Analyte sensor and method of manufacturing an analyte sensor

文档序号：1617737 发布日期：2020-01-10 浏览：22次中文

阅读说明：本技术 分析物传感器和制造分析物传感器的方法 (Analyte sensor and method of manufacturing an analyte sensor ) 是由特洛伊·M·布雷默丹尼尔·A·巴塞洛缪斯于 2018-02-28 设计创作，主要内容包括：一种制造层压结构的方法,包括以下步骤：提供波导结构,所述波导结构具有多个波导芯并且包括第一表面；在所述波导结构的所述第一表面中产生氧气感测聚合物腔体以接收氧气感测聚合物；用所述氧气感测聚合物填充所述氧气感测聚合物腔体并使所述氧气感测聚合物固化；在所述波导结构的所述第一表面的顶部上添加第一层材料,其中所述第一层材料包括与所述氧气感测聚合物相连的反应室腔体；用酶促水凝胶填充所述反应室腔体并使所述酶促水凝胶固化；在所述第一层材料的顶部上添加第二层材料,其中所述第二层材料包括导管腔体以接收导管水凝胶；用导管水凝胶填充所述导管腔体并使所述导管水凝胶固化；以及在所述第二层材料的顶部上添加顶盖。(A method of manufacturing a laminated structure comprising the steps of: providing a waveguide structure having a plurality of waveguide cores and comprising a first surface; creating an oxygen-sensing polymer cavity in the first surface of the waveguide structure to receive an oxygen-sensing polymer; filling the oxygen sensing polymer cavity with the oxygen sensing polymer and curing the oxygen sensing polymer; adding a first layer of material on top of the first surface of the waveguide structure, wherein the first layer of material comprises a reaction chamber cavity in communication with the oxygen-sensing polymer; filling the reaction chamber cavity with an enzymatic hydrogel and allowing the enzymatic hydrogel to solidify; adding a second layer of material on top of the first layer of material, wherein the second layer of material comprises a catheter lumen to receive a catheter hydrogel; filling the catheter lumen with a catheter hydrogel and allowing the catheter hydrogel to cure; and adding a top cap on top of the second layer of material.)

1. A dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution that forms a hydrogel upon curing, the dispensable, heat-curable, reversible oxygen-binding molecule-albumin nanogel comprising: a reversible oxygen-binding molecule-albumin nanoparticle, wherein the reversible oxygen-binding molecule and the construct albumin are interconnected by a bifunctional linker, wherein the reversible oxygen-binding molecule-albumin nanoparticle is coupled to poly (ethylene glycol) (PEG) by a sulfur bond, and wherein the reversible oxygen-binding molecule-albumin nanoparticle is functionalized to the nanogel matrix by a PEG-based linker.

2. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of claim 1, wherein the reversible oxygen-binding molecule-albumin nanoparticles and the PEG-based linker of the nanogel are represented by formula (I):

wherein the bifunctional linker (L) is a direct link between a homobifunctional linker, a heterobifunctional linker, or a reversible oxygen-binding molecule and albumin. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of claim 1, wherein the homo-or hetero-bifunctional linker (L) is selected from the group consisting of: amino acids, peptides, nucleotides, nucleic acids, organic linker molecules, disulfide linkers, and polymer linkers.

3. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of claim 1, wherein the reversible oxygen-binding molecule-albumin nanoparticles and the PG-based linker are represented by one of:

wherein R is¹、R²、R³And R⁴Independently selected from the group consisting of: -CH₂-、-CF₂-、-(CH(R-OH)-、-(CH₂O)CH₂-、-(CF₂CF₂O)-CF₂CF₂-、-(CH₂CH₂CH₂O)-CH₂CH₂CH₂、-(CF₂CF₂CF₂O)-CF₂CF₂CF₂And a is an integer ranging from 0 to 1000.

4. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of claim 1, wherein the reversible oxygen-binding molecule-albumin nanoparticles and the PG-based linker are represented by formula (Ia); wherein a is an integer of 1 to 20.

5. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1-8, wherein the reversible oxygen-binding molecule-albumin nanoparticles and the PEG-based linker of the nanogel are represented by formula (II):

wherein c is selected from the group consisting of-C (O) (CH)₂)_p-and-N ═ CH (CH)₂)_p-and p is an integer ranging from 1 to 10;

d is- (CH)_2-)_q-, wherein q is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 1000; and is

R⁵Is selected from the group consisting of-C_1-4Alkyl and H.

6. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1-9, wherein the reversible oxygen-binding molecule-albumin nanogel comprises:

wherein e is an integer ranging from 1 to 10; and is

R⁵Is selected from the group consisting of-C_1-4Alkyl and H.

7. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1-10, wherein the heat-curable, reversible oxygen-binding molecule nanoparticle solution further comprises a diacrylate monomer.

8. The dispensable, curable, reversible oxygen binding molecule-albumin nanogel solution of claim 11, wherein the diacrylate monomer is represented by the formula:

wherein e is an integer ranging from 1 to 10; and is

Wherein R is⁵Is selected from the group consisting of-C_1-4Alkyl and H.

9. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of claim 12, wherein R is ⁵is-CH₃And e is 1.

10. The dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1-13, wherein the dispensable, heat-curable, reversible oxygen-binding molecule nanoparticle solution has a viscosity of less than about 1000 cP.

11. The dispensable curable reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1 to 14 wherein the solution is characterized as capable of passing through a 20g needle using less than 60N pressure.

12. The dispensable curable reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1 to 15, wherein the reversible oxygen-binding molecule is selected from the group consisting of: hemoglobin, myoglobin, hemocyanin, heme protein, neurospher, cytoglobin, leghemoglobin, or combinations thereof.

13. The dispensable curable reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 1-16 wherein the reversible oxygen-binding molecule-albumin nanogel is cured using UV light, a UV initiator, a thermal initiator, or a combination thereof.

14. A method of preparing a dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution, the method comprising:

forming a reversible oxygen-binding molecule-albumin nanoparticle of formula (I) by covalently linking a reversible oxygen-binding molecule with albumin by incubation with a bifunctional linker;

thiolating the reversible oxygen-binding molecule-albumin nanoparticles with a thiolating agent;

conjugating the thiolated, reversible oxygen-binding molecule-albumin nanoparticle using maleimide poly (ethylene glycol) -methacrylate (PEG-MA); and

crosslinking the pegylated reversible oxygen-binding molecule-albumin nanoparticles with a first diacrylate crosslinker to form the dispensable, heat-curable, reversible oxygen-binding molecule-albumin nanogel solution.

15. The method of claim 18, wherein reversible oxygen-binding molecule-albumin nanoparticle crosslinking is performed at a low temperature and low oxygen concentration at a pH between about 7.0 and about 8.0 for at least about 1 hour to 24 hours.

16. The method of claim 18 or 19, further comprising adding a second crosslinking agent to the crosslinked nanogel solution.

17. A method of making a crosslinked reversible oxygen-binding molecule based material, the method comprising exposing the dispensable, curable reversible oxygen-binding molecule nanogel solution of any one of claims 18-20 to UV light, a free radical initiator, a thermal initiator, or a combination thereof.

18. A crosslinked oxygen-binding molecule-based material prepared by exposing the dispensable, curable, reversible oxygen-binding molecule-albumin nanogel solution of any one of claims 18-21 to UV light, a free radical initiator, a thermal initiator, or a combination thereof.

19. A material based on crosslinked reversible oxygen-binding molecules comprising:

a hydrogel matrix; and

a reversible oxygen-binding molecule-albumin nanoparticle having an albumin molecule covalently linked to at least one reversible oxygen-binding molecule by a bifunctional linker of formula (I);

wherein the reversible oxygen-binding molecule-albumin nanoparticles are pegylated; and is

Wherein the reversible oxygen-binding molecule-albumin nanoparticles are functionalized to the hydrogel matrix by a PEG-based linker.

20. The crosslinked reversible oxygen-binding molecule based material of claim 23, wherein the reversible oxygen-binding molecule-albumin nanoparticle and the PEG-based linker are represented by one of the following structures:

21. The crosslinked reversible oxygen-binding molecule-based material of claim 23, wherein the hemoglobin-albumin nanoparticle and the PEG-based linker are represented by the following structures:

wherein a is an integer of 1 to 20.

22. The crosslinked reversible oxygen-binding molecule based material of any one of claims 23-25, wherein the reversible oxygen-binding molecule-albumin nanoparticle is further represented by formula (III):

wherein c is selected from the group consisting of-C (O) (CH)₂)_p-and-N ═ CH (CH)₂)_p-a group of compositions; p is an integer in the range of 1 to 10;

d is- (CH)_2-)_q-, wherein q is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 1000; and is

R⁵Is selected from the group consisting of-C_1-4Alkyl and H.

23. The crosslinked reversible oxygen-binding molecule based material of any one of claims 23 to 26, wherein the reversible oxygen-binding molecule-albumin nanoparticle comprises a ratio of reversible oxygen-binding molecules to albumin of at least about 1: 1.

24. The crosslinked reversible oxygen-binding molecule-based material of any one of claims 23-27, wherein the hydrogel matrix comprises:

wherein e is an integer ranging from 1 to 10; and is

Wherein R is⁵Is selected from the group consisting of-C_1-4Alkyl and H.

25. The crosslinked reversible oxygen-binding molecule-based material of any one of claims 23-28, wherein the hydrogel matrix comprises:

26. the crosslinked reversible oxygen-binding molecule based material of any one of claims 23-29, wherein the crosslinked reversible oxygen-binding molecule based material has a storage modulus of at least about 1GPa at a total material concentration of less than about 10 mg/mL.

27. The crosslinked reversible oxygen-binding molecule-based material of any one of claims 23-30, wherein the crosslinked reversible oxygen-binding molecule-based material has a water content of at least about 99% percent.

