IP Library › Granted Patent US 10,156,573

Granted Patent B2

US 10,156,573 · App. 14/210,357 · Granted Dec 18, 2018

Tri-color dual glucose and oxygen sensors and methods of preparing and using them

Inventors: Yanqing Tian (Tempe, AZ); Liqiang Zhang (Chandler, AZ); Fengyu Su (Tempe, AZ); Deirdre Meldrum (Phoenix, AZ); Sean Buizer (Tempe, AZ)

Assignee: Arizona Board of Regents, a body corporate of the State of Arizona, acting for and on behalf of Arizona State University

G01N33/66 G01N21/6486 G01N33/582 C12Q1/54 Y10T436/144444 Y10T436/207497

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Quick Facts

Patent No.: US 10,156,573
App. No.: 14/210,357
Granted: Dec 18, 2018
Kind: B2

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Abstract

The present disclosure relates to an optical fluorescence sensor comprising a probe for sensing glucose, an intra-reference probe, and a matrix. The present disclosure also relates to an optical fluorescence dual sensor comprising a probe for sensing glucose having two boronic acid moieties, a probe for sensing oxygen comprising modified porphyrin, an intra-reference probe that is rhodamine-based, and a matrix. The present disclosure additionally relates to methods of preparing these sensors and methods of using them.

Claims (181)

1. An optical fluorescence sensor comprising:

a probe for sensing glucose, an intra-reference probe and a matrix, wherein

the probe for sensing glucose is prepared from a compound having formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

R 3 is selected from the group consisting of (CH 2 ) n C(O)OH, O(CH 2 ) n C(O)OH, NH(CH 2 ) n C(O)OH, (CH 2 ) n C(O)OR 4 , O(CH 2 ) n C(O)OR 4 , NH(CH 2 ) n C(O)OR 4 , (CH 2 ) n C(O)NH(CH 2 ) n NH-A, O(CH 2 ) n C(O)NH(CH 2 ) n NH-A, NH(CH 2 ) n C(O)NH(CH 2 ) n NH-A, (CH 2 ) n C(O)O(CH 2 ) n NH-A, O(CH 2 ) n C(O)O(CH 2 ) n NH-A, NH(CH 2 ) n C(O)O(CH 2 ) n NH-A, (CH 2 ) n C(O)NH(CH 2 ) n NH-M′A, O(CH 2 ) n C(O)NH(CH 2 ) n NH-M′A, NH(CH 2 ) n C(O)NH(CH 2 ) n NH-M′A, (CH 2 ) n C(O)O(CH 2 ) n NH-M′A, O(CH 2 ) n C(O)O(CH 2 ) n NH-M′A, NH(CH 2 ) n C(O)O(CH 2 ) n NH-M′A, (CH 2 ) n C(O)NH(CH 2 ) n NH-VA, O(CH 2 ) n C(O)NH(CH 2 ) n NH-VA, NH(CH 2 ) n C(O)NH(CH 2 ) n NH-VA, (CH 2 ) n C(O)O(CH 2 ) n NH-VA, O(CH 2 ) n C(O)O(CH 2 ) n NH-VA, and NH(CH 2 ) n C(O)O(CH 2 ) n NH-VA;

n is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

the intra-reference probe is prepared from a compound having formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

Z is selected from the group consisting of: (CH 2 ) p OH, O(CH 2 ) p OH, NH(CH 2 ) p OH, (CH 2 ) p OM′A, O(CH 2 ) p OM′A, NH(CH 2 ) p OM′A, (CH 2 ) p OA, O(CH 2 ) p OA, NH(CH 2 ) p OA, (CH 2 ) p OVA, O(CH 2 ) p OVA, NH(CH 2 ) p OVA, (OCH 2 CH 2 ) q OH, NH(CH 2 CH 2 O) q H, (OCH 2 CH 2 ) q OM′A, NH(CH 2 CH 2 O) q M′A, (OCH 2 CH 2 ) q OA, NH(CH 2 CH 2 O) q A, (OCH 2 CH 2 ) q OVA, NH(CH 2 CH 2 O) q VA, CH 2 (OCH 2 CH 2 ) r OA, CH 2 (OCH 2 CH 2 ) r OM′A, and CH 2 (OCH 2 CH 2 ) r OVA;

