Implantable system with drug-eluting cells for on-demand local drug delivery

• US 20010000802A1
• Filed: 12/20/2000
• Published: 05/03/2001
• Est. Priority Date: 04/30/1998
• Status: Active Grant

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Soykan, Orhan, Donovan, Maura G.
• Granted Patent: US 6,824,561 B2
• Time in Patent Office: Days
• US Class Current: 623/1.13
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2/88 the wire-like elements formed as helical or spiral coils forming a net-like or mesh-like structure A61F2/90
• CPC Class Codes: A61F 2250/0001 Means for transferring electromagnetic energy to implants
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 2035/126 Immunoprotecting barriers, e.g. jackets, diffusion chambers
• CPC Class Codes: A61K 38/4866 Protein C (3.4.21.69)
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 2300/22 Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/254 Enzymes, proenzymes
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/64 : Animal cells
• CPC Class Codes: A61L 27/3804 : characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/3808 : Endothelial cells
• CPC Class Codes: A61L 27/3843 : Connective tissue
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/005 : Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/005 : Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61N 1/36542 : controlled by body motion, e.g. acceleration
• CPC Class Codes: C12N 5/069 : Vascular Endothelial cells

Abstract

An implantable system that includes a carrier and eukaryotic cells, which produce and release a therapeutic agent, and a stimulating element for stimulating the release of the therapeutic agent. The system can also include a sensing element for monitoring a physiological condition and triggering the stimulating element to stimulate the delivery device to release the therapeutic agent. Alternatively, the patient in which the system is implanted can activate the stimulating element to release the therapeutic agent.

Claims

1. An implantable system comprising:

(a) a delivery device comprising a carrier and eukaryotic cells that produce at least one therapeutic agent;

(b) a stimulating element for stimulating the release of the therapeutic agent from the delivery device; and

(c) a sensing element for monitoring at least one physiological property of a patient in which the system is implanted and communicating with the stimulating element to stimulate the release of the therapeutic agent from the delivery device.

2. The implantable system of

claim 1

wherein the delivery device comprises a carrier selected from stents, vascular grafts, stent grafts, synthetic patches, infusion sleeves, medical electrical leads, medical electrial electrodes, and indwelling catheters.

3. The implantable system of

claim 2

wherein the delivery device comprises:

(a) an intraluminal stent comprising;

(i) a lumen-wall contacting surface;

(ii) a lumen-exposed surface;

(iii) a first polymer composition covering at least a portion of the stent; and

(b) eukaryotic cells associated with the first polymer composition.

4. The implantable system of

claim 3

wherein the first polymer composition is capable of dehydration and rehydration.

5. The implantable system of

claim 3

wherein the first polymer composition comprises one or more polymers selected from fibrins, collagens, alginates, polylactic acids, polyglycolic acids, celluloses, hyaluronic acids, polyurethanes, silicones, polycarbonates, mixtures and copolymers thereof.

6. The implantable system of

claim 1

eukaryotic cells comprise endothelial cells, fibroblasts, or mixtures thereof.

7. The implantable system of

claim 6

wherein the eukaryotic cells comprise endothelial cells.

8. The implantable system of

claim 7

wherein the endothelial cells are autologous.

9. The implantable system of

claim 7

wherein the endothelial cells are genetically engineered.

10. The implantable system of

claim 1

wherein the therapeutic agent is selected from anticoagulant agents, antiplatelet agents, antifibrinolytic agents, angiogenesis factors, and mixtures thereof.

11. The implantable system of

claim 10

wherein the therapeutic agent is selected from activated protein C, tissue plasminogen activator, prostacyclin, and vascular endothelial growth factor.

12. The implantable system of

claim 11

wherein the therapeutic agent is tissue plasminogen activator.

13. The implantable system of

claim 1

wherein the delivery device further comprises a containment vehicle in which the cells are located.

14. The implantable system of

claim 1

wherein the stimulating element comprises an implantable pulse generator.