28. The crosslinked reversible oxygen-binding molecule based material of any one of claims 23-31, wherein the reversible oxygen-binding molecule-albumin nanoparticles comprise at least about 5% of the dry weight of the crosslinked reversible oxygen-binding molecule based material.

29. The crosslinked reversible oxygen-binding molecule-based material of any one of claims 23-32, wherein the reversible oxygen-binding molecule is selected from the group consisting of: hemoglobin, myoglobin, cytoglobin, hemoprotein, neurosglobin, phytoglobin, or a combination thereof.

30. A method of preparing a dispensable, curable enzyme-albumin nanogel solution, the method comprising:

covalently linking an enzyme to albumin by incubating the enzyme with albumin and a bifunctional linker to form an enzyme-albumin nanoparticle of formula (IV));

thiolating the enzyme-albumin nanoparticles with a thiolating agent to form thiolated enzyme-albumin nanoparticles of formula (V);

conjugating the thiolated enzyme-albumin nanoparticle with poly (ethylene glycol) methacrylate to form a pegylated enzyme-albumin nanoparticle of formula (VI);

thiolating the reversible oxygen-binding molecule-albumin nanoparticles with a thiolating agent;

conjugating the thiolated, reversible oxygen-binding molecule-albumin nanoparticles with poly (ethylene glycol) methacrylic acid to form pegylated glucose oxidase-albumin nanoparticles;

mixing the pegylated enzyme-albumin nanoparticles and a first diacrylate to form a pre-nanogel solution;

crosslinking the pre-nanogel solution to form a crosslinked enzymatic nanogel; and

adding the crosslinked enzymatic nanogel to a solution to form the dispensable, heat-curable enzyme-albumin nanogel solution,

wherein the bifunctional linker (L) is a direct linkage between a homobifunctional linker, a heterobifunctional linker, or an enzyme and albumin;

i is selected from the group consisting of-C (O) (CH)₂)_p-and-N ═ CH (CH)₂)_p-a group of compositions; wherein p is an integer ranging from 1 to 10;

j is- (CH)_2-)_q-, wherein q is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 1000; and is

R⁶Is selected from the group consisting of-C_1-4Alkyl and H;

wherein the enzyme is selected from the group consisting of: glucose oxidase, glutamate oxidase, alcohol oxidase, lactate oxidase, ascorbate oxidase, cholesterol oxidase, choline oxidase, laccase and tyrosinase.

31. The dispensable curable enzyme-albumin nanogel solution of claim 34 wherein the homo-or hetero-bifunctional linker (L) is selected from the group consisting of: amino acids, peptides, nucleotides, nucleic acids, organic linker molecules, disulfide linkers, and polymer linkers.

32. The dispensable curable enzyme-albumin nanogel solution of claim 34, wherein the enzyme-albumin nanoparticles are represented by one of:

wherein R is⁷、R⁸、R⁹、R¹⁰Independently selected from the group consisting of: -CH₂-、-CF₂-、-(CH(R-OH)-、-(CH₂O)CH₂-、(CF₂CF₂O)CF₂CF₂-、(CH₂CH₂CH₂O)CH₂CH₂CH₂、(CF₂CF₂CF₂O)CF₂CF₂CF₂And b is an integer ranging from 0 to 1000.

33. The dispensable, curable enzyme-albumin nanogel solution of claim 34, wherein the enzyme-albumin nanoparticle and the PG-based linker are represented by formula (IVa); wherein b is an integer from 1 to 20.

34. The dispensable curable enzyme-albumin nanogel solution of any one of claims 34-37 wherein the enzyme is selected from the group consisting of: glucose oxidase, glutamate oxidase, alcohol oxidase, lactate oxidase, ascorbate oxidase, cholesterol oxidase, choline oxidase, laccase and tyrosinase.

35. The method of claim 34, further comprising covalently linking a catalase enzyme to albumin by incubating the catalase enzyme (CAT) with albumin and a bifunctional linker to form catalase-albumin nanoparticles of formula (VII);

thiolating the catalase-albumin nanoparticles with a thiolating agent to form thiolated catalase-albumin nanoparticles;

conjugating the thiolated catalase-albumin nanoparticles with poly (ethylene glycol) methacrylate to form pegylated catalase-albumin nanoparticles

And

mixing the pegylated catalase-albumin nanoparticles into the pre-nanogel solution;

wherein the bifunctional linker (L) is a direct link between a homobifunctional linker, a heterobifunctional linker, or catalase and albumin;

i is selected from the group consisting of-C (O) (CH)₂)_p-and-N ═ CH (CH)₂)_p-a group of compositions; wherein p is an integer ranging from 1 to 10;

j is- (CH)_2-)_q-, wherein q is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 1000; and is

R⁶Is selected from the group consisting of-C_1-4Alkyl and H.

36. The method of any one of claims 34-39, wherein the solution comprises a second diacrylate.

37. A method of preparing a crosslinked enzyme-based material, the method comprising exposing the dispensable, curable enzyme nanoparticle solution of claim 40 to UV light, a free radical initiator, a thermal initiator, or a combination thereof.

38. A method of preparing a dispensable, curable, enzymatic nanogel solution, the method comprising:

conjugating an enzyme and CAT to albumin by incubating with a bifunctional linker for at least about 24 hours at a low temperature and low oxygen concentration at a pH between about 7.0 and 8.0 to form enzymatic nanoparticles;

adding a thiol group to the nanoparticle to form a thiolated enzymatic nanoparticle;

conjugating the thiolated enzymatic nanoparticle with poly (ethylene glycol) -methacrylate (PEG-MA) to form a pegylated enzymatic nanoparticle; and

crosslinking the pegylated enzymatic nanoparticles with a methacrylate hydrogel monomer to form the dispensable, thermally curable, enzymatic nanogel solution.

39. A dispensable, curable enzyme-albumin nanogel solution configured to form a hydrogel after thermal curing, the enzyme-albumin nanogel comprising:

a nanogel matrix comprising:

wherein e is an integer from 1 to 10, and R⁵Is selected from the group consisting of-C_1-4Alkyl and H;

an enzyme-albumin nanoparticle, wherein the enzyme and albumin are interconnected with a bifunctional linker, wherein the enzyme-albumin nanoparticle is coupled to poly (ethylene glycol) (PEG) through a sulfur bond, and wherein the enzyme-albumin nanoparticle is functionalized to the nanogel matrix through a PEG-based linker; and

40. The dispensable, curable enzyme-albumin nanogel solution of claim 43, further comprising catalase-albumin nanoparticles, wherein catalase and albumin are interconnected by a bifunctional linker, wherein the catalase-albumin nanoparticles are coupled to polyethylene glycol (PEG) through a sulfur bond, and wherein the catalase-albumin nanoparticles are functionalized to the nanogel matrix through a PEG-based linker.

41. The dispensable, curable enzyme-albumin nanogel solution of claim 43 or 44, wherein R is an integer ranging from 4, and wherein R is¹Is H.

42. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 45 wherein the nanogel matrix further comprises:

wherein t is an integer ranging from 1 to 1000; and is

R¹¹Is selected from the group consisting of-C_1-4Alkyl and H.

43. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 46, wherein the nanogel matrix further comprises a diamine represented by:

wherein the diamine is linear, branched, or cyclic; and is

Wherein l is an integer in the range of 1 to 10.

44. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 47 wherein the nanogel matrix comprises:

wherein n is an integer in the range of 1 to 1000.

45. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 48 wherein the nanogel matrix comprises:

wherein the diamine is linear, branched, or cyclic; and is

Wherein l is an integer in the range of 1 to 10.

46. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 49 wherein the nanogel matrix comprises:

wherein n is an integer ranging from 1 to 1000;

wherein the diamine is linear, branched or cyclic; and is

Wherein l is an integer in the range of 1 to 10.

47. The dispensable curable enzyme-albumin nanogel solution of any one of claims 53 to 50 wherein the diamine is 1, 6-hexanediamine:

48. the dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 51 wherein the dispensable curable enzyme-albumin nanogel solution further comprises a diacrylate monomer.

49. The dispensable curable enzyme-albumin nanogel solution of claim 51 wherein the diacrylate monomer is represented by the formula:

wherein k is an integer ranging from 1 to 10; and is

R¹²Is selected from the group consisting of-C_1-4Alkyl and H.

50. The dispensable, curable enzyme-albumin nanogel solution of claim 53, wherein R is¹²is-CH₃And r is 1.

51. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 54 wherein the viscosity of the dispensable curable enzyme-albumin nanogel solution is less than about 1000 cP.

52. The dispensable curable enzyme-albumin nanogel solution of any one of claims 43 to 55 wherein the solution is characterized as capable of passing through a 20g needle using less than 60N pressure.

53. A cross-linked enzyme-nanoparticle-based material comprising:

a hydrogel matrix;

an enzyme-functionalized albumin nanoparticle having an albumin molecule covalently linked to at least one enzyme by a bifunctional-based linker, wherein the enzyme-albumin nanoparticle is pegylated, and wherein the enzyme-albumin nanoparticle is functionalized to a hydrogel matrix; and

a reversible oxygen-binding molecule-albumin nanoparticle having an albumin molecule covalently linked to at least one reversible oxygen-binding molecule by a bifunctional linker, wherein the reversible oxygen-binding molecule-albumin nanoparticle is pegylated, and wherein the reversible oxygen-binding molecule-albumin nanoparticle is functionalized to the hydrogel matrix by a PEG-based linker.

54. The crosslinked enzymatic nanoparticle-based material of claim 57, wherein the diamine linker is represented by the structure:

wherein l is an integer in the range of 1 to 10.

55. The crosslinked enzymatic nanoparticle-based material of claim 57 or 58, wherein the enzyme-albumin nanoparticle comprises the enzyme and albumin in a ratio of at least about 1: 1.

56. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 59, wherein the enzyme comprises one or more of glucose oxidase (GOx) and Catalase (CAT).

57. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 60, wherein the hydrogel matrix comprises:

wherein u is an integer ranging from 1 to 10; and is

Wherein R is¹³Is selected from the group consisting of-C_1-4Alkyl and H.

58. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 60, wherein the hydrogel matrix comprises:

wherein

Wherein t is an integer ranging from 1 to 1000; and is

R¹¹Is selected from the group consisting of-C_1-4Alkyl and H.

59. The crosslinked enzymatic nanoparticle based material of any one of claims 57 to 61, wherein the hydrogel matrix comprises a diamine represented by:

wherein

Wherein the diamine is linear, branched or cyclic, and u is an integer in the range of 1 to 10.

60. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 62, wherein the hydrogel matrix comprises:

wherein n is an integer in the range of 1 to 1000.

61. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 62, wherein the hydrogel matrix comprises:

wherein the diamine is linear, branched, or cyclic; and is

Wherein l is an integer in the range of 1 to 10.

62. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 62, wherein the hydrogel matrix comprises:

wherein n is an integer ranging from 1 to 1000;

wherein the diamine is linear, branched or cyclic; and is

Wherein l is an integer in the range of 1 to 10.

63. The crosslinked enzymatic nanoparticle based material of any one of claims 57 to 6 wherein the diamine is 1, 6-hexanediamine.

64. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 66, wherein the enzyme-functionalized albumin nanoparticles are attached to the hydrogel as follows:

wherein i is selected from the group consisting of-C (O) (CH)₂)_p-and N ═ CH (CH)₂)_p-wherein p is an integer ranging from 1 to 10;

j is- (CH)_2-)_q-, wherein q is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 1000;

R⁶Is selected from the group consisting of-C_1-4Alkyl and H.

65. The crosslinked enzymatic nanoparticle based material of any one of claims 57 to 67, wherein said crosslinked hemoglobin based material has a p50 of at least about 3.5 kPa.

66. The crosslinked enzymatic nanoparticle based material of any one of claims 57 to 69, wherein said crosslinked enzymatic nanoparticle based material has a storage modulus of at least about 1GPa at a total material concentration of less than about 10 mg/mL.

67. The crosslinked enzymatic nanoparticle based material of any one of claims 57 to 70, wherein said crosslinked enzymatic nanoparticle based material has a water content of at least about 99%.

68. The crosslinked enzymatic nanoparticle-based material of any one of claims 57 to 71, wherein said enzyme-nanoparticle based material comprises at least about 5% of the dry weight of said crosslinked enzymatic nanoparticle-based material.

69. A dispensable curable oxygen-sensing mixture comprising an oxygen-detecting luminescent dye configured to reversibly bind oxygen and emit light when bound to oxygen, wherein the luminescent dye is distributed within a co-polymer matrix comprising a blend of polystyrene and polysiloxane.

70. An oxygen sensing polymer comprising:

an oxygen-detecting luminescent dye distributed within a polymer matrix, the polymer matrix comprising:

blends of polystyrene and polystyrene acrylonitrile distributed in a polysiloxane matrix

Wherein the oxygen-detecting luminescent dye is configured to reversibly bind oxygen and is configured to emit light when oxygen is bound.

71. The oxygen sensing polymer of claim 74, wherein the luminescent dye is selected from the group consisting of: polyaromatics, fullerenes, phosphorescent organic probes, metal-ligand complexes such as Pt complexes, PD complexes, Ru (II) complexes, Ir complexes, Os complexes, Re complexes, lanthanide complexes, porphyrins, metalloporphyrins, and luminescent nanomaterials.

72. The oxygen sensing polymer of claim 74, wherein the oxygen detecting porphyrin dye is platinum tetrakis (pentafluorophenyl) porphyrin.

73. An analyte sensor, comprising:

a first layer comprising a crosslinked reversible oxygen-binding material, the first layer comprising:

a first reversible oxygen binding material-albumin nanoparticle,which is configured to transport O₂And having albumin and reversible oxygen binding material interconnected by bifunctional linkers

Wherein the reversible oxygen-binding material-albumin nanoparticles are pegylated;

wherein the reversible oxygen-binding material-albumin nanoparticles are functionalized within a first hydrogel matrix;

a second layer, the second layer comprising:

first and second enzymatically active nanoparticles and a construct for delivering O₂The second reversible oxygen binding material-albumin nanoparticles of (a);

the first enzymatically active nanoparticle comprises albumin interconnected with an enzyme;

the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and is

The second reversible oxygen-binding material-albumin nanoparticle comprises albumin and a reversible oxygen-binding material interconnected by a bifunctional linker, wherein the second reversible oxygen-binding material-albumin nanoparticle is pegylated;

wherein the first enzymatically active nanoparticle, the second enzymatically active nanoparticle, and the second reversible oxygen-binding material-albumin nanoparticle are functionalized within a second hydrogel matrix;

a sensing region in communication with the second layer, the sensing region comprising a luminescent dye covalently or non-covalently attached to a polymer matrix.

74. An analyte sensor, comprising:

a first layer comprising a crosslinked reversible oxygen-binding material, the first layer comprising:

a first reversible oxygen binding material-albumin nanoparticle configured to transport O₂And having albumin and reversible oxygen binding material interconnected by bifunctional linkers

Wherein the reversible oxygen-binding material-albumin nanoparticles are pegylated;

wherein the reversible oxygen-binding material-albumin nanoparticles are functionalized within a first hydrogel matrix;

a second layer, the second layer comprising:

first and second enzymatically active nanoparticles and a construct for delivering O₂The second reversible oxygen binding material-albumin nanoparticles of (a);

the first enzymatically active nanoparticle comprises albumin interconnected with glucose oxidase (GOx);

the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and is

a sensing region in communication with the second layer, the sensing region comprising a luminescent dye covalently or non-covalently attached to a polymer matrix.

75. An active hydrogel composition prepared by the steps of:

dispersing a nanogel in a liquid medium, the nanogel comprising nanostructures covalently linked to a macromolecule and conjugated to a polymer network;

adding a cross-linking agent to the nanogel dispersed in the liquid medium; and

performing a crosslinking step to form the reactive hydrogel composition.

76. A method of making a polymer laminated film waveguide structure comprising the steps of:

providing a first material to be imprinted, wherein the first material has a first refractive index;

imprinting at least one waveguide structure into the first material;

filling the imprinted waveguide structure with a second material having a second refractive index; and

applying a third material on top of the first material and the second material, wherein the third material has a third refractive index.

77. The method of claim 80, wherein the second refractive index is higher than the first refractive index and the third refractive index.

78. The method of claim 81, wherein the first refractive index is 1.42, the second refractive index is 1.5037, and the third refractive index is 1.42.

79. The method of claim 80, wherein the first material is PVDF.

80. The method of claim 80, wherein the second material is a UV curable epoxy.

81. The method of claim 80, wherein the third material is a cladding coating.

82. The method of claim 80, wherein the steps are performed using a reel-to-reel manufacturing process.

83. The method of claim 80, wherein a plurality of waveguide structures are imprinted in a single imprinting step.

84. The method of claim 80, wherein the plurality of waveguide structures are filled in a single filling step.

85. A method of manufacturing a laminate structure for use in an analyte sensor, comprising the steps of:

structuring a waveguide layer stack structure, comprising the steps of:

providing a waveguide first material to be imprinted, wherein the waveguide first material has a first refractive index;

imprinting at least one waveguide structure into the waveguide first material, wherein the at least one waveguide structure comprises four waveguide cores, and wherein at least one of the waveguide cores is an oxygen reference waveguide core;

filling the imprinted waveguide structure with a second waveguide material having a second refractive index; and

applying a waveguide third material on top of the waveguide first material and the waveguide second material, wherein the waveguide third material has a third refractive index.

86. The method of claim 89, wherein the second refractive index is higher than the first and third refractive indices.

87. The method of claim 90, wherein the first refractive index is 1.42, the second refractive index is 1.5037, and the third refractive index is 1.42.

88. The method of claim 89, wherein the waveguide first material is PVDF.

89. The method of claim 89, wherein the waveguide second material is a UV curable epoxy.

90. The method of claim 89, wherein the waveguide third material is a cladding coating.

91. The method of claim 89, wherein a plurality of waveguide structures are imprinted in a single imprinting step.

92. The method of claim 89, wherein a plurality of waveguide structures are filled in a single filling step.

93. The method of any one of claims 89 to 96, wherein the steps are performed using a reel-to-reel manufacturing process.

94. The method of any one of claims 89 to 97, further comprising constructing a chamber laminate structure comprising the steps of:

providing a reaction chamber first material structure comprising a first PSA having a first PSA first liner and a first PSA second liner;

cutting a first feature into the reaction chamber first material structure;

providing a reaction chamber second material structure comprising a reaction chamber material and a reaction chamber material liner;

removing the first PSA first liner; and

attaching the reaction chamber second material to the reaction chamber first material structure, thereby forming the reaction chamber laminate structure having a thickness.

95. The method of claim 98, wherein the first feature is a nose feature of the reaction chamber laminate structure in a region where a sensor ring is to be located.

96. The method of claim 98, wherein a plurality of first features are cut into the reaction chamber first material structure.

97. The method of claim 98, further comprising the steps of: cutting at least a second feature through an entire thickness of the chamber laminate structure.

98. The method of claim 101, further comprising the steps of: cutting a plurality of second features through an entire thickness of the chamber laminate structure.

99. The method of claim 98, further comprising the steps of: cutting at least three additional features through an entire thickness of the reaction chamber laminate structure.

100. The method of claim 101, wherein the three additional features include an optical chip opening, an oxygen-sensing polymer filled cell, and a vent opening.

101. The method of claim 98, further comprising the steps of: a plurality of three additional features are cut through the entire thickness of the reaction chamber laminate structure.

102. The method of claim 105, wherein the plurality of three additional features includes an optical chip opening, an oxygen-sensing polymer filled cell, and a vent opening.