p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

q is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 38, 39, 40, 41, 42, 43, 44, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 and 150; and

r is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 38, 39, 40, 41, 42, 43, 44, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 and 150; and

the matrix is prepared from a monomer selected from the group consisting of acrylamide, N-(6-aminohexyl) methacrylamide, poly(ethylene glycol) dimethacrylate, methoxy-poly(ethylene glycol) methacrylate, 2-hydroxyethyl methacrylate and combinations thereof

wherein the probe for sensing glucose and the intra-reference probe are attached to or immobilized in the matrix.

2. The optical fluorescence sensor according to claim 1 , wherein the compound of formula I is:

or an activated ester thereof.

3. The optical fluorescence sensor according to claim 1 , wherein the compound of formula III is:

4. An optical fluorescence dual sensor comprising:

a probe for sensing glucose, a probe for sensing oxygen, an intra-reference probe and a matrix, wherein

the probe for sensing glucose is prepared from a compound having formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

R 3 is selected from the group consisting of (CH 2 ) m C(O)OH, O(CH 2 ) m C(O)OH, NH(CH 2 ) m C(O)OH, (CH 2 ) m C(O)OR 4 , O(CH 2 ) m C(O)OR 4 , NH(CH 2 ) m C(O)OR 4 , (CH 2 ) m C(O)NH(CH 2 ) m NH-A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-A, (CH 2 ) m C(O)O(CH 2 ) m NH-A, O(CH 2 ) m C(O)O(CH 2 ) m NH-A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-A (CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, (CH 2 ) m C(O)O(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, (CH 2 ) m C(O)NH(CH 2 ) m NH-VA, O(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, (CH 2 ) m C(O)O(CH 2 ) m NH-VA, O(CH 2 ) m C(O)O(CH 2 ) m NH-VA, and NH(CH 2 ) m C(O)O(CH 2 ) m NH-VA;

m is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

the probe for sensing oxygen is prepared from a compound having formula II:

wherein M is selected from Pt or Pd;

R 11 and R 12 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 13 and R 14 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 5 and R 6 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 7 , R 8 , R 9 and R 10 can be the same or different and are independently selected from the group consisting of (CH 2 ) p OH, O(CH 2 ) p OH, NH(CH 2 ) p OH, (CH 2 ) p OM′A, O(CH 2 ) p OM′A, NH(CH 2 ) p OM′A, (CH 2 ) p OA, O(CH 2 ) p OA, NH(CH 2 ) p OA, (CH 2 ) p OVA, O(CH 2 ) p OVA, NH(CH 2 ) p OVA, (OCH 2 CH 2 ) q OH, NH(CH 2 CH 2 O) q H, (OCH 2 CH 2 ) q OM′A, NH(CH 2 CH 2 O) q M′A, (OCH 2 CH 2 ) q OA, NH(CH 2 CH 2 O) q A, (OCH 2 CH 2 ) q OVA, and NH(CH 2 CH 2 O) q VA, where

p is an integer selected from the group of consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

the intra-reference probe is prepared from a compound having formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

p is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

the matrix comprising is prepared from a polymer monomer selected from the group consisting of acrylamide, 6-aminohexyl methacrylamide, and poly(ethylene glycol) dimethacrylate, methoxy-poly(ethylene glycol) methacrylate, 2-hydroxyethyl methacrylate and combinations thereof;

wherein the probe for sensing glucose, the probe for sensing oxygen and the intra-reference probe are attached to or immobilized in the matrix.

5. The optical fluorescence dual sensor according to claim 4 , wherein the compound of formula I is:

or an activated ester thereof.

