Hydrogel compositions, devices, and microscale components

• US 20040248326A1
• Filed: 07/29/2004
• Published: 12/09/2004
• Est. Priority Date: 11/01/2001
• Status: Active Grant

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Lei, Ming, Gu, Yuandong, Ziaie, Babak, Loftness, Paul E, Siegel, Ronald A, Baldi, Antoni, Misra, Gauri P
• Granted Patent: US 7,988,685 B2
• Time in Patent Office: Days
• US Class Current: 438/1
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/80 characterised by a special chemical form
• CPC Class Codes: A61L 29/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids

Abstract

The invention provides hydrogel compositions, components, and hydrogel-actuated or mediated devices, and methods for the incorporation of hydrogel microscale components in microscale devices and systems. The methods and devices result in active microvalves that are useful in microfluidic applications, including analyte sensing, in process chemical and fermentation stream monitoring, and drug delivery. In particular, the devices are useful for controlled drug delivery either in response to a pre-determined stimulus or for pulsatile delivery.

Claims

1. A method of manufacturing a microscale component comprising:

(a) providing a substrate;

(b) removing at least a portion of the substrate to form a first set of one or more microscale channels on a first surface of the substrate, the channels of the first set having a depth of more than half of the cross-section depth of the substrate; and

(c) producing the microscale component by removing at least a portion of the substrate to form a second set of one or more microscale channels on a second surface of the substrate, the channels of the second set having a depth of more than half of the cross-section depth of the substrate, and the second set in an orientation to the first set to allow the first and second sets to intersect.

2. The method according to claim 1, further comprising:

(a) introducing a liquid polymerizable mixture into the first and second sets of microscale channels;

(b) polymerizing the liquid polymerizable mixture in the first and second sets of microscale channels; and

(c) removing residual unreacted liquid polymerizable mixture from the first and second sets of microscale channels to result in a hydrogel at the intersection of the first and second sets.

3. The method of claim 1, wherein said substrate is chosen from the group consisting of glass, plastic, silicon, and a transparent mineral.

4. The method of claim 1, wherein the substrate has a cross-section depth of about 100-1000 μ

m.

5. The method of claim 1, wherein the first and second set of channels are independently formed by a process chosen from the group consisting of lithography and deep trench etching.

6. The method of claim 1, wherein the second set of one or more microscale channels in step (c) is in a perpendicular orientation to the first set.

7. The method of claim 1, wherein the microscale channels of the first and second sets independently have an aspect ratio of from about 10:

1 to about 1;

10.

8. The method of claim 2, wherein the liquid polymerizable mixture comprises:

(a) a comonomer; and

(b) a crosslinker.

9. The method of claim 8, wherein the liquid polymerizable mixture further comprises a responsive composition.

10. The method of claim 9, wherein the responsive composition is selected from the group consisting of 3-methylacrylamidophenylboronic acid and 3-acrylamido-4-nitrobenzeneboronic acid.

11. The method of claim 8, wherein the liquid polymerizable mixture comprises the monomer acrylamide and the crosslinker N,N′

-methylenebisacrylamide.

12. The method of claim 2, wherein the hydrogel is capable of undergoing a volume change in response to a predetermined stimulus in a medium contacting the hydrogel.

13. The method of claim 12, wherein the predetermined stimulus is a physical change, a chemical change, a chemical compound, or a biological agent.

14. The method of claim 13, wherein the predetermined stimulus is a physical change in the medium contacting the hydrogel.

15. The method of claim 14, wherein the physical change is chosen from the group consisting of a temperature change, an electric field change, a change in light absorption, a change in light emission, a magnetic field change, and a pressure change.

16. The method of claim 12, wherein the predetermined stimulus is a chemical change in the medium contacting the hydrogel.

17. The method of claim 16, wherein the chemical change is chosen from the group consisting of a pH change and an ionic strength change.

18. The method of claim 12, wherein the predetermined stimulus is a chemical compound in the medium contacting the hydrogel.

