U.S. patent application number 11/090895 was filed with the patent office on 2005-10-06 for medical device applications of nanostructured surfaces.
This patent application is currently assigned to Nanosys, Inc.. Invention is credited to Alfaro, Arthur A., Collier, Matthew D., Dubrow, Robert S., Gertner, Michael E., Kronenthal, Richard L., Rogers, Erica J., Sloan, L. Douglas.
Application Number | 20050221072 11/090895 |
Document ID | / |
Family ID | 35054679 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050221072 |
Kind Code |
A1 |
Dubrow, Robert S. ; et
al. |
October 6, 2005 |
Medical device applications of nanostructured surfaces
Abstract
This invention provides novel nanofiber enhanced surface area
substrates and structures comprising such substrates for use in
various medical devices, as well as methods and uses for such
substrates and medical devices. In one particular embodiment,
methods for enhancing cellular functions on a surface of a medical
device implant are disclosed which generally comprise providing a
medical device implant comprising a plurality of nanofibers (e.g.,
nanowires) thereon and exposing the medical device implant to cells
such as osteoblasts.
Inventors: |
Dubrow, Robert S.; (San
Carlos, CA) ; Sloan, L. Douglas; (Santa Rosa, CA)
; Kronenthal, Richard L.; (Rutherford, NJ) ;
Alfaro, Arthur A.; (Colts Neck, NJ) ; Collier,
Matthew D.; (Los Altos, CA) ; Rogers, Erica J.;
(Emerald Hills, CA) ; Gertner, Michael E.; (Menlo
Park, CA) |
Correspondence
Address: |
NANOSYS INC.
2625 HANOVER ST.
PALO ALTO
CA
94304
US
|
Assignee: |
Nanosys, Inc.
Palo Alto
CA
94304
|
Family ID: |
35054679 |
Appl. No.: |
11/090895 |
Filed: |
March 24, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11090895 |
Mar 24, 2005 |
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10902700 |
Jul 29, 2004 |
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11090895 |
Mar 24, 2005 |
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10828100 |
Apr 19, 2004 |
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10828100 |
Apr 19, 2004 |
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10661381 |
Sep 12, 2003 |
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11090895 |
Mar 24, 2005 |
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10833944 |
Apr 27, 2004 |
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11090895 |
Mar 24, 2005 |
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10840794 |
May 5, 2004 |
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10840794 |
May 5, 2004 |
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10792402 |
Mar 2, 2004 |
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60549711 |
Mar 2, 2004 |
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60463766 |
Apr 17, 2003 |
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60466229 |
Apr 28, 2003 |
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60468390 |
May 6, 2003 |
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60468606 |
May 5, 2003 |
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Current U.S.
Class: |
428/292.1 |
Current CPC
Class: |
A61K 47/6957 20170801;
A61F 2002/3084 20130101; A61F 2310/0097 20130101; A61F 2/36
20130101; A61F 2002/30827 20130101; A61F 2002/30322 20130101; A61F
2/3676 20130101; A61L 27/50 20130101; A61F 2/30767 20130101; A61F
2310/00616 20130101; A61F 2/3662 20130101; A61L 2400/12 20130101;
A61F 2310/00982 20130101; A61F 2250/0026 20130101; Y10T 428/249924
20150401; A61F 2230/0006 20130101; A61L 2430/02 20130101; A61L
27/3839 20130101; A61L 27/3821 20130101; B82Y 5/00 20130101; A61F
2002/30113 20130101; A61F 2002/3631 20130101 |
Class at
Publication: |
428/292.1 |
International
Class: |
D04H 003/00 |
Claims
1. A method for enhancing osteoblast functions on a surface of a
medical device implant comprising providing a medical device
implant comprising a plurality of nanofibers grown thereon and
exposing said medical device implant to osteoblast cells.
2. The method according to claim 1, wherein the nanofibers comprise
nanowires having an average length of from about 1 micron to at
least about 100 microns.
3. The method according to claim 2, wherein the nanowires have an
average density on the medical device implant of from about 20
nanowires per square micron to at least about 100 nanowires per
square micron.
4. The method of claim 1, wherein the plurality of nanofibers
comprise a material independently selected from the group
consisting of: silicon, glass, quartz, plastic, metal and metal
alloys, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS,
HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS,
BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb, PbS, PbSe,
PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2, silicon carbide,
silicon nitride, polyacrylonitrile (PAN), polyetherketone,
polyimide, an aromatic polymer, and an aliphatic polymer.
5-6. (canceled)
7. The method of claim 1, wherein the medical device implant is
selected from at least one of the following: total knee joints,
total hip joints, ankle, elbow, wrist, and shoulder implants
including those replacing or augmenting cartilage, long bone
implants such as for fracture repair and external fixation of
tibia, fibula, femur, radius, and ulna, spinal implants including
fixation and fusion devices, maxillofacial implants including
cranial bone fixation devices, artificial bone replacements, dental
implants, orthopedic cements and glues comprised of polymers,
resins, metals, alloys, plastics and combinations thereof, nails,
screws, plates, fixator devices, wires and pins.
8. The method of claim 1, wherein the medical device implant
contains an agent selected from the group consisting of
antiinfectives, hormones, analgesics, anti-inflammatory agents,
growth factors, chemotherapeutic agents, anti-rejection agents,
prostaglandins, RDG peptides and combinations thereof.
9. The method of claim 1, wherein the medical device implant
contains one or more agents selected from the group consisting of
medicated coatings, drug-eluting coatings, drugs or other
compounds, hydrophilic coatings, smoothing coatings, collagen
coatings, and human cell seeding coatings.
10. A method for the repair or regeneration of tissue comprising
contacting cells with a nanostructured surface comprising a
plurality of nanofibers having an average length of at least about
1 micron and an average density of at least about 1 nanofiber per
square micron.
11. The method of claim 10, wherein the nanostructured surface is
implanted in an animal and contacted with the cells.
12. The method of claim 10, wherein the nanostructed surface is
seeded with cells and the nanostructued surface and cells are
placed in a cell culturing device and the cells are allowed to
multiply on the nanostructured surface.
13. The method of claim 10, wherein the cells comprise
osteoblasts.
14. The method of claim 10, wherein the cells are selected from the
group consisting of myocytes, adipocytes, fibromyoblasts,
ectodermal cell, muscle cells, osteoblasts, chondrocytes,
endothelial cells, pancreatic cells, hepatocytes, bile duct cells,
bone marrow cells, neural cells, genitourinary cells and
combinations thereof.
15. The method of claim 10, wherein the nanostructured surface
contains one or more agents selected from the group consisting of
antiinfectives, hormones, analgesics, anti-inflammatory agents,
growth factors, chemotherapeutic agents, anti-rejection agents,
prostaglandins, RDG peptides and combinations thereof.
16. The method of claim 10, wherein the nanostructured surface
contains one or more agents selected from the group consisting of:
medicated coatings, drug-eluting coatings, drugs or other
compounds, hydrophilic coatings, smoothing coatings, collagen
coatings, and human cell seeding coatings.
17. The method of claim 12, wherein after the cells are allowed to
multiply on the nanostructured surface, the nanostructured surface
and the cells are implanted into an animal.
18. The method of claim 10, wherein the nanofibers are attached to
the nanostructured surface by growing the nanofibers directly on
the surface.
19. The method of claim 10, wherein the nanofibers are attached to
or otherwise associated with the nanostructured surface by
covalently attaching the nanofibers to the surface.
20. The method of claim 10, wherein the nanofibers have an average
length of at least about 25 microns and an average density of at
least about 20 nanofibers per square micron.
21. The method according to claim 10, wherein the nanofibers
comprisie nanowires having an average length of from about 25
microns to at least about 100 microns.
22. The method according to claim 10, wherein the nanofibers
comprise nanowires having an average density on the medical device
implant of from about 20 nanowires per square micron to at least
about 100 nanowires per square micron.
23. The method of claim 10, wherein the plurality of nanofibers
comprise a material independently selected from the group
consisting of: silicon, glass, quartz, plastic, metal and metal
alloys, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS,
HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS,
BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb, PbS, PbSe,
PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2, silicon carbide,
silicon nitride, polyacrylonitrile (PAN), polyetherketone,
polyimide, an aromatic polymer, and an aliphatic polymer.
24. The method of claim 10, wherein the plurality of nanofibers
comprise nanowires made from silicon.
25. The method of claim 24, wherein the silicon nanowires have a
coating of a titanium oxide compound deposited thereon.
26. The method of claim 25, wherein the titanium oxide compound
comprises titanium dioxide.
27. The method of claim 25, wherein the titanium oxide coating is
deposited by atomic layer deposition.
28. The method of claim 10, wherein at least a portion of the
nanostructured nanofiber surface is functionalized with a coating
material to render it hydrophobic, lipophobic, or amphiphobic.
29. The method of claim 28, wherein the coating material comprises
one or more material selected from the group consisting of:
Teflon.RTM., Tri-sil, tridecafluoro
1,1,2,2,tetrahydrooctyl-1-tricholorosilane, a fluoride containing
compound, a silane containing compound, PTFE, hexamethyldisilazane,
an aliphatic hydrocarbon containing molecule, an aromatic
hydrocarbon containing molecule, a halogen containing molecule and
paralyene.
30. The method of claim 29, wherein the coating material is
deposited by one or more of sputtering, atomic layer deposition and
a plasma process.
31. The method of claim 30, wherein at least a portion of the
nanofiber surface with the coating material deposited thereon is
functionalized to promote cellular adhesion and/or
proliferation.
32. The method of claim 31, wherein the nanofiber surface is
functionalized with one or more of fibronectin, collagen, or an RGD
containing peptide.
33. A method for enhancing osteoblast functions on a surface of a
medical device implant comprising providing a medical device
implant comprising a plurality of silicon nanofibers and exposing
said medical device implant to osteoblast cells.
34. The method of claim 33, wherein the silicon nanofibers are
grown directly on the medical device implant.
35. The method of claim 33, wherein the silicon nanofibers have a
length of at least about 1 micron.
36. The method of claim 33, wherein the silicon nanofibers have a
length of at least about 10 microns
37. The method of claim 33, wherein the silicon nanofibers are
grown on the surface of the medical device implant by a VLS growth
process.
38. A method for enhancing osteoblast adhesion and/or proliferation
on a medical device implant surface comprising growing a plurality
of nanofibers directly on the surface.
39. The method of claim 38, wherein the nanofibers comprise silicon
nanofibers.
40. The method of claim 38, wherein the nanofibers have a length of
at least about 1 micron.
41. The method of claim 40, wherein the nanofibers have a length of
at least about 10 microns
42. The method of claim 39, wherein the silicon nanofibers are
grown on the surface of the medical device implant by a VLS growth
process.
43. An orthopedic or dental implant comprising a substrate having a
surface and a plurality of silicon nanofibers deposited on the
surface.
44. The implant of claim 43, wherein the silicon nanofibers are
grown directly on the substrate surface.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
U.S. patent Application Ser. No. 10/902,700 filed Jul. 29, 2004,
which claims priority to U.S. Provisional Patent Application Ser.
No. 60/549,711, filed Mar. 2, 2004. This application also claims
priority as a continuation-in-part application of U.S. patent
application Ser. No. 10/828,100, filed Apr. 19, 2004, which is a
continuation-in-part of U.S. patent application Ser. No.
10/661,381, filed Sep. 12, 2003, which claims priority to U.S.
Provisional Patent Application No. 60/463,766, filed Apr. 17, 2003;
and as a continuation-in-part of U.S. patent application Ser. No.
10/833,944, filed Apr. 27, 2004, which claims priority to U.S.
Provisional Application Ser. No. 60/466,229, filed Apr. 28, 2003;
and as a continuation-in-part application of U.S. patent
application Ser. No. 10/840,794 filed May 5, 2004, which is a
continuation-in-part of U.S. patent application Ser. No.
10/792,402, filed Mar. 2, 2004, which claims priority to U.S.
Provisional Patent Application Ser. Nos. 60/468,390, filed May 6,
2003 and 60/468,606 filed May 5, 2003, each of which is
incorporated by reference in their entirety herein.
FIELD OF THE INVENTION
[0002] The invention relates primarily to the field of
nanotechnology. More specifically, the invention pertains to
medical devices and methods comprising nanofibers.
BACKGROUND OF THE INVENTION
[0003] Medical devices including, for example, intracorporeal or
extracorporeal devices (e.g., catheters), temporary or permanent
implants, stents, vascular grafts, anastomotic devices, aneurysm
repair devices, embolic devices, and implantable devices (e.g.,
orthopedic implants) are commonly infected with opportunistic
bacteria and other infectious micro-organisms, in some cases
necessitating the removal of implantable devices. Such infections
can also result in illness, long hospital stays, or even death. The
prevention of biofilm formation and infection on indwelling
catheters, orthopedic implants, pacemakers, contact lenses, stents,
vascular grafts, embolic devices, aneurysm repair devices and other
medical devices is therefore highly desirous.
[0004] Enhancement of resistance of biomaterials to bacterial
growth and promotion of rapid tissue integration and grafting of
biomaterial surfaces are both areas of research. However, despite
advances in sterilization and aseptic procedures as well as
advances in biomaterials, bacterial and other microbial infection
remains a serious issue in the use of medical implants. For
example, greater than half of all nosocomial infections are caused
by implanted medical devices. These infections are often the result
of biofilms forming at the insertion site of the medical implant.
Unfortunately, such infections are often resistant to innate immune
system responses as well as to conventional antibiotic treatments.
It will be appreciated that such infections are problematic not
just in treatment of humans, but also in treatment of a number of
other organisms as well.
[0005] A welcome addition to the art would be medical devices
having enhanced surface areas and structures/devices comprising
such, as well as methods of using enhanced area surfaces in medical
devices. The current invention provides these and other benefits
which will be apparent upon examination of the following.
SUMMARY OF THE INVENTION
[0006] The embodiments of the current invention comprise various
medical devices, such as clamps, valves, intracorporeal or
extracorporeal devices (e.g., catheters), temporary or permanent
implants, stents, vascular grafts, anastomotic devices, aneurysm
repair devices, embolic devices, and implantable devices (e.g.,
orthopedic implants) and the like which comprise nanofiber enhanced
surfaces. Such enhanced surfaces provide many enhanced attributes
to the medical devices in, on, or within which they are used
including, e.g., to prevent/reduce bio-fouling, increase fluid flow
due to hydrophobicity, increase adhesion, biointegration, etc.
[0007] In a first aspect of the invention, a medical device is
disclosed comprising a body structure having one or more surfaces
having a plurality of nanostructured components associated
therewith. The medical device may comprise an intracorporeal or
extracorporeal device, a temporary or permanent implant, a stent, a
vascular graft, an anastomotic device, an aneurysm repair device,
an embolic device, an implantable device, a catheter, valve or
other device which would benefit from a nanostructured surface
according to the teachings of the present invention. The plurality
of nanostructured components may comprise, for example, a plurality
of nanofibers or nanowires. The plurality of nanostructured
components enhance one or more of adhesion, non-adhesion, friction,
patency or biointegration of the device with one or more tissue
surfaces of a body of a patient depending on the particular
application of the device. The nanofibers (or other nanostructured
components) on the surfaces of the medical device can optionally be
embedded in a slowly-soluble biocompatible polymer (or other)
matrix to make the nanofiber surfaces more robust. The polymer
matrix can protect most of the length of each nanofiber, leaving
only the ends susceptible to damage. The generation of water
soluble polymers can be accomplished in a number of different ways.
For example, polymer chains can be formed in situ in a dilute
aqueous solution primarily consisting of a monomer and an oxidizing
agent. In this case, the polymer is actually created in the
solution and subsequently spontaneously adsorbed onto the nanofiber
surfaces as a uniform, ultra-thin film of between approximately 10
to greater than 250 angstroms in thickness, more preferably between
10 and 100 angstroms.
[0008] The plurality of nanofibers or nanowires may comprise an
average length, for example, of from about 1 micron to at least
about 500 microns, from about 5 microns to at least about 150
microns, from about 10 microns to at least about 125 microns, or
from about 50 microns to at least about 100 microns. The plurality
of nanofibers or nanowires may comprise an average diameter, for
example, of from about 5 nm to at least about 1 micron, from about
5 nm to at least about 500 nm, from about 20 nm to at least about
250 nm, from about 20 nm to at least about 200 nm, from about 40 nm
to at least about 200 nm, from about 50 nm to at least about 150
nm, or from about 75 nm to at least about 100 nm. The plurality of
nanofibers or nanowires may comprise an average density on the one
or more surfaces of the medical device, for example, of from about
0.11 nanofibers per square micron to at least about 1000 nanofibers
per square micron, from about 1 nanofiber per square micron to at
least about 500 nanofibers per square micron, from about 10
nanofibers per square micron to at least about 250 nanofibers per
square micron, or from about 50 nanofibers per square micron to at
least about 100 nanofibers per square micron. The plurality of
nanofibers or nanowires may comprise a material independently
selected from the group consisting of: silicon, glass, quartz,
plastic, metal and metal alloys, polymers, TiO, ZnO, ZnS, ZnSe,
ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe,
CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN,
InP, InAs, InSb, PbS, PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1,
SiO.sub.2, silicon carbide, silicon nitride, polyacrylonitrile
(PAN), polyetherketone, polyimide, an aromatic polymer, and an
aliphatic polymer.
