Microneedle arrays for biosensing and drug delivery

• US 9,737,247 B2
• Filed: 08/31/2012
• Issued: 08/22/2017
• Est. Priority Date: 09/02/2011
• Status: Active Grant

• Current Assignee: National Technology & Engineering Solutions Of Sandia LLC (Honeywell International Inc.), Regents of the University of California (University of California), North Carolina State University (University of North Carolina System)
• Original Assignee: National Technology & Engineering Solutions Of Sandia LLC (Honeywell International Inc.), Regents of the University of California (University of California), North Carolina State University (University of North Carolina System)
• Inventors: Wang, Joseph, Windmiller, Joshua Ray, Narayan, Roger, Miller, Philip, Polsky, Ronen, Edwards, Thayne L.
• Primary Examiner(s): WEARE, MEREDITH H
• Application Number:
  US14/342,536
• Publication Number:
  US 20140336487A1
• Time in Patent Office: 1,817 Days
• CPC Class Codes: A61B 10/0045 Devices for taking samples of body liquids devices for taking blood samples A61B5/15
• CPC Class Codes: A61B 2010/008 Interstitial fluid
• CPC Class Codes: A61B 2562/028 Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 2562/046 in a matrix array
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/150984 Microneedles or microblades
• CPC Class Codes: A61B 5/157 Devices characterised by integrated means for measuring characteristics of blood
• CPC Class Codes: A61B 5/276 Protection against electrode failure
• CPC Class Codes: A61B 5/4845 Toxicology, e.g. by detection of alcohol, drug or toxic products A61B5/4848 takes precedence
• CPC Class Codes: A61B 5/6833 Adhesive patches
• CPC Class Codes: A61B 5/685 Microneedles
• CPC Class Codes: A61B 5/7282 Event detection, e.g. detecting unique waveforms indicative of a medical condition A61B5/4094, A61B5/4818, A61B5/349, A61B5/0823 take precedence
• CPC Class Codes: A61M 2005/1726 the body parameters being measured at, or proximate to, the infusion site
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/003 having a lumen
• CPC Class Codes: A61M 5/158 Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
• CPC Class Codes: A61M 5/1723 : using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: G01N 33/48785 : Electrical and electronic details of measuring devices for physical analysis of liquid biological material not specific to a particular test method, e.g. user interface or power supply

Abstract

Methods, structures, and systems are disclosed for biosensing and drug delivery techniques. In one aspect, a^ device for detecting an analyte and/or releasing a biochemical into a biological fluid can include an array of hollowed needles, in which each needle includes a protruded needle structure including an exterior wall forming a hollow interior and an opening at a terminal end of the protruded needle structure that exposes the hollow interior, and a probe inside the exterior wall to interact with one or more chemical or biological substances that come in contact with the probe via the opening to produce a probe sensing signal, and an array of wires that are coupled to probes of the array of hollowed needles, respectively, each wire being electrically conductive to transmit the probe sensing signal produced by a respective probe.

Claims

1. A device, comprising:

an array of microneedles, wherein each microneedle comprises;

a protruded needle structure including an exterior wall circumscribing the protruded needle structure, a hollow interior defined by an interior wall, and an opening to the hollow interior at a terminal end of the protruded needle structure, and

an electrically-conducting probe vertically oriented within the hollowed interior of the protruded needle structure and spaced away from the interior wall, wherein the electrically-conducting probe is configured to interact with one or more chemical or biological substances that come in contact with the probe via the opening to the hollow interior to produce a probe sensing signal,

wherein the probe includes a conducting polymer on a surface of the probe,

wherein the exterior wall comprises a non-conducting, non-detecting material; and

an array of electrically-conducting channels that are electrically coupled to the probes of the array of microneedles to transmit the probe sensing signal produced by a respective probe.

2. The device of claim 1, wherein the conducting polymer is configured in an enzyme-functionalized coating on the surface of the probe, wherein the enzyme-functionalized coating is configured to interact with an analyte within a fluid.

3. The device of claim 2, wherein the analyte includes at least one of a biochemical, metabolite, electrolyte, ion, pathogen, or microorganism.

4. The device of claim 2, wherein an electrochemical interaction between the analyte and the conducting polymer on the probe is detectable using at least one of amperometry, voltammetry, or potentiometry.

5. The device of claim 2, wherein the conducting polymer comprises an interface that causes the analyte to be immobilized at the interface by at least one of electropolymerization/polymer entrapment, electrostatic interactions, covalent attachment, or direct adsorption.