19. The method of claim 18, wherein the chemical compound is chosen from the group consisting of glucose, lactate, lactic acid, ethanol, glycerol, and ammonia.

20. The method of claim 12, wherein the predetermined stimulus is a biological agent in the medium contacting the polymer gel.

21. The method of claim 20, wherein the biological agent is chosen from the group consisting of a toxin, a pathogen, a protein, an antibody, an antigen, a virus, a peptide, and a nucleic acid.

22. A microscale component comprising a substrate having:

a) a first set of one or more microscale channels on a first surface of the substrate, the channels of the first set having a depth of more than half of the cross-section depth of the substrate; and

b) a second set of one or more microscale channels on a second surface of the substrate, the channels of the second set having a depth of more than half of the cross-section depth of the substrate, and the second set in an orientation to the first set to allow the first and second sets to intersect.

23. The microscale component of claim 22, further comprising a hydrogel at the intersection of the first and second sets of microscale channels.

24. The microscale component of claim 23, wherein the hydrogel is capable of undergoing a volume change in response to a pre-determined stimulus in a medium contacting the hydrogel.

25. The microscale component of claim 24, wherein the pre-determined stimulus is selected from the group consisting of a pH change, a temperature change, and a chemical compound.

26. An implantable medical device comprising a microscale component.

27. The implantable medical device of claim 26, further comprising a drug reservoir in communication with the microscale component.

28. The implantable medical device of claim 27, wherein the drug reservoir communicates with the microscale component through a catheter.

29. The implantable medical device of claim 28, further comprising a pump to deliver the drug from the drug reservoir to the microscale component.

30. An implantable microscale system for drug delivery to a patient comprising:

a) a microscale component;

b) a catheter, one end of the catheter in communication with the microscale component;

c) a reservoir comprising a drug, the reservoir in communication with the second end of the catheter; and

d) a pump, the pump capable of delivering the drug from the reservoir through the catheter to the microscale component.

31. The system of claim 30, wherein the end of the catheter in communication with the microscale component is positioned intraperitoneally, subcutaneously, or intravascularly in the patient.

32. The system of claim 30, wherein the pump is selected from the group consisting of a volatile liquid/bellows pump, an osmotic pump, and an electromechanical pump.

33. A method of manufacturing a microscale component comprising:

(a) providing a substrate; and

(b) producing the microscale component by removing at least a portion of said substrate to leave a substrate member having a plurality of radial projections, wherein said substrate member has an axis substantially perpendicular to a first surface of said substrate, wherein said substrate member substantially spans the cross-sectional depth of said substrate, and wherein said plurality of radial projections span a portion of the cross-sectional depth of said substrate.

34. The method of claim 33, wherein said substrate is removed by:

a) etching said substrate to produce a set of microscale orifices on said substrate, wherein said set of orifices are positioned around a substrate member, wherein said substrate member has an axis substantially perpendicular to a first surface of said substrate, wherein said substrate member substantially spans the cross-sectional depth of said substrate, wherein said substrate member has a plurality of radial projections, and wherein said substrate member and said radial projections extend the cross-sectional depth of said substrate; and

b) etching said radial projections so that they span a portion of the cross-sectional depth of said substrate.

35. The method of claim 33, further comprising:

(a) introducing a liquid polymerizable mixture into the microscale component;

(b) polymerizing the liquid polymerizable mixture in the microscale component; and

(c) removing residual unreacted liquid polymerizable mixture to result in a hydrogel positioned within the microscale component.

36. A microscale component comprising a substrate having a substrate member substantially spanning the cross-sectional depth of the substrate, wherein said substrate member has an axis substantially perpendicular to a first surface of said substrate, wherein said substrate member has a plurality of radial projections, and wherein said radial projections span a portion of the cross-sectional depth of said substrate.

37. The microscale component of claim 36, further comprising a hydrogel positioned within said substrate.

38. The microscale component of claim 37, wherein said hydrogel is positioned adjacent to said substrate member and wherein said hydrogel is tethered to one or more of said plurality of radial projections.

