glutamine utilizing pork kidney tissue as the bio-catalytic medium, in = terms=20 of mV electrode response on the ordinate vs.-log concentration, M, of = the=20 substrate (sample) in test as abscissa.

DETAILED DESCRIPTION OF = THE=20 INVENTION

Referring to FIGS. 1A and 1B, there is shown in = longitudinal=20 cross-section the tip region of a conventional ammonia gas sensing = electrode,=20 e.g., an Orion Model 95-10. This electrode comprises a polymeric body = tube 19=20 threaded at the outboard end to accept an annular screw cap 19a. =

As=20 marketed, the electrode is provided with gas-permeable membrane 16, = maintained=20 in place against base ring 19b by the compression of screw cap 19a, = internal=20 electrolyte solution 17, and pH sensing glass membrane 18.

In = the=20 practice of this invention, catalytic degradation of amino acid in clear = or=20 turbid aqueous medium samples is achieved by attaching, in the tip = region of the=20 electrode, a thin layer 10 of the fresh animal tissue containing, as a = natural=20 constituent thereof, a preselected enzyme effective to catalyze = degradation of=20 the amino acid in analysis to either ammonia or to an intermediate = compound=20 subject to further degradation to ammonia in the presence of an = additional=20 preselected enzyme. Conveniently, tissue layer 10 is maintained snugly = against=20 the electrode tip of FIG. 1A by a piece of monofilament nylon mesh 11, = (mesh=20 size typically 105 microns) which is secured in place by assembly under = screw=20 cap 19a. It is not essential that tissue layer 10 overlie the entire = open area=20 of base ring 19b, good results being achieved where the tissue layer=20 approximates the pH sensing glass membrane 18 tip area and is generally = aligned=20 therewith. Protective dialysis membrane 15 is interposed between tissue = slice 10=20 and gas-permeable membrane 16, as it has been found that tissue slice 10 = otherwise causes deterioration of membrane 16 over a prolonged period.=20

In the analysis of the amino acid glutamine, we have found that = pork=20 kidney possesses high glutaminase activity which rapidly degrades = glutamine to=20 products including ammonia, thereby permitting direct amino acid = concentration=20 determination without the necessity for additional enzyme = supplementation.=20

The kidney tissue is obtained in the fresh state from hogs = immediately=20 after their slaughter from the cortex region of the kidney, the = thickness=20 typically being approximately 0.05 mm and a typical size of 12 mm = diameter. Pork=20 kidneys are preferably stored at 4.degree. C. before use. Dialysis = membrane 15=20 typically has a molecular weight cutoff of about 12,000. If desired, a = dialysis=20 membrane of the same characteristics as membrane 15 can be substituted = for nylon=20 mesh 11 as the retainer for tissue slice 10.

The potentiometric = response=20 of the kidney slice electrode was evaluated at 26.degree. C. in 0.1 M = phosphate=20 buffer, pH 7.8, containing 0.02% sodium azide as preservative. The = response to=20 buffer solely is that indicated by the horizontal line to the right of = point O,=20 upper right hand portion of FIG. 2, and this constitutes the background=20 potential. Between experiments, the electrodes were stored in the buffer = at room=20 temperatures.

FIG. 2, full line plot, is a typical calibration = curve of=20 the electrode for L-glutamine. The slope, linear range and detection = limit=20 remain unchanged over at least 28 days of electrode use. Typically, 5-7 = minutes=20 are required for the electrode to attain a steady potential value after = each=20 addition of glutamine to the test solution.

The kidney tissue = electrode=20 yielded negligible response to such possible interferents as urea, = L-alanine,=20 L-arginine, L-histidine, L-valine, L-serine, L-glutamic acid, = L-aspargine,=20 L-aspartic acid, D-alanine, D-aspartic acid, glycine and creatinine. The = dotted=20 plot at the upper right-hand section of FIG. 2 represents the maximum = response=20 (curve a) to the thirteen possible interferents tested. It will be seen = from=20 curve a that, in terms of equivalent glutamine, the maximum interference = which=20 can possibly exist is approximately two and one half orders of magnitude = less=20 than a given glutamine concentration, so that, practically, there is no=20 interference problem.

In service, potentiometric measurements = are=20 conducted in the conventional manner using a commercially available pH = meter or=20 similar device. Thermostating of samples is desirable. An acceptable = procedure=20 involves placing 10-25 ml of the glutamine-containing sample into the=20 thermostated cell, stirring and thereafter immersing the electrode = probe. A=20 steady potential is normally reached in 5-10 minutes. Calibration curves = are=20 prepared using known standards, and the pH should be held constant = throughout. A=20 pH of about 7.8 is optimal. Between measurements, the electrode is = returned to=20 the buffer solution to stabilize the background potential.

The=20 quantitative relationship of sensed potential to NH.sub.3 concentration = is=20 expressed by the following equation:

where

E=3Dthe = sensed=20 potential in mV, and

E.sub.o =3Dthe background (buffer = potential)=20

As shown in FIG. 2, the electrode probe hereinbefore described = can=20 measure glutamine over the concentration range of at least 10.sup.-2 to=20 5.times.10.sup.-5 molar with response slopes of approximately 53 mV per = 10-fold=20 concentration change. When prepared from fresh pork kidney, the = electrode=20 displays good selectivity for glutamine over other amino acids and over=20 substances such as urea.

As another example, an arginine sensing = electrode was prepared using a beef liver slice as the tissue layer 10. = This=20 electrode is more complex than the glutamine electrode because the beef = liver=20 enzyme arginase carries the degradation of arginine only to urea, which = must=20 then be finally degraded to ammonia by supplementation with the enzyme = urease.=20

The arginine electrode is constructed exactly as described for = the=20 glutamine electrode of FIGS. 1A and 1B, except that assembly is = completed with a=20 second dialytic membrane (replacing nylon mesh 11) mounted outboard of = the=20 elements shown in FIG. 1A and interfacing with the test solution. A few = drops of=20 the supplemental enzyme urease are applied to the outward face of the = beef liver=20 tissue and the second dialytic membrane maintains it in place and = against loss=20 to the solution.

We have found that a suitable buffer solution = for the=20 arginine electrode is 0.2 molar tris HCl having a pH of 8.5.

By = way of=20 comparison, parallel electrode experiments were conducted using the = isolated=20 porcine kidney glutaminase enzyme (Sigma, grade VI) known to be = thermally=20 unstable. Small volumes (approx. 15 .mu.l) of enzyme suspension were = immobilized=20 at the surface of the ammonia gas sensing electrode by means of a = dialysis=20 membrane and electrode response toward L-glutamine was evaluated in the = buffer=20 medium.

Freshly prepared enzyme electrodes yielded moderate=20 potentiometric response (e.g., 44 millivolts per tenfold change in = substrate=20 concentration) but lost more than 50% of their activity within two days, = and=20 showed negligible response after four days at room temperature. Thus, it = is=20 clear that the kidney tissue electrode affords a very substantial = improvement in=20 terms of both lifetime and response, over the conventional enzyme = electrode.=20

It is clear that other tissue-based electrodes can be readily = prepared=20 for the concentration determination of yet other specific amino acids = using the=20 teachings of this invention, and no limitations are intended beyond = those of the=20 appended claims.

* * * * *
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