6. The device of claim 2, further comprising a processing unit in communication with the electrically-conducting channels that receives the probe sensing signals and uses the probe sensing signals as data.

7. The device of claim 6, wherein the processing unit compares the data to a threshold value to determine whether the analyte concentration reflects a healthy or disease state.

8. The device of claim 6, wherein the processing unit determines a pattern in the data that indicates whether the analyte concentration reflects a healthy or disease state.

9. The device of claim 6, wherein the processing unit multiplexes the received probe sensing signals from the probes.

10. The device of claim 2, wherein the device is integrated into an adhesive patch for placement on skin to detect the analyte residing in transdermal fluid.

11. The device of claim 1, wherein the probe further includes an ion-selective coating.

12. The device of claim 1, wherein the probes include at least one of a carbon fiber, carbon paste, conducting metal, or the conducting polymer.

13. A device, comprising:

a substrate that includes a microneedle located on one side of the substrate, wherein the microneedle includes a hollowed interior defined by an interior wall, and an external wall with an opening to the hollowed interior;

an electrode including a probe, wherein the probe is disposed inside the hollowed interior and spaced away from the interior wall;

wherein the probe includes a conducting polymer on a surface of the probe;

wherein the external wall comprises a non-conducting, non-detecting material; and

a wire, wherein the wire is electrically connected to the probe,

wherein the electrode is functionalized by the conducting polymer to interact with an analyte to produce an electrical signal.

14. The device of claim 13, wherein the probe includes at least one of a carbon fiber, carbon paste, conducting metal, or the conducting polymer.

15. The device of claim 13, wherein the probe further includes an ion-selective coating.

16. The device of claim 13, wherein the analyte includes at least one of a biochemical, metabolite, electrolyte, ion, pathogen, or microorganism.

17. The device of claim 13, wherein an electrochemical interaction between the analyte and the conducting polymer on the functionalized electrode is detectable using at least one of amperometry, voltammetry, or potentiometry.

18. The device of claim 13, further comprising a processing unit in communication with the wire that receives the electrical signal and uses the electrical signal as data.

19. The device of claim 18, wherein the processing unit compares the data to a threshold value to determine whether the analyte concentration reflects a healthy or disease state.

20. The device of claim 18, wherein the processing unit determines a pattern in the data that indicates whether the analyte concentration reflects a healthy or disease state.

21. The device of claim 13, wherein the device is integrated into an adhesive patch for placement on skin to detect the analyte residing in transdermal fluid.

22. The device of claim 13, further comprising:

a polymer film having pores of a reversibly tunable porosity, wherein the polymer film is attached to an opposite side of the substrate;

a protrusion structure configured on the one side of the substrate, the protrusion structure having a channel between an opening in the substrate exposing the polymer film and an opening at a terminal end of the protrusion structure;

a containment structure that contains a chemical substance, the containment structure including one or more openings attached to the polymer film positioned above the protrusion structure; and

an electrode attached to the polymer film,

wherein the electrode provides an electrical stimulus to trigger an expansion of the pores of the polymer film to an open state or a contraction the pores of the polymer film to a closed state.

23. The device of claim 22, wherein the chemical substance is a therapeutic agent including at least one of a drug, vaccine, hormone, or pharmacological agent.

24. The device of claim 22, further comprising a processing unit in communication with the wire that receives the electrical signal to use as data and in communication with the electrode to generate the electrical stimulus.

25. The device of claim 24, wherein the processing unit processes the data to determine whether the analyte concentration reflects a healthy or disease state.

26. The device of claim 24, wherein the processing unit actuates the electrode to apply an electrical stimulus to the polymer film to alter its permeability from the closed state to the open state, thereby releasing the chemical substance from the device.

27. The device of claim 26, further comprising:

a second polymer film having pores of a reversibly tunable porosity, wherein the second polymer film is attached to an opposite side of the substrate;

one other protrusion structure configured on the one side of the substrate, the other protrusion structure including a channel between an opening in the substrate exposing the second polymer film and an opening at a terminal end of the other protrusion structure;

a second containment structure that contains a second chemical substance, the second containment structure including one or more openings attached to the second polymer film positioned above the other protrusion structure; and

a second electrode attached to the second polymer film,

wherein the second electrode provides a second electrical stimulus to trigger an expansion of the pores of the second polymer film to an open state or a contraction the pores of the polymer film to a closed state.

28. The device of claim 27, wherein the processing unit multiplexes the received electrical signals from the probe and the actuation of the electrical stimuli to the electrode and second electrode to release the chemical substance and the second chemical substance, respectively.