15. The implantable system of

claim 14

wherein the stimulating element is selected from the group of an electrical stimulating element, a mechanical stimulating element, an acoustic stimulating element, a chemical stimulating element, a thermal stimulating element, and combinations thereof.

16. The implantable system of

claim 15

wherein the stimulating element is an electrical stimulating element.

17. The implantable system of

claim 1

wherein the sensing element comprises one or more sensors.

18. The implantable system of

claim 1

wherein the sensing element comprises a pseudo-surface electrocardiogram using a subcutaneous electrode array for detecting a reduction in blood flow.

19. The implantable system of

claim 1

wherein the sensing element comprises a blood gas sensor, pH sensor, blood flow sensor, or combinations thereof.

20. An implantable system comprising:

(a) a delivery device comprising;

(i) an intraluminal stent comprising;

(A) a lumenwall contacting surface;

(B) a lumen-exposed surface;

(C) a first polymer composition covering at least a portion of the stent; and

(ii) endothelial cells associated with the first polymer composition;

wherein the endothelial cells produce at least one therapeutic agent;

(b) an electrical stimulating element for stimulating the release of the therapeutic agent from the delivery device; and

(c) a sensing element for monitoring at least one physiological property of a patient in which the system is implanted and communicating with the electrical stimulating element to stimulate the release of the therapeutic agent from the delivery device.

21. A method of local delivery of a therapeutic agent to a patient, the method comprising:

(a) providing an implantable system comprising;

(i) a delivery device comprising a carrier and eukaryotic cells that produce at least one therapeutic agent;

(ii) a stimulating element for stimulating the release of the therapeutic agent from the delivery device; and

(iii) a sensing element for monitoring at least one physiological property of a patient in which the system is implanted and communicating with the stimulating element to stimulate the release of the therapeutic agent from the delivery device; and

(b) implanting the implantable system into the body of a patient;

wherein the therapeutic agent is released from the delivery device when the sensing element detects a predetermined level of a physiological property and communicates with the stimulating element to trigger the release of the therapeutic agent.

22. The method of

claim 21

wherein the stimulating element stimulates the cells to release the therapeutic agent.

23. The method of

claim 21

wherein the delivery device further comprises a containment vehicle in which the cells are located.

24. The method of

claim 23

wherein the stimulating element stimulates the containment vehicle to release the therapeutic agent.

25. The method of

claim 23

wherein the stimulating element is selected from the group of an electrical stimulating element, a mechanical stimulating element, an acoustic stimulating element, a chemical stimulating element, a thermal stimulating element, and combinations thereof.

26. The method of

claim 25

wherein the stimulating element electrically stimulates the cells to release the therapeutic agent.

27. The method of

claim 21

wherein the sensing element comprises one or more sensors.

28. The method of

claim 21

wherein the sensing element comprises a blood gas sensor, pH sensor, blood flow sensor, or combinations thereof.

29. A method of local delivery of a therapeutic agent comprising:

(a) providing an implantable system comprising;

(i) a delivery device comprising;

(A) an intraluminal stent comprising;

(I) a lumen-wall contacting surface;

(II) a lumen-exposed surface;

(III) a first polymer composition covering at least a portion of the stent; and

(B) endothelial cells associated with the first polymer composition;

wherein the endothelial cells produce at least one therapeutic agent;

(ii) an electrical stimulating element for electrically stimulating the release of the therapeutic agent from the delivery device; and

(iii) a sensing element for monitoring at least one physiological property of a patient in which the system is implanted and communicating with the stimulating element to stimulate the release of the therapeutic agent from the delivery device; and

(b) implanting the implantable system into the body of a patient;

wherein the therapeutic agent is released from the delivery device when the sensing element detects a predetermined level of a physiological property and communicates with the electrical stimulating element to trigger the release of the therapeutic agent.