103. The method of any one of claims 98-106, wherein the reaction chamber material is PEEK.

104. The method of any one of claims 98 to 107, wherein the steps are performed using a reel-to-reel manufacturing process.

105. The method of any one of claims 98-107, further comprising the step of: removing the first PSA second liner from the reaction chamber first material structure, thereby exposing the first PSA.

106. The method of claim 109, further comprising the steps of: attaching the first PSA to the waveguide third material of the waveguide lamination structure, thereby forming a waveguide reactor lamination structure.

107. The method of claim 110, further comprising the steps of: at least one reaction chamber is formed in the waveguide reaction chamber laminate structure.

108. The method of claim 110, further comprising the steps of: cutting a control port over the oxygen reference waveguide core, thereby exposing at least a portion of the oxygen reference waveguide core.

109. The method of claim 112, further comprising the steps of: cutting a reaction chamber cavity above the non-oxygen reference waveguide core, thereby exposing at least a portion of the non-oxygen reference waveguide core.

110. The method of claim 113, further comprising the steps of: a dispensing port is cut adjacent to and contiguous with the reaction chamber cavity.

111. The method of claim 114, further comprising the steps of: open slots are cut across the top of the waveguide cores to connect all four waveguide cores to the distribution port.

112. The method of claim 115, further comprising the steps of: a slanted surface or a stepped surface is cut into each of the waveguide cores.

113. The method of claim 115, further comprising the steps of: dispensing an oxygen sensing polymer into the dispensing port.

114. The method of claim 117, further comprising the steps of: curing the oxygen sensing polymer.

115. The method of claim 118, further comprising the steps of: dispensing an enzymatic hydrogel into the dispensing port.

116. The method of claim 119, further comprising the steps of: allowing the enzymatic hydrogel to solidify.

117. The method of claim 120, further comprising the steps of: a catheter laminate structure is provided.

118. The method of claim 121, wherein the catheter laminate structure comprises a catheter first liner, a first silicon PSA layer, a PET layer, a second silicon PSA layer, and a catheter second liner.

119. The method of claim 122, wherein the catheter first liner and the catheter second liner are PET material.

120. The method of any one of claims 121 to 123, wherein the conduit laminate structure is configured to include features that align with features in the waveguide reactor laminate structure.

121. The method of any one of claims 121-124, further comprising the step of:

removing the chamber material liner from the waveguide chamber laminate structure;

removing the catheter first liner from the catheter laminate; and

attaching the conduit laminate structure to the reaction chamber laminate structure.

122. The method of any one of claims 121 to 125, further comprising the step of: adding a capping layer to the catheter laminate structure.

123. The method of claim 125 wherein the capping layer comprises a plurality of openings therein.

124. A method of manufacturing a laminate structure for use in an analyte sensor, comprising the steps of:

providing a waveguide lamination structure comprising at least one waveguide structure;

providing a reaction chamber lamination structure comprising

A reaction chamber first material structure comprising a first PSA having a PSA liner;

a first feature included in a first material structure of the reaction chamber; and

a reaction chamber second material structure comprising a reaction chamber material and a reaction chamber material liner;

removing the PSA from the reaction chamber first material structure, thereby exposing the first PSA; and

attaching the first PSA to the waveguiding lamination structure, thereby forming the lamination structure.

125. A method for manufacturing a laminated structure, comprising the steps of:

providing a waveguide structure comprising a plurality of waveguide cores and having a first surface;

creating an oxygen-sensing polymer cavity in the first surface of the waveguide structure to receive an oxygen-sensing polymer;

filling the oxygen sensing polymer cavity with the oxygen sensing polymer and curing the oxygen sensing polymer;

adding a first layer of material on top of the first surface of the waveguide structure, wherein the first layer of material comprises a reaction chamber cavity in communication with the oxygen-sensing polymer;

filling the reaction chamber cavity with an enzymatic hydrogel and allowing the enzymatic hydrogel to solidify;

adding a second layer of material on top of the first layer of material, wherein the second layer of material comprises a catheter lumen to receive a catheter hydrogel;

filling the catheter lumen with a catheter hydrogel and allowing the catheter hydrogel to cure; and

a cap is added on top of the second layer of material.

126. The method of claim 129, wherein the oxygen-sensing polymer cavity is created by laser cutting.

127. The method of any one of claims 129 to 130, wherein the waveguide structure comprises an imprinted layer and a clad layer with a liner.

128. The method of any one of claims 129 to 131, wherein at least a portion of the oxygen sensing cavity forms a control port.

129. The method of any one of claims 129 to 132, wherein the oxygen-sensing cavity is filled with the oxygen-sensing polymer using a doctor blade method.

130. The method of any one of claims 129 to 133, wherein the first layer of material comprises a PEEK material having a PSA on a first surface and a liner on a second surface.

131. The method of any one of claims 129 to 134, wherein the cap comprises a plurality of openings therein.

132. A method of manufacturing a laminated structure comprising the steps of:

providing a waveguide structure comprising a plurality of waveguide cores filled with a core material and a first surface having a cladding coating with a cladding lining thereon;

laser cutting an oxygen-sensing polymer cavity in the first surface of the waveguide structure to receive an oxygen-sensing polymer, wherein the oxygen-sensing polymer cavity is connected to the waveguide core;

filling the oxygen sensing polymer cavity with the oxygen sensing polymer and curing the oxygen sensing polymer;

removing the cladding lining from the cladding coating;

attaching a layer of PEEK material on top of the cladding coating, wherein the layer of PEEK material comprises:

a PSA on a first surface for adhering to the cladding coating;

a PEEK liner on the second surface; and

a reaction chamber cavity coupled to the oxygen sensing polymer;

filling the reaction chamber cavity in the layer of PEEK material with an enzymatic hydrogel and allowing the enzymatic hydrogel to cure;

removing the PEEK liner from the PEEK material layer;

attaching a catheter layer material on top of the PEEK material layer, wherein the catheter layer material comprises a PVDF material having a first surface, a second surface, and a catheter hydrogel cavity, wherein the first surface and the second face comprise a silicone PSA layer thereon;

filling the catheter hydrogel cavity with a catheter hydrogel and allowing the catheter hydrogel to solidify; and

attaching a cap including a plurality of perforations therein on top of the layer of conduit material.

133. A laminated structure, comprising:

a waveguide structure comprising a plurality of waveguide cores filled with a core material and a cladding coating;

an oxygen sensing polymer cavity filled with an oxygen sensing polymer in the waveguide structure, wherein the oxygen sensing polymer cavity is connected to the waveguide core, and wherein the oxygen sensing polymer is in optical communication with the waveguide core;

a layer of PEEK material on top of the cladding coating, wherein the PEEK material layer comprises:

a PSA on a first surface for adhering to the cladding coating;

a PEEK liner on the second surface; and

a reaction chamber cavity in communication with the oxygen sensing polymer and filled with an enzymatic hydrogel;

a catheter layer material on top of the PEEK material layer, wherein the catheter layer material comprises a PVDF material having a first surface, a second surface, and a catheter hydrogel cavity filled with a catheter hydrogel, wherein the first surface and the second surface comprise a silicone PSA layer thereon; and

a cap on top of the layer of conduit material including a plurality of perforations therein.

134. A method of manufacturing a thin film sensing element, comprising:

producing a polymer laminated film waveguide structure comprising the steps of:

providing a first material to be imprinted, wherein the material has a first refractive index;

imprinting at least one waveguide structure into the material;

filling the imprinted waveguide structure with a second material having a second refractive index; and

applying a third material on top of the first material, wherein the third material has a third index of refraction;

creating a chamber laminate structure comprising the steps of:

providing a first layer comprising an adhesive;

providing a second layer comprising a PEEK material;

joining the first layer to the second layer;

cutting at least a portion of the first layer away from the second layer;

joining the polymer laminate film waveguide structure to the first layer of the reaction chamber laminate structure;

cutting a reaction chamber at least partially into the filled waveguide structure through the reaction chamber laminate structure; and

the reaction chamber is microfluidically filled with an oxygen sensing polymer and an enzymatic hydrogel.

135. A method of manufacturing a thin film sensing element, comprising:

producing a polymer laminated film waveguide structure comprising the steps of:

providing a first material to be imprinted, wherein the material has a first refractive index;

imprinting at least one waveguide structure into the material;

filling the imprinted waveguide structure with a second material having a second refractive index; and

applying a third material on top of the first material, wherein the third material has a third index of refraction;

creating a chamber laminate structure comprising the steps of:

providing a first layer comprising an adhesive;

providing a second layer comprising a PEEK material;

joining the first layer to the second layer;

cutting at least a portion of the first layer away from the second layer;

joining the polymer laminate film waveguide structure to the first layer of the reaction chamber laminate structure;

cutting a reaction chamber at least partially into the filled waveguide structure through the reaction chamber laminate structure; and

the reaction chamber is microfluidically filled with an oxygen sensing polymer and an enzymatic hydrogel.

136. A glucose sensor, comprising:

a first layer comprising a cross-linked hemoglobin-based material, the first layer comprising:

a first hemoglobin-albumin nanoparticle configured to transport O₂And having albumin and hemoglobin interconnected by bifunctional linkers

Wherein the hemoglobin-albumin nanoparticles are pegylated;

wherein the hemoglobin-albumin nanoparticles are functionalized within a first hydrogel matrix;

a second layer, the second layer comprising:

first and second enzymatically active nanoparticles and a construct for delivering O₂The second hemoglobin-albumin nanoparticle of (a);

the first enzymatically active nanoparticle comprises albumin interconnected with glucose oxidase (GOx);

the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and is

The second hemoglobin-albumin nanoparticle comprises albumin and hemoglobin interconnected by a bifunctional linker, wherein the second hemoglobin-albumin nanoparticle is pegylated;

wherein the first enzymatically active nanoparticle, the second enzymatically active nanoparticle, and the second hemoglobin-albumin nanoparticle are functionalized within a second hydrogel matrix;

a sensing region in communication with the second layer, the sensing region comprising a porphyrin dye covalently or non-covalently attached to a polymer matrix.