29. A method to sense an analyte and deliver a therapeutic agent, comprising:

detecting a signal produced by an analyte at an interface with a chemically functionalized probe configured to electrochemically interact with the analyte within a biological fluid, wherein the signal is transduced to an electrical signal by the chemically functionalized probe, wherein the chemically functionalized probe includes a conducting polymer at the interface, and wherein the probe is contained within a hollow interior of a protruded needle structure circumscribed by an exterior wall comprising a non-conducting, non-detecting material, the probe vertically oriented and spaced away from an interior wall within the hollow interior of the protruded needle structure;

processing the electrical signal to determine a parameter of the analyte; and

based on the determined parameter, applying an electrical stimulus to a valve comprising a porous polymer film having pores of a reversibly tunable porosity, the valve attached to a container containing a therapeutic agent,

wherein the electrical stimulus alters the permeability of the pores from a closed state to an open state, thereby releasing the therapeutic agent into the biological fluid.

30. The method of claim 29, wherein the analyte includes at least one of a biochemical, metabolite, electrolyte, ion, pathogen, or microorganism.

31. The method of claim 29, wherein the therapeutic agent includes at least one of a drug, vaccine, hormone, vitamin, anti-oxidant, or pharmacological agent.

32. The method of claim 29, wherein the biological fluid includes at least one of transdermal fluid, intraocular fluid, vitreous humor, cerebrospinal fluid, extracellular fluid, interstitial fluid, plasma, serum, lacrimal fluid, saliva, perspiration, mucus, or blood.

33. The method of claim 29, wherein the one or more signals are detected using at least one of amperometry, voltammetry, or potentiometry.

34. The method of claim 29, wherein the parameter includes a concentration level of the analyte.

35. A device, comprising:

a substrate that includes a plurality of microneedles located on one side of the substrate, wherein each of the microneedles includes a protruded needle structure including an exterior wall circumscribing the protruded needle structure, and a hollow interior defined by an interior wall, wherein the exterior wall comprises a non-conducting, non-detecting material;

a biosensor module, comprising;

a plurality of sensing electrodes disposed inside the hollowed interiors of a first group of the plurality of microneedles, wherein each sensing electrode is vertically oriented within the hollow interior of the protruded needle structure and spaced away from the interior wall, the sensing electrodes including a probe configured to interact with an analyte within a fluid to produce an electrical signal,

wherein the probe includes a conducting polymer on a surface of the probe, and

a plurality of wires, wherein one wire of the plurality of wires is electrically connected to the probe of the sensing electrodes;

a processing unit in communication with the plurality of wires to receive the electrical signal and use the received electrical signal as data; and

an actuator module, comprising;

a polymer film having pores of a reversibly tunable porosity, wherein the polymer film is attached to an opposite side of the substrate,

a plurality of protrusion structures disposed inside the hollowed interiors of a second group of the plurality of microneedles, the protrusion structures including a channel between an opening in the substrate exposing the polymer film and an opening at a terminal end of the protrusion structure,

a containment structure that contains a chemical substance positioned above the polymer film, wherein the containment structure includes one or more openings coupled to the polymer film positioned above the protrusion structures, and

an actuator electrode attached to the polymer film, wherein the actuator electrode provides an electrical stimulus to trigger an expansion of the pores of the polymer film to an open state or a contraction the pores of the polymer film to a closed state,

wherein the processing unit is in communication with the actuator electrode to generate the electrical stimulus based on the data.

36. The device of claim 35, wherein the analyte includes at least one of a biochemical, metabolite, electrolyte, ion, pathogen, or microorganism.

37. The device of claim 35, wherein the chemical substance is a therapeutic agent including at least one of a drug, vaccine, hormone, or pharmacological agent.

38. The device of claim 35, wherein the processing unit compares the data to a threshold value to determines whether the analyte concentration reflects a healthy or disease state.

39. The device of claim 35, wherein the processing unit determines a pattern in the data that indicates whether the analyte concentration reflects a healthy or disease state.

40. The device of claim 35, wherein the processing unit actuates the actuator electrode to apply the electrical stimulus to the polymer film to alter its permeability from the closed state to the open state, thereby releasing the chemical substance into the fluid.

41. The device of claim 40, wherein the processing unit multiplexes the received electrical signals from the probe and the actuation of the electrical stimuli to the actuator electrode.

42. The device of claim 40, wherein the processing unit includes logic gates configured on the substrate.

43. The device of claim 35, wherein the device is integrated into an adhesive patch for placement on skin to detect the analyte residing in transdermal fluid.