Implantable biosensor from stratified nanostructured membranes

• US 7,863,038 B2
• Filed: 03/31/2003
• Issued: 01/04/2011
• Est. Priority Date: 03/29/2002
• Status: Active Grant

• Current Assignee: Board of Regents of Oklahoma State University
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Kotov, Nicholas A., Motamedi, Massoud, Esenaliev, Rinat, Wicksted, James P.
• Primary Examiner(s): YANG, NELSON C
• Application Number:
  US10/403,845
• Publication Number:
  US 20040023317A1
• Time in Patent Office: 2,836 Days
• Field of Search: 424/9.1, 424/9.6, 424/9.8, 424/422, 424/423, 436/14, 123/635
• US Class Current: 435/287.8
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: C12Q 1/006 for glucose
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings

Abstract

A new class of biosensors and methods for making and using same are disclosed. The biosensors are multi-layered membrane composites, where at least one layer is prepared by the layer-by-layer process and at least one layer is responsive to changes is a property of a biological system such as changes in the concentration of an atom, ion, molecule or molecular assembly. Because the biosensors are multi-layered, a single biosensor is capable monitor a number of different properties of a biological system simultaneously. The biosensors are monitored by systems that impinge an excitation waveform on the biosensors and analyze a reflected and/or a transmitted resultant waveform. Additionally, the biosensors can be associated with field activated electronic components so that implantable, self-contained analytical devices can be constructed and monitored by field generators, where data is transmitted to an analyzer after field activation.

Claims

1. A biosensor/detector apparatus comprising:

an external excitation electronic component adapted to generate an input waveform,

a biosensor membrane component comprising;

a multiple layered film including;

at least two layer-by-layer assembled (LBL) layers, each LBL layer including at least one positively charged layer and at least one negatively charged layer, where the layers alternate between a positively charged layer and a negatively charged layer,

at least one responsive layer interposed between the two LBL layers, where the responsive layer has a detectable property that undergoes a change due to a change in a concentration of a target agent associated with a biological system,

at least one of the negatively charged layers includes a detection enhancing component comprising nano-particles, where the detection enhancing component improves detection of the detectable property of the at least one responsive layer, and

at least one bio-compatible layer deposited on each LBL layer, where the bio-compatible layer reduces cytotoxicity of the detection enhancing components,

where the membrane component is adapted to be placed in contact with or implanted into a living biological system and where the member interacts with the input waveform to produce an output waveform,

an external detection electronic component adapted to receive the output waveform and to generate a response signal corresponding to the output waveform, where the response signal corresponds to a value of the detectable property of the at least one responsive layer, and an external analyzer adapted to convert the response signal into a corresponding value of the detectable property, which corresponds to a concentration of the target agent associated with the living biological system.

2. The apparatus of claim 1, wherein the film further includes a plurality of responsive layers, where the responsive layers are the same or different.

3. The apparatus of claim 1, wherein the film further includes a plurality of responsive layers interposed between LBL layers, where the responsive layers are the same or different.

4. The apparatus of claim 1, wherein the membrane component further comprises a mesh surrounding the film.

5. The apparatus of claim 4, wherein the membrane component further comprises a coating surrounding the mesh.

6. The apparatus of claim 1, wherein the responsive layers forms a pattern, where the pattern comprises vertical strips, horizontal strips or patches.

7. The apparatus of claim 1, wherein the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent or responsive layer includes a marker that undergoes a change in response to the change in the concentration of the target agent, where the marker includes a dye, a fluorescent dye, a fluorescent donor-acceptor pair, a dye capable of undergoing FRET, or mixtures and combinations thereof.

8. The apparatus of claim 1, wherein the target agent comprises an atom, ion, molecule and/or molecular assembly.

9. The apparatus of claim 1, wherein the target agent comprises glucose and the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent.

10. The apparatus of claim 1, wherein the detection electronic component comprises an electromagnetic detection system, an acoustic detection system, or a spectroscopic detection system.

11. The apparatus of claim 1, wherein the living biological system comprises a tissue, an organ, a cell culture, a tissue culture, or a mixture or combination thereof.

12. The apparatus of claim 1, wherein the positively charged organic polymer comprises poly(diallyldimethylammonium) polycation (PDDA) or collagen.

13. The apparatus of claim 1, wherein the membrane component further comprises end caps coated on, pressed on or applied to ends of the membrane component.

14. The apparatus of claim 1, wherein the nano-particles comprise semiconductor nano-particles and the bio-compatible layer comprises collagen.

15. The apparatus of claim 14, wherein the semiconductor nano-particles comprise CdTe nano-particles.

16. A biosensor/detector apparatus comprising:

a membrane comprising;

an excitation electronic component adapted to generate an input waveform,

a biosensor component comprising;

at least two layer-by-layer assembled (LBL) layers, each LBL layer including at least one positively charged layer and at least one negatively charged layer, where the layers alternate between a positively charged layer and a negatively charged layer,

at least one responsive layer interposed between the two LBL layers, where the responsive layer has a detectable property that undergoes a change due to a change in a concentration of a target agent associated with a biological system,

at least one of the negatively charged layers includes a detection enhancing component comprising nano-particles, where the detection enhancing component improves detection of the detectable property of the at least one responsive layer, and

at least one bio-compatible layer deposited on each LBL layer, where the bio-compatible layer reduces cytotoxicity of the detection enhancing components,

where the biosensor component interacts with the input waveform to produce an output waveform, and

a detection electronic component adapted to receive the output waveform and to generate a response signal corresponding to the output waveform, where the response signal corresponds to a value of the detectable property of the at least one responsive layer and where the detection electronic component includes a transmitter for transmitting the response signal,

where the components are collinearly disposed with the biosensor component interposed between the excitation electronic component and the detection electronic component and where the membrane is adapted to be placed in contact with or implanted into a living biological system, and

an external analyzer adapted to convert the response signal into a corresponding value of the detectable property, which corresponds to a concentration of the target agent associated with the living biological system.