137. An active hydrogel composition prepared by the steps of:

dispersing a nanogel in a liquid medium, the nanogel comprising nanostructures covalently linked to a macromolecule and conjugated to a polymer network;

adding a cross-linking agent to the nanogel dispersed in the liquid medium; and

performing a crosslinking step to form the reactive hydrogel composition.

Technical Field

The disclosed and described technology relates generally to optical enzyme analyte sensors (such as, for example, glucose sensors) using waveguides with separate emission and excitation paths to target material, and methods of making such optical enzyme analyte sensors.

Background

Disclosure of Invention

The methods and apparatus or devices disclosed herein each have several aspects, no single one of which is solely responsible for its desirable attributes. Without limiting the scope of this disclosure, for example, as expressed by the claims that follow, its more prominent features will now be discussed briefly. After considering this discussion, and particularly after reading the section entitled "detailed description of certain embodiments" one will understand how the features disclosed and described provide advantages that include monitoring, diagnosing, and treating patients using results obtained from analyte sensors.

Various embodiments described herein relate to continuous analyte monitors, components thereof, and methods of making the same. In some embodiments, methods of making an assembly layer for a sensor tip of an analyte monitoring device are described. In some embodiments, the methods involve making a sensor tip small enough to be subcutaneously inserted into a patient. In some embodiments, the sensor tip comprises an oxygen conduit, an enzymatic layer, and a sensing layer.

Certain embodiments described herein relate to continuous glucose monitors, components thereof, and methods of making the same. In some embodiments, methods of making an assembly layer for a sensor tip for a glucose monitoring device are described. In some embodiments, the methods involve making a sensor tip small enough to be subcutaneously inserted into a patient. In some embodiments, the sensor tip comprises an oxygen conduit, an enzymatic layer, and a sensing layer.

Embodiments of a dispensable, curable, reversible oxygen binding molecule-albumin nanogel solution configured to form a hydrogel upon curing are disclosed. The dispensable, heat-curable, reversible oxygen-binding molecule-albumin nanogel comprises reversible oxygen-binding molecule albumin nanoparticles, wherein the reversible oxygen-binding molecule and albumin are interconnected by a bifunctional linker, wherein the reversible oxygen-binding molecule albumin nanoparticles are coupled to poly (ethylene glycol) (PEG) through a sulfur bond, and wherein the reversible oxygen-binding molecule albumin nanoparticles are functionalized to the nanogel matrix through a PEG-based linker.

In addition, certain embodiments relate to a method of preparing a dispensable, curable, reversible oxygen binding molecule-albumin nanogel solution, wherein the method comprises: forming a reversible oxygen-binding molecule-albumin nanoparticle of formula (I) by covalently linking a reversible oxygen-binding molecule with albumin by incubation with a bifunctional linker;

thiolating the reversible oxygen-binding molecule-albumin nanoparticles with a thiolating agent; conjugating the thiolated, reversible oxygen-binding molecule-albumin nanoparticle using maleimide poly (ethylene glycol) -methacrylate (PEG-MA); and crosslinking the pegylated reversible oxygen-binding molecule-albumin nanoparticles with a first diacrylate crosslinker to form the dispensable, heat-curable, reversible oxygen-binding molecule-albumin nanogel solution.

Disclosed are embodiments of a crosslinked reversible oxygen-binding molecule based material comprising a hydrogel matrix and reversible oxygen-binding molecule-albumin nanoparticles having albumin molecules covalently linked to at least one reversible oxygen-binding molecule by a bifunctional linker of formula (I), wherein the reversible oxygen-binding molecule-albumin nanoparticles are pegylated, and wherein the reversible oxygen-binding molecule-albumin nanoparticles are functionalized to the hydrogel matrix by a PEG-based linker.

Disclosed is a process for preparing a dispensable, curable enzyme-albumin nanogel solution, wherein the process comprises: covalently linking an enzyme to albumin by incubating the enzyme with albumin and a bifunctional linker to form an enzyme-albumin nanoparticle of formula (IV));

thiolating the enzyme albumin nanoparticles with a thiolating agent to form thiolated enzyme albumin nanoparticles of formula (V);

conjugating the thiolated enzyme albumin nanoparticles with poly (ethylene glycol) methacrylate to form pegylated enzyme-albumin nanoparticles of formula (VI);

thiolating the reversible oxygen-binding molecule albumin nanoparticles with a thiolating agent; conjugating the thiolated, reversible oxygen-binding molecule albumin nanoparticles with poly (ethylene glycol) methacrylic acid to form pegylated glucose oxidase-albumin nanoparticles; mixing the pegylated enzyme-albumin nanoparticles and a first diacrylate to form a pre-nanogel solution; crosslinking the pre-nanogel solution to form a crosslinked enzymatic nanogel; and adding the crosslinked enzymatic nanogel to a solution to form the dispensable, heat-curable enzyme-albumin nanogel solution, wherein the bifunctional linker (L) is a direct link between a homobifunctional linker, a heterobifunctional linker, or an enzyme and albumin; i is selected from the group consisting of-C (O) (CH2)_p-And N ═ CH (CH2)_p-A group of (a); wherein p is an integer ranging from 1 to 10; j is- (CH2-)_q-Wherein q is an integer ranging from 1 to 10; n is an integer ranging from 1 to 1000; and R is⁶Is selected from the group consisting of-C_1-4Alkyl and H; wherein the enzyme is selected from the group consisting of: glucose oxidase, glutamate oxidase, alcohol oxidase, lactate oxidase, ascorbate oxidase, cholesterol oxidase, choline oxidase, laccase and tyrosinase.

Also provided is a method for preparing a dispensable, curable, enzymatic nanogel solution, wherein the method comprises: conjugating an enzyme and CAT to albumin by incubating with a bifunctional linker for at least about 24 hours at a low temperature and low oxygen concentration at a pH between about 7.0 and 8.0 to form enzymatic nanoparticles; adding a thiol group to the nanoparticle to form a thiolated enzymatic nanoparticle; conjugating the thiolated enzymatic nanoparticle with poly (ethylene glycol) -methacrylate (PEG-MA) to form a pegylated enzymatic nanoparticle; and crosslinking the pegylated enzymatic nanoparticles with a methacrylate hydrogel monomer to form the dispensable, thermally curable, enzymatic nanogel solution.

Further, a dispensable, curable enzyme-albumin nanogel solution configured to form a hydrogel after thermal curing, the enzyme-albumin nanogel, is disclosed. The enzyme-albumin nanogel solution comprises: a nanogel matrix comprising:

wherein e is an integer ranging from 1 to 10, and R⁵Is selected from the group consisting of-C_1-4Alkyl and H; an enzyme albumin nanoparticle, wherein the enzyme and albumin are interconnected by a bifunctional linker, wherein the enzyme albumin nanoparticle is coupled to poly (ethylene glycol) (PEG) by a sulfide bond, and wherein the enzyme albumin nanoparticle is functionalized to the nanogel matrix by a PEG-based linker; and an enzyme albumin nanoparticle, wherein the enzyme and albumin are interconnected by a bifunctional linker, wherein the enzyme albumin nanoparticle is coupled to poly (ethylene glycol) (PEG) by a sulfide bond, and wherein the enzyme albumin nanoparticle is functionalized to the nanogel matrix by a PEG-based linker.

Also disclosed is a crosslinked enzymatic nanoparticle-based material comprising a hydrogel matrix; an enzyme-functionalized albumin nanoparticle having an albumin molecule covalently linked to at least one enzyme by a bifunctional linker, wherein the enzyme-albumin nanoparticle is pegylated, and wherein the enzyme-albumin nanoparticle is functionalized to a hydrogel matrix; and a reversible oxygen-binding molecule-albumin nanoparticle having an albumin molecule covalently linked to at least one reversible oxygen-binding molecule by a bifunctional linker, wherein the reversible oxygen-binding molecule-albumin nanoparticle is pegylated, and wherein the reversible oxygen-binding molecule-albumin nanoparticle is functionalized to the hydrogel matrix by a PEG-based linker.

Embodiments of a dispensable curable oxygen-sensing mixture comprising an oxygen-detecting luminescent dye configured to reversibly bind oxygen and emit light when oxygen is bound, wherein the luminescent dye is distributed within a copolymeric matrix comprising a blend of polystyrene and polysiloxane.

Also disclosed is an oxygen-sensing polymer comprising an oxygen-detecting luminescent dye distributed within a polymer matrix, wherein the polymer matrix comprises a blend of polystyrene and polystyrene acrylonitrile distributed within a polysiloxane matrix, wherein the oxygen-detecting luminescent dye is configured to reversibly bind oxygen and is configured to emit light when oxygen is bound.

Embodiments of an analyte sensor are disclosed, in some embodiments, comprising: a first layer having a crosslinked reversible oxygen-binding material, the first layer comprising: a first reversible oxygen-binding material-albumin nanoparticle configured to transport O₂And having albumin and a reversible oxygen-binding material linked by a bifunctional linker, wherein the reversible oxygen-binding material-albumin nanoparticles are pegylated, wherein the reversible oxygen-binding material-albumin nanoparticles are functionalized within a first hydrogel matrix; a second layer, the second layer comprising: first and second enzymatically active nanoparticles and a second reversible oxygen-binding material-albumin nanoparticle configured to deliver O2; the first enzymatically active nanoparticle comprises albumin interconnected with an enzyme; the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and the second reversible oxygen-binding material-albumin nanoparticle comprises albumin and reversible oxygen-binding material interconnected by a bifunctional linker, wherein the second reversible oxygen-binding material-albumin nanoparticle is pegylated, whichWherein the first enzymatically active nanoparticle, the second enzymatically active nanoparticle, and the second reversible oxygen-binding material-albumin nanoparticle are functionalized in a second hydrogel matrix; and a sensing region in communication with the second layer, the sensing region comprising a luminescent dye covalently or non-covalently attached to a polymer matrix.