6. The optical fluorescence dual sensor according to claim 4 , wherein the compound of formula II is:

wherein X′ is

7. The optical fluorescence dual sensor according to claim 4 , wherein the compound of formula III is:

8. A method of preparing an optical fluorescence sensor comprising the steps of:

(a) copolymerizing an intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide onto a modified substrate; and

(b) attaching or immobilizing a probe for sensing glucose onto the substrate;

wherein the probe for sensing glucose has formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

n is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

and the intra-reference probe has formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

p is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

9. The method according to claim 8 , wherein copolymerizing the intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide forms poly(2-hydroxyethyl methacrylate), poly(N-(6-aminohexyl) methacrylamide), poly(acrylamide), poly(2-hydroxyethyl methacrylate)-co-polyacrylamide-co-poly(N-(6-aminohexyl) methacrylamide) and their composites with the polymerized intra-reference probe.

10. A method of preparing an optical fluorescence sensor comprising the step of:

copolymerizing a probe for sensing glucose and an intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide onto a modified substrate;

wherein the probe for sensing glucose has formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

n is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

and the intra-reference probe has formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

p is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

11. The method according to claim 9 , wherein copolymerizing the probe for sensing glucose and the intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide forms poly(2-hydroxyethyl methacrylate), poly(N-(6-aminohexyl) methacrylamide), poly(acrylamide), poly(2-hydroxyethyl methacrylate)-co-polyacrylamide-co-poly(N-(6-aminohexyl) methacrylamide) and their composites with the polymerized probe for sensing glucose and the polymerized intra-reference probe.

12. A method of preparing an optical fluorescence dual sensor comprising the steps of:

(a) copolymerizing a probe for sensing oxygen and an intra-reference probe, with poly(2-hydroxyethyl methacrylate), polyacrylamide, and poly(2-hydroxyethyl methacrylate)-co-polyacrylamide onto a modified substrate; and

(b) attaching or immobilizing a probe for sensing glucose onto the substrate;

wherein the probe for sensing glucose has formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

R 3 is selected from the group consisting of (CH 2 ) m C(O)OH, O(CH 2 ) m C(O)OH, NH(CH 2 ) m C(O)OH, (CH 2 ) m C(O)OR 4 , O(CH 2 ) m C(O)OR 4 , NH(CH 2 ) m C(O)OR 4 , (CH 2 ) m C(O)NH(CH 2 ) m NH-A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-A, (CH 2 ) m C(O)O(CH 2 ) m NH-A, O(CH 2 ) m C(O)O(CH 2 ) m NH-A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-A, (CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, (CH 2 ) m C(O)O(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, (CH 2 ) m C(O)NH(CH 2 ) m NH-VA, O(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, (CH 2 ) m C(O)O(CH 2 ) m NH-VA, O(CH 2 ) m C(O)O(CH 2 ) m NH-VA, and NH(CH 2 ) m C(O)O(CH 2 ) m NH-VA;

m is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

the probe for sensing oxygen has formula II:

wherein M is selected from Pt or Pd;

R 11 and R 12 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 13 and R 14 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 5 and R 6 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

where

p is an integer selected from the group of consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

and the intra-reference probe has formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

p is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

13. A method of preparing an optical fluorescence dual sensor comprising the step of:

copolymerizing a probe for sensing glucose, a probe for sensing oxygen and an intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide onto a modified substrate;

wherein the probe for sensing glucose has formula I:

wherein R 1 and R 2 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

R 3 is selected from the group consisting of (CH 2 ) m C(O)OH, O(CH 2 ) m C(O)OH, NH(CH 2 ) m C(O)OH, (CH 2 ) m C(O)OR 4 , O(CH 2 ) m C(O)OR 4 , NH(CH 2 ) m C(O)OR 4 , (CH 2 ) m C(O)NH(CH 2 ) m NH-A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-A, (CH 2 ) m C(O)O(CH 2 ) m NH-A, O(CH 2 ) m C(O)O(CH 2 ) m NH-A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-A, (CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-M′A, (CH 2 ) m C(O)O(CH 2 ) m NH-M′A, O(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, NH(CH 2 ) m C(O)O(CH 2 ) m NH-M′A, (CH 2 ) m C(O)NH(CH 2 ) m NH-VA, O(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, NH(CH 2 ) m C(O)NH(CH 2 ) m NH-VA, (CH 2 ) m C(O)O(CH 2 ) m NH-VA, O(CH 2 ) m C(O)O(CH 2 ) m NH-VA, and NH(CH 2 ) m C(O)O(CH 2 ) m NH-VA;

m is an integer selected from the group of consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

