Conducting polymer nanotube actuators for precisely controlled release of medicine and bioactive molecules

• US 8,936,794 B2
• Filed: 08/24/2007
• Issued: 01/20/2015
• Est. Priority Date: 08/25/2006
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Martin, David C., Abidian, Mohammad Reza
• Primary Examiner(s): DICKINSON, PAUL W
• Application Number:
  US11/895,515
• Publication Number:
  US 20080097280A1
• Time in Patent Office: 2,706 Days
• Field of Search: None
• US Class Current: 424/400
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Abstract

Drug delivery devices, their manufacture, and their use comprising electrocontractile nanotubes that can be used for precise controlled bioactive substance release for example, medical, veterinary, pharmaceutical compounds and growth factors. The conducting polymer nanotubes significantly decrease the impedance and increase the charge capacity of recording electrode sites on microfabricated electrode devices. Bioactive substances released from the nanotubes can be controlled in a desired fashion by controlled electrical stimulation of the nanotubes.

Claims

1. A biocompatible electrode comprising:

a first electrically conductive substrate; and

a second electrically conductive substrate which comprises a plurality of electrocontractile nanotubes comprising walls of conductive polymer defining lumens or cavities therein containing at least one bioactive substance, said second electrically conductive substrate contacting at least a portion of said first conductive substrate;

wherein electrical actuation of said nanotubes induces contraction of said nanotube walls causing the release of at least a portion of said bioactive substance from said lumens or cavities.

2. A sensor device comprising:

(1) a substrate having one or more sealed microchannels and at least one reaction chamber forming a microfluidic assembly;

(2) a power source capable of providing a voltage to said microfluidic assembly; and

(3) a data recorder for recording changes in electronic signals provided by said microfluidic assembly;

the microfluidic assembly comprises;

(i) a reaction chamber comprising the electrode of claim 1

wherein release of said bioactive substance enables binding of said bioactive substance with a test analyte thereby producing a change in electronic signal capable of being transduced by said microfluidic assembly to said data recorder.

3. The sensor device according to claim 2, wherein the target analyte is selected from the group consisting of glucose, troponin I, troponin T, myoglobin, prostate serum antigen, CA, 19-9, CEA, EGFr, p53, p27, and amyloid-beta peptide.

4. A method for controlled release of a bioactive substance in a biological tissue, comprising the steps:

(i) providing a biocompatible electrode according to claim 1 and a power source operably connected to said first and second conductive substrates;

(ii) placing said electrode in contact with the biological tissue, and

(iii) applying a voltage to at least one of said first and said second electrically conductive substrates of said electrode so as to supply a voltage to said nanotubes, thereby causing a contraction of said nanotube walls and concomitant release of said bioactive substance.

5. The method according to claim 4, wherein the bioactive substance is released from said nanotubes after applying to said at least one of said first and said second electrically conductive substrate a voltage ranging from about +0.1 V to about +5 V with a scan rate of between 0.01 to 1 V/sec for a period of 0.1 seconds to 6 hours.

6. The method according to claim 4, wherein said conductive polymer comprises poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyanilines, polyacetylenes, polythiophenes, or polymer blends thereof.

7. The method according to claim 4, wherein said plurality of nanotubes are formed on at least a portion of said first electrically conductive substrate comprising the steps:

(i) electrospinning a solution comprising a biodegradable polymer and at least one bioactive substance onto at least a portion of a surface of said first electrically conductive substrate thereby forming a mesh of nanofibers in contact with said first electrically conductive substrate;

(ii) electrochemically depositing a conductive polymer around said nanofibers forming a plurality of nanotubes; and

(iii) degrading said biodegradable polymer of said nanofibers with a solvent, thereby leaving said at least one bioactive substance inside a lumen or cavity of said nanotubes.

8. The method according to claim 7, wherein the concentration ratio of biodegradable polymer to bioactive substance ranges from 1:

99 to 99;

1.

9. The method according to claim 7, wherein the conductive polymer comprise poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), or polymer blends thereof.

10. The method according to claim 7, wherein the biodegradable polymer comprises a member selected from the group consisting of poly(D-lactic acid) (PDLA), poly(L-lactic acid) (PLLA), poly(lactide-co-glycolide) (PLGA) poly(glycolic acid) (PGA), and their derivatives, poly(epsilon caprolactone) (PCL), chitosan, nylon, PEOxide, alginates, poly vinyl alcohol and combinations thereof.

11. A method for treating a disease site in a patient, comprising the steps:

(i) providing a biocompatible electrode according to claim 1 and a power source operably connected to said first and said second electrically conductive substrates;

(ii) placing said electrode in contact or near the disease site in said patient,

(iii) applying a voltage to at least one of said first and said second electrically conductive substrates of said electrode so as to supply current to said electrically conductive nanotubes, thereby causing contraction of said nanotubes and concomitant release of said bioactive substance at or near the disease site.

12. The method according to claim 11, wherein the disease is selected from the group consisting of neurological disease, cardiac disease, cardiovascular disease, muscular disease, endocrinology disease, immunological disease, circulatory disease and combinations thereof.

13. The method according to claim 11, wherein the disease to be treated is any one or more of Parkinson'"'"'s disease, muscular dystrophy, Alzheimer'"'"'s disease, epilepsy, diabetes, and coronary artery disease.

14. The biocompatible electrode according to claim 1, wherein the first and second electrically conductive substrates independently comprise a metal, a carbon composite, silicon, a metal oxide, conductive polymer, or combinations thereof.

15. The biocompatible electrode according to claim 1, wherein the conductive polymer comprises poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyanilines, polyacetylenes, polythiophenes, or polymer blends thereof.

16. The biocompatible electrode according to claim 1, wherein the conductive polymer comprises poly(3,4-ethylenedioxythiophene) (PEDOT).

17. The biocompatible electrode according to claim 1, wherein the conductive polymer further comprises a dopant selected from the group consisting of poly(styrene sulfonate), LiClO₄, phosphate-buffered saline (PBS), Hank'"'"'s Balanced Salt Solution (HBSS), collagen, poly-D-lysine (PDL), poly-L-lysine, poly-ornithine, poly acrylic acid, serum, dodecylbenzene sulfonic acid (DBSA), p-toluenesulfonic acid (p-TSA), and combinations thereof.

18. The biocompatible electrode according to claim 1, wherein the bioactive substance is selected from the group consisting of a pharmaceutical active, a growth factor, a polypeptide, a lipid, a nucleic acid, a amino acid, a receptor, a steroid, a carbohydrate, a glycoprotein, a glycolipid, a neurotransmitter, an antineoplastic agent, an antiproliferative agent, an antithrombogenic agent, an anticoagulant, an antiplatelet agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, a therapeutic substance, and combinations thereof.

19. The biocompatible electrode according to claim 1, wherein the nanotubes comprise a diameter ranging from about 10 nm to about 1000 nm.

20. The biocompatible electrode according to claim 1, wherein the nanotubes comprise a wall thickness ranging from about 1 nm to about 500 nm.

21. The biocompatible electrode according to claim 1, further comprising a power source operably connected to the first and second conductive substrates.

22. The biocompatible electrode according to claim 1, wherein a hydrogel scaffold comprises the second electrically conductive substrate, the hydrogel scaffold being coated with a conducting polymer.