Additional embodiments of an analyte sensor are disclosed, wherein the analyte sensor comprises: a first layer having a crosslinked reversible oxygen-binding material, the first layer comprising: a first reversible oxygen-binding material-albumin nanoparticle configured to transport O2 and having albumin and a reversible oxygen-binding material connected by a bifunctional linker, wherein the reversible oxygen-binding material-albumin nanoparticle is pegylated, wherein the reversible oxygen-binding material-albumin nanoparticle is functionalized within a first hydrogel matrix; a second layer, the second layer comprising: first and second enzymatically active nanoparticles and a second reversible oxygen-binding material-albumin nanoparticle configured to deliver O2; the first enzymatically active nanoparticle comprises albumin interconnected with glucose oxidase (GOx); the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and the second reversible oxygen-binding material-albumin nanoparticle comprises albumin and a reversible oxygen-binding material interconnected by a bifunctional linker, wherein the second reversible oxygen-binding material-albumin nanoparticle is pegylated, wherein the first enzymatically active nanoparticle, the second enzymatically active nanoparticle, and the second reversible oxygen-binding material-albumin nanoparticle are functionalized in a second hydrogel matrix; and a sensing region in communication with the second layer, the sensing region comprising a luminescent dye covalently or non-covalently attached to a polymer matrix.

Also disclosed is an active hydrogel composition prepared by the steps of: dispersing a nanogel in a liquid medium, the nanogel comprising nanostructures covalently linked to a macromolecule and conjugated to a polymer network; adding a cross-linking agent to the nanogel dispersed in the liquid medium; and performing a crosslinking step to form the reactive hydrogel composition.

An embodiment of a glucose sensor, comprising: a first layer having a cross-linked hemoglobin-based material, the first layer comprising: a first hemoglobin-albumin nanoparticle configured for delivery) and having albumin and hemoglobin interconnected by a bifunctional linker, wherein the hemoglobin-albumin nanoparticle is pegylated; wherein the hemoglobin-albumin nanoparticles are functionalized in a first hydrogel matrix; a second layer, the second layer comprising: first and second enzymatically active nanoparticles and a construct for delivering O₂The second hemoglobin-albumin nanoparticle of (a); the first enzymatically active nanoparticle comprises albumin interconnected with glucose oxidase (GOx); the second enzymatically active nanoparticle comprises albumin interconnected with Catalase (CAT); and the second hemoglobin-albumin nanoparticle comprises albumin and hemoglobin interconnected by a bifunctional linker, wherein the second hemoglobin-albumin nanoparticle is pegylated; wherein the first enzymatically active nanoparticle, the second enzymatically active nanoparticle, and the second hemoglobin-albumin nanoparticle are functionalized within a second hydrogel matrix; and a sensing region in communication with the second layer, the sensing region comprising a porphyrin dye covalently or non-covalently attached to a polymer matrix.

Embodiments of the present invention relate to a method of making a polymer laminated film waveguide structure, comprising the steps of: providing a first material to be imprinted, wherein the first material has a first refractive index; imprinting at least one waveguide structure into the first material; filling the imprinted waveguide structure with a second material having a second refractive index; and applying a third material on top of the first and second materials, wherein the third material has a third refractive index.

Also disclosed is a method of manufacturing a laminate structure for use in a glucose sensor, comprising the steps of: structuring a waveguide layer stack structure, comprising the steps of: providing a waveguide first material to be imprinted, wherein the waveguide first material has a first refractive index; imprinting at least one waveguide structure into the waveguide first material, wherein the at least one waveguide structure comprises four waveguide cores, and wherein at least one of the waveguide cores is an oxygen reference waveguide core; filling the imprinted waveguide structure with a waveguide second material having a second refractive index; and applying a waveguide third material on top of the waveguide first material and the waveguide second material, wherein the waveguide third material has a third refractive index. In some embodiments, the method further comprises constructing a reaction chamber laminate structure comprising the steps of: providing a reaction chamber first material structure comprising a first PSA having a first PSA first liner and a first PSA second liner; cutting a first feature into the reaction chamber first material structure; providing a reaction chamber second material structure comprising a reaction chamber material and a reaction chamber material liner; removing the first PSA first liner; and attaching the reaction chamber second material to the reaction chamber first material structure, thereby forming the reaction chamber laminate structure having a thickness.

A method of manufacturing a laminate structure for use in an analyte sensor is disclosed, wherein the method comprises the steps of: providing a waveguide lamination structure comprising at least one waveguide structure; providing a reaction chamber laminate structure comprising: a reaction chamber first material structure comprising a first PSA having a PSA liner; a first feature included in a first material structure of the reaction chamber; and a reaction chamber second material structure comprising a reaction chamber material and a reaction chamber material liner; removing the PSA from the reaction chamber first material structure, thereby exposing the first PSA; and attaching the first PSA to the waveguiding lamination, thereby forming the lamination.

Further methods of manufacturing a laminate structure are disclosed, comprising the steps of: providing a waveguide structure comprising a plurality of waveguide cores and having a first surface; creating an oxygen-sensing polymer cavity in the first surface of the waveguide structure to receive an oxygen-sensing polymer; filling the oxygen sensing polymer cavity with the oxygen sensing polymer and curing the oxygen sensing polymer; adding a first layer of material on top of the first surface of the waveguide structure, wherein the first layer of material comprises a reaction chamber cavity in communication with the oxygen-sensing polymer; filling the reaction chamber cavity with an enzymatic hydrogel and allowing the enzymatic hydrogel to solidify; adding a second layer of material on top of the first layer of material, wherein the second layer of material comprises a catheter lumen to receive a catheter hydrogel; filling the catheter lumen with a catheter hydrogel and allowing the catheter hydrogel to cure; and adding a top cap on top of the second layer of material.

Further, embodiments of the present invention relate to a method of manufacturing a laminated structure, comprising the steps of: providing a waveguide structure comprising a plurality of waveguide cores filled with a core material and a first surface having a cladding coating with a cladding lining thereon; laser cutting an oxygen-sensing polymer cavity in the first surface of the waveguide structure to receive an oxygen-sensing polymer, wherein the oxygen-sensing polymer cavity is connected to the waveguide core; filling the oxygen sensing polymer cavity with the oxygen sensing polymer and curing the oxygen sensing polymer; removing the cladding lining from the cladding coating; attaching a layer of PEEK material on top of the cladding coating, wherein the layer of PEEK material comprises: a PSA on a first surface for adhering to the cladding coating; a PEEK liner on the second surface; and a reaction chamber cavity coupled to the oxygen sensing polymer; filling the reaction chamber cavity in the layer of PEEK material with an enzymatic hydrogel and allowing the enzymatic hydrogel to cure; removing the PEEK liner from the PEEK material layer; attaching a catheter layer material on top of the PEEK material layer, wherein the catheter layer material comprises a PVDF material having a first surface, a second surface, and a catheter hydrogel cavity, wherein the first surface and the second surface comprise a silicone PSA layer thereon; filling the catheter hydrogel cavity with a catheter hydrogel and allowing the catheter hydrogel to solidify; and attaching a cap including a plurality of perforations therein on top of the layer of conduit material.

Embodiments of the present invention also relate to a laminate structure comprising: a waveguide structure comprising a plurality of waveguide cores filled with a core material and a cladding coating; an oxygen-sensing polymer cavity filled with an oxygen-sensing polymer in the waveguide structure, wherein the oxygen-sensing polymer cavity is contiguous with the waveguide core, and wherein the oxygen-sensing polymer is in optical communication with the waveguide core; a layer of PEEK material on top of the cladding coating, wherein the layer of PEEK material comprises: a PSA on the first surface to adhere to the cladding coating; a PEEK liner on the second surface; and a reaction chamber cavity contiguous with the oxygen sensing polymer and filled with an enzymatic hydrogel; a conductive layer material on top of the PEEK material layer, wherein the catheter layer material comprises a PVDF material having a first surface, a second surface, and a catheter hydrogel cavity filled with a catheter hydrogel, wherein a silicone PSA layer is included on the first and second surfaces; and a cap including a plurality of perforations therein atop the layer of conduit material.

Drawings

The above aspects and other features, aspects, and advantages of the present technology will now be described with reference to the accompanying drawings in conjunction with various embodiments. However, the illustrated implementations are merely examples and are not intended to be limiting. Throughout the drawings, similar symbols typically identify similar components, unless context dictates otherwise. Note that the relative dimensions of the following figures may not be drawn to scale.

FIG. 1A is a block diagram illustrating an example of a continuous health monitoring system including a sensor, a controller, and an analysis engine, according to one embodiment of the present invention.

FIG. 1B is a diagram of the sensor of FIG. 1A and the controller of FIG. 1A before they are connected to each other, according to one embodiment of the present invention.

FIG. 1C is a diagram of the sensor of FIG. 1A and the controller of FIG. 1A connected to each other according to one embodiment of the invention.

Fig. 2A is a functional block diagram of the sensor of fig. 1 according to one embodiment of the present invention.

Fig. 2B is a diagram of the sensor of fig. 2A, according to an embodiment of the present invention.

FIG. 2C is a graph of oxygen consumption as a function of distance from a glucose inlet according to an embodiment of the present invention.

Fig. 3A is a functional block diagram of the controller of fig. 1 according to one embodiment of the present invention.

Fig. 3B is a diagram of the controller of fig. 3A, according to an embodiment of the present invention.

Fig. 4 is a functional block diagram illustrating an example of a continuous health monitoring system including sensors, controllers, analysis engines, knowledge bases, smart cards, and/or portable computing devices according to an embodiment of the present invention.