[0009] The nanofibers or nanowires may be attached to the one or
more surfaces of the body structure of the medical device by
growing the nanofibers or nanowires directly on the one or more
surfaces, or the nanofibers or wires may be attached to the one or
more surfaces of the body structure by attaching (e.g., via a
covalent linkage) the nanofibers or nanowires to the one or more
surfaces using one or more functional moieties, for example. The
body structure of the medical device may be made from a variety of
materials, and the plurality of nanostructured components may
optionally be incorporated into the material(s) of the body
structure. The nanofibers (or other nanomaterial) may be stiffened
by sintering the fibers together (or otherwise cross-linking the
fibers, e.g., by chemical means) prior to incorporating the
nanofibers into the material of the body structure to provide
enhanced rigidity and strength. The medical device may further
comprise one or more biologically compatible or bioactive coatings
applied to the one or more nanostructured surfaces, and/or the
nanofibers or nanowires may be incorporated into a matrix material
(e.g., a polymer material) to provide greater durability for the
fibers or wires.
[0010] In another aspect of the invention, a vascular stent is
disclosed which comprises a plurality of nanostructured components
associated with one or more surfaces of the stent. The plurality of
nanostructured components may comprise, for example, a plurality of
nanofibers or nanowires. The plurality of nanofibers or nanowires
may comprise, for example, a material independently selected from
the group consisting of: silicon, glass, quartz, plastic, metal and
metal alloys, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe,
HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe,
BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb, PbS,
PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2, silicon carbide,
silicon nitride, polyacrylonitrile (PAN), polyetherketone,
polyimide, an aromatic polymer, and an aliphatic polymer. The
nanofibers or nanowires may be attached to the one or more surfaces
of the stent by growing the nanofibers directly on the one or more
surfaces, or, for example, by separately covalently attaching the
nanofibers or nanowires to the one or more surfaces by using, e.g.,
one or more functional moieties or linkage chemistries. The stent
may be made from a variety of materials selected from Nitinol,
nickel alloy, tin alloy, stainless steel, cobalt, chromium, gold,
polymer, or ceramic. The stent may comprise a drug compound that is
directly adsorbed to the nanostructured surface or otherwise
associated with the nanostructured surface (e.g., via covalent,
ionic, van der waals etc. attachment) via the use of one or more
silane groups or other linkage chemistries.
[0011] In another embodiment of the invention, an aneurysm repair
device is disclosed which comprises a graft member which is
configured to be positioned within a patient's body in a region of
an aneurysm, the graft member comprising a plurality of
nanostructured components associated with one or more surfaces of
the graft member. The plurality of nanostructured components may
comprise, for example, a plurality of nanofibers or nanowires. The
plurality of nanofibers may comprise a material independently
selected from the group consisting of: silicon, glass, quartz,
plastic, metal or metal alloys, polymers, TiO, ZnO, ZnS, ZnSe,
ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe,
CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN,
InP, InAs, InSb, PbS, PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1,
SiO.sub.2, silicon carbide, silicon nitride, polyacrylonitrile
(PAN), polyetherketone, polyimide, an aromatic polymer, and an
aliphatic polymer. The nanofibers or nanowires may be attached to
the one or more surfaces of the graft member by growing the
nanofibers directly on the one or more surfaces, or the nanofibers
or nanowires may be attached to the one or more surfaces of the
graft member by attaching the nanofibers or nanowires to the one or
more surfaces, e.g., via covalent, ionic, or other attachment
mechanism. The graft member may be made from one or more of treated
natural tissue, laboratory-engineered tissue, and synthetic polymer
fabrics including without limitation a synthetic polymer selected
from Dacron, Teflon, metal or alloy mesh, ceramic or glass fabrics.
The graft member may comprise one or more biocompatible coatings
applied to the one or more nanostructured surfaces of the graft
member. In one embodiment, the graft member is configured to be
positioned within an aorta of the patient in a region of an
aneurysm. The graft member may be configured to be positioned
proximate to a side wall of a vessel that supplies blood to or from
the brain in a region of an aneurysm.
[0012] In another embodiment of the invention, a medical device is
disclosed for creating an anastamosis in a patient coupling a first
vessel to a second vessel in an end-to-end or end-to-side
anastomosis, the device comprising a tubular member comprising a
plurality of nanostructured components associated with one or more
surfaces of the tubular member. The plurality of nanostructured
components may comprise, for example, a plurality of nanofibers or
nanowires. The plurality of nanofibers or nanowires may comprise a
material independently selected from the group consisting of:
silicon, glass, quartz, plastic, metal, polymers, TiO, ZnO, ZnS,
ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS,
CaSe, CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb,
InN, InP, InAs, InSb, PbS, PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1,
SiO.sub.2, silicon carbide, silicon nitride, polyacrylonitrile
(PAN), polyetherketone, polyimide, an aromatic polymer, and an
aliphatic polymer. The nanofibers or nanowires may be attached to
the one or more surfaces of the tubular member by growing the
nanofibers directly on the one or more surfaces or by attaching the
nanofibers to the one or more surfaces, e.g., using covalent, ionic
or other attachment means. The tubular member may be made from one
or more of treated natural tissue, laboratory-engineered tissue,
de-natured animal tissue, stainless steel, metal, alloys, ceramic
or glass fabrics, polymers, plastic, silicone, and synthetic
polymer fabrics. In one embodiment, the tubular member may comprise
a T-tube for performing an end-to-side anastomosis or a straight
tube for performing an end-to-end anastomosis. The tubular member
may comprise one or more biocompatible or bioactive coatings
applied to the one or more nanostructured surfaces of the tubular
member. The tubular member can have a cross-sectional shape
selected from circular, semi-circular, elliptical, and polygonal,
for example.
[0013] In another embodiment of the invention, an implantable
orthopedic device is disclosed which comprises a body structure
comprising a plurality of nanostructured components associated with
one or more surfaces of the body structure. The implantable
orthopedic device may be selected from at least one of the
following: total knee joints, total hip joints, ankle, elbow,
wrist, and shoulder implants including those replacing or
augmenting cartilage, long bone implants such as for fracture
repair and external fixation of tibia, fibula, femur, radius, and
ulna, spinal implants including fixation and fusion devices,
maxillofacial implants including cranial bone fixation devices,
artificial bone replacements, dental implants, orthopedic cements
and glues comprised of polymers, resins, metals, alloys, plastics
and combinations thereof, nails, screws, plates, fixator devices,
wires and pins. The plurality of nanostructured components may
comprise a plurality of nanofibers or nanowires, for example. The
plurality of nanofibers or nanowires may comprise a material
independently selected from the group consisting of: silicon,
glass, quartz, plastic, metal, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe,
CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe,
SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP,
InAs, InSb, PbS, PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2,
silicon carbide, silicon nitride, polyacrylonitrile (PAN),
polyetherketone, polyimide, an aromatic polymer, and an aliphatic
polymer. The nanofibers or nanowires may be attached to the one or
more surfaces of the body structure by growing the nanofibers
directly on the one or more surfaces or by separately attaching
(e.g., covalently, ionic ally, etc.) the nanofibers to the one or
more surfaces. The body structure of the device may be made from
one or more of treated natural tissue, laboratory-engineered
tissue, de-natured animal tissue, stainless steel, metal, alloys,
ceramic or glass fabrics, polymers, plastic, silicone, and
synthetic polymer fabrics. The body structure may comprise one or
more biocompatible or bioactive coatings applied to the one or more
nanostructured surfaces of the body structure.
[0014] In another embodiment of the invention, a bioengineered
scaffold device for providing a scaffold for nerve regeneration is
disclosed which comprises a base membrane or matrix having a
plurality of nanostructured components associated therewith. The
membrane or matrix may be made from one or more of the following
materials: natural or synthetic polymers, electrically conducting
polymers, metals, alloys, ceramics, glass fabrics, or silicone. The
plurality of nanostructured components may comprise, for example, a
plurality of nanofibers or nanowires. The nanostructured surface of
the membrane or matrix may be impregnated or bound with one or more
drugs, cells, fibroblasts, nerve growth factors (NGF), cell seeding
compounds, neurotrophic growth factors or genetically engineered
cells producing such factors, VEGF, laminin or other drugs or
substances to encourage axonal elongation and functional nerve
performance.
[0015] In another aspect of the invention, a medical device for
implantation in the uterus or fallopian tubes is disclosed which
comprises a surface and a plurality of nanofibers or nanowires
associated with the surface.
[0016] In another aspect of the invention, a medical device in
which one or more surfaces are adapted to resist crystallization of
body fluids is disclosed which comprises a surface and a plurality
of nanofibers or nanowires associated with the surface.
[0017] In another embodiment of the invention, a medical device is
disclosed in which one or more surfaces of the device are adapted
to resist formation of thrombus and which comprises a surface and a
plurality of nanofibers or nanowires.
[0018] In another embodiment of the invention, a medical device in
which one or more surfaces are adapted to resist tissue in-growth
is disclosed which comprises a surface and a plurality of
nanofibers or nanowires associated with the surface said nanofibers
or nanowires adapted to be hydrophobic.
[0019] Methods of use are also disclosed for treating patients with
any one or more of the medical devices disclosed herein, which
include, for example, a method of therapeutically treating a
patient comprising contacting the patient with a medical device
comprising a surface and plurality of nanofibers associated with
the surface. Methods are disclosed for administering a drug
compound to a body of a patient which comprises, for example,
providing a drug-eluting device comprising at least one surface, a
plurality of nanofibers associated with the surface, and a drug
compound associated with the plurality of nanofibers; introducing
the drug-eluting device into a body of a patient; and delivering
the drug compound into the body of the patient. The drug-eluting
device in one embodiment comprises a coronary stent, although any
device which would benefit from local drug delivery at the site of
disease (e.g., lesion) could be used in the methods of the
invention. Where a coronary stent is used as the drug-eluting
device, the drug compound may comprise paclitaxel or sirolimus, for
example, or a variety of other medications including without
limitation one or more of the following: anti-inflammatory
immunomodulators such as Dexamethasone, M-prednisolone, Interferon,
Leflunomide, Tacrolimus, Mizoribine, statins, Cyclosporine,
Tranilast, and Biorest; antiproliferative compounds such as Taxol,
Methotrexate, Actinomycin, Angiopeptin, Vincristine, Mitomycin,
RestenASE, and PCNA ribozyme; migration inhibitors such as
Batimastat, Prolyl hydroxylase inhibitors, Halofuginone,
C-proteinase inhibitors, and Probucol; and compounds which promote
healing and re-endothelialization such as VEGF, Estradiols,
antibodies, NO donors, and BCP671. The drug compound may be
adsorbed directly to the nanofiber surface of the drug-eluting
device or otherwise associated with it via the use of one or more
silane groups, linker molecules or other covalent, ionic, van der
waals etc. attachment means. The nanofiber surface may be
configured such that the drug compound elutes slowly over time. The
plurality of nanofibers optionally are embedded in a biocompatible,
non-thrombogenic polymer coating to provide enhanced durability to
the nanofibers.
[0020] In other embodiments of the present invention, methods for
enhancing osteoblast (or other cellular) functions on a surface of
a medical device implant are disclosed which generally comprise
providing a medical device implant comprising a plurality of
nanowires thereon and exposing the medical device implant to
osteoblast (or other cell type) cells. In one exemplary embodiment
for increased cellular integration and adhesion, the nanowires may
have an average length of from about 25 microns to at least about
100 microns and an average density on the nanostructured surface of
from about 20 nanowires per square micron to at least about 100
nanowires per square micron. The plurality of nanowires may
comprise a material independently selected from the group
consisting of: silicon, glass, quartz, plastic, metal and metal
alloys, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS,
HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS,
BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb, PbS, PbSe,
PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2, silicon carbide,
silicon nitride, polyacrylonitrile (PAN), polyetherketone,
polyimide, an aromatic polymer, and an aliphatic polymer. The
nanowires may be attached to the surface of the medical device
implant by growing the nanowires directly on the surface, or by
covalently or otherwise attaching the nanowires to the surface. The
medical device implant may be selected from at least one of the
following: total knee joints, total hip joints, ankle, elbow,
wrist, and shoulder implants including those replacing or
augmenting cartilage, long bone implants such as for fracture
repair and external fixation of tibia, fibula, femur, radius, and
ulna, spinal implants including fixation and fusion devices,
maxillofacial implants including cranial bone fixation devices,
artificial bone replacements, dental implants, orthopedic cements
and glues comprised of polymers, resins, metals, alloys, plastics
and combinations thereof, nails, screws, plates, fixator devices,
wires, pins, and the like. The medical device implant may also
contain one or more agent selected from the group consisting of
anti-infective, hormones, analgesics, anti-inflammatory agents,
growth factors, chemotherapeutic agents, anti-rejection agents,
prostaglandins, RDG peptides, medicated coatings, drug-eluting
coatings, drugs or other compounds, hydrophilic coatings, smoothing
coatings, collagen coatings, and human cell seeding coatings.
[0021] These and other objects and features of the invention will
become more fully apparent when the following detailed description
is read in conjunction with the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 displays a photomicrograph of an exemplary adherent
nanofiber structure of the invention;
[0023] FIG. 2A is an illustration of a Prior Art stent and stent
delivery catheter.
[0024] FIG. 2B shows placement of the stent of FIG. 2A at the site
of a lesion in a vessel of a patient such as a coronary artery.
[0025] FIG. 2C displays a photomicrograph of a vascular stent prior
to deposition of a nanostructured surface on the stent.
[0026] FIG. 2D displays a photomicrograph of a vascular stent
following growth of a plurality of nanofibers on the exposed
surfaces of the stent.
[0027] FIG. 3A diagrammatically illustrates an endovascular aortic
prosthetic delivery system for delivering an aortic aneurysm graft
having a nanostructured surface to the site of an aortic aneurysm
in a body of a patient;
[0028] FIG. 3B illustrates placement of an endovascular aortic
graft having a nanostructured surface adjacent an aneurysm in an
aorta of a body of a patient;
[0029] FIG. 4A illustrates a detailed view of a patient's head
region showing advancement of a neurovascular catheter delivery
system for treatment of an aneurysm in a side wall of a cerebral
vessel of a patient in accordance with the invention;
[0030] FIG. 4B illustrates a side wall aneurysm in a cerebral
vessel of a patient;
[0031] FIG. 4C illustrates placement of a patch having a
nanostructured surface at the site of the side wall aneurysm of
FIG. 4B;
[0032] FIG. 4D is one example of a commercially available embolic
device (i.e., Hilal Embolization Microcoils.TM. available
commercially from Cook, Inc. (Bloomington, Ind.)) that can be
provided with a nanostructured surface according to the teachings
of the present invention to enhance the treatment of intracranial
aneurysms and AV malformations;
[0033] FIGURE 5A is an illustration of a tubular device having a
nanostructured surface for performance of an end-to-end
anastomosis;
[0034] FIG. 5B is an illustration of a T-tube device having a
nanostructured surface for performance of an end-to-side
anastomosis;
[0035] FIG. 6A is a perspective view of a an exemplary orthopedic
implant (in this case a hip stem) having a nanofibers attached
thereto in accordance with the illustrated embodiment,
[0036] FIG. 6B is a cross sectional view taken along line 6A-A of
FIG. 6A;
[0037] FIG. 7 illustrates osteoblast adhesion and proliferation on
various nanowire surfaces and on a control (reference) quartz
surface;
[0038] FIGS. 8A-F illustrate fluorescence microscope images of
adhered and proliferated cells on various nanowire surfaces after 1
day (FIG. 8B) and 4 days (FIGS. 8D and F) and on quartz surfaces
after 1 day (FIG. 8A) and 4 days (FIGS. 8C and E);
[0039] FIG. 9 shows the alkaline phosphatase activity for
osteoblasts adhered on nanowire and reference surfaces for a 4 week
period;
[0040] FIG. 10 shows calcium concentration as measured by
colorimetric assay for nanowire and quartz (reference)
surfaces;
[0041] FIGS. 11A-B show calcium concentration (FIG. 11A) and
phosphorous concentration (FIG. 11B) on nanowire and reference
surfaces measured using XPS;
[0042] FIGS. 12A-H show SEM images of osteoblasts adhered on quartz
(reference) surfaces after 1 week (FIGS. 12A-B), 2 weeks (FIGS.
12C-D), 3 weeks (FIGS. 12E-F) and 4 weeks (FIGS. 12G-H);
[0043] FIGS. 121-P show SEM images of osteoblasts adhered on
nanowire surfaces after 1 week (FIGS. 121-J), 2 weeks (FIGS.
12K-L), 3 weeks (FIGS. 12M-N) and 4 weeks (FIGS. 120-P);
[0044] FIGS. 13A-B show the results of a competitive cell adhesion
assay after 1 day (FIG. 13A) and 3 days (FIG. 13B) showing
significantly more competitive adhesion and proliferation of
osteoblasts (bone forming cells) on nanowire surfaces of the
present invention compared to current materials used in orthopedic
implant applications.
DETAILED DESCRIPTION
[0045] It should be appreciated that specific embodiments and
illustrations herein of uses or devices, etc., which comprise
nanofiber enhanced surface areas should not be construed as
limiting. In other words, the current invention is illustrated by
the descriptions herein, but is not constrained by individual
specifics of the descriptions unless specifically stated. The
embodiments are illustrative of various uses/applications of the
enhanced surface area nanofiber surfaces and constructs thereof.
Again, the enumeration of specific embodiments herein is not to be
taken as limiting on other uses/applications which comprise the
enhanced surface area nanofiber structures of the current
invention. fibronectin, collagen, RGD containing peptides and other
cell binding motifs
[0046] As seen in FIG. 1, the nanofibers optionally form a complex
three-dimensional structure on the medical device surfaces to which
they are applied. Again, it will be appreciated that in other
embodiments of the invention, the nanofibers are more uniform in
height, conformation, etc. The degree of such complexity depends in
part upon, e.g., the length of the nanofibers, the diameter of the
nanofibers, the length:diameter aspect ratio of the nanofibers,
moieties (if any) attached to the nanofibers, and the growth
conditions of the nanofibers, etc. The bending, interlacing, etc.
of nanofibers, which help affect the degree of intimate contact
with a secondary surface, are optionally manipulated through, e.g.,
control of the number of nanofibers per unit area as well as
through the diameter of the nanofibers, the length and the
composition of the nanofibers, etc. Thus, it will be appreciated
that the bio-utility of the nanofiber substrates herein is
optionally controlled through manipulation of these and other
parameters. The nanofibers (or other nanomaterial) may be stiffened
by sintering the fibers together (or otherwise cross-linking the
fibers, e.g., by chemical means) prior to or after incorporating
the nanofibers into or onto the material of the body structure to
provide enhanced rigidity and strength.
