Apparatuses and methods for treating biological tissue to mitigate calcification

• US RE40,570 E1
• Filed: 04/03/2003
• Issued: 11/11/2008
• Est. Priority Date: 07/29/1994
• Status: Expired due to Term

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Schreck, Stefan G., Carpentier, Alain F., Wang, Jong H., Quintero, Lillian J., Packham, Victor S., Carpentier, Sophie
• Primary Examiner(s): Mruk; Brian P
• Application Number:
  US10/406,354
• Time in Patent Office: 2,049 Days
• Field of Search: 8 9/41.R, 8 9/411, 600/36, 623/2.13, 623/23.72, 623/915, 435/284.1, 435/289.1, 435/297.1, 435/297.2, 435/297.5, 435/303.1, 435/307.1
• US Class Current: 435/284.1
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation

Abstract

An apparatus for treating fixed biological tissue to inhibit calcification of the biological tissue following implantation thereof in a mammalian body. The apparatus includes a container for placing the biological tissue in contact with a treatment solution, structure to induce relative tissue/solution movement, and structure to heat the solution. The relative movement may be induced by shaking a container in which the tissue is immersed in the treatment solution, or by stirring the solution within the container. The movement may also be induced by flowing a treatment solution past the tissue to be treated. The tissue may be free to move in the treatment container, or may be restrained from gross movements. The flow may be part of a circulation system having a reservoir, with a heater being provided to heat the treatment solution in the reservoir. Alternatively, a treatment apparatus, including a fluid circulation system if desired, may be enclosed in an incubator. The tissue may be mounted in a planar configuration generally parallel to the direction of fluid flow. A flow column having a plurality of sections divided by perforated baffles may be used to treat multiple tissues at once.

Claims

1. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a flow container;

a reservoir containing treatment fluid suitable for fixing the tissue;

a fluid input to the container;

a fluid output from the container;

a tissue mount for positioning the at least partially fixed biological tissue within the container between the input and ouput output and restrain its gross movement therein; and

means for heating the fluid to a temperature greater than body temperature (>

37°

C.) comprising a heater for heating fluid in the reservoir.

2. The apparatus of claim 1, wherein the flow container is divided into at least two sections in series separated by perforated baffles, with at least one tissue mount in each section.

3. The apparatus of claim 2, wherein the flow container is an elongated tube and the baffles are circular.

4. The apparatus of claim 1, wherein the tissue mount is configured to mount the tissue in a planar configuration substantially parallel to the direction of flow of the solution flowing through the container.

5. The apparatus of claim 1, further including at least one baffle positioned in the flow container and upstream of the tissue mount, the baffle being configured to create a substantially uniform downstream flow profile over a cross-section of the flow container.

6. The apparatus of claim 5, wherein the baffles are perforated plates oriented substantially normal to the direction of flow of the solution flowing through the container, and the flow container is divided into at least two sections in series, each two adjacent sections being separated by a baffle, with at least one tissue mount in each section removably secured to one of the baffles.

7. The apparatus of claim 1, further including a sensor for monitoring the fluid temperature in the reservoir, and a feedback control loop responsive to the sensed temperature for adjusting the heater temperature.

8. The apparatus of claim 1, wherein the flow container comprises an upstanding tube, the fluid input being located at the lower end of the tube and the fluid output being located at the upper end of the tube, the apparatus further comprising a velocity reducer above the fluid input, and a flow straightener above the velocity reducer and below the first tissue mount.

9. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a piece of at least partially fixed biological tissue;

a container suitable for containing tissue treatment fluid and immersing the piece of at least partially fixed biological tissue in the fluid;

a shaker for causing treatment fluid movement within the container;

means for heating the treatment fluid and tissue within the container; and

means for restraining the immersed tissue from gross movement within the container.

10. The apparatus of claim 9, wherein the piece of at least partially fixed biological tissue is a bioprosthetic heart valve leaflet.

11. The apparatus of claim 9, wherein the shaker is an orbital shaker.

12. An apparatus for treating at least partially faced fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a piece of at least partially fixed biological tissue,

a container suitable for containing tissue treatment fluid and immersing the piece of at least partially fixed biological tissue in the fluid,

means for causing treatment fluid movement within the container comprising a stirrer immersed in the treatment fluid,

means for heating the treatment fluid; and

means for restraining the immersed tissue from gross movement within the container.