Fig. 5 is a functional block diagram of the smart card of fig. 4 according to one embodiment of the present invention.

FIG. 6A is a functional block diagram of the portable computing device in FIG. 4, according to one embodiment of the present invention.

FIG. 6B is an illustration of one embodiment of the portable computing device of FIG. 6A, in accordance with one embodiment of the present invention.

Fig. 7 is a functional block diagram illustrating an example of a continuous health monitoring system including sensors, controllers, analysis engines, knowledge bases, smart cards, portable computing devices, biosensor systems, and/or activity sensor systems, according to an embodiment of the present invention.

Fig. 8 is a functional block diagram of the biosensor system of fig. 7 according to an embodiment of the present invention.

Fig. 9 is a functional block diagram of the activity sensor system of fig. 7 according to an embodiment of the present invention.

Fig. 10 is a functional block diagram illustrating an example of a continuous health monitoring system including sensors, controllers, analysis engines, knowledge bases, smart cards, portable computing devices, biosensor systems, activity sensor systems, networks, and/or health provider networks/monitors in accordance with an embodiment of the present invention.

Fig. 11 is a functional block diagram of a health provider network/monitor according to one embodiment of the present invention.

Fig. 12 is a functional block diagram illustrating an example of a continuous health monitoring system including sensors, controllers, analysis engines, knowledge bases, smart cards, portable computing devices, biosensor systems, activity sensor systems, routers, networks, and/or health provider networks/monitors in accordance with an embodiment of the present invention.

Fig. 13 is a flow chart illustrating one example of a method of continuous health monitoring in accordance with one embodiment of the present invention.

FIG. 14 is a flow diagram illustrating one example of a workflow for continuous health monitoring by a sensor, controller and analysis engine according to one embodiment of the present invention.

FIG. 15 is a flow diagram illustrating one example of a workflow of continuous health monitoring incorporating physician orders, according to one embodiment of the present invention.

FIG. 16 is a flow diagram illustrating an example of a workflow of continuous health monitoring incorporating activity data according to an embodiment of the present invention.

FIG. 17 is a flow chart illustrating one example of a method of continuous health monitoring in accordance with one embodiment of the present invention.

FIG. 18 illustrates the different layers of one embodiment of a layered optical sensor according to one embodiment of the present invention.

FIG. 19 illustrates a close-up view of an intermediate layer of a layered optical sensor according to one embodiment of the present invention.

FIG. 20A illustrates a layered optical sensor constructed in accordance with an embodiment of the invention.

FIG. 20B illustrates a cross-section of a layered optical sensor, according to an embodiment of the present invention.

Fig. 20C illustrates a top view of a layered optical sensor, according to an embodiment of the invention.

Fig. 20D is a cross-sectional view taken along line a-a in fig. 20C.

Fig. 20E is a cross-sectional view taken along line B-B in fig. 20D.

Fig. 21 illustrates front and back filled embossing of a layered optical sensor according to one embodiment of the present invention.

FIG. 22 illustrates a fill direction for capillary filling of a layered optical sensor, according to one embodiment of the present invention.

FIG. 23 illustrates a method of mass manufacturing a layered optical sensor, according to one embodiment of the invention.

FIG. 24 illustrates a fill-ready sheet of a layered optical sensor according to one embodiment of the present invention.

Fig. 25 illustrates a retrospectively calibrated sensor 20/20 performance plot of hysteresis adjustment.

Fig. 26 illustrates a retrospectively calibrated sensor 20/20 performance plot of hysteresis adjustment with outliers removed.

Fig. 27 shows a table of retrospectively calibrated sensor 20/20 performance plots for hysteresis adjustments where outliers have been removed.

Fig. 28A-C are exploded, side and top views of an adhesive system for attaching a photo-enzymatic device to a skin surface according to one embodiment of the invention.

Fig. 29A is an exploded view, a side view, and a top view of an adhesive system for attaching a photo-enzyme device to a skin surface, according to one embodiment of the invention.

Fig. 29B is a cross-sectional view taken along line a-a in fig. 29A.

Fig. 29C is a top view of an adhesive system in a relaxed state on skin according to one embodiment of the invention.

Fig. 29D is a top view of the adhesive system depicted in fig. 29C on skin as the skin is stretched according to one embodiment of the present invention.

Fig. 29E is a top view of an adhesive system according to an embodiment of the invention.

Fig. 29F is an exploded view of the adhesive system of fig. 29E, in accordance with one embodiment of the present invention.

Fig. 29G is a top view of the top layer of the adhesive system in fig. 29E, according to one embodiment of the invention.

Fig. 29H is a front perspective view of a bottom layer of the adhesive system of fig. 29E, according to one embodiment of the invention.

Fig. 29I is a detail view of the perforations in the top layer of the adhesive system in fig. 29G, according to one embodiment of the invention.

FIG. 29J is a bottom view of the adhesive system of FIG. 29E, according to an embodiment of the present invention.

Fig. 29K is an exploded view of an adhesive system according to an embodiment of the invention.

Fig. 29L is an exploded view of an adhesive system according to an embodiment of the invention.

Fig. 29M is a top view of an adhesive system according to an embodiment of the invention.

Fig. 29N is an exploded view of the adhesive system of fig. 29M, according to one embodiment of the invention.

Fig. 29O is an exploded view of an adhesive system according to an embodiment of the invention.

FIG. 29P is a bottom view of the adhesive system of FIG. 29O, according to an embodiment of the present invention.

Fig. 29Q is an exploded view of an adhesive system according to an embodiment of the invention.

FIG. 29R is a bottom view of the adhesive system of FIG. 29Q, according to an embodiment of the present invention.

Fig. 29S is a detail view of a modification of an adhesive system layer according to an embodiment of the invention.

Fig. 29T is a chart summarizing strain test results for different adhesive system embodiments according to the present disclosure.

Fig. 29U is an illustration of an adhesive system according to an embodiment of the invention attached to relaxed skin.

Fig. 29V is fig. 29U on skin when the skin is stretched while the skin is in a stretched state, according to one embodiment of the present invention.

Fig. 29W is a graph of the voltage across the skin when the skin returns to a relaxed state when stretched, according to one embodiment of the invention, at 29V.

FIG. 30 is a schematic illustration of moisture flux from a skin surface through an adhesive system and an additional photo-enzyme sensor system, according to one embodiment of the present invention.

Figure 31A is a schematic diagram of a connection between a sensor system and an interposer system according to one embodiment of the present invention.

Figure 31B is a schematic diagram of a connection between a sensor system and an interposer system according to one embodiment of the present invention.

FIG. 32 is a schematic diagram of an inserter system for a sensor, according to one embodiment of the invention.

Fig. 33A is a side view of an inserter system according to one embodiment of the invention.

Fig. 33B-C are perspective and front views of an inserter system with the cover removed, according to one embodiment of the invention.

Figure 33D is a front view of the external and internal components of the interposer assembly according to one embodiment of the present invention.

Figure 34A is a top view of a lancet according to one embodiment of the present invention.

Figure 34B is a side view of the lancet depicted in figure 34A, in accordance with one embodiment of the present invention.

Fig. 35A is a top perspective view of a distal portion of a lancet according to one embodiment of the invention.

Fig. 35B is a top perspective view of the distal portion of the lancet depicted in fig. 35A with the sensor attached, in accordance with an embodiment of the present invention.

Fig. 35C is a top perspective view of a distal portion of a lancet according to one embodiment of the invention.

Fig. 35D is a top view of the distal portion of the lancet depicted in fig. 35C, in accordance with an embodiment of the present invention.

Fig. 35E is a side view of the distal portion of the lancet depicted in fig. 35C, in accordance with an embodiment of the present invention.

Fig. 35F is a bottom perspective view of the distal portion of the lancet depicted in fig. 35C, in accordance with an embodiment of the present invention.

Fig. 35G is a bottom perspective view of the distal portion of the lancet depicted in fig. 35C, in accordance with an embodiment of the present invention.

Fig. 35H is a top perspective view of the distal portion of the lancet depicted in fig. 35C with the sensor attached in accordance with an embodiment of the present invention.

Fig. 35I is a side view of the distal portion of the lancet depicted in fig. 35H, in accordance with an embodiment of the present invention.

Fig. 35J is a bottom perspective view of the distal portion of the lancet depicted in fig. 35H, in accordance with an embodiment of the present invention.

Fig. 35K is a bottom view of the distal portion of the lancet depicted in fig. 35H in accordance with an embodiment of the present invention.

Fig. 35L is a top perspective view of a distal portion of a lancet according to one embodiment of the invention.

Fig. 35M is a top view of the distal portion of the lancet depicted in fig. 35L, in accordance with an embodiment of the present invention.

Fig. 35N is a side view of the distal portion of the lancet depicted in fig. 35L, in accordance with an embodiment of the present invention.

Fig. 35O is a top perspective view of the distal portion of the lancet depicted in fig. 35L with the sensor attached in accordance with an embodiment of the present invention.

Fig. 35P is a top perspective view of the distal portion of the lancet depicted in fig. 35L with the sensor attached, in accordance with an embodiment of the present invention.

Fig. 35Q is a top view of the distal portion of the lancet depicted in fig. 35L with the sensor attached, in accordance with an embodiment of the present invention.

FIG. 35R is a top perspective view of a sensor loaded onto a lancet according to one embodiment of the invention.

Fig. 36A is a side view depicting a distal portion of a lancet of a retaining structure, in accordance with an embodiment of the present invention.

Fig. 36B is a side view depicting a distal portion of a lancet of a retaining structure, in accordance with an embodiment of the present invention.

Fig. 36C is a side view of a distal portion of a lancet depicting a retaining structure, in accordance with an embodiment of the invention.

Fig. 36D is a side view of a distal portion of a lancet depicting a retaining structure, in accordance with an embodiment of the invention.