30. A method of making an implantable system for local delivery of a therapeutic agent, the method comprising:

(a) providing a delivery device comprising a carrier and eukaryotic cells that produce at least one therapeutic agent;

(b) providing a stimulating element for stimulating the release of the therapeutic agent from the delivery device;

(c) providing a sensing element for monitoring at least one physiological property of a patient in which the system is implanted; and

(d) connecting the stimulating element and sensing element such that they communicate with each other to stimulate the release of the therapeutic agent from the delivery device when implanted in the body of a patient and the sensing element detects a predetermined level of a physiological property.

31. The method of

claim 30

wherein the step of providing a delivery device comprises:

(a) providing a carrier;

(b) isolating eukaryotic cells from a patient;

(c) culturing the eukaryotic cells;

(d) delivering nucleic acid of a desired therapeutic agent to the eukaryotic cells to form genetically engineered eukaryotic cells; and

(e) contacting the carrier with the genetically engineered eukaryotic cells.

32. The method of

claim 31

wherein the eukaryotic cells are endothelial cells.

33. The method of

claim 32

wherein the nucleic acid encodes tissue plasminogen activator.

34. The method of

claim 31

wherein the step of delivering nucleic acid comprises infecting the eukaryotic cells with a retrovirus comprising the nucleic acid to form genetically engineered eukaryotic cells.

35. The method of

claim 31

wherein the nucleic acid is RNA or DNA.

36. The method of

claim 31

wherein the carrier comprises a stent comprising a lumen-wall contacting surface, a lumen-exposed surface, and a first polymer composition comprising fibrin covering at least a portion of the lumen-exposed surface to form a polymer covered stent.

37. The method of

claim 36

wherein the contacting step comprises dipping the polymer covered stent into a solution or gel comprising the genetically engineered eukaryotic cells.

38. The method of

claim 36

wherein the contacting step comprises placing the first polymer composition and genetically engineered eukaryotic cells into a mold.

39. The method of

claim 36

wherein the eukaryotic cells are contacted with the stent just prior to implantation.

40. A kit comprising:

a stent comprising a lumen-wall contacting surface, a lumen-exposed surface, and a first polymer composition comprising fibrin covering at least a portion of the stent;

a cell-loading composition to be applied to the stent; and

a container to house the stent and the composition during application of the cell-loading composition.

41. An implantable system comprising:

(a) a delivery device comprising a carrier and eukaryotic cells that produce at least one therapeutic agent; and

(b) a stimulating element for stimulating the release of the therapeutic agent from the delivery device;

wherein the stimulating element can be activated by a patient in which it is implanted on demand.

42. The implantable system of

claim 41

wherein the delivery device comprises:

(a) an intraluminal stent comprising;

(i) a lumen-wall contacting surface;

(ii) a lumen-exposed surface;

(iii) a first polymer composition covering at least a portion of the stent; and

(b) endothelial cells associated with the first polymer composition;

wherein the endothelial cells produce at least one therapeutic agent.

43. A method of local delivery of a therapeutic agent to a patient, the method comprising:

(a) providing an implantable system comprising;

(i) a delivery device comprising a carrier and eukaryotic cells that produce at least one therapeutic agent; and

(ii) a stimulating element for stimulating the release of the therapeutic agent from the delivery device; and

(b) implanting the implantable system into the body of a patient;

wherein the therapeutic agent is released from the delivery device when the patient detects a change in a physiological condition and communicates with the electrical stimulating element to trigger the release of the therapeutic agent.

44. The method of

claim 43

wherein the delivery device comprises:

(a) an intraluminal stent comprising;

(i) a lumen-wall contacting surface;

(ii) a lumen-exposed surface;

(iii) a first polymer composition covering at least a portion of the stent; and

(b) endothelial cells associated with the first polymer composition;

wherein the endothelial cells produce at least one therapeutic agent.

45. The method of

claim 43

wherein the patient activates the stimulating element using radio frequency, infrared, or acoustic pulses.