Process for the manufacture of wholly microfabricated biosensors
First Claim
1. A method of establishing a dispensed layer onto a substantially planar surface comprising:
- (a) preparing a fluid composition suitable for loading into a microsyringe assembly;
(b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of a predetermined volume on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of a substantially planar surface;
(c) treating said surface under conditions sufficient to bring its surface free energy, in terms of its hydrophilicity or hydrophobicity, within a desired range such that the contact angle and thickness of the dispensed fluid composition are controlled;
(d) contacting said droplet on said needle tip with a preselected area of said surface; and
(e) retracting said assembly away from said surface such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition having predictable and reproducible dimensions on said surface.
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Abstract
An efficient method for the microfabrication of electronic devices which have been adapted for the analyses of biologically significant analyte species is described. The techniques of the present invention allow for close control over the dimensional features of the various components and layers established on a suitable substrate. Such control extends to those parts of the devices which incorporate the biological components which enable these devices to function as biological sensors. The materials and methods disclosed herein thus provide an effective means for the mass production of uniform wholly microfabricated biosensors. Various embodiments of the devices themselves are described herein which are especially suited for real time analyses of biological samples in a clinical setting. In particular, the present invention describes assays which can be performed using certain ligand/ligand receptor-based biosensor embodiments. The present invention also discloses a novel method for the electrochemical detection of particular analyte species of biological and physiological significance using an substrate/label signal generating pair which produces a change in the concentration of electroactive species selected from the group consisting of dioxygen and hydrogen peroxide.
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Citations
63 Claims
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1. A method of establishing a dispensed layer onto a substantially planar surface comprising:
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(a) preparing a fluid composition suitable for loading into a microsyringe assembly; (b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of a predetermined volume on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of a substantially planar surface; (c) treating said surface under conditions sufficient to bring its surface free energy, in terms of its hydrophilicity or hydrophobicity, within a desired range such that the contact angle and thickness of the dispensed fluid composition are controlled; (d) contacting said droplet on said needle tip with a preselected area of said surface; and (e) retracting said assembly away from said surface such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition having predictable and reproducible dimensions on said surface. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)
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59. A method of establishing a dispensed layer which is sensitive to potassium ion onto a silver-silver chloride planar base sensor comprising:
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(a) preparing a fluid composition suitable for loading into a microsyringe assembly, said fluid composition, comprising N-methylpyrrolidone, propiophenone, cyclohexanone, bis(2-ethylhexyl)sebacate, poly(vinyl chloride) and valinomycin, in an amount sufficient to function as a potassium ion sensor; (b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of about ten nanoliters on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of said base sensor; (c) treating said base sensor first with an argon plasma and, subsequently, with a carbon tetrafluoride plasma under conditions sufficient to bring its surface free energy within a desired hydrophilic range; (d) contacting said droplet on said needle tip with a preselected area of said base sensor; and (e) retracting said assembly away from said base sensor such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition which is sensitive to potassium ion and having a thickness falling in the range of about 20-60 microns.
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60. A method of establishing a dispensed layer which is sensitive to sodium ion onto a silver-silver chloride planar base sensor comprising:
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(a) preparing a fluid composition suitable for loading into a microsyringe assembly, said fluid composition, comprising N-methylpyrrolidone, propiophenone, Tris-(2-ethylhexyl) phosphate, cyclohexanone, poly(vinyl chloride) and methyl monensin, in an amount sufficient to function as a sodium sensor; (b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of about ten nanoliters on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of said base sensor; (c) treating said base sensor first with an argon plasma and, subsequently, with a carbon tetrafluoride plasma under conditions sufficient to bring its surface free energy within a desired hydrophilic range; (d) contacting said droplet on said needle tip with a preselected area of said base sensor; and (e) retracting said assembly away from said base sensor such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition which is sensitive to sodium ion and having a thickness falling in the range of about 20-40 microns.
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61. A method of establishing a dispensed layer which is sensitive to chloride ion onto a silver-silver chloride planar base sensor comprising:
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(a) preparing a fluid composition suitable for loading into a microsyringe assembly, said fluid composition, comprising propiophenone, cyclohexanone, 5-phenyl-1-pentanone, poly(vinyl chloride), tridodecylmethylammonium chloride and kemamine BQ-9702C fatty amine, in an amount sufficient to function as a chloride sensor; (b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of about ten nanoliters on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of said base sensor; (c) treating said base sensor first with an argon plasma and, subsequently, with a carbon tetrafluoride plasma under conditions sufficient to bring its surface free energy within a desired hydrophilic range; (d) contacting said droplet on said needle tip with a preselected area of said base sensor; and (e) retracting said assembly away from said base sensor such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition which is sensitive to chloride ion and having a thickness falling in the range of about 20-60 microns.
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62. A method of establishing a dispensed layer which is sensitive to ammonium ion onto a planar silver-silver chloride base sensor comprising:
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(a) preparing a fluid composition suitable for loading into a microsyringe assembly, said fluid composition, comprising N-methylpyrrolidone, propiophenone, cyclohexanone, Tris-(2 ethylhexyl)phosphate, poly(vinyl chloride) and nonactin, in an amount sufficient to function as an ammonium ion sensor; (b) loading said fluid composition into said microsyringe assembly, which assembly comprises (i) a reservoir for holding said fluid composition, (ii) a microsyringe needle, including an elongated member and a needle tip, (iii) means for delivering said fluid composition from said reservoir to said microsyringe needle, (iv) means for forcing controlled amounts of said fluid composition through said elongated member to form an emerging droplet of about ten nanoliters on said needle tip, and (v) means for controlling the multidirectional movement of said assembly such that said droplet may be brought into contact with a preselected area of said base sensor; (c) treating said base sensor first with an argon plasma and, subsequently, with a carbon tetrafluoride plasma under conditions sufficient to bring its surface free energy within a desired hydrophilic range; (d) contacting said droplet on said needle tip with a pressletted area of said base sensor; and (e) retracting said assembly away from said base sensor such that said droplet disengages from said needle tip in a manner that provides a dispensed layer of said fluid composition which is sensitive to ammonium ion and having a thickness falling in the range of about 10-20 microns. - View Dependent Claims (63)
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Specification