System and method for determining an in vivo concentration of a small molecule substance of interest in a noninvasive manner

• US 9,883,823 B2
• Filed: 02/04/2013
• Issued: 02/06/2018
• Est. Priority Date: 02/03/2012
• Status: Active Grant

• Current Assignee: University of Maryland Baltimore County (University of Maryland)
• Original Assignee: University of Maryland Baltimore County (University of Maryland)
• Inventors: Tolosa, Leah, Ge, Xudong, Kostov, Yordan, Tolosa, Michael, Rao, Govind
• Primary Examiner(s): Agahi, Puya
• Application Number:
  US13/758,867
• Publication Number:
  US 20130253295A1
• Time in Patent Office: 1,828 Days
• CPC Class Codes: A61B 10/0045 Devices for taking samples of body liquids devices for taking blood samples A61B5/15
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/15 Devices for taking samples of blood hypodermic syringes A61M5/178
• CPC Class Codes: A61B 5/150343 Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes sampling from within body cavities A61B5/150015, A61B5/150045
• CPC Class Codes: B01L 2300/0663 Whole sensors
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 3/5029 using swabs
• CPC Class Codes: G01N 33/542 with steric inhibition or signal modification, e.g. fluorescent quenching

Abstract

Systems and methods for determining an in vivo concentration of a small molecule substance of interest is provided that takes advantage of the semi-permeable nature of skin, which allows small molecules to passively diffuse through the skin and onto the skin surface. The systems and methods of the present invention allow for the collection of these small molecules that have passively diffused through the skin without skin disruption or breaking of the skin. The systems and methods of the present invention are noninvasive, painless and safe even for delicate newborns, and are particularly suited for the determination of blood glucose in newborns and infants in a noninvasive manner.

Claims

1. A method of determining blood glucose in a subject, comprising:

placing a glucose collector in contact with an area of the skin of the subject, wherein the glucose collector is adapted to collect glucose that has passively diffused through the skin of the subject (“

skin glucose”

);

maintaining the glucose collector in contact with the skin area for a predetermined time that is sufficient to collect at least some of the skin glucose;

measuring a concentration of the skin glucose collected by the glucose collector with a glucose detector that is adapted to measure the skin glucose collected by the glucose collector, wherein the glucose detector comprises a glucose binding protein sensor; and

extrapolating blood glucose concentration in the subject based on a correlation between the blood glucose concentration in the subject and the measured skin glucose concentrations;

wherein the glucose collector comprises a swab moistened with buffer solution, and wherein measuring a concentration of skin glucose on the swab with a glucose detector comprises,

submerging the swab containing skin glucose in a buffer solution for a predetermined time that is sufficient to transfer at least some of the skin glucose from the swab to the buffer solution,

placing the at least some of the skin glucose containing buffer solution in contact with the glucose binding protein sensor,

measuring the fluorescence response of the glucose binding protein sensor after it has come into contact with the skin glucose containing buffer solution, and

calculating a skin glucose concentration value based on the fluorescence response of the glucose binding protein sensor.

2. The method of claim 1, wherein the swab is pressed against the skin for the predetermined time.

3. The method of claim 1, further comprising washing the skin area for a predetermined period of time prior to placing the collector in contact with the skin area.

4. The method of claim 1, wherein the glucose binding protein sensor comprises a signal transducing fluorophore and a reference fluorophore.

5. The method of claim 4, wherein the glucose binding protein sensor is immobilized on Sepharose beads.

6. The method of claim 4, wherein the signal transducing fluorophore comprises acrylodan and the reference fluorophore comprises a ruthenium metal ligand complex or a europium metal ligand complex.

7. The method of claim 1, wherein the fluorescence response of the glucose binding protein sensor is determined with a fluorimeter.

8. The method of claim 7, wherein the fluorimeter is adapted to perform lifetime assisted ratiometric sensing.

9. The method of claim 1, wherein the swab comprises:

a housing;

a recess formed in the housing; and

a glucose absorbing material positioned in the recess such that when the swab is pressed against the skin the glucose absorbing material comes in contact with the skin.

10. The method of claim 9, wherein the housing comprises a pliable plastic housing.

11. The method of claim 1, wherein the swab containing skin glucose is submerged in buffer solution by placing the swab in a vessel that contains the buffer solution.

12. The method of claim 11, wherein the vessel comprises:

a reservoir for holding the buffer solution; and

a flexible septum attached to the reservoir and adapted to receive a syringe for withdrawing a sample of the buffer solution.

13. The method of claim 1, wherein the glucose detector comprises a microfluidic chip.

14. The method of claim 13, wherein the microfluidic chip comprises:

a substrate; and

a reservoir positioned on the substrate adapted to hold the buffer solution and to receive the swab such that the swab is immersed in the buffer solution;

at least one sensor well formed on the substrate that is fluidly coupled to the reservoir, wherein the sensor well is adapted to hold the glucose binding protein sensor.

15. The method of claim 14, wherein the glucose binding protein sensor comprises a signal transducing fluorophore and a reference fluorophore.

16. The method of claim 15, wherein the glucose binding protein sensor is immobilized on Sepharose beads.