Biliary barrier

• US 20070048727A1
• Filed: 05/17/2006
• Published: 03/01/2007
• Est. Priority Date: 04/25/2001
• Status: Abandoned Application

• Current Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Original Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Inventors: Freedman, Robert, Shuler, Michael, Meyers, Scott, Sin, Aaron, Baxter, Gregory, Harrison, Andrew
• Application Number:
  US11/436,042
• Publication Number:
  US 20070048727A1
• Time in Patent Office: Days
• US Class Current: 435/1.200
• CPC Class Codes: B01L 3/5027 by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: C12M 21/08 for producing artificial tissue or for ex-vivo cultivation of tissue prostheses A61F2/00, grafts A61L27/00
• CPC Class Codes: C12M 23/16 Microfluidic devices; Capillary tubes integrated microfluidic structures B01L3/5027; microreactors B01J19/0093
• CPC Class Codes: C12M 23/34 Internal compartments or partitions
• CPC Class Codes: C12M 23/44 Multiple separable units; Modules
• CPC Class Codes: C12M 29/04 Filters; Permeable or porous membranes or plates, e.g. dialysis
• CPC Class Codes: C12M 35/08 Chemical, biochemical or biological means, e.g. plasma jet, co-culture

Abstract

Systems and methods are disclosed for microscale pharmacokinetics. Various organs and their interactions with drug compounds can be simulated in vitro by use of microscale compartments that can be interconnected by microscale channels. Cells or cellular materials associated with the organs can be cultured in such compartments to allow interactions with drug compounds in one or more fluidic flows. Such fluidic systems can include, by way of examples, gastrointestinal flow, blood flow, bile flow, urinary flow, and brain fluid flow. Interactions between fluidic systems can be simulated by a microscale permeable member. In one example, blood-biliary interaction can be simulated by a microscale permeable material having hepatocytes bound to a permeable substrate via a binder.

Claims

1. A device comprising:

microscale permeable material; and

at least one binder configured to polarize a substance wherein the substance manifests at least one characteristic of liver function.

2. The device of claim 1 wherein the substance is one or more hepatocytes.

3. The device of claim 1 wherein the substance is a genetically engineered biological material.

4. The device of claim 1 wherein the binder binds and polarizes hepatocytes to the microscale permeable material.

5. The device of claim 1 further comprising a second substance type.

6. The device of claim 1 further comprising one or more fibroblasts located near at least one surface of the microscale permeable material.

7. The device of claim 1 wherein the microscale permeable material is selected from at least one of the group consisting of organic material, inorganic material, a membrane, a porous membrane, microporous silicon, a semi-permeable membrane, a microporous material, a microporous polymer, alginate, collagen, MATRIGEL, cells, cellular material, tissue, and pieces of tissue.

8. The device of claim 1 wherein the microscale permeable material is in, on or near a microporous surface.

9. The device of claim 1 wherein the microscale permeable material is configured to simulate at least one of a biological barrier, passage of substances in or through a biological barrier, or absorption of substances in, through or by a biological barrier.

10. The device of claim 1 wherein the device processes the substance in by or through the microscale permeable material.

11. The device of claim 10 wherein the processing further comprises at least one of the group consisting of absorption, extraction, excretion, metabolism, and distribution of molecules.

12. The device of claim 1 wherein the microscale permeable material is located in or external to the device.

13. The device of claim 1 further comprising at least one microfluidic channel connected to the microscale permeable material.

14. The device of claim 1 wherein the characteristics of fluid flow through the device are based on a mathematical model.

15. The device of claim 14 wherein the mathematical model is a physiologically-based pharmacokinetic (“

PBPK”

) model.

16. The device of claim 1 wherein the feature or the microscale permeable material is integrated into a chip format.

17. The device of claim 1 wherein the device provides absorption characteristics, metabolic enzyme activity and/or expression levels.

18. The device of claim 1 further comprising locating biological material in, on or near both sides of the microscale permeable material.

19. The device of claim 18 wherein the biological material on either side of the microscale permeable material are of the same type or of different types.

20. The device of claim 1 wherein the microscale permeable material comprises a cell line capable of forming a confluent monolayer.