[0047] It also will be appreciated that nanofibers can, in optional
embodiments, curve or curl, etc., thus, presenting increased
surface area for contact between the nanofibers and the substrate
surfaces involved. The increased intimate contact, due to multiple
touchings of a nanofiber with a second surface, increases the van
der Waals attractions, friction forces, or other similar forces of
adhesion/interaction between the nanofiber and the second
substrate. For example, a single curling nanofiber can optionally
make intimate contact with a second substrate a number of times. Of
course, in some optional embodiments, a nanofiber can even retouch
the first surface if it curls/curves from the second surface back
to the first surface. Due to possible multiple contact points (or
even larger contact points, e.g., when a curved nanofiber presents
a larger intimate contact area than just its tip diameter, e.g., if
a side length of a nanofiber touches a substrate surface) between a
single nanofiber and a second substrate/surface, the intimate
contact area from curled/curved nanofibers can be greater in some
instances than when the nanofibers tend not to curl or curve (i.e.,
and therefore typically present a "straight" aspect to the second
surface). Therefore, in some, but not all, embodiments herein, the
nanofibers of the invention comprise bent, curved, or even curled
forms. As can be appreciated, if a single nanofiber snakes or coils
over a surface (but is still just a single fiber per unit area
bound to a first surface), the fiber can still provide multiple,
intimate contact points, each optionally with a relatively high
contact area, with a secondary surface
[0048] I) Nanofiber Surfaces as Bacteriostatic, Hydrophobic &
Antithrombotic Catheter Lumens
[0049] Catheters are widely used in medical applications, e.g., for
intravenous, arterial, peritoneal, pleural, intrathecal, subdural,
urological, synovial, gynecological, percutaneous,
gastrointestinal, abscess drains, and subcutaneous applications.
Intravenous infusions are used for introducing fluids, nutrition,
blood or its products, and medications to patients. These catheters
are placed for short-term, intermediate, and long-term usage. Types
of catheters include standard IV, peripherally inserted central
catheters (PICC)/midline, central venous catheters (CVC),
angiographic catheters, guide catheters, feeding tubes, endoscopy
catheters, Foley catheters, drainage catheters, and needles.
Catheter complications include phlebitis, localized infection and
thrombosis.
[0050] Intravenous therapy is a critical element in the treatment
of patients. One out of eight persons will undergo intravenous
therapy of some form annually in the United States. Today, infusion
therapy is almost routine. In hospitals, 90 percent of surgical
patients and a third of non-surgical inpatients receive some form
of intravenous therapy. American medical device manufacturers
dominate the catheter industry, producing 70 to 80 percent of the
catheters used around the world. In 1997, worldwide sales of
catheter products totaled approximately $7.3 billion, and is
growing at a healthy pace of 10.4% annually. The largest segment,
however, is the renal market, which is comprised primarily of
urinary catheters and dialysis catheters. It is currently a $4
billion segment, and is expected to reach $7.1 billion soon.
[0051] The best-known urology catheters are Foley catheters, which
have been commercially available since the 1930s. These catheters
and others, both internal and external condom-type catheters, are
used for incontinence, for dying patients, and often for bladder
drainage following surgery or an incapacitating injury or illness.
These relatively easy-to-use catheters are used throughout the
world in hospitals, nursing homes, and home-care settings. There
are two types of dialysis catheters: hemodialysis and peritoneal.
End users for this catheter segment are vascular surgeons and
interventional radiologists, although once long-term catheter ports
are in place, nephrologists monitor access sites and catheter-based
dialysis treatments.
[0052] Therefore, in various embodiments herein, nanofiber enhanced
surfaces are used in, on or within material surfaces to construct
catheters and related medical devices. The bacteriostatic
characteristics of the nanofiber surface catheters herein can
optionally decrease infection, while the hydrophobic
characteristics can optionally increase fluid flow properties. The
anti-thrombotic characteristics of such devices can optionally
decrease thrombosis which leads to catheter plugging and emboli.
Catheter manufacturers desire improvement of catheter materials and
catheter design to make them more biocompatible, and to offer
better infection control. However, in spite of progress, infection
at present has remained a major problem. Use of nanofiber enhanced
surfaces in construction of catheters, however, can optionally aid
with such concerns.
[0053] The performance advantage of catheter lumens with decreased
infection, increased flow and decreased clot formation arising from
use of nanofiber enhanced surfaces are features of the invention.
Such features can optionally lead to reduction in catheter
complications and an increase in the amount of time a catheter
could remain in place before having to be replaced (as a result of
using the nanofiber coated catheter lumens).
[0054] Catheters are optionally placed anywhere in the body (i.e.,
the class of catheters comprises more than just IVs) and are
typically plastic, which is strong enough to place in, e.g., a
vein, but flexible enough to bend within the patient's body. It is
typically desired to reduce catheter care (e.g., replacement time)
and to decrease catheter contamination, e.g., from skin "crawling
down," biofouling, etc. It is also desirable to avoid phlebosis or
any problem disturbing flow which can arise through use of a
"flush" to blow clots, etc. downstream. The current embodiments
avoid such because they are inherently antibacterial, hydrophobic
and antithrombogenic.
[0055] The antifouling aspects of the current invention are also
optionally useful in catheters used for wound drainage. Such
catheters typically present problems with bacterial contamination,
etc. Use of the embodiments of the invention can, thus, reduce drug
use (e.g., antibiotics), reduce pain, reduce need for further
operations, and reduce infection rates. As explained herein the
catheters of the invention are also optionally coated with
compounds, e.g., silver compounds, titanium oxides, antibiotics,
etc. which can further help in reducing infection, etc.
[0056] II) Nanofiber Enhanced Surfaces in Disposable Surgical
Retractors, Dental Retractors and Placement Devices.
[0057] Retractors and forceps are commonly used in surgery to
position or move (e.g., manipulate) organs and tissues for better
visualization, surgical approach, and placement of implants.
Dentistry commonly uses forceps to position small tooth
restorations (e.g., crowns, inlays, on lays, veneers,
implants/implant abutments, etc.) and position gingival tissues in
a variety of periodontal, oral surgical and endodontic procedures.
The current existing dental device in this market sector is a
sticky ended probe (Grabits.TM.) that is disliked by dentists as it
is non-sterile, cannot adhere to living tissue and is difficult to
release from the implant it is adhered to.
[0058] The high traction forces generated at minimal pressures by
nanofiber enhanced surfaces can optionally create minimal tissue
damage in surgical organ movement and retraction. The high traction
forces generated at small point loads can optionally allow for
increased dental surgical control and placement of dental
restorations. The advantage of a sterilizable probe that attaches
to living tissue as well as inert implants is thought to provide
significant advantage over existing technology.
[0059] The performance advantage, increased surgical speed and
decreased tissue damage over toothed and crushing (serrated)
forceps emphasizes the benefits of the current invention. Reduction
in post surgery tissue trauma and consequent inflammation
accompanied by an increase in healing rate are expected to arise as
a result of using the nanofiber coated retractors herein, thus
allowing for ease of use, increased speed of dental surgery, and
security of handling implants.
[0060] Some embodiments of the invention comprise disposable
retractors having nanofiber enhanced surfaces. Additionally, other
embodiments involve, e.g., upside down pyramid shapes (e.g., 1 cm
in height). The points of such pyramids can be used to touch
nerves, etc. Also, the flat sizes can be used for larger objects,
while the edges can be used for still other differently sized
objects. Retractors of the invention can optionally come in a
variety of sizes and shapes depending upon the specific intended
use. Again, for example, in dentistry a retractor of the invention
can be used for handling and placement of crowns, etc.
[0061] III) Enhanced Traction in Laparoscopy Clips Arising Through
Use of Nanofiber Enhanced Surfaces.
[0062] Termination clips are applied laparoscopically during
gallbladder surgery. About 10 clips come integrated in a $60.00
disposable cartridge. Five or six clips are typically used to seal
off arteries and veins during gallbladder surgery. The small U
shaped clips, about the size of a staple, are made of titanium and
are crimped in place. They do not have a tractive surface and rely
on the crimping force to stay in place. Trauma caused by the clip
can cause the growth of adhesions or a cut in the vessel.
[0063] The high traction forces generated at minimal pressures by
the nanofiber surfaces of the invention would make such clips ideal
for laparoscopic surgery, as well as for other surgeries.
[0064] The performance advantage of a significantly higher traction
surface (.about.2.times.) from the nanofiber enhanced devices
herein would be highly desirable. This is true especially because
there are about 600,000 gallbladder removals a year in the United
States alone. If other laparoscopic surgeries such as appendix
removals were added in this number would grow to more then
1,000,000. If one $60 cartridge is used per surgery the market is
at least $60,000,00.
[0065] Other applications of such clips or clamps can be to, e.g.,
clip or clamp the aorta, use as atraumatic clamps, etc. Such clamps
are also expected to be useful in beating heart surgery to help
stabilize heart motion. Such products optionally comprise arms with
pads (with nanofibers, etc.). Eye and/or eyelid surgery also
desires such clamps to stabilize the eye. Yet other common surgical
uses include, e.g., retracting dura for opening scalp, holding
pericardium in heart surgery, holding skin grafts in place, holding
organs/tissues in place, etc. Yet other embodiments comprise
wherein the substrate is dissolvable, e.g., liver sock, etc.
[0066] Surgeries often deal with organs, etc. that are slimy,
slippery, delicate, etc. Also, while anatomical elements that are
tubular or sheet-like can be grasped with suturers, etc., more
irregularly shaped organs (e.g., liver, heart, etc.) are more
problematic. Thus, retractors, disposable sleeves, and universal
contact surfaces for myriad clamp types which comprise nanofiber
surfaces are all desired. They can help eliminate constant
repositioning of medical devices (e.g., point retractors can touch
a tissue and hold it until release is needed). The devices of the
invention also can find placement in laparoscopic devices and
stabilization pads.
[0067] IV) External Fixator Implant Bacteriostatic Surfacing
[0068] External fixators are pins and wires inserted through the
skin into bone for the purpose of healing bone fractures. These
pins and wires are then connected externally with rods and clamps
in order to provide rigidity and stability so the fractured bone
can heal. The advantage of these devices over internally placed
plates, screws, pins and cerclage wires is in the decreased amount
of tissue and vascular disruption caused when compared to surgical
placement of internal implants. This lesser surgical invasion
allows the fracture to heal much faster and with lesser muscle and
subcutaneous scarring, implant-related osteosarcomas,
osteoarthritic changes, or painful cold-sensation complications and
obviates the need of surgical implant removal at a later date.
There has been a move over the past ten years towards this
"biologic" orthopedic method of healing over internal implants.
Minimization of tissue damage reduces healing time which is
paramount in bone healing. Complications arising from the use of
external fixators are bacterial infection from the skin, and
excessive movement of the pins if the connecting apparatus is
insufficiently stable. The use of the nanofiber bacteriostatic
surfacing is expected to decrease or eliminate what is perceived as
the major of these two problems.
[0069] The nanofiber coated bacteriostatic stainless surface of
external fixators would decrease the degree of skin surface
bacterial communication and subsequent contamination of the
threaded pin insertion, bone interface which causes pin loosening
and fracture healing failure. The performance advantage of a
bacteriostatic, externally placed bone pin would undoubtedly be
desired especially to reduce post surgery infection and pin
loosening complications. In various embodiments, all of the
implanted material is coated with nanofibers. In other embodiments,
screw threads, pins, and/or bonds are nanofiber coated. Other
embodiments comprise nanofiber coating of the bottom of a plate and
the top of a screw head, flexible wires (e.g., k-wires, k-pins,
etc.), straight pins, etc. It will be appreciated that such
external fixators of the invention are also optionally used in
limb-lengthening procedures.
[0070] V) Butterfly Skin Bandage/Patch
[0071] Many skin lacerations are clean wounds in need of simple
surface closure if suturing is unavailable or unnecessary.
Currently available butterfly skin bandages function well, but fail
rapidly as adhesion decreases with movement of skin and hydration
at the bandage site. A hydrophobic adhesive butterfly bandage
comprising nanofiber surfaces would be an elegant solution to this
need.
[0072] Corneal abrasions are a common ophthalmic injury causing
blepharospasm, ciliary spasm and pain. The majority of these
lesions take 24-72 hours to heal. Corneal ulcers take 3-5 days to
heal. Treatment with mydriatics which block ciliary spasm, reduce
pain in the ciliary body but increase photophobia. The patients are
hence more comfortable in dark environments. The use of a dermal
adhesive, hydrophobic butterfly patch comprising nanofiber surfaces
to close the eyelids would solve the photophobia problem and
increase the rate of corneal healing due to increased bathing of
the cornea with lachrymal secretions under a closed palpebrum.
[0073] The high traction forces generated at minimal pressures, and
hydrophobic characteristics would make nanofiber coated flexible
butterfly skin patches ideal for closing skin wounds and eyelids.
The performance advantage of such butterfly devices is expected to
be greatly desired. In some embodiments, the adhesive device is
flesh colored, or allows patients to bathe without the device
loosening. Such devices help patients avoid surgery and avoid
"puckers" at end of sutures (especially important for plastic
surgery). Other advantages of such devices include, e.g., no curing
of the adhesion needed, a good splinting material, not plaster that
would need to be wet, etc., the device can be "breathable" when,
e.g., the nanofibers are on a mesh material, etc. Such devices can
also optionally comprise drugs or the like to be released
transdermally (either continuous, concomitant with a rise in
temperature, etc.). Such devices are also optionally used with
decabitous ulcers, in venostatis situations (in diabetic patients,
pressure on the skin and bone causes erosion and ulcer). In
addition, such a wound dressing device can be coupled with a
moiety, such that the moiety can enhance wound healing (e.g., cell
growth). Nanofiber dimensions on the bandage can be designed to
capture cells.
[0074] VI) Enhanced Traction Clamping Devices for Cardiac
Surgery
[0075] Clamps are used extensively in cardiac surgery to
temporarily stop blood flow. There has been a move over the past
ten years towards disposable rubber atraumatic clamp inserts that
reduce arterial damage compared to traditional steel jawed clamps.
Mininimization of damage reduces recovery time and complications
due to scarring. Rubber inserts have made inroads into the market
but their limited traction still requires clamping forces high
enough to damage many arteries. The high traction forces generated
at minimal pressures by the devices herein would make nanofiber
coated clamp inserts ideal for cardiac surgery. The performance
advantage of a significantly higher traction surface
(.about.2.times.) would undoubtedly be desired, e.g., to reduce
post surgery complications.
[0076] VII) Adhesive Hydrophobic Otic Plug
[0077] Tympanic punctures, lacerations or rupture from infection
are a common nuisance to patients when showering and swimming.
Mechanical ear plugs are uncomfortable and often leak causing
vestibulitis (loss of balance) and otitis media (inner ear
infection). Reengineered otic plugs using nanofiber surface
adhesion properties in combination with hydrophobic characteristics
is expected to provide a significant improvement for millions of
patients with open tympanums. The high traction forces generated at
minimal pressures would make nanofiber coated and hydrophobic
coated ear plugs more comfortable and form a better seal against
water entry than existing technologies. The performance advantage
of a significantly higher traction surface (.about.2.times.) would
be desired, especially to reduce post otitis media complications
and vestibulitis.
[0078] The hydrophobic action and traction of the nanofibers would
be expected to create a secure plug. In various embodiments, the
plug fits within the ear canal, while in other embodiments, it
comprises a cap or disk to cover the ear or ear canal. Similar
embodiments are optionally used for other meati or orifices (e.g.,
to prevent nose bleeds, etc.). In some embodiments, the nanofibers
release from their substrate backing, e.g., to remain behind on the
patient so as to, e.g., not remove a scab or clot. Other
embodiments can optionally include anti-biofouling properties
and/or anti-microbial properties. See below. Some embodiments are
expected to optionally be used for urinary plugs, and the like. For
example some embodiments can optionally be used for fallopian tube
obstruction to prevent pregnancy.
[0079] VIII) Surgical Adhesion Preventative
[0080] Post-operative adhesions are a common surgical complication.
Presently, and historically, there has been a great deal of
activity to develop methods for the prevention of post-operative
adhesions. Some of the approaches, e.g., the ingestion of iron
powder-laced oatmeal followed by the application of magnets to the
abdomen to jostle the bowel and prevent adhesions, are interesting
approaches. Adhesions are particularly troublesome in a variety of
locations, e.g., between the pericardium and sternum following open
heart surgery, in the abdominal cavity following bowel procedures
and, especially, in the retroperitoneal space involved with
gynecological reconstruction. Two primary approaches have been
explored. The first involves implantable barrier films prepared,
for example, from hyaluronic acid or hydrogonic acid or oxidized
cellulose, but has not met with success because the location of
where to place the film to prevent adhesions is not determinable.
The second approach involves the instillation of a bolus of
solution, e.g., N,O-acetylchitosan, to wet the general area where
adhesions might be expected. This seems to be the superior
therapeutic direction, but no satisfactory product along this line
has been commercialized. If a suitable, proven product were made
available, it would have the potential to be used prophylactically
in practically every surgical procedure. It should be noted that
post-operative adhesions usually form during the first
post-operative week and, if not formed during this time, they
usually do not occur. Therefore, the task is to prevent fibroblasts
(which produce the collagenous adhesions) to adhere to local tissue
surfaces because, without cellular attachment during the first
week, adhesions will not form. The anti-adhesion solutions of the
current invention are expected to prevent such cell attachment. The
anti-adhesion embodiments herein are optionally in various forms
(e.g., liquid application forms, film application forms, etc.).