17. The apparatus of claim 16, wherein the biosensor further includes a plurality of responsive layers, where the responsive layers are the same or different.

18. The apparatus of claim 16, wherein the biosensor further includes a plurality of responsive layers interposed between LBL layers, where the responsive layers are the same or different.

19. The apparatus of claim 16, wherein the membrane further comprises a mesh surrounding the membrane.

20. The apparatus of claim 19, wherein the membrane further comprises a coating surrounding the mesh.

21. The apparatus of claim 16, wherein the responsive layers forms a pattern, where the pattern comprises vertical strips, horizontal strips or patches.

22. The apparatus of claim 16, wherein the living biological system is a tissue, an organ, a cell culture, a tissue culture, or a mixture or combination thereof.

23. The apparatus of claim 16, wherein the electronic components are field activated components.

24. The apparatus of claim 16, wherein the detectable property is a physical, a chemical, a biochemical, and/or a molecular property and where the target agent comprises an atom, an ion, a molecule and/or a molecular assembly.

25. The apparatus of claim 16, wherein the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent or responsive layer includes a marker that undergoes a change in response to the change in the concentration of the target agent, where the marker includes a dye, a fluorescent dye, a fluorescent donor-acceptor pair, a dye capable of undergoing FRET, or mixtures and combinations thereof.

26. The apparatus of claim 16, wherein the target agent comprises an atom, ion, molecule and molecular assembly.

27. The apparatus of claim 16, wherein the target agent comprises glucose and the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent.

28. The apparatus of claim 16, wherein the positively charged organic polymer comprises poly(diallyldimethylammonium) polycation (PDDA) or collagen.

29. The apparatus of claim 16, wherein the membrane further comprises end caps coated on, pressed on or applied to ends of the membrane.

30. The apparatus of claim 16, wherein the nano-particles comprise semiconductor nano-particles and the bio-compatible layer comprises collagen.

31. The apparatus of claim 30, wherein the semiconductor nano-particles comprise CdTe nano-particles.

32. A biosensor/detector apparatus comprising:

a membrane comprising;

an excitation electronic component adapted to generate an input waveform,

a biosensor component comprising;

at least two layer-by-layer assembled (LBL) layers, each LBL layer including at least one positively charged layer and at least one negatively charged layer, where the layers alternate between a positively charged layer and a negatively charged layer,

at least one responsive layer interposed between the two LBL layers, where the responsive layer has a detectable property that undergoes a change due to a change in a concentration of a target agent associated with a biological system,

at least one of the negatively charged layers includes a detection enhancing component comprising nano-particles, where the detection enhancing component improves detection of the detectable property of the at least one responsive layer,

at least one bio-compatible layer deposited on each LBL layer, where the bio-compatible layer reduces cytotoxicity of the detection enhancing components, and

a mesh surrounding the biosensor,

where the biosensor component interacts with the input waveform to produce an output waveform, and

a detection electronic component adapted to receive the output waveform and to generate a response signal corresponding to the output waveform, where the response signal corresponds to a value of the detectable property of the at least one responsive layer and where the detection electronic component includes a transmitter for transmitting the response signal,

where the components are collinearly disposed with the biosensor component interposed between the excitation electronic component and the detection electronic component and where the membrane is adapted to be placed in contact with or implanted into a living biological system, and

an external analyzer adapted to convert the response signal into a corresponding value of the detectable property, which corresponds to a concentration of the target agent associated with the living biological system.

33. The apparatus of claim 32, wherein the membrane further comprises a coating surrounding the mesh.

34. The apparatus of claim 32, wherein the biosensor further includes a plurality of responsive layers, where the responsive layers are the same or different.

35. The apparatus of claim 32, wherein the biosensor further includes a plurality of responsive layers interposed between LBL layers, where the responsive layers are the same or different.

36. The apparatus of claim 32, wherein the responsive layers forms a pattern, where the pattern comprises vertical strips, horizontal strips or patches.

37. The apparatus of claim 32, wherein the living biological system is a tissue, an organ, a cell culture, a tissue culture, or a mixture or combination thereof.

38. The apparatus of claim 32, wherein the electronic components are field activated components.

39. The apparatus of claim 32, wherein the detectable property is a physical, a chemical, a biochemical, and/or a molecular property and where the target agent comprises an atom, an ion, a molecule and/or a molecular assembly.

40. The apparatus of claim 32, wherein the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent or responsive layer includes a marker that undergoes a change in response to the change in the concentration of the target agent, where the marker includes a dye, a fluorescent dye, a fluorescent donor-acceptor pair, a dye capable of undergoing FRET, or mixtures and combinations thereof.

41. The apparatus of claim 32, wherein the target agent comprises an atom, ion, molecule and molecular assembly.

42. The apparatus of claim 32, wherein the target agent comprises glucose and the detectable property is a physical dimension, which changes in response to the change in the concentration of the target agent.

43. The apparatus of claim 32, wherein the positively charged organic polymer comprises poly(diallyldimethylammonium) polycation (PDDA) or collagen.

44. The apparatus of claim 32, wherein the membrane further comprises end caps coated on, pressed on or applied to ends of the membrane.

45. The apparatus of claim 32, wherein the nano-particles comprise semiconductor nano-particles and the bio-compatible layer comprises collagen.

46. The apparatus of claim 45, wherein the semiconductor nano-particles comprise CdTe nano-particles.