39. An implantable, hydrogel-actuated microvalve comprising:

(a) a first substrate permeable to a predetermined chemical compound;

(b) a volume-responsive hydrogel adjacent to the permeable first substrate, the volume-responsive hydrogel undergoing a volume change in response to the predetermined chemical compound;

(c) a second substrate adjacent to the volume-responsive hydrogel, the second substrate deformable in response to the volume-responsive hydrogel; and

(d) a third substrate adjacent to the second substrate, the third substrate comprising an orifice capable of being sealed by the second substrate upon the deformation of the second substrate.

42. The hydrogel-actuated microvalve of any of claims 39-41, wherein the first substrate is resistant to deformation.

43. The hydrogel-actuated microvalve of any of claims 39-41, wherein the first substrate comprises a porous glass plate.

44. The hydrogel-actuated microvalve of any of claims 39-41, wherein the first substrate comprises a porous aluminum oxide plate.

45. The hydrogel-actuated microvalve of any of claims 39-41, wherein the first substrate comprises a porous plate having homogenous pores in the range of about 10 nm to about 50 μ

m.

46. The hydrogel-actuated microvalve of any of claims 39-41, wherein the first substrate comprises a porous plate having a thickness of about 50 to about 1000 μ

m.

47. The hydrogel-actuated microvalve of any of claims 39-41, wherein the volume-responsive hydrogel undergoes a volume increase or a volume decrease in response to the predetermined chemical compound glucose.

48. The hydrogel-actuated microvalve of claim 47, wherein the hydrogel comprises 3-methacrylamidophenylboronic acid and wherein the hydrogel undergoes a volume increase in response to glucose.

49. The hydrogel-actuated microvalve of claim 47, wherein the hydrogel comprises 3-acrylamido-4-nitrobenzeneboronic acid and wherein the hydrogel undergoes a volume decrease in response to glucose.

50. The hydrogel-actuated microvalve of any of claims 39-41, wherein the second substrate is selected from the group consisting of a low modulus silicone, neoprene, and isoprene rubber.

51. A catheter comprising the hydrogel-actuated microvalve of any of claims 39-41.

40. An implantable, hydrogel-actuated microvalve comprising:

(a) a first substrate permeable to a predetermined chemical compound;

(b) a volume-responsive hydrogel adjacent to the permeable first substrate, the volume-responsive hydrogel undergoing a volume change in response to the predetermined chemical compound;

(c) a second substrate adjacent to the volume-responsive hydrogel, the second substrate deformable in response to the volume-responsive hydrogel;

(d) a third substrate adjacent to the second substrate, the third substrate comprising a member, the member moveable in response to deformation of the second substrate;

(e) a fourth substrate adjacent to the third substrate, the fourth substrate comprising an orifice capable of being sealed by the member of the third substrate upon movement of the member.

41. An implantable, hydrogel-actuated microvalve comprising:

(a) a first substrate permeable to a predetermined chemical compound;

(b) a volume-responsive hydrogel adjacent to the permeable first substrate, the volume-responsive hydrogel undergoing a volume change in response to the predetermined chemical compound;

(c) a second substrate adjacent to the volume-responsive hydrogel, the second substrate deformable in response to the volume-responsive hydrogel;

(d) a third substrate adjacent to the second substrate, the third substrate comprising a member, the member moveable in response to deformation of the second substrate; and

(e) a fourth substrate adjacent to the third substrate, the fourth substrate comprising a flexible body, the flexible body controlling access, upon movement of the member, to a channel disposed between the third substrate and the fourth substrate.

52. A system for delivering a drug to a patient comprising:

a) an implantable, hydrogel-actuated microvalve;

b) a catheter, one end of the catheter in communication with the hydrogel-actuated microvalve;

c) a reservoir comprising a drug, the reservoir in communication with the second end of the catheter; and

d) a pump, the pump capable of delivering the drug from the reservoir through the catheter to the hydrogel-actuated microvalve.

53. The system of claim 52, wherein the drug is insulin.