Creation of adhesions are especially bad for fertility surgery.
Because adhesions form relatively quickly, it is desired to avoid
fibroblast for 5 days post operations.
[0081] An aqueous microcapsule or particle suspension prepared from
an absorbable natural (e.g., collagen) or synthetic (e.g.,
polyglycolic acid) polymer and coated with a nanofiber surface to
provide extreme lubricity is a feature of the invention. About 200
ml of this suspension could be poured into the appropriate cavity
and would coat the tissue with a surface not hospitable to
fibroblast cell attachment and subsequent adhesion formation. The
material would be harmlessly absorbed after a few weeks. Some
embodiments can optionally be a mesh (e.g., synthetic, metal,
fabric) coated with nanofibers or nanowires that is laid directly
over the cavity.
[0082] IX) Endoscopes and Catheters
[0083] One of the more difficult aspects of endoscopy, e.g.,
colonoscopy, involves the frictional resistance of the device
passing through the tubular organ, e.g., bowel, urethra, esophagus,
trachea, blood vessel, etc. Besides being difficult to transport
the scope or catheter, the friction causes significant discomfort
to the patient. Slippery catheters, coated with, for example,
polyvinylpyrrolidone have been designed to provide easier passage
but these devices have not enjoyed wide market acceptance. A
lubricious scope or catheter comprising nanofiber surfaces of the
invention, would be expected to provide significantly increased
patient comfort and well as more facile transport for the
physician.
[0084] X) Intraluminal Cameras
[0085] One of the latest diagnostic advances is the use of
miniaturized, untethered cameras to observe internal organs. Such
cameras, the size of pills, may be ingested or injected and float
downstream, sending images back to the medical observer. It is
expected that improved lubricity due to nanofiber surfaces of the
invention will enhance the performance of such devices. An
appropriate nanofiber coating is expected to make it easier for the
camera to be ingested and manipulated along its path. Other similar
embodiments comprise nanofiber coatings on devices to, e.g., create
hydrophobic shields (e.g., windows) on devices such as cameras,
keep a coating layer (e.g., hyluonic acid, etc.) on a device, to
create a transparent coating on contact lenses (which optionally
also helps prevent protein build-up), etc.
[0086] XI) Mechanical Heart Valves
[0087] There are two types of heart valve prostheses used for
replacement of aortic and mitral valves. Mechanical valves commonly
are metallic cages with a disc that opens at systole to allow blood
to flow and closes at diastole to prevent backflow. These valves
last indefinitely but require the daily administration of an
anticoagulant drug to prevent thrombotic complications. The dose
must be carefully regulated to prevent thrombus formation on one
hand and internal hemorrhage on the other. The other type of valve
is the tissue valve, sometimes isolated en bloc from porcine hearts
and sometimes constructed from bovine pericardial tissue. These
leaflet valves are more like natural valves and usually do not
require anticoagulant drug administration. However, they are
susceptible to degradation and have more finite life expectancies
than do the mechanical valves. Fortunately, they fail slowly and
provide ample time for surgical replacement. It would be of
inestimable medical advantage if the long lasting mechanical valves
could function successfully without anticoagulation therapy.
Nanofiber enhanced surfaces of the invention used thusly are part
of the invention. Additionally, nanofiber surfaces also can be used
in the improvement of the hemodynamic performance of left
ventricular assist devices (LVADs).
[0088] With nanofiber specially designed mechanical heart valves,
it is expected that: there will be improved hemodynamics resulting
from laminar flow; there will be improved blood throughput per
systole; the need for anticoagulation will be eliminated or
significantly reduced; the incidence of thrombosis will be
eliminated or significantly reduced; and the level of hemolysis
will be reduced or eliminated.
[0089] XII) Small Caliber Vascular Grafts
[0090] Presently, a variety of vascular prostheses larger than
about 6 mm in diameter perform adequately when implanted from the
thoracic aorta through the iliac/femoral regions. Below about 6 mm
in diameter, such grafts fail when implanted either as
interpositional or bypass grafts, secondary to full lumen
thrombosis. Similarly, there is no graft material available for
venous reconstruction. For many years, workers have tried to
develop a small diameter vascular graft, particularly for coronary
artery bypass procedures, to avoid the need to harvest saphenous
veins from the leg. Generally, small diameter grafts in the 2-5 mm
range fail because a 0.5-1.0 mm thick layer of protein is rapidly
deposited on the luminal surface causing a further reduction in
luminal diameter which, in turn, induces the formation of mural
thrombi. Even conventionally non-wettable surfaces such as
polytetrafluoroethylene (Teflon.RTM.) and polyurethanes do not
resist protein intimal layering.
[0091] The ultra non-wettability of nanofiber enhanced surfaces may
affect two factors of extreme importance. First, the avoidance of
deposition of plasma protein on the luminal surface will preserve
the original graft diameter. Equally important, a nanofiber surface
may provide close to ideal laminar blood flow which would be
expected to reduce or entirely eliminate luminal thrombus
formation. This is optionally of great importance in preventing
graft thrombosis and/or minimizing anastomotic intimal hyperplasia,
well-know causes of graft failure secondary to turbulent flow,
particularly at the sutured anastomosis.
[0092] Specifically, the nanofiber surface may be beneficially
employed for the following grafts: femoral/popliteal (and
infrapopliteal) reconstruction; coronary bypass grafts (possibly
replacing saphenous veins and IMA procedures); A-V shunts
(hemodialysis access); microvascular reconstruction (e.g., hand
surgery); and vein reconstruction. Use of such for A-C bypass
grafts and for peripheral vascular reconstruction, especially in
the diabetic patient population, are contemplated. Microvascular
and A-V shunt and vein uses are also contemplated. More detailed
descriptions of the use of nanofiber enhanced surfaces for
sutureless anastomotic procedures is described further below.
[0093] XIII) Bulking Agent for Cosmesis
[0094] The Collagen bulking business has taken off in the arena of
cosmesis with 800,000 procedures thought to be performed in 2003.
The annual revenues of the space for the materials provider(s) is
closing in on $500 Million. The primary issue with Collagen when
used for cosmesis (e.g., lips and deep wrinkles, etc.) is
durability. The typical collagen bulking injection will last 34
months prior to subsidence of results and need for reapplication.
Thus, non-resorbable, yet biocompatible micro-spheres are desired
to create a durable cosmetic effect.
[0095] The ability to create non-bioburden micro-spheres injectable
through a standard gauge needle, is greatly desired in this area,
especially if: they are easily applied, injectable and lubricous
enough for easy placement; there are durable results; there are no
biocompatibility issues; and there is no migration over time. There
are reasons to believe that the ability to combine an optimized
lubricity (e.g., through balancing hydrophobia & hydrophilia
with nanofibers) in conjunction with a non-bioburden technology on
a micro-sphere carrier could create a competitive winner. Other
embodiments comprise possible reduction of scar tissue and those
having erodable polymers with nanofiber scaffold which is
optionally functionalized.
[0096] XIV) Enhanced Flow and Reduced Thrombogenicity Mechanical
Heart Valve
[0097] Replacement valve implantation is a large and valuable
market that is approaching $1 Billion in sales. First, there has
been an on-going pendulum swing between mechanical and tissue valve
implantation driven primarily by the real and perceived differences
between the two in the areas of longevity, thrombogenicity and flow
dynamics. Second, product based competition has ossified as new
product development cycles have been protracted on the back of ever
more rigorous regulatory/clinical requirements. With the
possibility of modifying existing products (resulting in a much
shorter regulatory path) potentially delivering improvements in 2
of the key valve metrics (thrombogenicity and fluid dynamics),
nanofibers could potentially have a dramatic impact upon the market
share within mechanical valve players and between mechanical and
tissue valve products.
[0098] Although not entirely understood, thrombogenicity and flow
dynamics are interrelated issues. In fact, the flow eddies created
downstream of the hinge seat for the most popular bi-leaflet valve
design is still blamed for much of the thrombogenic effect of such
products. A hydrophobic surface coating such as that made possible
by nanofiber enhanced surfaces may have dramatic effect in reducing
such problems.
[0099] This embodiment of the invention offers the benefit of being
an addendum to a current product thereby allowing a dramatically
reduced cycle time while at the same time delivering true product
based differential advantage.
[0100] XV) More Durable Functionality of Implantable Sensors and
Pacing Leads
[0101] The implantable sensor market is in its infancy with the
variety of early applications including; glucose sensors, cardiac
function sensors (either on-lead or off) and neurological implants
of various stripes. Many of these companies have similar problems
associated with bio-fouling over time and the difficulty of
creating durable reagent beds. It may be possible that the
combination of reagent doping pads, arranged in concert with highly
hydrophobic structures will deliver a significantly longer lasting
functionality to sensors of all types. Current technologies are
either accepting this shortcoming (e.g., glucose sensors limited to
3 days of functionality) or are combating it with costly and
difficult to engineer solutions involving mechanically active
packaging and/or massive parallelization.
[0102] A further and related application for the nanofibers herein
would be the coating of pacing leads to provide both a better
electrical contact with tissue and a non-fouling shaft. Much of the
sensor/reagent technology employed in these markets is no longer
proprietary due to the long mature run in traditional non-implant
diagnostics and the packaging may in-fact be the critical
proprietary technology that enables the space. How does one package
a sensor (be it reagent or electrical) for long term survival in
the highly corrosive and actively encapsulating environment of the
human body. This is a significant challenge for all of the
indwelling companies. The uniquely non-fouling approach delivered
by the nanofibers herein, has the additional property that it
leaves no-imprint down-stream or in proximity to the non-fouling
surface. This would enable a creative packaging with
reagent/sensors to gamer accurate readings. Furthermore, with
reagent durability being of concern, it may be possible to create
reagent doped pads comprising nanofibers in much the same way as
the drug doped pads discussed in the drug-eluting stent summary
below.
[0103] In the arena of pace-maker leads, there are two issues that
bother the clinicians involved. The occasional dislodged or poorly
placed lead that delivers inadequate charge to the tissue and the
over-growth of tissue around the leads over time that can, in some
patients who have had multiple leads placed over time, actually
cause flow resistance. These can further complicate subsequent
procedures/surgeries. Further, abandoned but not removed leads can
cause complications. Such devices comprising nanofibers herein
could likely remove both of these issues with nanofibers on the
sensor head and an anti-bio-fouling coating along the shaft.
[0104] Glucose sensors: The holy grail of the .about.$2 Billion
world-wide glucose sensing market has been to get away from the
finger-stick devices and into a sustained glucose device either
through a truly non-invasive approach or an indwelling approach.
The two paths remain in fundamental technological competition with
neither approach yet showing a clear edge in embodiment or
time-to-market over the other. The implantable glucose sensing
technologies under development today all bring with them
substantial enough limitations so as not to be considered for broad
market adoption. While this cannot be said of the non-invasive
approaches they face hurdles in development that have for 15 years
stymied the market leaders in their quest for workable units.
Nanofiber addition to such sensors would prevent/ameliorate several
problems listed above.
[0105] Cardio Sensors: In its very earliest stages this market
promises to provide full cardiac output metrics without the need
for an interventional cardiological procedure (perhaps on an
on-going basis as an alert) and/or to provide superior real-time
control of an active cardiology device (e.g., BV-Pacer, left
ventricular assist device (LVAD)). Again, addition of nanofibers to
such devices would prevent/ameliorate many problems above.
[0106] Neuro sensors/emitters: Again, another early stage space but
in this case the primary focus in the area of stimulation as
opposed to sensing. Neuromodulation and neurostimulation rely on
consistent, uninterrupted contact with nervous tissue. Nanofibers
on the tissue contact end of the leads can secure the lead and
prevent scar formation (e.g., glial scar) leading to improved
conduction. Additionally, nanofibers can be used as conductive
materials in the shaft of the lead.
[0107] ICD and Pacemaker leads: The numbers in the combined market
are large in unit volume with .about.1,000,000 implantations per
year. This is further experiencing growth as bi-ventricular pacing
has taken off even more rapidly than the all ready optimistic
projections. The issue with the leads has been that while they, at
one time, took quite a large share of the value chain their
price-point has been steadily eroded. Nanofibers on the ICD and
pacemaker leads help to create a high surface-to-volume ratio on
the lead surface to help secure the lead in place and further to
provide improved mechanical and electrical connectivity to the
tissue surface. For example, it has been demonstrated that
semiconductor nanofibers (e.g., silicon nanowires) often grow
nearly normal (e.g., vertical) to the surface of a (111)-oriented
Si wafer and make good electrical and mechanical connection to the
substrate. See, e.g., Islam M. S. et al., Ultahigh-density silicon
nanobridges formed between two vertical silicon surfaces,
Nanotechnology 15 (2004) L5-L8; Tan Q et al., Materials Research
Society Fall Mtg. (Boston, Mass., December 2002) (Paper F6.9), the
entire contents of which are each incorporated by reference herein.
By depositing nanofibers (e.g., nanowires) directly on ICD and
pacemaker lead surfaces, the nanofibers can provide enhanced
electrical connectivity between the ICD and pacemaker lead and the
tissue surface (e.g., heart tissue) to which it is attached. Thus,
the use of nanofiber enhanced surfaces is attractive for ICD and
pacemaker leads, sensors and other medical device applications
requiring electrical (and mechanical) conduction including bone,
nerve and muscle stimulation and the like. In addition, the high
surface-to-volume ratio created by the nanostructured surface
allows for the continued miniaturization of ICD and pacemaker
leads, sensors and the like due to the enhanced area of electrical
contact to thereby achieve improved size reductions comparable to
conventional devices.
[0108] XVI) Vascular Stents and Next Generation Drug Eluting
Coronary Stents
[0109] Vascular stents are small metallic devices which are used to
keep the blood vessels open following balloon angioplasty. The
development of coronary stents, for example, has revolutionized the
practice of interventional cardiology over the past 10 years. More
than 70 coronary stents have been approved in Europe and over 20
stents are commercially available in the United States such as the
Multi-Link Vision.TM. Coronary Stent System available commercially
from Guidant Corporation (Indianapolis, Ind.), and the Driver.TM.
Coronary Stent System or BeStent2.TM. available commercially from
Medtronic, Inc. (Minneapolis, Minn.).
[0110] Commercially available stents can take a variety of forms.
For example, one such stent 210, as shown, for example, in FIGS.
2A-B, is a stainless steel wire which is expanded by balloon
dilatation. The stent 210 may be crimped onto a balloon 212, as
shown in FIG. 2A, for delivery to the affected region 214 of a
vessel 216 such as a coronary artery. For the sake of simplicity,
the multiple layers of the vessel wall 216 are shown as a single
layer, although it will be understood by those skilled in the art
that the lesion typically is a plaque deposit within the intima of
the vessel 216.
[0111] One suitable balloon for delivery of the stent 210 is the
Maverick.RTM. PTCA balloon commercially available from Boston
Scientific Corporation (Natick, Mass.). The stent-carrying balloon
212 is then advanced to the affected area and across the lesion 214
in a conventional manner, such as by use of a guide wire and a
guide catheter 205. A suitable guide wire is the 0.014" Forte.TM.
manufactured by Boston Scientific Corp. and a suitable guiding
catheter is the ET 0.76 lumen guide catheter.
[0112] Once the balloon 212 is in place across the lesion 214, as
shown in FIG. 2A, the balloon 212 may be inflated, again
substantially in a conventional manner. In selecting a balloon, it
is helpful to ensure that the balloon will provide radially uniform
inflation so that the stent 210 will expand equally along each of
the peaks. The inflation of the balloon 212 causes the expansion of
the stent 210 from its crimped configuration to its expanded
position shown in FIG. 2B. The amount of inflation, and
commensurate amount of expansion of the stent 210, may be varied as
dictated by the lesion itself.
[0113] Following inflation of the balloon 212 and expansion of the
stent 210 within the vessel 216, the balloon is deflated and
removed. The exterior wall of the vessel 216 returns to its
original shape through elastic recoil. The stent 210, however,
remains in its expanded form within the vessel, and prevents
further restenosis of the vessel. The stent maintains an open
passageway through the vessel, as shown in FIG. 2B, so long as the
tendency toward restenosis is not greater than the mechanical
strength of the stent 210.
[0114] Another form of stent is a self-expanding stent device, such
as those made of Nitinol. The stent is exposed at the implantation
site and allowed to self expand.
[0115] Significant difficulties have been encountered with all
prior art stents. Each has its percentage of thrombosis, restenosis
and tissue in-growth, as well as varying degrees of difficulty in
deployment. Another difficulty with at least some of the prior art
stents is that they do not readily conform to the vessel shape.
Anticoagulants have historically been required at least for the
first three months after placement.
[0116] Thus there has been a long felt need for a stent which is
effective to maintain a vessel open, without resulting in
significant thrombosis, which may be easily delivered to the
affected area and easily conformed to the affected vessel.
[0117] The present embodiment of the invention is generally
directed to endovascular support devices (e.g., commonly referred
to as "stents") that are employed to enhance and support existing
passages, channels, conduits, or the like, and particularly animal,
and particularly mammalian or human lumens, e.g., vasculature or
other conductive organs. In particular, the present embodiment of
the invention provides such stent devices that employ
nanostructured components as shown, for example, in FIG. 1 and FIG.