13. The apparatus of claim 12, wherein the stirrer is a stirring rod.

14. The apparatus of claim 13, further including a shaft drive for the stirring rod.

15. The apparatus of claim 13, further including a magnetic drive for the stirring rod.

16. The apparatus of claim 12, wherein the means for restraining tissue from gross movement within the container comprises a porous substrate separating the tissue from the stirrer.

17. The apparatus of claim 16, wherein the container has an open mouth and the porous substrate is draped over the open mouth and separates the container into an upper portion for receiving the tissue and a lower portion for receiving the stirrer.

18. The apparatus of claim 12, wherein the means for heating comprises a heater adjacent to the container that applies heat to the outside of the container and indirectly heats the treatment fluid therein.

19. The apparatus of claim 18, wherein the heater comprises a resistive heater.

20. The apparatus of claim 12, wherein the means for heating comprises a heater that applies heat directly to the treatment fluid.

21. The apparatus of claim 12, wherein the heater is external to the container.

22. The apparatus of claim 12, wherein the heater comprises a convective flow heater.

23. An apparatus for treating an at least partially fixed sheet of biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

treatment fluid suitable for fixing the tissue;

a container suitable for containing the tissue treatment fluid having a fluid input and a fluid output;

a system for continuously flowing the treatment fluid through the flow container between the input and output;

a tissue mount for positioning the at least partially fixed sheet of biological tissue within the container between the input and output and restrain its gross movement therein, the tissue mount being adapted to mount the tissue sheet in a planar configuration substantially parallel to the direction of flow of the treatment fluid, the sheet of biological tissue being immersed in the continuous flow of treatment fluid; and

means for heating the treatment fluid.

24. The apparatus of claim 23, wherein the flow container has a cross-section oriented substantially normal to the direction of flow of the treatment fluid, the apparatus further including a baffle positioned upstream of the mount which creates a substantially uniform downstream flow profile over the container cross-section in the region of the mount.

25. The apparatus of claim 24, further comprising a plurality of perforated baffles dividing the flow container into a series of sections, and a plurality of said mounts in each section for mounting multiple tissue pieces within each section.

26. The apparatus of claim 23, further comprising a reservoir external to the container, the flow container having an inlet and an outlet, and a pump for circulating treatment fluid from the reservoir to the flow container and expelling fluid from the flow container outlet back to the reservoir.

27. The apparatus of claim 26, wherein the means for heating heats the treatment solution in the reservoir.

28. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a flow container divided into at least two sections in series separated by perforated baffles;

a supply of treatment fluid;

a fluid input to the container;

a fluid output from the container;

at least one tissue mount in each section for positioning the at least partially fixed biological tissue within the container between the input and output and restrain its gross movement therein; and

means for heating the fluid.

29. The apparatus of claim 28, wherein the flow container is an elongated tube and the baffles are circular.

30. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a flow container;

a supply of treatment fluid;

a fluid input to the container;

a fluid output from the container;

a tissue mount for positioning the at least partially fixed biological tissue within the container between the input and output and restrain its gross movement therein;

means for heating the fluid; and

at least one baffle positioned in the flow container and upstream of the tissue mount, the baffle being configured to create a substantially uniform downstream flow profile over a cross-section of the flow container.

31. The apparatus of claim 30, wherein the baffle is a perforated plate oriented substantially normal to the direction of flow of the solution flowing through the container, and the flow container is divided into at least two sections in series, each two adjacent sections being separated by a baffle, with at least one tissue mount in each section removably secured to one of the baffles.

32. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a flow container comprising an upstanding tube;

a supply of treatment fluid;

a fluid input to the container at a lower end of the tube;

a fluid output from the container at an upper end of the tube;

a tissue mount for positioning the at least partially fixed biological tissue within the container between the input and output and restrain its gross movement therein;

means for heating the fluid; and

a velocity reducer above the inlet aperture, and a flow straightener above the velocity reducer and below the first tissue mount.

33. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a container suitable for containing tissue treatment fluid;

means for causing treatment fluid movement within the container including a stirrer immersed in the treatment fluid;

means for heating the treatment fluid; and

means for restraining the immersed tissue from gross movement within the container.

34. The apparatus of claim 33, wherein the means for restraining tissue from gross movement within the container comprises a porous substrate separating the tissue from the stirrer.

35. The apparatus of claim 34, wherein the container has an open mouth and the porous substrate is draped over the open mouth and separates the container into an upper portion for receiving the tissue and a lower portion for receiving the stirrer.

