Detection of biological molecules using boronate-based chemical amplification and optical sensors

• US 6,750,311 B1
• Filed: 12/14/1999
• Issued: 06/15/2004
• Est. Priority Date: 11/21/1996
• Status: Expired due to Term

• Current Assignee: Lawrence Livermore National Security LLC (Government of the United States of America)
• Original Assignee: Minimed, Inc. (Medtronic Plc), Regents of the University of California (University of California)
• Inventors: Harder, Jennifer, Peyser, Thomas A., Satcher, Joe H. Jr., Lane, Stephen M., Mastrototaro, John Joseph, Van Antwerp, William Peter, Darrow, Christopher B.
• Primary Examiner(s): COONEY, JOHN M
• Application Number:
  US09/461,627
• Time in Patent Office: 1,645 Days
• Field of Search: 528/77, 528/85, 427/2.12, 427/58, 428/423.1, 428/426
• US Class Current: 528/77
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: Y10T 428/31551 Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]

Abstract

Methods are provided for the determination of the concentration of biological levels of polyhydroxylated compounds, particularly glucose. The methods utilize an amplification system that is an analyte transducer immobilized in a polymeric matrix, where the system is implantable and biocompatible. Upon interrogation by an optical system, the amplification system produces a signal capable of detection external to the skin of the patient. Quantitation of the analyte of interest is achieved by measurement of the emitted signal.

Claims

1. A method of preparing a biocompatible polymer matrix for immobilizing a compound of the formula

wherein:

D¹ is a dye selected from the group consisting of fluorescent dyes, luminescent dyes and calorimetric dyes;

R¹, R³ and R⁴ are each independently substituents which alter the electrode properties of the groups to which they are attached or are functional groups which can form covalent linkages to the surrounding polymer matrix;

each R² is a member independently selected from the group consisting of hydrogen or C₁-C₄ alkyl;

each L¹ and L² is a linking group having from zero to four contiguous atoms selected from the group consisting of carbon, oxygen, nitrogen, sulfur and phosphorus;

Z is a heteroatom selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus; and

x is an integer from zero to four, said method comprising;

admixing the compound of Formula I with a diisocyanate and a hydrophilic polymer, wherein said hydrophilic polymer is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, wherein said diisocyanate comprises about 50 mol % of the reactants in said admixture to form said biocompatible polymer matrix.

2. A method in accordance with claim 1, wherein said biocompatible polymer matrix further comprises an outer hydrogel coating.

3. A method in accordance with claim 2, wherein said hydrogel coating is made by:

admixing a diisocyanate, a hydrophilic polymer, wherein said hydrophilic polymer is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, and, optionally, adding a chain extender, wherein said diisocyanate comprises about 50 mol % of the reactants in said admixture to form said biocompatible polymer matrix with a hydrogel coating, said hydrogel having a water pickup of from about 120% to about 400% by weight.

4. A method in accordance with claim 1, further comprising admixing a siloxane polymer having amino, hydroxyl or carboxylic acid functional groups at the chain termini.

5. A biocompatible polymer matrix comprising a compound of the formula

wherein:

D¹ is a dye selected from the group consisting of fluorescent dyes, luminescent dyes and colorimetric dyes;

R¹, R³ and R⁴ are each independently substituents which alter the electronic properties of the groups to which they are attached or are functional groups which can form covalent linkages to the surrounding polymer matrix;

each R² is a member independently selected from the group consisting of hydrogen or C₁-C₄ alkyl;

each L¹ and L² is a linking group having from zero to four contiguous atoms selected from the group consisting of carbon, oxygen, nitrogen, sulfur and phosphorus;

Z is a heteroatom selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus;

and x is an integer from zero to four.

6. A biocompatible polymer matrix in accordance with claim 5, further comprising a permeable coating.

7. A biocompatible polymer matrix in accordance with claim 5, further comprising a chain extender.

8. A biocompatible polymer matrix in accordance with claim 5, wherein said compound of Formula I is immobilized by covalent attachment to said matrix.

9. A biocompatible polymer matrix in accordance with claim 5, wherein said polymer matrix is a member of the group selected from a polyurethane polymer, an acrylate polymer, a hydrogel polymer, a silicon-containing polymer and mixtures thereof.

10. A biocompatible polymer matrix in accordance with claim 9, wherein said acrylate polymer is poly-hydroxymethylacrylate (P-HEMA).

11. A biocompatible polymer matrix in accordance with claim 6, wherein said permeate coating is a member selected from the group consisting of hydrogel, cellulose, acetate, poly-hydroxymethylacrylate (P-HEMA), nafion, and glutaraldehyde.

12. A biocompatible polymer matrix in accordance with claim 9, wherein said silicone-containing polymer is a siloxane.

13. A biocompatible polymer matrix in accordance with claim 5, wherein said polymer matrix is formed by reacting (a) a diisocyanate and (b) a hydrophilic polymer.