2D, to enhance the interaction of the stent with the passages in
which they are used. Typically, such nanostructured surfaces are
employed to improve adhesion, friction, biointegration or other
properties of the device to enhance its patency in the subject
passage. Such enhanced interactivity is generally provided by
providing a nanostructured surface that interacts with the surface
of the passage, e.g., an inner or outer wall surface, to promote
integration therewith or attachment thereto. The nanostructured
components (e.g., nanofibers) can either be attached to the outer
or inner surface of the stent, e.g., by growing the nanofibers
directly on the outer and/or inner surface of the stent, or by
separately covalently or ionically attaching the fibers to the
stent surfaces. In addition, the nanofibers or other nanostructures
can be embedded into the stent material itself to enhance the
rigidity and strength of the stent within the vessel into which it
is inserted. The shape and size of the nanofibers as well as their
density on the graft surfaces can be varied to tune the adhesive
(or other) properties of the stent to the desired levels. In
particularly preferred aspects, higher aspect ratio nanofibers are
used as the nanostructures. Examples of such nanofibers include
polymeric nanofibers, metallic nanofibers and semiconductor
nanofibers as described previously.
[0118] The stents of this invention may also be coated on the
inside and/or outside with other materials to still further enhance
their bio-utility. Examples of suitable coatings are medicated
coatings, drug-eluting coatings (as described below), hydrophilic
coatings, smoothing coatings, collagen coatings, human cell seeding
coatings, etc. The above-described nanofiber coatings on the stent
can provide a high surface area that helps the stent to retain
these coatings. The coatings can be adsorbed directly to the
nanostructured surface of the stent. Alternatively, the
nanostructured surface may be provided with a linking agent which
is capable of forming a link to the nanostructure components (e.g.,
nanofibers) as well as to the coating material which is applied
thereto. In such cases, the coating may be directly linked to the
nanostructured surface, e.g., through silane groups, or it may be
coupled via linker binding groups or other appropriate chemical
reactive groups to participate in linkage chemistries
(derivitization) with linking agents such as, e.g., substituted
silanes, diacetylenes, acrylates, acrylamides, vinyl, styryls,
silicon oxide, boron oxide, phosphorus oxide,
N-(3-aminopropyl)3-mercapto-benzamide, 3-aminopropyl-trimethoxysil-
ane, 3-mercaptopropyl-trimethoxysilane,
3-maleimidopropyl-trimethoxysilane- ,
3-hydrazidopropyl-trimethoxysilane, hydroxysuccinimides,
maleimides, haloacetyls, pyridyl disulfides, hydrazines,
ethyldiethylamino propylcarbodiimide, and/or the like.
[0119] The coronary stent market is enormous and hotly contested by
the largest device players. There is, at the moment, a gold rush
amongst competitors to gain advantage thorough product
development/acquisition in the newest sector--drug eluting coronary
stents, such as the U.S. FDA-approved Cordis Cypher.TM.
sirolimus-eluting stent and the Boston Scientific Taxus.TM.
paclitaxel-eluting stent system. Drug eluting stents are rapidly
gaining market share and may become the standard of care in
coronary revascularization by the year 2005. This new therapy
involves coating the outer aspect of a standard coronary stent with
a thin polymer containing medication that can prevent the formation
of scar tissue at the site of coronary intervention. Examples of
the medications on the currently available stents are sirolimus and
paclitaxel, as well as anti-inflammatory immunomodulators such as
Dexamethasone, M-prednisolone, Interferon, Leflunomide, Tacrolimus,
Mizoribine, statins, Cyclosporine, Tranilast, and Biorest;
antiproliferative compounds such as Taxol, Methotrexate,
Actinomycin, Angiopeptin, Vincristine, Mitomycin, RestenASE, and
PCNA ribozyme; migration inhibitors such as Batimastat, Prolyl
hydroxylase inhibitors, Halofuginone, C-proteinase inhibitors, and
Probucol; and compounds which promote healing and
re-endothelialization such as VEGF, Estradiols, antibodies, NO
donors, BCP671, and the like. Sirolimus, for example, had been used
previously to prevent rejection following organ transplantation.
Unfortunately, the use of polymer coatings on stents can lead to
thrombosis and other complications; anticoagulants are typically
required at least for the first three months after placement to
alleviate some of these issues.
[0120] However, the provision of a nanostructured surface on these
newer stents according to the teachings of the present invention
can eliminate the need for such polymer coatings and thus minimize
some of these complications. Increasing surface area (e.g., through
spring coil, micropockets, etc.) through nanofibers is quite
desirable. Thus, nanofibers are optionally embedded/empended into
tissue to give a more sustained benefit and better drug release.
The nanofiber surfaces give greatly enhanced surface area and a
longer length of elution and a more intense concentration. The
drugs can be directly tethered (e.g., via silane groups) to the
nanofibers (or other nanostructured components) or can be linked
(e.g., covalently) to the nanofibers through suitable linkage
chemistries such as those described above. The linkage chemistry
can be tailored to provide for customized drug elution profiles and
for the controlled release of the drug compounds over time.
[0121] The manufacturers of drug eluting stents are very interested
in the several facets of this new technology: increased contact
surface area between coated metal and arterial wall; increased
depth/durability of coating for pro-longed elution times; and
intriguing possibilities of multiple, layers of differing drugs for
novel elution profiles. The basic stent structure (conformity, ease
of deployment, branching utilization, etc.) still matters a great
deal in winning doctors over from other products.
[0122] By developing a coating that enables increased contact area
and "dose density", that likely can be applied to any and all
existing stents, the nanofiber devices herein can pursue a variety
of market strategies, e.g., through improved fluid dynamics with a
hydrophobic surface coating on the inside, drug elution
improvement, etc. By applying a nanofiber coating to the outside
surface of the stent it may be possible to then have a thicker and
more durable drug coating on the stent than would be possible
without the nanofiber technology. Furthermore, the high surface
area contact intrinsic to the nanofiber technology may yield
improvements in tissue response to the attached drug. Furthermore,
there may be the opportunity to apply a hydrophobic coating to the
inside of the stent to improve flow dynamics--particularly within
small arteries.
[0123] In addition to coronary stents, the use of nanostructured
surfaces may also be beneficially applied to other stents which are
used in other parts of the body of a patient, such as urethral and
biliary stents. In these body lumens, it is desired to prevent
crystallization on the struts of the stents. In the biliary tree,
for example, bilirubin crystals deposit on foreign surfaces such as
sutures and permanent or temporary stents. Such deposition
typically decreases the useful life of the stents and can require
patients to undergo multiple procedures for successful therapies. A
similar situation exists in the urinary tract. Uric acid
precipitates on stents and leads to "stent encrustation," which
ultimately leads to device failure. Stents otherwise may be a
promising therapy for conditions such as Benign Prostatic
Hyperplasia (BPH). A stent with a super hydrophobic nanofiber
coating would resist crystal formation because the aqueous phase
would not "see" the stent and crystal inducing elements would not
have a chance to deposit.
[0124] XVII) Small Caliber Vascular Grafts
[0125] Presently, a variety of vascular prostheses larger than
about 6 mm in diameter perform adequately when implanted from the
thoracic aorta through the iliac/femoral regions. Below about 6 mm
in diameter, such grafts fail when implanted either as
interpositional or bypass grafts, secondary to full lumen
thrombosis. Similarly, there is no graft material available for
venous reconstruction. For many years, workers have tried to
develop a small diameter vascular graft, particularly for coronary
artery bypass procedures, to avoid the need to harvest saphenous
veins from the leg. Generally, small diameter grafts in the 2-5 mm
range fail because a 0.5-1.0 mm thick layer of protein rapidly is
deposited on the luminal surface causing a further reduction in
luminal diameter which, in turn, induces the formation of mural
thrombi. Even conventionally non-wettable surfaces such as
polytetrafluoroethylene (Teflon.RTM.) and polyurethanes do not
resist protein intimal layering. The peripheral vascular market
represents a huge, relatively untapped market because of the
limitations of small diameter grafts. The nanofiber surfaces herein
can aid in reducing bio-fouling, increasing hydrophobicity,
etc.
[0126] It is suggested that the ultra non-wettability
(hydrophobicity) of nanofiber surfaces may affect two factors of
extreme importance. First, the avoidance of deposition of plasma
protein on the luminal surface will preserve the original graft
diameter. Equally important, a nanofiber surface can optionally
provide close to ideal laminar blood flow which would be expected
to reduce or entirely eliminate luminal thrombus formation. This
may be of great importance in preventing graft thrombosis and/or
minimizing anastomotic intimal hyperplasia, well-known causes of
graft failure secondary to turbulent flow, particularly at the
sutured anastomosis.
[0127] The nanofiber surface may be beneficially employed for the
following grafts: Femoral/popliteal (and below the knee)
revascularization; Coronary bypass grafts (possibly replacing
saphenous veins and IMA procedures); A-V shunts (hemodialysis
access); Cranial (Supra Temporal Artery/Medial Cerebral Artery
[STA/MCA]); Microvascular reconstruction (e.g., hand surgery); vein
reconstruction By far, coronary bypass grafts have significant
medical and commercial value followed by femoral revascularization.
In some embodiments the graft material is simply coated with
nanofibers herein, while others comprise entirely new substrates
specifically designed for nanofiber coating. A nanofiber A-C bypass
graft would be quite desirable, particularly if it could be
implanted using advanced least invasive surgical procedures to
avoid splitting the sternum. A large market exists for peripheral
reconstruction, especially in the diabetic patient population. The
microvascular, A-V shunt and vein markets are relatively small but
together, may be form a significant business. There is potential to
carry the vascular graft business into an entirely new level of
performance.
[0128] Current grafts in small vessels present problems. Current
choices include, e.g., Dacron fabric, PTTFE (similar to Gortex),
etc. Problems can arise with small diameters and protein layers
that are put down (especially true for diameters under 6 mm). Ideal
grafts want the vessel to look like a wet noodle for impeding into
vein structures and not have film forming. Thus, prevention of
protein buildup and perfection of laminar flow in the vessel is
desired. Also, less invasive procedures are desired. The current
nanofiber devices can optionally fulfill these needs, e.g., be less
invasive because devices could be preloaded and, e.g., stapled into
the vessel. The hydrophobicity of various embodiments herein can be
quite useful in typical uses. The grafts herein are optionally
temporary or permanent within the patient. Other embodiments
include wherein the nanofiber grafts also comprise drug coatings,
etc. (e.g., heparin, etc.).
[0129] Other embodiments deal with concerns of, e.g., working with
collagen spun vascular grafts. Also, host vessel sutured to a graft
can get puckered at interface from sutures, thus, leading to eddies
at interface. Thrombus can form at interface and intimal
hyperplasia can lead to vessel narrowing at the anastomotic site.
Such can cause narrowing of the vessels until the vessel closes
down. This is not usually a problem in large vessels, but can be
quite problematic in smaller vessels. Therefore, nanofiber surfaces
of the invention can be incorporated into grafts at such
interfaces. Also, coated spiral structures which are optionally
removed are incorporated herein. Sutures, staples, etc. are also
optionally nanofiber enhanced.
[0130] Other embodiments include nanofiber enhancement with, e.g.,
blood treatment, left ventricular assist devices (LVAD) treatment
regimes (e.g., preventing thrombosis), patent foramen ovale (PFO),
atrial septal defects (ASDs), treatment of left atrium aneurysms,
treatment of diabetic small vessel disease (i.e., instead of
amputation), treatment of venous thrombosis (e.g., over long term,
etc.). The nanofiber surfaces herein typically provide longevity,
can allow flexibility, provide strength of holding staple/suture.
They can be used in, e.g., growth of specific cells for wound
healing, as scaffolding for bone growth to occur, etc. For example,
with respect to atrial septal defects, when there is a large hole
between the right and left atria, oxygen rich blood leaks back to
the right side of the heart. The result can be pulmonary
hypertension. These defects are often treated surgically, through
open heart surgery. A device that could be placed percutaneously,
and permanently close the hole, would be desirable over the
morbidity associated with open chest surgery. A device
incorporating nanofibers can be placed via a catheter through the
arterial system, and serve as a patch or plug over or in the
defect.
[0131] XVIII) Timed Release Nanowire Balls
[0132] The past 20 years has seen many research efforts aimed at
orally delivered targeted delivery drug vehicles. Specificity,
controlled release and low toxicity have been difficult hurdles to
overcome and most of these efforts are still in the research phase.
Polymers, dendrimers, liposomes and antibodies are four
well-studied drug carriers. These structures range from the micron
size to several nanometers. The larger particles tend to stick to
the desired tissue and then the drug erodes out; the smaller
structures often carry only several drug molecules and work on
contact or when a bond is broken to the carrier structure
(dendrimers). Nanostructures could span this size range from small
dots (3-10 nm) to clusters of nanowires (20-500 nm). These
structures could be readily conjugated to drug molecules and can be
dispersed in aqueous solution.
[0133] High drug capacity and ease of functionalization are typical
advantages of the current invention. Typical embodiments are chosen
based upon, e.g., toxicity testing for patient application, as well
as nanofiber accumulation. Some embodiments comprise tericoated
tabs and can depend on pH values in the stomach, e.g., for time
release due to recognition of an enzyme or the proper pH. Other
embodiments comprise air-filled nanofiber balls, e.g., as contrast
agents in ultrasound and the like, or drug encapsulated,
biodegradable spheres. Also, PEGylated liposomes not taken up by
the reticuloendothelial system (RES) are provided. Another
advantage of the use of nanofiber surfaces for drug release balls
or capsules is that the adherent properties of the nanofiber
surfaces can cause attachment of the surface of the drug-release
structure to, for example, the mucosal membrane so they might
adhere sublingually or in the esophageal pathway prior to exposure
to the stomach (or other targheted organ) leading to the precise
delivery of drugs over a controlled (e.g., prolonged) period.
[0134] XIX) Surgical Needles
[0135] Some embodiments herein comprise nanofiber coated surgical
needles. Cutting needles are better when serrated. When passing a
needle through tissue, the apparent sharpness is based on
resistance (correlated to dullness). Protein attaching to the
surface of such needles gives the apparent dullness. Thus, coatings
(e.g., as with nanofibers) can be more important than "sharpness"
of the needles. Such concepts are also applicable to scalpels,
etc.
[0136] XX) Wound Dressing
[0137] Wound dressings are used extensively in trauma, at catheter
skin-sites and post surgical applications. This is a very
competitive field with an excess of OTC and ethical supply products
available. Minimization of infection, allowance of air penetration,
adhesion ability, water repellency, ease of application, ease of
removal are all important characteristics that influence physician,
nurse and patient product preference. All of these characteristics
can be found in separate wound dressings but not as an "all-in-one"
package. A flexible, breathable, hydrophobic, bacteriostatic sided
dressing with an adhesive, bacteriostatic backside would be
revolutionary to the medical field. The current nanofiber surfaces
herein can optionally supply many or all of such characteristics.
This dressing would be able to access ethical as well as OTC
markets.
[0138] The combination of nanowire coated characteristics would
allow patients to shower or bathe, avoid infection, heal, and
decrease the need for painful bandage changes. Various embodiments
can comprise bacteriostatic dressings and/or bactericidal
dressings. Various embodiments can comprise silver and/or zinc
and/or titanium oxides. Such dressings are especially contemplated
for, e.g., burn victims, etc.
[0139] The current invention comprises a number of different
embodiments focused on nanofiber enhanced area surface substrates
and uses thereof (e.g., in medical devices/uses). As will be
apparent upon examination of the present specification and claims,
substrates having such enhanced surface areas present improved and
unique aspects that are beneficial in a wide variety of
applications for medical use. It will be appreciated that enhanced
surface areas herein are sometimes labeled as "nanofiber enhanced
surface areas" or "NFS" or, alternatively depending upon context,
as "nanowire enhanced surface areas" or "NWS."
[0140] A common factor in the embodiments is the special morphology
of nanofiber surfaces (typically silicon oxide nanowires herein,
but also encompassing other compositions and forms) which are
optionally functionalized with one or more moiety.
[0141] XXI) Abdominal (or Thoracic) Aortic Aneurysm (AAA) Medical
Procedures
[0142] The compositions, apparatus, systems and methods described
herein relating to nanostructured surface enhanced coatings can be
used, for example, to assist in the device, function and deployment
of prostheses during the repair of thoracic or abdominal aortic
aneurysms.
[0143] An aortic aneurysm generally is an abnormal widening,
stretching or ballooning of the thoracic or abdominal portion of
the aorta, which is the major artery from the heart which delivers
blood to the major organs of the body. The thoracic and abdominal
portions of the aorta represent the upper, arched portion and
lower, abdominal portion of the aorta, respectively. The exact
cause of aneurysm is unknown, but risks include atherosclerosis and
hypertension. A common complication is ruptured aortic aneurysm, a
medical emergency in which the aneurysm breaks open, resulting in
profuse bleeding. Aortic dissection occurs when the lining of the
artery tears and blood leaks into the wall of the artery. An
aneurysm that dissects is at even greater risk of rupture. Aortic
aneurysms occur in approximately 5-7% of people over the age of 60
in the United States alone. Over 15,000 people die each year of
ruptured aneurysm, the 13.sup.th leading cause of death in the
U.S.
[0144] Generally, when an abdominal or thoracic aortic aneurysm
reaches a size of about 5 cm, surgical intervention is necessary.
To repair an abdominal or thoracic aortic aneurysm by
intraoperative procedure, the thoracic cavity can be accessed by a
midline or retroperitoneal incision in the case of an open
procedure, or by percutaneous access in a minimally invasive
endograft procedure, and an autogenous or prosthetic graft is used
to isolate the aneurysm from blood flow and pressurization, thus
precluding aneurysm expansion and minimizing the risk of rupture.
Typically, the first choice for replacement is typically the
autogenous saphenous vein (ASV), but when it is unavailable for
transplant, artificial prosthetic grafts may be used. Generally
they are used for large diameter vessel applications such as aortic
aneurysm repair, however recent research efforts have been directed
towards finding suitable methods for medium and small diameter
vessel repair as well.