36. An apparatus for treating at least partially fixed biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, comprising:

a flow container suitable for containing tissue treatment fluid;

a system for flowing treatment fluid through the flow container, wherein the flow container has a cross-section oriented substantially normal to the direction of flow of the treatment fluid;

means for restraining the tissue from gross movement within the flow container comprising a mount for mounting the tissue in a planar configuration substantially parallel to the direction of flow of the treatment fluid;

a baffle positioned upstream of the mount which creates a substantially uniform downstream flow profile over the container cross-section in the region of the mount; and

means for heating fluid.

37. The apparatus of claim 36, further comprising a plurality of perforated baffles dividing the flow container into a series of sections, and a plurality of said mounts in each section for mounting multiple tissue pieces within each section.

38. A method for treating biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, the method comprising:

fixing the tissue in a fixative solution; and

prior to implantation, heat treating the fixed tissue in a glutaraldehyde solution at a temperature in the range of 45-55°

C. for a period of time.

39. The method of claim 38, wherein heat treating is done at a temperature in the range of 50°

C.±

1°

C.

40. The method of claim 38, wherein the period of time is in the range of about a few days to 22 weeks.

41. The method of claim 38, wherein the period of time is in the range of about 4 to 22 weeks.

42. The method of claim 38, wherein the period of time is in the range of about 14 days to 2 months.

43. The method of claim 38, wherein the period of time is in the range of about 30 days to 60 days.

44. The method of claim 38, further including immersing the tissue in a solution comprising an alcohol, formaldehyde and Tween 80.

45. The method of claim 44, including immersing the tissue in the solution comprising an alcohol, formaldehyde and Tween 80 for about 2 hours at room temperature so as to sterilize the tissue.

46. The method of claim 38, further including inducing relative and repeated tissue/solution movement during the step of heat treating.

47. The method of claim 46, further including enclosing the treatment solution in a container.

48. The method of claim 46, wherein the step of inducing comprises shaking the container.

49. The method of claim 46, wherein the step of inducing comprises rolling the container.

50. A method for treating biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, the method comprising:

fixing the tissue in a glutaraldehyde solution while heating the glutaraldehyde solution to a temperature in the range of about 50°

C.±

1°

C. for a period of time.

51. The method of claim 50, wherein the tissue is heat treated in a glutaraldehyde solution.

52. The method of claim 50, wherein the period of time is in the range of about a few days to 22 weeks.

53. The method of claim 50, wherein the period of time is in the range of about 4 to 22 weeks.

54. The method of claim 50, wherein the period of time is in the range of about 14 days to 22 months.

55. The method of claim 50, wherein the period of time is in the range of about 30 days to 60 days.

56. The method of claim 50, further including immersing the tissue in a solution comprising an alcohol, formaldehyde and Tween 80.

57. The method of claim 56, including immersing the tissue in the solution comprising an alcohol, formaldehyde and Tween 80 for about 2 hours at room temperature so as to sterilize the tissue.

58. The method of claim 50, further including inducing relative and repeated tissue/solution movement during the step of heat treating.

59. The method of claim 58, further including enclosing the treatment solution in a container.

60. The method of claim 58, wherein the step of inducing comprises shaking the container.

61. The method of claim 58, wherein the step of inducing comprises rolling the container.

62. A method for treating biological tissue to inhibit calcification of the tissue following implantation in a mammalian body, the method comprising:

prior to fixing the tissue, heat treating the tissue in a saline solution only to a temperature of about 50°

C.±

1°

C. for a period of time.

63. The method of claim 62, wherein the period of time is in the range of about a few days to 22 weeks.

64. The method of claim 62, wherein the period of time is in the range of about 4 to 22 weeks.

65. The method of claim 62, wherein the period of time is in the range of about 14 days to 2 months.

66. The method of claim 62, wherein the period of time is in the range of about 30 days to 60 days.

67. The method of claim 62, further including immersing the tissue in a solution comprising an alcohol, formaldehyde and Tween 80.

68. The method of claim 67, including immersing the tissue in the solution comprising an alcohol, formaldehyde and Tween 80 for about 2 hours at room temperature so as to sterilize the tissue.

69. The method of claim 62, further including inducing relative and repeated tissue/solution movement during the step of heat treating.

70. The method of claim 69, further including enclosing the treatment shown in a container.

71. The method of claim 69, wherein the step of inducing comprises shaking the container.

72. The method of claim 69, wherein the step of inducing comprises rolling the container.