Implantable devices for delivery of bioactive agents
An implantable delivery device and method for utilizing the device to delivery a bioactive agent to a subject in need thereof is described. The device includes a pattern of structures fabricated on a surface of the device to form a nanotopography. A random or non-random pattern of structures may be fabricated such as a complex pattern including structures of differing sizes and/or shapes. The device may be located adjacent tissue such as an endovascular implant or a perivascular implant, and may deliver the bioactive agent without triggering an immune or foreign body response to the bioactive agent.
1. A fully implantable delivery device configured to deliver a bioactive agent to a subject, the device comprising:
the bioactive agent;
a wall having a surface;
a plurality of nanostructures extending from the surface of the wall, at least a portion of the nanostructures having a cross-sectional dimension of greater than about 5 nanometers and less than about 500 nanometers, and a height of greater than about 5 nanometers to less than about 1 micrometer, and wherein at least a portion of the nanostructures have a center-to-center spacing of greater than about 50 nanometers to less than about 1 micrometer, and
a plurality of microstructures extending from the surface of the wall, at least a portion of the microstructures having a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, wherein the cross-sectional dimension of each nanostructure of the plurality of nanostructures is smaller than the cross-sectional dimension of each microstructure of the plurality of microstructures;
wherein the plurality of nanostructures and plurality of microstructures are arranged in a fractal dimension of greater than about 1; and
wherein the surface containing the plurality of nanostructures and plurality of microstructures has an average surface roughness, as determined by an arithmetical mean height of a surface area roughness parameter as defined by ISO 25178, between about 10 nanometers and about 200 nanometers.
2. The fully implantable delivery device according to claim 1 , wherein the bioactive agent is a component of a composition, the composition further comprising one or more pharmaceutically acceptable excipients.
3. A fully implantable delivery device configured to deliver a bioactive agent to a subject, the device comprising:
the bioactive agent;
a wall having a surface;
a plurality of nanostructures extending from the surface of the wall, at least a portion of the nanostructures having a cross-sectional dimension of greater than about 5 nanometers and less than about 300 nanometers, and a height of greater than about 5 nanometers to less than about 1 micrometer, and wherein at least a portion of the nanostructures have a center-to-center spacing of greater than about 50 nanometers to less than about 1 micrometer, and
a plurality of microstructures extending from the surface of the wall, at least a portion of the microstructures having a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, wherein the cross-sectional dimension of each nanostructure of the plurality of nanostructures is smaller than the cross-sectional dimension of each microstructure of the plurality of microstructures;
wherein the plurality of nanostructures and plurality of microstructures are arranged in a fractal dimension of greater than about 1;
wherein the surface containing the plurality of nanostructures and plurality of microstructures has an average surface roughness, as determined by an arithmetical mean height of a surface area roughness parameter as defined by ISO 25178, between about 10 nanometers and about 200 nanometers.
4. The fully implantable delivery device according to claim 1 , wherein the plurality of nanostructures comprises first nanostructures and second nanostructures, and wherein the second nanostructures have a cross-sectional dimension less than the cross-sectional dimension of the microstructures and greater than the cross-sectional dimension of the first nanostructures.
5. The fully implantable delivery device according to claim 1 , wherein the surface containing the plurality of nanostructures has an effective shear modulus between about 4 MPa and about 320 MPa.
6. A fully implantable delivery device for delivery of a bioactive agent to a subject, the device comprising:
a wall having a surface;
a plurality of nanostructures extending from the surface of the wall, at least a portion of the nanostructures having a cross-sectional dimension of greater than about 5 nanometers and less than about 500 nanometers, and a height of greater than about 5 nanometers to less than about 1 micrometer, and wherein at least a portion of the nanostructures have a center-to-center spacing of greater than about 50 nanometers to less than about 1 micrometer,
a plurality of microstructures extending from the surface of the wall, at least a portion of the microstructures having a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer; and
a reservoir defined by the wall and containing the bioactive agent suitable for delivering to the subject using the implantable delivery device,
wherein the entire implantable delivery device is suitable for implanting in the subject and configured to interact with tissue near a site of implantation within the subject;
wherein the plurality of nanostructures and plurality of microstructures are arranged in a fractal dimension of greater than about 1; and
wherein the surface containing the plurality of nanostructures and plurality of microstructures has an average surface roughness, as determined by an arithmetical mean height of a surface area roughness parameter as defined by ISO 25178, between about 10 nanometers and about 200 nanometers.
7. The fully implantable delivery device according to claim 1 , the device comprising a groove on a surface of the device, wherein the bioactive agent is contained within the groove.
8. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.2 to about 5.
9. The fully implantable delivery device according to claim 1 , wherein the bioactive agent is a component of a composition, the composition further comprising a sustained release matrix.
10. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 100 to about 300 nanometers.
11. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have approximately the same cross-sectional dimension.
12. The fully implantable delivery device according to claim 1 , wherein a ratio of the cross-sectional dimension of two adjacent nanostructures to the center-to-center spacing between those the two nanostructures is between about 1:1 and about 1:4.
13. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have an equidistant spacing.
14. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 20 to about 400 nanometers and at least a portion of the microstructures have a cross-sectional dimension of from about 600 nanometers to about 1.5 micrometers.
15. The fully implantable delivery device according to claim 1 , wherein at least a portion of the microstructures have a height of from about 20 nanometers to about 1 micrometer.
16. The fully implantable delivery device according to claim 1 , wherein at least a portion of the microstructures have an aspect ratio of from about 0.2 to about 5.
17. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.5 to about 3.5.
18. The fully implantable delivery device according to claim 1 , wherein the cross-sectional dimension of the microstructures is greater than the height of the microstructures.
19. The fully implantable delivery device according to claim 18 , wherein at least a portion of the microstructures have an aspect ratio of from about 0.15 to 1.
20. The fully implantable delivery device according to claim 1 , wherein at least a portion of the nanostructures have a height greater than a cross-sectional dimension.