[0145] Inaccurate deployment of aortic prostheses can lead to
inadequate sealing of the aneurysm which can cause further aneurysm
expansion due to blood flow around the graft, and/or inadvertent
blockage of collateral vessels supplied by the aorta, for example,
such as the renal arteries. Aortic prostheses can also slip out of
position. To date, as noted below, at least two stent grafts have
been pulled from the market due to high rate of failure, and others
continue to fail. A need exists to improve the outcome of aortic
aneurysm repair by improving the materials of the grafts to make
them more adherent thereby minimizing or eliminating failures of
conventional devices caused by such complications as leakage and/or
mal-positioning or slippage of the prosthetic devices.
[0146] Using the methods and compositions disclosed herein, both
open and minimally invasive endovascular repair procedures can be
performed to ensure that an aortic prosthesis, when placed properly
at the site of an aneurysm, will adhere firmly to the tissue
surface and maintain its patency for longer periods of time than
conventional devices. The outer (and/or inner) diameter of the
graft prosthesis is coated with nanofibers (or other nanostructured
material such as nanotetrapods, nanotubes, nanowires, nanodots,
etc.) either by directly growing the nanofibers on the surface of
the graft, or by coating the graft with harvested nanofibers, thus
providing the graft with a dry adhesive surface. The disclosed
methods described above and herein can provide enhanced accuracy,
for example, with respect to location and orientation, in the
placement of the prostheses within a region of a patient's aorta
having an aneurysm or other diseased or damaged condition
therein.
[0147] Although the techniques of the present invention can be used
to facilitate both open and minimally invasive abdominal or
thoracic aortic aneurysm procedures (or any other aneurysm
procedure in the aorta or other areas of the body as well), the
following illustration describes only an endovascular minimally
invasive repair procedure which is less traumatic to the patient
than an open-chest procedure. One of ordinary skill in the art,
however, will appreciate that the techniques disclosed can be
readily applied to open chest procedures as well in which access to
the thoracic cavity is achieved through a midline partial or median
sternotomy, a mini-thoracotomy incision, or a retroperitoneal
incision, for example.
[0148] Referring now to FIGS. 3A-B, a system is schematically
illustrated for placing a prosthetic graft during a closed-chest
abdominal or thoracic aortic aneurysm repair procedure using the
methods and compositions of the present invention. In one
embodiment, a patient is anesthesized and generally prepared for
surgery in a conventional manner. The procedure then involves
positioning the stent graft deployment mechanism and stent graft
372 (FIG. 3B) within the abdominal aorta 354 (or thoracic aorta
356) at the site of aneurysm 370. Endovascular devices which can be
used for aortic aneurysm repair include, for example,
balloon-expandable or self-expandable devices. Balloon-expandable
stent designs are described, for example, in Parodi et al., Ann.
Vasc. Surg. 1991; 5:491-499 and White et al., J. Endovasc. Surg.
1994; 1:16-24, the disclosures of which are incorporated by
reference herein. The following devices have received FDA approval
for use in the abdominal aorta and are examples of systems that can
be used in practicing the present invention:
[0149] (1) Ancure.RTM. Endograft.RTM. System (Guidant Corporation).
In this system, which was approved in 1999, the endograft is placed
in the aorta and expanded using balloon dilation. The graft is
anchored to the vessel wall using sutureless hooks at its superior
and inferior ends. On Mar. 16, 2001, Guidant suspended production
of this system and announced a recall of all existing inventories.
The company reported to the FDA that they had failed to report many
device malfunctions and adverse events, including severe vessel
damage associated with problems with the deployment of the device.
There were also manufacturing changes that were not properly
reported to the FDA. The FDA issued a Public Health Notification:
Problems with Endovascular Grafts for Treatment of Abdominal Aortic
Aneurysm (AAA), regarding both this device and the AneuRx
device.
[0150] (2) Ancure.RTM. Aortoiliac System (Guidant Corporation).
This new version was approved in 2002 and is identical to the
earlier Guidant Endovascular Grafting System except that the
aortoiliac Ancure.RTM. grafts have suture loops on the superior and
inferior attachment systems. The device is intended for use in
patients whose anatomy is not suited for the use of the single tube
or bifurcated endograft device.
[0151] (3) AneuRx.RTM. Stent Graft System (Medtronic AVE). The
AneuRx system, approved in 1999, consists of a woven polyester
interior surface with a self-expanding Nitinol exoskeleton. The
radial force of the expanding stent embeds in the exoskeleton into
the aneurysm wall, and thus constitutes the attachment mechanism.
This device was also the subject of the above FDA Public Health
Notification. In December 2003, the FDA published updated
information on the mortality risks associated with the AneuRx.RTM.
Stent Graft System based on an analysis of longer term follow-up
data from the premarket study. Based on the findings of the study,
the FDA recommended that the AneuRx.RTM. Stent Graft be used "only
in patients who meet the appropriate risk-benefit profile and who
can be treated in accordance with instructions for use."
[0152] (4) EXCLUDER.TM. Bifurcated Endoprosthesis (W.L. Gore and
Associates, Inc.). Approved in 2002, this device self-expands
inside the aorta to the diameter of the aorta and iliac arteries,
thus sealing off the aneurysm and relining the artery wall.
[0153] (5) Zenith.TM. AAA Endovascular Graft and H&L-B
One-Shot.TM. Introduction System (Cook, Inc.). This device was
approved in 2003; it is self-expanding and attaches to the vessel
wall via barbs.
[0154] Each of these devices are deployed across the aneurysm such
that the aneurysm is effectively "excluded" from the circulation
with subsequent restoration of normal blood flow. The
above-referenced systems generally consist of an endograft
prosthesis 372 (FIG. 3B) and a corresponding delivery catheter 330.
The prosthesis is a vascular graft which isolates the aneurysm 370
from blood flow and pressurization, thus precluding aneurysm
expansion and minimizing the risk of rupture. The delivery catheter
330 is an over-the wire system which is subcutaneously inserted
into a femoral or iliac artery 350, 352 in the groin area using
known techniques such as a cut-down or a percutaneous technique
such as the Seldinger technique. The delivery catheter 330 is
advanced into the aorta 354 under image (e.g., fluoroscopic,
echocardiographic, MRI, or CT scan) guidance to the site of the
aneurysm 370 and is designed to transport the preloaded prosthesis
to the aorta. The compressed prosthesis is pre-loaded within a
special delivery sheath. Some prostheses consist of modular
components such that the delivery is comprised of the primary
prosthesis plus one or two "docking limbs." Due to the large size
of the delivery sheaths, open surgical exposure of one or both
groins is required to establish vascular access. After entry into
the arterial system, the prosthesis is fluoroscopically guided
through the iliac arteries into the aneurysm site, followed by
deployment of the prosthesis with the use of a compliant
low-pressure balloon.
[0155] Artificial grafts can include, for example, treated natural
tissue, laboratory-engineered tissue, and synthetic polymer
fabrics. Synthetic polymers such as Dacron.RTM. and Teflon.RTM.
(i.e., expanded polytetrafluoroethylene (ePTFE)) are the most
commonly used of the synthetic grafts. See, for example, "Tissue
Engineering of Vascular Prosthetic Grafts," P. P. Zilla, H. P.
Griesler, and P. Zilla, Pub. by Landes Bioscience (May 1999), the
entire contents of which are incorporated by reference herein.
Other synthetic materials can be used as well such as poly
(alpha-hydroxy ester)s, polyanhydrides, polyorthoesters,
polyphosphazens, as well as synthetics such as tyrosine-derived
polycarbonates and polyarylates, lactide based polydepsipeptide
polymer, poly(L-lactide acid-co-L-aspartic acid), and lactide based
poly(ethylene glycol). Metals such as stainless steel, titanium, or
Nitinol metal mesh may also be used as the synthetic graft
material, as well as other alloys as well such as woven glass
(e.g., knitted or spun) or ceramics. The present embodiment of the
invention entails the further use of nanostructured components
(e.g.,. nanofibers or nanowires) to enhance the interaction of the
graft with the passages in which they are used as shown, for
example, in FIG. 1. Typically, such nanostructured surfaces are
employed to improve adhesion, friction, biointegration or other
properties of the device to enhance its patency in the subject
passage. Such enhanced interactivity is generally provided by a
nanostructured surface that interacts with the surface of the
passage, e.g., an inner or outer wall surface, to promote
integration therewith or attachment thereto.
[0156] As described above, the nanostructured components can take a
variety of forms and configurations depending on the application,
such as nanofibers or other nanostructured component, e.g.,
nanowires, nanorods, nanotetrapods, nanodots and the like as
described in more detail below, which are incorporated into or onto
the synthetic graft to improve its properties such as adhesion. The
nanofibers can either be attached to the outer or inner surface of
the synthetic graft, e.g., by growing the nanofibers directly on
the outer and/or inner surface of the graft, or by separately
covalently (or otherwise) attaching the fibers to the graft
surfaces. In addition, the nanofibers or other nanostructures can
be embedded into the graft material to provide it with enhanced
properties such as improved rigidity and strength within the aorta.
The shape and size of the nanofibers as well as their density on
the graft surfaces can be varied to tune the adhesive properties of
the graft to the desired levels.
[0157] The artificial grafts of this invention may also be coated
(in the case of tubular grafts, on the inside and/or outside) with
other materials to still further enhance their bio-utility.
Examples of suitable coatings are medicated coatings, hydrophilic
coatings, smoothing coatings, collagen coatings, human cell seeding
coatings, etc. The above-described nanofiber coatings on the graft
provide a high surface area to volume ratio that helps the graft to
retain these coatings. For example, the artificial graft may be
coated with additional biocompatible materials to minimize
thrombogeneity of the graft. Coatings such as endothelial cell
linings found in autologous vessels, polymers, polysaccharides, etc
can provide a non-thrombogenic surface to increase endothelial cell
proliferation. The graft can also be modified with one or more
proteins or growth factors to increase cell adhesion, growth, and
proliferation such as, for example, VEGF, FGF-2 and other HBGF
(Heparin Binding Growth Factors).
[0158] If used, the coatings can be adsorbed directly to the
nanostructured surface of the graft. Alternatively, the
nanostructured surface may be provided with a linking agent which
is capable of forming a link to the nanostructured components
(e.g., nanofibers) as well as to the coating material which is
applied thereto. In such cases, the coating may be directly linked
to the nanostructured surface, e.g., through silane groups, or it
may be coupled via linker binding groups or other appropriate
chemical reactive groups to participate in linkage chemistries
(derivitization) with linking agents such as, e.g., substituted
silanes, diacetylenes, acrylates, acrylamides, vinyl, styryls,
silicon oxide, boron oxide, phosphorus oxide,
N-(3-aminopropyl)3-mercapto-benzamide,
3-aminopropyl-trimethoxysilane, 3-mercaptopropyl-trimethoxysilane,
3-maleimidopropyl-trimethoxysilane,
3-hydrazidopropyl-trimethoxysilane, hydroxysuccinimides,
maleimides, haloacetyls, pyridyl disulfides, hydrazines,
ethyldiethylamino propylcarbodiimide, and/or the like.
[0159] XXII) Occlusion of Blood Vessels in the Brain and Other
Organs of the Body
[0160] The compositions, apparatus, systems and methods relating to
nanostructured surface coatings described herein can further be
used in the treatment of various diseases and conditions of the
circulatory system and other organs of the body that are
beneficially treated by the occlusion of blood vessels. Examples of
the numerous diseases that can be treated by blocking associated
blood vessels using, for example, intravascular coils, beads,
synthetic grafts or other liquid embolic agents which are treated
with nanofibers (or other nanostructured components), include
arteriovenous (AV) fistulas, AV malformations, aneurysms and
pseudoaneurysms, patent ductus arteriosus, patent foramen ovale,
gastrointestinal bleeding, renal and pelvic bleeding, and
tumors.
[0161] Placement of various substances (e.g., a liquid adhesive
such as isobutylcyanoacrylate (IBCA)) within the blood vessels is
one of the methods of encouraging the formation of thrombus (clot)
which leads to the complete occlusion of the vessels. Occlusive
coils have also been used to occlude blood vessels. The purpose of
the coil is to encourage quick formation of a thrombus around the
coil.
[0162] Of the many diseases that may be treated with embolic coils,
cerebral aneurysms are of particular interest. Ruptured and
unruptured cerebral aneurysms may in some cases be treated by a
surgical approach in which the aneurysm is visualized directly and
then surgically clipped thereby blocking blood flow into the
aneurysm. Once the aneurysm is eliminated from the blood flow the
risk of hemorrhage is eliminated. Another less invasive approach to
the treatment of cerebral aneurysms is an endovascular approach, in
which a catheter is introduced into the cerebral vascular system
from a peripheral access point, such as a femoral artery, to access
the aneurysm internally. The catheters can be used to deliver
embolic devices, such as a balloon or a coil, to the site of the
aneurysm to block blood flow into the aneurysm. The use of embolic
coils, however, can lead to complications because the coils can
compact over time and allow re-filling of the aneurysm, posing risk
of rupture.
[0163] The present embodiment of the invention involves the use of
an endoluminal patch for the repair of, for example, side wall
aneurysms in the brain or elsewhere in the arterial vasculature.
Although the present methods are discussed in relation to the
treatment of cerebral side wall aneurysms in particular, it is to
be appreciated that the systems and methods of the present
invention may be used in connection with a variety of other
embolotherapy procedures in various blood vessels and organs of the
body where an embolic device, such as a coil or embolic patch
material, may be deployed.
[0164] The systems and methods disclosed can be used to facilitate
the accurate deployment of embolic devices and/or materials within
the cerebral vasculature system of a patient, such as at the site
of an aneurysm, as schematically illustrated in FIGS. 4A-C. A patch
of any suitable biocompatible material including, for example,
metal mesh, alloys, treated natural tissue, laboratory-engineered
tissue, and synthetic polymer fabrics or other polymeric material,
is coated with nanostructured components (e.g., nanofibers,
nanowires, nanotetrapods, nanodots and the like) on all or select
portions of its exterior (and/or interior) surface rendering it
adhesive. The size, shape and density of the nanofibers can be
varied as described above in relation to previous embodiments to
alter and control the adhesive properties of the patch. The
nanofibers, for example, may be grown directly on the external
(and/or internal) surfaces of the patch or grown separately and
applied to the patch material after harvesting. The nanofibers may
also be incorporated directly into the material of the patch to
further strengthen its rigidity.
[0165] The artificial patches of this invention may be coated with
other materials to still further enhance their bio-utility.
Examples of suitable coatings are medicated coatings, hydrophilic
coatings, smoothing coatings, collagen coatings, human cell seeding
coatings, etc. The above-described nanofiber coatings on the patch
helps the patch to retain these coatings. For example, the patch
may be coated with additional biocompatible materials to minimize
thrombogeneity of the patch. Coatings such as endothelial cell
linings found in autologous vessels, polymers, polysaccharides,
etc. can provide a non-thrombogenic surface to increase endothelial
cell proliferation. The patch can also be modified with one or more
proteins or growth factors to increase cell adhesion, growth, and
proliferation such as, for example, VEGF, FGF-2 and other HBGF
(Heparin Binding Growth Factors).
[0166] The coatings can be adsorbed directly to the nanostructured
surface of the patch. Alternatively, the nanostructured surface may
be provided with a linking agent which is capable of forming a link
to the nanostructured components (e.g., nanofibers) as well as to
the coating material which is applied thereto. In such cases, the
coating may be directly linked to the nanostructured surface, e.g.,
through silane groups, or it may be coupled via linker binding
groups or other appropriate chemical reactive groups to participate
in linkage chemistries (derivitization) with linking agents such
as, e.g., substituted silanes, diacetylenes, acrylates,
acrylamides, vinyl, styryls, silicon oxide, boron oxide, phosphorus
oxide, N-(3-aminopropyl)3-mercapto-benzamide,
3-aminopropyl-trimethoxysilane, 3-mercaptopropyl-trimethoxysilane,
3-maleimidopropyl-trimethoxysilane,
3-hydrazidopropyl-trimethoxysilane, hydroxysuccinimides,
maleimides, haloacetyls, pyridyl disulfides, hydrazines,
ethyldiethylamino propylcarbodiimide, and/or the like.
[0167] The endoluminal patch 490 (FIG. 4C) is mounted on a
compliant, low-pressure balloon catheter such as those shown in
U.S. Pat. Nos. 4,739,768 and 4,884,575, the disclosures are of
which are incorporated by reference herein. These procedures use
catheters introduced into the cerebral vascular system from a
peripheral access point, e.g. a femoral artery, to access the
aneurysm internally. The catheters can be used to deliver the patch
490 to the site of the aneurysm 480 to block blood flow into the
aneurysm. The embolic delivery catheter 440 is introduced into a
blood vessel in the brain having a side wall aneurysm or other
disease condition therein. The diseased site may be an aneurysm 480
as shown in FIG. 4A, or a fistula, AV malformation, or other
disease in which deployment at, on or near the disease condition
would result in reduced or stopped flow to the abnormal area. To
accomplish this; FIGS. 4A-C show one exemplary use in which the
embolic device, in this case a patch 490, is placed via the
delivery catheter 440 over the aneurysm neck, to block blood from
entering the aneurysm. The catheter 440 is typically introduced
into the cerebral vasculature system of the patient from a
peripheral access point such as a femoral artery and guided with
the aid of fluoroscopy to the brain through the aorta 456 and
through one of the carotid (or vertebral) arteries 467 in the neck.
Once the insertion catheter 440 and the patch are threaded through
the vasculature system to the site of the aneurysm 480 in the
brain, the patch is aligned with the aneurysm neck 492 under
radioscopic guidance. The patch is applied to the vessel wall by
dilating the balloon catheter 440 to press-fit the patch onto the
vessel wall.