R 4 is an activating group;

M′A is

A is

and

VA is

the probe for sensing oxygen has formula II:

wherein M is selected from Pt or Pd;

R 11 and R 12 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 13 and R 14 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

R 5 and R 6 can be the same or different and are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 and OC 2 H 5 ;

where

p is an integer selected from the group of consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

and the intra-reference probe has formula III:

wherein R 15 , R 16 , R 17 , and R 18 can be the same or different and are C n H 2n+1 , where n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

X is an anion; and

p is an integer selected from the group of consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

14. The method according to claim 13 , wherein copolymerizing the probe for sensing glucose, the probe for sensing oxygen and the intra-reference probe, with 2-hydroxyethyl methacrylate, N-(6-aminohexyl) methacrylamide, and acrylamide forms poly(2-hydroxyethyl methacrylate), poly(N-(6-aminohexyl) methacrylamide), poly(acrylamide), poly(2-hydroxyethyl methacrylate)-co-polyacrylamide-co-poly(N-(6-aminohexyl) methacrylamide) and their composites with the polymerized probe for sensing glucose, the polymerized probe for sensing oxygen and the polymerized intra-reference probe.

15. The method according to claim 8 or 12 , wherein the probe for sensing glucose is:

or an activated ester thereof.

16. The method according to claim 12 or 13 , wherein the probe for sensing oxygen is:

wherein X′ is

17. The method according to any one of claims 8 to 13 , wherein the intra-reference probe is:

18. A method of determining the concentration of glucose in a sample comprising:

(a) exposing the sample to an optical fluorescence sensor according to claim 1 or an optical fluorescence dual sensor according to claim 4 ;

(b) irradiating the sensor at a first wavelength to produce a glucose indicator emission signal at a second wavelength and an intra-reference emission signal at a third wavelength;

(d) measuring the intra-reference emission signal at the third emission wavelength; and

(e) ratiometrically determining the concentration of glucose in the sample.

19. The method according to claim 18 , wherein more than one sample is used.

20. The method according to claim 18 , wherein the sample comprises a bodily fluid.

21. The method according to claim 20 , wherein the bodily fluid comprises blood.

22. The method according to claim 18 , wherein the sample is obtained from a cell culture or a subject.

23. The method according to claim 18 , wherein the sample is selected from the group consisting of live single cells, live several cells, live cell clusters, and live tissue.

24. A method of determining the concentration of oxygen in a sample comprising:

(a) exposing the sample to an optical fluorescence dual sensor according to claim 4 ;

(b) irradiating the sensor at a first wavelength to produce an oxygen indicator emission signal at a second wavelength and an intra-reference emission signal at a third wavelength;

(d) measuring the intra-reference emission signal at the third wavelength; and

(e) ratiometrically determining the oxygen concentration in the sample.

25. A method of simultaneously determining the concentration of glucose and the concentration of oxygen in a sample comprising

(a) exposing the sample to an optical fluorescence dual sensor according to claim 4 ;

(b) irradiating the sensor at a first wavelength to produce a glucose indicator emission signal at a second wavelength, an oxygen indicator emission signal at a third wavelength and an intra-reference emission signal at a fourth wavelength;

(d) measuring the oxygen indicator emission signal at the third wavelength;

(e) measuring the intra-reference emission signal at the fourth wavelength;

(f) ratiometrically determining the concentration of glucose in the sample using the measurements obtained in steps (c) and (e); and

(g) ratiometrically determining the oxygen concentration in the sample using the measurements obtained in steps (d) and (e).

Assignments (2)

CONFIRMATORY LICENSE Recorded Dec 7, 2017

From: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 044753/0365 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2014

From: TIAN, YANQING; ZHANG, LIQIANG; SU, FENGYU; MELDRUM, DEIRDRE; BUIZER, SEAN

To: ARIZONA BOARD OF REGENTS

Reel/Frame 032996/0101 →

Continuity (2)

Provisional Application 61786046 · Mar 14, 2013

Related Publication 20140273043A1 · Sep 18, 2014

Cited By (1)

US 12,285,250