21. The device of claim 1 wherein the binder comprises at least one selected from the group consisting of a protein, connexin 32, a tight junction protein, occludin, claudin-1, ZO-1, ZO-2, an adherens junction protein, E-cadherin, beta-catenin, a cell adhesion molecule, and uvomorulin.

22. The device of claim 1 further comprising a blood surrogate flow in proximity to a first side of the microscale permeable material.

23. The device of claim 22 further comprising a bile surrogate flow in proximity to a second side of the microscale permeable material.

24. A method comprising binding a substance that manifests at least one characteristic of liver function to a microscale permeable material in a manner that polarizes the substance.

25. The method of claim 24 wherein the substance is one or more hepatocytes.

26. The method of claim 24 wherein the substance is a genetically engineered biological material.

27. The method of claim 24 further comprising providing a second substance type.

28. The method of claim 24 further comprising locating one or more fibroblasts near at least one surface of the microscale permeable material.

29. The method of claim 24 wherein the microscale permeable material is selected from at least one of the group consisting of a organic material, inorganic material, a membrane, a porous membrane, microporous silicon, a semi-permeable membrane, a microporous material, a microporous polymer, alginate, collagen, MATRIGEL, cells, cellular material, tissue, and pieces of tissue.

30. The method of claim 24 further comprising locating the microscale permeable material in, on or near a microporous surface.

31. The method of claim 24 wherein the microscale permeable material simulates at least one of a biological barrier, passage of substances in or through a biological barrier, or absorption of substances in, through or by a biological barrier.

32. The method of claim 24 further comprising processing the substance in, through or by the microscale permeable material.

33. The method of claim 32 wherein the processing further comprises at least one of the group consisting of absorption, extraction, excretion, metabolism, and distribution of molecules.

34. The method of claim 24 further comprising locating the microscale permeable material in or external to a device.

35. The method of claim 24 further comprising providing at least one microfluidic channel connected to the microscale permeable material.

36. The method of claim 24 wherein the characteristics of fluid flow associated with the at least one characteristic of liver function are based on a mathematical model.

37. The method of claim 36 wherein the mathematical model is a physiologically-based pharmacokinetic (“

PBPK”

) model.

38. The method of claim 24 further comprising integrating the microscale permeable material into a chip format.

39. The method of claim 24 further comprising providing absorption characteristics, metabolic enzyme activity and/or expression levels.

40. The method of claim 24 further comprising locating biological material in, on or near both sides of the microscale permeable material.

41. The method of claim 40 wherein the biological material is on either side of the microscale permeable material is of the same type or of different types.

42. The method of claim 24 wherein the microscale permeable material comprises a cell line capable of forming a confluent monolayer.

43. The method of claim 24 wherein the binding comprises providing a binder selected from at least one of the group consisting of a protein, connexin 32, a tight junction protein, occludin, claudin-1, ZO-1, ZO-2, an adherens junction protein, E-cadherin, beta-catenin, a cell adhesion molecule, and uvomorulin.

44. The method of claim 24 further comprising providing a blood surrogate flow in proximity to a first side of the microscale permeable material.

45. The method of claim 24 further comprising providing a bile surrogate flow in proximity to a second side of the microscale permeable material.

46. A method of forming a device comprising forming a microscale permeable material that is configured to bind to and polarize a substance that manifests at least one characteristic of liver function.

47. A microscale apparatus comprising:

means for binding a substance that manifests at least one characteristic of liver function to a microscale permeable material in a manner that polarizes the substance.

48. A device comprising:

a microscale permeable material; and

at least one substance configured to manifest at least one characteristic of liver function, wherein molecules processed by the substance are directed to pass through at least a portion of the microscale permeable material.

49. A method comprising directing molecules processed by a substance through at least a portion of a microscale permeable material, wherein the substance is configured to manifest at least one characteristic of liver function.

50. A method of forming a device comprising forming a microscale permeable material that is configured to direct molecules processed by a substance through at least a portion of the microscale permeable material, wherein the substance is configured to manifest at least one characteristic of liver function.

51. A device comprising means for directing molecules processed by a substance through at least a portion of a microscale permeable material, wherein the substance is configured to manifest at least one characteristic of liver function.