[0168] In yet another embodiment, nanostructures (e.g., nanofibers)
grown on an embolic device, such as aneurysm coils or beads, e.g.,
Hilal Embolization Microcoils.TM. available commercially from Cook,
Inc. (Bloomington, Ind.) shown in FIG. 4D, can enhance the
thrombogenicity of the embolic device through hydrophilic native
platelets from sticking and forming thrombosis.
[0169] XXII) Sutureless Graft Prostheses
[0170] The methods, devices and systems of the invention generally
described above may also be used in the performance of anastomosis
of blood vessels, ducts, lumens or other tubular organs, e.g., for
sutureless anastomosis procedures in which one vessel is joined to
another vessel without the use of sutures.
[0171] Arterial bypass surgery is a common modality for the
treatment of occlusive vascular disease. Such surgery typically
involves an incision and exposure of the occluded vessel followed
by the joinder of a graft, e.g., a mammary artery, saphenous vein,
or synthetic graft (all collectively referred to hereinafter as the
"bypass graft"), to the occluded vessel (hereinafter the "native"
blood vessel) distally (downstream) of the occlusion. The upstream
or proximal end of the bypass graft is secured to a suitable blood
vessel upstream of the occlusion, e.g., the aorta, to divert the
flow of blood around the blockage. Other occluded or diseased blood
vessels, such as the carotid artery, may be similarly treated.
Moreover, similar procedures are conducted to place a graft between
an artery and a vein in dialysis patients.
[0172] Current methods available for creating an anastomosis
include hand suturing the vessels together. Suturing the
anastomosis is time-consuming and often does not provide a
leak-free seal and can lead to a site of turbulent blood flow on
occlusion. Thus, it is desirable to reduce the difficulty of
creating the vascular anastomosis and provide a rapid method for
making a reliable anastomosis between a graft vessel and
artery.
[0173] One method currently available involves the use of stapling
devices. These instruments are not easily adaptable for use in
vascular anastomosis. It is often difficult to manipulate these
devices through the vessels without inadvertently piercing a side
wall of the vessel. In addition to being difficult to operate,
these devices often do not provide a reliable leak-free seal.
[0174] Myriad other attempts to develop a successful sutureless
anastomotic technique are represented by U.S. Pat. Nos. 3,221,746,
3,357,432, 3,648,295, 3,683,926 and 4,267,842, for example. All of
these feature an inner tube-like device placed inside the vessels
to be anastomosed. Various other devices and methods of use have
been disclosed for effecting anastomosis of blood or other vessels,
ducts, lumens or other tubular organs. Examples of such devices and
methods are found, for example, in U.S. Pat. Nos. 3,221,746,
3,357,432, 3,648,295, 4,366,819, 4,470,415, 4,553,542, 5,591,226,
5,586,987, 5,591,226, and 6,402,767, the contents of which are
incorporated by reference herein.
[0175] The present embodiment of the invention involves
improvements to conventional devices and methods for performing
vascular anastomoses. The invention facilitates positioning one
vessel in the fluid path of another vessel to enhance the fluid
flow juncture therebetween. The invention provides artificial graft
tubing by which anatomical structures, such as blood vessels,
fallopian tubes, intestine, bowel, ureters, vas deferens and outer
nerve sheaths are anastomosed, preferably without the use of
sutures. The new tubing may be artificial graft tubing in the form
of a simple tube (as shown in FIG. 5A, for example), or a T-tube as
shown in FIG. 5B, for example, or any other suitable tubing shape
or configuration. Alternatively, the new tubing may be a
combination of artificial and natural tubing (e.g., natural tubing
disposed substantially concentrically inside artificial
tubing).
[0176] The artificial tubing may be made from any suitable
biocompatible material including, for example, a flexible,
semi-porous metal mesh (e.g., Nitinol mesh, stainless steel mesh,
titanium mesh and the like), treated natural tissue,
laboratory-engineered tissue, and synthetic polymer fabrics or
other polymeric material such as Dacron.RTM., PTFE, polyimide mesh,
ceramic, glass fabrics and the like.
[0177] The present embodiment of the invention entails the further
use of nanostructured components to enhance the interaction of the
tubing with the passages in which it is used as shown, for example,
in FIG. 1. Typically, such nanostructured surfaces are employed to
improve adhesion, friction, biointegration or other properties of
the device to enhance its patency in the subject passage. Such
enhanced interactivity is generally provided by providing a
nanostructured surface that interacts with the surface of the
passage, e.g., an inner or outer wall surface, to promote
integration therewith or attachment thereto.
[0178] The new tubing for sutureless anastomosis is coated with
nanofibers or other nanostructured components such as nanowires,
nanotetrapods, nanodots and the like on all or select portions of
its exterior (and/or interior) surface rendering it adhesive. The
nanofibers may also be incorporated into the tubing material itself
to form a composite material with added rigidity and strength. The
size, shape and density of the nanofibers can be varied as
described above in relation to previous embodiments to alter and
control the adhesive properties of the tubing. The nanofibers may
be grown directly on the external (and/or internal) surfaces of the
tubing or grown separately and applied to the tubing material after
harvesting.
[0179] The artificial grafts of this invention may be coated (in
the case of tubular grafts, on the inside and/or outside) with
other materials to still further enhance their bio-utility.
Examples of suitable coatings are medicated coatings, hydrophilic
coatings, smoothing coatings, collagen coatings, human cell seeding
coatings, etc. The above-described nanofiber coatings on the graft
helps the graft to retain these coatings. For example, the graft
tubings may be coated with additional biocompatible materials to
minimize thrombogeneity of the tubing. Coatings such as endothelial
cell linings found in autologous vessels, polymers,
polysaccharides, etc can provide a non-thrombogenic surface to
increase endothelial cell proliferation. The nanofibers or tubing
material can also be modified with one or more proteins or growth
factors to increase cell adhesion, growth, and proliferation such
as, for example, VEGF, FGF-2 and other HBGF (Heparin Binding Growth
Factors). The coatings can be adsorbed directly to the
nanostructured surface of the tubing. Alternatively, the
nanostructured surface may be provided with a linking agent which
is capable of forming a link to the nanostructure components (e.g.,
nanofibers) as well as to the coating material which is applied
thereto. In such cases, the coating may be directly linked to the
nanostructured surface, e.g., through silane groups, or it may be
coupled via linker binding groups or other appropriate chemical
reactive groups to participate in linkage chemistries
(derivitization) with linking agents such as, e.g., substituted
silanes, diacetylenes, acrylates, acrylamides, vinyl, styryls,
silicon oxide, boron oxide, phosphorus oxide,
N-(3-aminopropyl)3-mercapto-benzamide, 3-aminopropyl-trimethoxysil-
ane, 3-mercaptopropyl-trimethoxysilane,
3-maleimidopropyl-trimethoxysilane- ,
3-hydrazidopropyl-trimethoxysilane, hydroxysuccinimides,
maleimides, haloacetyls, pyridyl disulfides, hydrazines,
ethyldiethylamino propylcarbodiimide, and/or the like.
[0180] The nanofibers on the inside and/or outside diameter of the
tubing have substantial dry adhesive properties that allow a firm
press-fit into the inner (or outer) diameter of the native host
vessel or to connect other synthetic graft vessels.
[0181] An exemplary form of artificial tubing includes a tube frame
of a first highly elastic material (such as Nitinol) covered with a
second highly elastic material (such as silicone rubber) to
substantially fill in the apertures in the frame. This combination
produces an artificial graft that is distensible like natural body
organ tubing such as a natural artery. Additional advantages of the
artificial grafts of this invention are their elasticity and
distensibility (mentioned above), their ability to be deployed
through tubes of smaller diameter (after which they automatically
return to their full diameter), the possibility of making them
modular, their ability to accept natural body organ tubing
concentrically inside themselves, their ability to support
development of an endothelial layer, their compatibility with MRI
procedures, their ability to be made fluoroscopically visible,
etc.
[0182] A first method of the present invention is for coupling a
first vessel 502 and a second vessel 504 in an end-to-end
anastomosis (e.g., FIG. 5A) and generally includes inserting an
artificial tubular graft 506 as described above with a nanofiber
coating into an opening in a bypass graft vessel (which can include
a natural or synthetic graft vessel) and a native vessel to be
connected, and preferably radially expanding (e.g., with the use of
a balloon catheter, for example) at least a portion of the tubular
graft to sealingly press-fit and secure the tubular graft to the
inner wall of the vessels. The tubular graft member preferably is
sufficiently rigid to substantially retain the tubular member in
its preformed configuration after the tubular member is radially
expanded. The tubular graft member may be radially self-expandable
to a pre-formed configuration (e.g., via the use of a shape memory
alloy for the tubing such as Nitinol, for example), and thus may
assume a press-fit configuration within the vessels to sealingly
join them without the use of an access device such as a balloon
catheter. In another aspect of the present invention, the tubular
member is in the form of a T-tube 508 for an end-to-side
anastomosis in which a bypass graft vessel 510 is secured to an
opening 511 in a side wall of the native vessel 512 as shown in
FIG. 5B. Although grafts in the form of tubing are described above,
certain aspects of the invention are equally applicable to other
graft procedures and to grafts having virtually any cross-sectional
shape depending upon the desired application, including, e.g.,
circular, elliptical, polygonal, e.g., square, rectangular,
pentagonal, hexagonal, octagonal, trapezoidal, rhomboid, etc.
Further, it will be appreciated that the cross-sectional shape of
the body structure of the graft may be the same as or different
from the cross-sectional shape of the vessel into which it is
inserted, depending upon a number of factors, including, e.g., the
method used to fabricate the graft, and/or its desired
application.
[0183] XXIV. Orthopedic (and Dental) Implants
[0184] Nanostructures (e.g., nanowires, nanorods, nanotetrapods,
nanodots and other similar structures) incorporated into or onto
orthopedic implants can improve biocompatibility, infection
resistance, bone integration, prevention of unwanted cell growth,
and durability of those implants when used in and around orthopedic
tissues, such as bone, ligaments, muscles, etc. Examples of
orthopedic implants that can benefit from nanofiber enhanced
surfaces include without limitation total knee joints, total hip
joints, ankle, elbow, wrist, and shoulder implants including those
replacing or augmenting cartilage, long bone implants such as for
fracture repair and external fixation of tibia, fibula, femur,
radius, and ulna, spinal implants including fixation and fusion
devices, maxillofacial implants including cranial bone fixation
devices, artificial bone replacements, dental implants, orthopedic
cements and glues comprised of polymers, resins, metals, alloys,
plastics and combinations thereof, nails, screws, plates, fixator
devices, wires and pins and the like that are used in such
implants, and other orthopedic implant structures as would be known
to those of ordinary skill in the art. As shown in FIG. 6A, for
example, an orthopedic implant 610 in the form of hip stem 612
comprises a substrate 611 and porous layer 614. Porous layer 614
can include beads, fibers, wire mesh and other known materials and
shapes thereof used to form porous layer 614. Nanostructured
components can be applied to substrate 611 by any of the methods
described herein to form nanostructured surfaces, as shown, for
example in FIG. 1.
[0185] In particular, the present embodiment of the invention
provides such orthopedic implantable devices with nanostructured
components to enhance the interaction of the devices with the
tissues, joints, cartilage, bones, and other bodily structures with
which they make contact at the implantation site. The
nanostructured components (e.g., nanofibers) can either be attached
to the outer or inner surface of the implantable device, e.g., by
growing the nanofibers directly on the outer and/or inner surface
of the device, or by separately covalently attaching the fibers to
the device surfaces. Nanostructures on the surface of implants can
enhance bone growth reaction at the implant site by encouraging and
enhancing proliferation of osteoblasts, versus fibroblasts and
other undesirable cells. It is to be appreciated that the
nanostructured (e.g., nanofiber or nanowire) surfaces of the
present invention can be used to encourage and enhance the
proliferation of other cell types as well, including, for example,
myocytes, adipocytes, fibromyoblasts, ectodermal cell, muscle
cells, chondrocytes, endothelial cells, pancreatic cells,
hepatocytes, bile duct cells, bone marrow cells, neural cells,
genitourinary cells and combinations thereof. Enhanced bone growth
activity encourages good fixation of the implant over time, e.g.,
by enhancing osteoblast differentiation and matrix production, and
prevents loosening from fibroblastic response. In addition,
nanostructured surfaces on orthopedic implants can prevent
infection at the implant site, e.g., by preventing the growth of
bacteria and other infectious organisms such as viruses, viral
spores and fungus. The shape and size of the nanofibers as well as
their density on the implant surfaces can be varied to allow
differentiation of cell types.
[0186] For example, as shown below in the Examples section, it has
been shown that the three-dimensional network formed by depositing
nanofibers (e.g., silicon nanowires) on an implant surface can be
tuned precisely to optimize osteoblast adhesion, proliferation and
function. Furthermore nanofibers offer an external surface that can
easily be modified using any number of chemistries (e.g., growth of
nitride or carbide layers for improved strength and durability,
growth of titanium oxide, Ag etc. layers for improved
biocompatibility with existing implant materials (e.g., titanium),
and/or growth of specific organosilanes to facilitate linkage
chemistries such as hydrophobic and/or hydrophilic coatings, etc.)
developed for attaching biomolecules. For example, the nanofiber
surface can be functionalized with a coating material to render it
hydrophobic, lipophobic, or amphiphobic. The coating material can
comprise, for example, polymers, inorganic materials, organic
materials, or organic/inorganic hybrid materials including, for
example, Teflon.TM., Tri-sil, tridecafluoro
1,1,2,2,tetrahydrooctyl-1-tricholorosilane, a fluoride containing
compound, a silane containing compound, PTFE, hexamethyldisilazane,
an aliphatic hydrocarbon containing molecule, an aromatic
hydrocarbon containing molecule, a halogen containing molecule and
paralyene. Interestingly, it has been found that higher density
nanofiber (e.g., nanowire) surfaces (e.g., using longer nanofibers)
showed highest adhesion and proliferation followed by high density
shorter nanofibers and lower density longer nanofibers. Without
being bound to any particular theory, it is believed that this is
because higher density, longer nanofibers provide high surface area
at a nanolevel which promotes osteoblast adhesion and eventually
proliferation. The plurality of nanofibers may comprise, for
example, nanowires having an average length, for example, of from
about 1 micron to at least about 500 microns, e.g. more preferably
from about 5 microns to at least about 150 microns, e.g. more
preferably from about 10 microns to at least about 125 microns,
e.g. more preferably from about 25 microns to at least about 100
microns. The plurality of nanowires may comprise an average density
on the one or more surfaces of the medical device implant, for
example, of from about 1 nanowire per square micron to at least
about 1000 nanowires per square micron, e.g. more preferably from
about 1 nanowire per square micron to at least about 500 nanowires
per square micron, e.g. more preferably from about 10 nanowires per
square micron to at least about 250 nanowires per square micron,
e.g. more preferably from about 10 to 25 nanowires per square
micron to at least about 100 nanowires per square micron.
[0187] Alternatively, or additionally, the nanofibers or other
nanostructures can be embedded into the implant material to enhance
the durability and resistance to wear that occurs in a load bearing
implantation site, thereby preventing microdegradation and
resultant debris in the joints. Further alternatively, the
nanofibers can be formed into a highly dense bioengineered scaffold
or mat and, in certain instances, can be used in lieu of an implant
for, e.g., insertion (e.g., injection) into and treatment of
widespread diseases such as delayed union and nonunion in
fractures, false joints (including infected ones), arthroses of the
big articulations of the body's members (e.g., femoral, knee,
humeral, ankle etc.) and the like. The nanoscale bioengineered
scaffold, which could be substantially three dimensional due to the
high surface area of the nanostructured components (e.g.,
nanofibers), can be used as an osteogenesis stimulator to encourage
osteoblast adhesion and proliferation at its insertion (e.g.,
injection) site at a fracture, joint etc. Examples of nanofiber
mats or scaffolds which could be used in practicing this aspect of
the current invention are described, for example, in co-pending and
commonly assigned U.S. patent application U.S. Ser. No. 60/634,472
filed Dec. 9, 2004, the entire contents of which are incorporated
by reference herein. The bioengineered scaffold may also comprise a
base membrane or matrix onto and/or into which the nanostructure
components (e.g., nanofibers) are incorporated or deposited. The
base membrane or matrix may be made from a variety of materials
such as natural or synthetic polymers including electrically
conducting polymers, metals, alloys, ceramics or glass fabrics,
silicone, etc. The bioengineered scaffold can be impregnated or
bound with drugs, cells (e.g., cells such as osteoblasts,
chondrocytes, stem cells or endothelial cells), or other specific
compounds such as RGD adhesion peptides, cell seeding compounds,
bioactive molecules such as BMP-2, or other such compounds, such
that when implanted, the compound(s) or cells encourage
osseointegration and stimulate new bone formation.
[0188] The implants of this invention (and/or the nanofibers) may
also be coated on the inside and/or outside with other materials to
still further enhance their bio-utility. Examples of suitable
coatings are medicated coatings, drug-eluting coatings, drugs or
other compounds, hydrophilic coatings, smoothing coatings, collagen
coatings, human cell seeding coatings, antiinfectives, hormones,
analgesics, anti-inflammatory agents, growth factors,
chemotherapeutic agents, anti-rejection agents, prostaglandins,
adhesion promoting peptides such as RDG peptides (described below)
and combinations thereof, or any other organic, inorganic or
organic/inorganic hybrid materials. For example, nanostructured
surfaces on orthopedic implants can deliver drugs or other
compounds to the implantation site. Drugs delivered from nanowires,
for example, by elution, binding, dissolution, and/or dissolving of
the nanowires themselves can prevent infection, enhance bone
growth, prevent scar tissue, hyperproliferation, and prevent
rejection of the implant. The above-described nanofiber coatings on
the implant can provide a high surface area that helps the implant
to retain these coatings. The coatings can be adsorbed directly to
the nanostructured surface of the implant. Alternatively, the
nanostructured surface may be provided with a linking agent which
is capable of forming a link to the nanostructured components
(e.g., nanofibers) as well as to the coating material which is
applied thereto. In such cases, the coating may be directly linked
to the nanostructured surface, e.g., through silane groups, or it
may be coupled via linker binding groups or other appropriate
chemical reactive groups to participate in linkage chemistries
(derivitization) with linking agents such as, e.g., substituted
silanes, diacetylenes, acrylates, acrylamides, vinyl, styryls,
silicon oxide, boron oxide, phosphorus oxide,
N-(3-aminopropyl)3-mercapto-benzamide, 3-aminopropyl-trimethoxysil-
ane, 3-mercaptopropyl-trimethoxysilane,
3-maleimidopropyl-trimethoxysilane- ,
3-hydrazidopropyl-trimethoxysilane, hydroxysuccinimides,
maleimides, haloacetyls, pyridyl disulfides, hydrazines,
ethyldiethylamino propylcarbodiimide, and/or the like.