Fig. 36E is a side view of a distal portion of a lancet depicting a retaining structure, in accordance with an embodiment of the invention.

Fig. 36F is a top view of a distal portion of a lancet according to an embodiment of the invention, depicting a cutting edge and a cutting surface.

Fig. 36G is a bottom view of the distal portion of the lancet depicted in fig. 36F showing the cutting edge and the cutting surface, in accordance with an embodiment of the present invention.

Fig. 36H is a top view of a distal portion of a lancet according to an embodiment of the invention, depicting a cutting edge and a cutting surface.

Fig. 36I is a bottom view of the distal portion of the lancet depicted in fig. 36H showing the cutting edge and the cutting surface, in accordance with an embodiment of the present invention.

Fig. 36J is a top view of a distal portion of a lancet according to one embodiment of the invention, depicting a cutting edge and a cutting surface.

Fig. 36K is a bottom view of the distal portion of the lancet depicted in fig. 36J showing the cutting edge and the cutting surface, in accordance with an embodiment of the present invention.

Fig. 36L is a top view of a distal portion of a lancet according to an embodiment of the invention, depicting a cutting edge and a cutting surface.

Fig. 36M is a bottom view of the distal portion of the lancet depicted in fig. 36L showing the cutting edge and the cutting surface, in accordance with an embodiment of the present invention.

FIG. 36N is a top view of a loop sensor lancet interface according to one embodiment of the present invention.

Fig. 36O is a top view of a distal portion of a lancet having a loop sensor lancet interface loaded thereon according to one embodiment of the present invention.

FIG. 37 is a schematic diagram of a method for inserting a sensor system for continuous glucose monitoring, according to an embodiment of the present invention.

FIG. 38 illustrates an enlarged view of a sensor tip for a glucose monitoring device according to one embodiment of the present invention.

FIG. 39 illustrates a diagram of a functional sensor tip according to one embodiment of the present invention.

FIG. 40 illustrates a second diagram of a functional sensor tip according to one embodiment of the present invention.

FIG. 41A illustrates an enlarged view of a sensor tip for a glucose monitoring device according to one embodiment of the present invention.

FIG. 41B illustrates a view of a sensor tip with a detection device, according to one embodiment of the present invention.

FIG. 41C illustrates a cross-sectional view of a sensor tip, according to one embodiment of the invention.

FIG. 42 illustrates a top view of a mold for making the various components of the sensor tip, according to one embodiment of the invention.

Fig. 43A illustrates an exemplary optical glucose sensor configured to be coupled to an optical interconnect and configured to deliver light to a target material and deliver a glucose measurement from the target material, according to an embodiment of the invention.

FIG. 43B illustrates a sensory body and waveguide of the exemplary optical glucose sensor illustrated in FIG. 43A, according to one embodiment of the invention.

FIG. 43C illustrates a portion of a waveguide of the exemplary optical glucose sensor of FIG. 43A in which the excitation path and the emission path are merged, according to an embodiment of the invention.

Fig. 44A and 44B illustrate a cross-sectional side view and a top view, respectively, of an exemplary sensor with relatively large misalignment tolerance parallel to an optical path in a waveguide, in accordance with one embodiment of the present invention.

Fig. 45A and 45B illustrate other exemplary embodiments of sensors having sensor optical interfaces configured to relay excitation light and emission light from a waveguide.

Fig. 46A and 46B illustrate an optical glucose sensor with two excitation sources per waveguide according to an embodiment of the invention.

FIGS. 47A-47C illustrate examples of optical routing of different optical signals in an exemplary optical glucose sensor, according to one embodiment of the invention.

Fig. 48A and 48B illustrate examples of signals in an optical glucose sensor used to calibrate the sensor and measure glucose concentration according to one embodiment of the invention.

FIG. 49 is SDS-PAGE after EDC coupling reaction with GOx and amine.

FIG. 50 is a log Molecular Weight (MW) versus R using the values obtained in FIG. 49 for the protein standards_fThe figure (a).

FIG. 51 depicts a manufacturing process that produces multiple waveguides according to one embodiment of the invention.

FIG. 52 depicts a waveguide platen according to an embodiment of the invention.

FIG. 53 depicts a set of waveguide fiducials and a barcode according to an embodiment of the present invention.

FIG. 54 depicts placement of an optical engine using fiducials according to an embodiment of the present invention.

Figure 55 depicts a card imprinted with a waveguide structure according to one embodiment of the invention.

Fig. 56 depicts a cross-section of a multilayer waveguide lamination structure according to an embodiment of the invention.

Fig. 57 depicts a reel-to-reel process for manufacturing an RC laminate structure, according to one embodiment of the present invention.

Fig. 58 is a bottom view of an RC laminate structure according to an embodiment of the invention.

Fig. 59 depicts a metal frame of a card including a waveguide structure for lamination according to one embodiment of the invention.

FIG. 60 depicts a distal portion of a waveguide structure according to an embodiment of the invention.

Figure 61 depicts a distal portion and a proximal portion of a waveguide structure according to an embodiment of the invention.

Fig. 62 depicts a process for preparing a waveguide structure to receive an oxygen sensitive/sensing polymer according to one embodiment of the present invention.

FIG. 63A depicts a bevel cut into a waveguide core according to one embodiment of the invention.

Fig. 63B depicts a stepped cut into a waveguide core according to one embodiment of the invention.

Fig. 64A depicts a cross-section taken along line a-a in fig. 62.

FIG. 64B depicts a cross-section taken along line B-B in FIG. 64A.

Fig. 65A is a top view of an RC laminate structure according to an embodiment of the invention.

Fig. 65B is a bottom view of an RC laminate structure according to an embodiment of the invention.

Fig. 66 is a cross-section of a completed composite laminate structure mounted in a metal frame, according to an embodiment of the present invention.

FIG. 67 is an enlarged top view of a composite laminate structure according to an embodiment of the invention.

Fig. 68 is a perspective view of a portion of the composite laminate structure depicted in fig. 67, in accordance with an embodiment of the present invention.

Fig. 69 depicts a portion of a composite laminate structure according to an embodiment of the invention.

Figure 70 depicts the relationship between an oxygen-sensitive/sensing polymer fill port, an oxygen-sensitive/sensing lateral fill channel, a vent opening, a waveguide core, a reaction chamber, and an enzymatic hydrogel dispensing port/reservoir according to one embodiment of the present invention.

Figure 71 depicts the construction of a catheter laminate according to one embodiment of the invention.

Figure 72 depicts combining a catheter laminate with a composite laminate structure according to one embodiment of the present invention.

Fig. 73 depicts a completed laminate structure, excluding a capping layer, according to an embodiment of the invention.

Figure 74 depicts a completed laminate structure in a laser cut individual sensor card according to one embodiment of the present invention.

Fig. 75 depicts a completed laminate structure with the addition of an optical chip/engine according to one embodiment of the present invention.

FIG. 76 depicts a waveguide structure in which an oxygen-sensing polymer filled cavity is cut, according to an embodiment of the invention.

FIG. 77 depicts the waveguide structure of FIG. 77 with a cladding coating and a liner according to one embodiment of the invention.

Fig. 78 depicts an oxygen sensing polymer filled cavity filled with an oxygen sensing polymer according to an embodiment of the present invention.

Figure 79 depicts a reaction chamber laminate structure held in place on a waveguide structure according to one embodiment of the invention.

FIG. 80 depicts a reaction chamber lamination filled with an enzymatic hydrogel according to one embodiment of the invention.

FIG. 81 depicts a reaction chamber lamination and an enzymatic hydrogel fill cell according to one embodiment of the invention.

Figure 82 depicts a laser cut multiple chamber laminate structure in a card configuration, according to one embodiment of the invention.

Figure 83 depicts a conduit laminate structure held in place on top of a reaction chamber laminate structure according to one embodiment of the invention.

Figure 84 depicts a catheter laminate structure filled with a catheter hydrogel according to an embodiment of the invention.

Figure 85 depicts a top cap with a plurality of microperforations applied to the top of a catheter laminate according to one embodiment of the present invention.

FIG. 86 depicts an exploded view of a sensor constructed in accordance with an embodiment of the invention.

Embodiments relate to a method of manufacturing a thin film sensing element, wherein the method comprises: producing a polymer laminated film waveguide structure comprising the steps of: providing a first material to be imprinted, wherein the material has a first refractive index; imprinting at least one waveguide structure into the material; filling the imprinted waveguide structure with a second material having a second refractive index; and applying a third material on top of the first material, wherein the third material has a third refractive index; creating a chamber laminate structure comprising the steps of: providing a first layer comprising an adhesive; providing a second layer comprising a PEEK material; joining the first layer to the second layer; cutting at least a portion of the first layer away from the second layer; joining the polymer laminate film waveguide structure to the first layer of the reaction chamber laminate structure; cutting a reaction chamber at least partially through the reaction chamber laminate structure to the filled waveguide structure; and microfluidically filling the reaction chamber with an oxygen-sensitive polymer and an enzymatic hydrogel.

The present disclosure also relates to a method of manufacturing a thin film sensing element, comprising: producing a polymer laminated film waveguide structure comprising the steps of: providing a first material to be imprinted, wherein the material has a first refractive index; imprinting at least one waveguide structure into the material; filling the imprinted waveguide structure with a second material having a second refractive index; and applying a third material on top of the first material, wherein the third material has a third refractive index; creating a chamber laminate structure comprising the steps of: providing a first layer comprising an adhesive; providing a second layer comprising a PEEK material; joining the first layer to the second layer; cutting at least a portion of the first layer away from the second layer; joining the polymer laminate film waveguide structure to the first layer of the reaction chamber laminate structure; cutting a reaction chamber at least partially through the reaction chamber laminate structure to the filled waveguide structure; and microfluidically filling the reaction chamber with an oxygen-sensitive polymer and an enzymatic hydrogel.

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