[0189] An orthopedic (or dental, etc.) implant according to the
present invention may include an adhesion-promoting peptide, if
desired. Peptides that promote adhesion between osteoblasts and a
substrate, for example, integrin-binding peptides containing the
Arginine-Glycine-Aspartic Acid (RGD) sequence [Puleo and Bizios,
Bone 12, 271-276 (1991)], are known. Published PCT application WO
97/25999, entitled "Peptides for Altering Osteoblast Adhesion,"
describes specific peptides, including peptides incorporating the
sequence KRSR, for enhancement of adhesion to substrates.
Adhesion-promoting materials are typically used by attaching the
peptide to the surface of a substrate to which adhesion is desired.
WO 97/25999 teaches a technique for immobilizing peptides on the
surface of a substrate by a silanization reaction. Substrates
include conventional orthopedic implants composed of titanium metal
or other conventional materials. This technique or others known in
the art may be used to immobilize adhesion-promoting peptides on
the surface of implants containing nanofibers (e.g., nanowires)
thereon.
[0190] Enhancement of long-term osteoblast functions, subsequent to
adhesion of osteoblasts to material surfaces, is required for
long-term osseointegration of orthopedic implants. Such functions
include osteoblast proliferation, alkaline phosphatase synthesis
and deposition of extracellular matrix calcium on the implant. It
has been unexpectedly found that manufacturing an orthopedic
implant to include nanofiber surfaces as described herein, and
exposing the implant to osteoblast cells leads to enhancement of
long-term functions and osseointegration of the implant, as
demonstrated in the following Examples provided below.
[0191] XXV. Bioengineered Nerve Scaffolds
[0192] Damage to peripheral and central nerves occurs during
trauma, other surgical procedures, and injury. Typically, pieces of
a patient's own nerve (e.g., autograft) have been used to bridge
the gap in a damaged nerve and provide a scaffold for nerve
regeneration. These autografts are less than 50% effective.
Attempts have been made to grow new peripheral nerves on artificial
substrates typically impregnated with compounds to enhance nerve
growth. New micro-devices to bridge the gap and induce nerve repair
would be useful, especially in connection with spinal cord injuries
and brain damage.
[0193] The present invention contemplates a nanoscale bioengineered
scaffold, which could be substantially three dimensional due to
high surface area of the nanostructured components incorporated
into and/or into the scaffold (e.g., nanofibers), to stimulate and
encourage nerve cell growth. In addition, 3-D shaped nanostructures
could encourage nerve regeneration. The bioengineered scaffold may
comprise a base membrane or matrix onto and/or into which the
nanostructure components (e.g., nanofibers) are incorporated. The
base membrane or matrix may be made from a variety of materials
such as natural or synthetic polymers including electrically
conducting polymers, metals, alloys, ceramics or glass fabrics,
silicone, etc. A useful method for fabricating a suitable membrane
or matrix from electrically conducting polymers, for example, which
may be useful in the present invention is disclosed in U.S. Pat.
Nos. 6,095,148 and 6,696,575, the entire contents of which are
incorporated by reference herein.
[0194] The scaffold material may be blended or coated on a suitable
support such as a polymeric film or polymeric beads. As described
by Langer et al., J. Ped. Surg. 23(1), 3-9 (1988), WO88/03785 and
EPA 88900726.6 by Massachusetts Institute of Technology, the
contents of which are incorporated by reference herein, a matrix
for implantation to form new tissue should be a pliable, non-toxic,
porous template for vascular in-growth. The pores should allow
vascular in-growth and the seeding of cells without damage to the
cells or patient. These are generally interconnected pores in the
range of between approximately 100 and 300 microns. The matrix
should be shaped to maximize surface area, to allow adequate
diffusion of nutrients and growth factors to the cells. In an
exemplary embodiment, the matrix is formed of a bioabsorbable, or
biodegradable, synthetic polymer such as a polyanhydride,
polyorthoester, or polyhydroxy acid such as polylactic acid,
polyglycolic acid, and copolymers or blends thereof. Non-degradable
materials can also be used to form the matrix. Examples of suitable
materials include ethylene vinyl acetate, derivatives of polyvinyl
alcohol, teflon, nylon, polymethacrylate and silicon polymers.
[0195] Alternatively, the scaffold can be made entirely of
nanostructures such as, but not limited to, organic and inorganic
nanocrystals as described above and below such as nanowires,
nanodots, nanotetrapods, and other shapes on the nanoscale. The
bioengineered scaffold can be impregnated or bound with drugs,
cells (e.g., nerve cells such as Schwann cells, stem cells or
embryonic cells), fibroblasts, or other specific compounds such as
nerve growth factor (NGF), cell seeding compounds, neurotrophic
growth factors (or genetically engineered cells producing such
factors), VEGF, laminin or other such compounds, such that when
implanted, the compound(s) encourage axonal elongation and
functional nerve performance. Nerve explants also may be cultured
and regenerated in vitro for implantation in vivo. For example,
primary sciatic nerve explants may be isolated from mammalian
tissue and cultured for example in high glucose DMEM supplemented
with glucose, fetal bovine serum (FBS), sodium pyruvate, and NGF.
Methods for isolating the sciatic nerve from 16-d chick embryos
have been described in: Y. -W. Hu and C. Mezei, Can. J. Biochem.,
49:320 (1971). Different compositions, including serum, serum
substitutes, growth factors, such as nerve growth factor, hormones,
and/or drugs can be used in the medium which are optimized for the
particular nerve cell being cultured, to enhance proliferation and
regeneration of nerve cells.
[0196] The coatings can be adsorbed directly to the nanostructured
surface of the scaffold. The high surface area of the
nanostructured components helps to retain the compound coatings on
the scaffold. Alternatively, the nanostructured surface may be
provided with a linking agent which is capable of forming a link to
the nanostructured components (e.g., nanofibers) as well as to the
coating material which is applied thereto. In such cases, the
coating containing the desired compounds may be directly linked to
the nanostructured surface, e.g., through silane groups, or it may
be coupled via linker binding groups or other appropriate chemical
reactive groups to participate in linkage chemistries
(derivitization) with linking agents as described previously.
[0197] The nanofibers (or other nanostructured components) on the
scaffold surfaces can optionally be embedded in a slowly-soluble
biocompatible polymer (or other) matrix to make the nanofiber
surfaces more robust. The polymer matrix can protect most of the
length of each nanofiber, leaving only the ends susceptible to
damage. The generation of water soluble polymers can be
accomplished in a number of different ways. For example, polymer
chains can be formed in situ in a dilute aqueous solution primarily
consisting of a monomer and an oxidizing agent. In this case, the
polymer is actually created in the solution and subsequently
spontaneously adsorbed onto the nanofiber surfaces as a uniform,
ultra-thin film of between approximately 10 to greater than 250
angstroms in thickness, more preferably between 10 and 100
angstroms.
[0198] Nerve gaps to be treated with such scaffold devices can
range in size from between about 5 mm to about 50 mm, for example
between about 10 to about 30 mm, for example between about 20 mm to
30 mm. The scaffold devices can be made in a range of sizes and
configurations to fit the application, and the nanostructures can
be doped as necessary to provide enhanced electrical conductivity
to transmit electrical nerve signals to nerve fibers. The scaffold
devices may be implanted in vivo into a patient in need of therapy
to repair or replace damaged cells or tissue, such as nervous
system tissue. Materials which can be used for implantation include
sutures, tubes, sheets, adhesion prevention devices (typically
films, polymeric coatings applied as liquids which are polymerized
in situ, or other physical barriers), and wound healing products
(which vary according to the wound to be healed from films and
coating to support structures).
[0199] To enhance the effectiveness of the treatment, compositions
which further promote nervous tissue healing, such as proteins,
antibodies, nerve growth factors, hormones, and attachment
molecules, can be applied together with the scaffold, and as
discussed above optionally can be covalently attached to the
nanofibers and/or the scaffold support material. Those skilled in
the art can readily determine exactly how to use these materials
and the conditions required without undue experimentation. The
scaffold may be implanted adjacent to or seeded with cells which
are to be affected. The scaffold device is optionally electrically
connected to a source of voltage or current. The electrical
connection can be, for example, needles which are inserted to
contact the scaffold, or electrodes attached to the nanostructured
surfaces or scaffold membrane which can be externally connected to
an appropriate electrical power source. Voltage or current may be
applied to the nanostructures and/or scaffold membrane in a range
which induces the desired effect on the cells while not damaging
the cells.
[0200] I) Characteristics of Nanofiber Surface Substrates
[0201] As noted previously, increased surface area is a property
that is sought after in many fields (e.g., in substrates for assays
or separation column matrices). For example, fields such as
tribology and those involving separations and adsorbents are quite
concerned with maximizing surface areas. The current invention
offers surfaces and applications having increased or enhanced
surface areas (i.e., increased or enhanced in relation to
structures or surfaces without nanofibers).
[0202] A "nanofiber enhanced surface area" herein corresponds to a
substrate comprising a plurality of nanofibers (e.g., nanowires,
nanotubes, etc.) attached to the substrate so that the surface area
within a certain "footprint" of the substrate is increased relative
to the surface area within the same footprint without the
nanofibers. In typical embodiments herein, the nanofibers (and
often the substrate) are composed of silicon oxides. It will be
noted that such compositions convey a number of benefits in certain
embodiments herein. Also, in many preferred embodiments herein, one
or more of the plurality of nanofibers is functionalized with one
or more moiety. See, below. However, it will also be noted that the
current invention is not specifically limited by the composition of
the nanofibers or substrate, unless otherwise noted.
[0203] The various embodiments of the current invention are
adaptable to, and useful for, a great number of different
applications. For example, as explained in more detail below,
various permutations of the invention can be used in, e.g., binding
applications (e.g., microarrays and the like), separations (e.g.,
bioscaffolds (e.g., as a base for cell culture and/or medical
implants, optionally which resist formation of biofilms, etc.), and
controlled release matrices, etc. Other uses and embodiments are
examined herein.
[0204] Examined herein, are other beneficial uses of various
embodiments of the current invention. For example, the distinct
morphology of the nanofiber surfaces herein can be utilized in
numerous biomedical applications such as scaffolding for growth of
cell culture (both in vitro and in vivo). In vivo uses can include,
e.g., aids in bone formation, etc. Additionally, the surface
morphology of some of the embodiments produces surfaces that are
resistant to biofilm formation and/or bacterial/microorganismal
colonization. Other possible biomedical uses herein, include, e.g.,
controlled release matrices of drugs, etc. See, above.
[0205] As also will be appreciated by those of skill in the art,
many aspects of the current invention are optionally variable
(e.g., surface chemistries on the nanofibers, surface chemistries
on any end of the nanofibers or on the substrate surface, etc.).
Specific illustration of various modifications, etc. herein, should
therefore not be taken as limiting the current invention. Also, it
will be appreciated, and is explained in more detail below, that
the length to thickness ratio of the nanofibers herein is
optionally varied, as is, e.g., the composition of the nanofibers.
Furthermore, a variety of methods can be employed to bring the
fibers in contact with surfaces. Additionally, while many
embodiments herein comprise nanofibers that are specifically
functionalized in one or more ways, e.g., through attachment of
moieties or functional groups to the nanofibers, other embodiments
comprise nanofibers which are not functionalized
[0206] II) Nanofibers and Nanofiber Construction
[0207] In typical embodiments herein the surfaces (i.e., the
nanofiber enhanced area surfaces) and the nanofibers themselves can
optionally comprise any number of materials. The actual composition
of the surfaces and the nanofibers is based upon a number of
possible factors. Such factors can include, for example, the
intended use of the enhanced area surfaces, the conditions under
which they will be used (e.g., temperature, pH, presence of light
(e.g., UV), atmosphere, etc.), the reactions for which they will be
used (e.g., within a patient, etc.), the durability of the surfaces
and the cost, etc. The ductility and breaking strength of nanowires
will vary depending on, e.g., their composition. For example,
ceramic ZnO wires can be more brittle than silicon or glass
nanowires, while carbon nanotubes may have a higher tensile
strength.
[0208] As explained more fully below, some possible materials used
to construct the nanofibers and nanofiber enhanced surfaces herein,
include, e.g., silicon, ZnO, TiO, carbon, carbon nanotubes, glass,
and quartz. See, below. The nanofibers of the invention are also
optionally coated or functionalized, e.g., to enhance or add
specific properties. For example, polymers, ceramics or small
molecules can optionally be used as coating materials. The optional
coatings can impart characteristics such as water resistance,
improved mechanical or electrical properties or specificities for
certain analytes. Additionally, specific moieties or functional
groups can also be attached to or associated with the nanofibers
herein.
[0209] Of course, it will be appreciated that the current invention
is not limited by recitation of particular nanofiber and/or
substrate compositions, and that, unless otherwise stated, any of a
number of other materials are optionally used in different
embodiments herein. Additionally, the materials used to comprise
the nanofibers can optionally be the same as the material used to
comprise the substrate surfaces or they can be different from the
materials used to construct the substrate surfaces.
[0210] In yet other embodiments herein, the nanofibers involved can
optionally comprise various physical conformations such as, e.g.,
nanotubules (e.g., hollow-cored structures), etc. A variety of
nanofiber types are optionally used in this invention including
carbon nanotubes, metallic nanotubes, metals and ceramics.
[0211] It is to be understood that this invention is not limited to
particular configurations, which can, of course, vary (e.g.,
different combinations of nanofibers and substrates and optional
moieties, etc. which are optionally present in a range of lengths,
densities, etc.). It is also to be understood that the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting. As used in this
specification and the appended claims, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise. Thus, for example, reference to "a nanofiber"
optionally includes a plurality of such nanofibers, and the like.
Unless defined otherwise, all scientific and technical terms are
understood to have the same meaning as commonly used in the art to
which they pertain. For the purpose of the present invention,
additional specific terms are defined throughout.
[0212] A) Nanofibers
[0213] The term "nanofiber" as used herein, refers to a
nanostructure typically characterized by at least one physical
dimension less than about 1000 nm, less than about 500 nm, less
than about 250 nm, less than about 150 nm, less than about 100 nm,
less than about 50 nm, less than about 25 nm or even less than
about 10 nm or 5 nm. In many cases, the region or characteristic
dimension will be along the smallest axis of the structure.
[0214] Nanofibers of this invention typically have one principle
axis that is longer than the other two principle axes and, thus,
have an aspect ratio greater than one, an aspect ratio of 2 or
greater, an aspect ratio greater than about 10, an aspect ratio
greater than about 20, or an aspect ratio greater than about 100,
200, or 500. In certain embodiments, nanofibers herein have a
substantially uniform diameter. In some embodiments, the diameter
shows a variance less than about 20%, less than about 10%, less
than about 5%, or less than about 1% over the region of greatest
variability and over a linear dimension of at least 5 nm, at least
10 nm, at least 20 nm, or at least 50 nm. For example, a wide range
of diameters could be desirable due to cost considerations and/or
to create a more random surface. Typically the diameter is
evaluated away from the ends of the nanofiber (e.g. over the
central 20%, 40%, 50%, or 80% of the nanofiber). In yet other
embodiments, the nanofibers herein have a non-uniform diameter
(i.e., they vary in diameter along their length). Also in certain
embodiments, the nanofibers of this invention are substantially
crystalline and/or substantially monocrystalline.
[0215] It will be appreciated that the term nanofiber, can
optionally include such structures as, e.g., nanowires,
nanowhiskers, semi-conducting nanofibers, carbon nanotubes or
nanotubules and the like.
[0216] The nanofibers of this invention can be substantially
homogeneous in material properties, or in certain embodiments they
are heterogeneous (e.g. nanofiber heterostructures) and can be
fabricated from essentially any convenient material or materials.
The nanofibers can comprise "pure" materials, substantially pure
materials, doped materials and the like and can include insulators,
conductors, and semiconductors. Additionally, while some
illustrative nanofibers herein are comprised of silicon (or silicon
oxides), as explained above, they optionally can be comprised of
any of a number of different materials, unless otherwise stated.
Composition of nanofibers can vary depending upon a number of
factors, e.g., specific functionalization (if any) to be associated
with or attached to the nanofibers, durability, cost, conditions of
use, etc. The composition of nanofibers is quite well known to
those of skill in the art. As will be appreciated by such skilled
persons, the nanofibers of the invention can, thus, be composed of
any of a myriad of possible substances (or combinations thereof).
Some embodiments herein comprise nanofibers composed of one or more
organic or inorganic compound or material. Any recitation of
specific nanofiber compositions herein should not be taken as
limiting.
[0217] Additionally, the nanofibers of the invention are optionally
constructed through any of a number of different methods, and
examples listed herein should not be taken as limiting. Thus,
nanofibers constructed through means not specifically described
herein, but which fall within the parameters as set forth herein
are still nanofibers of the invention and/or are used with the
methods of the invention.
[0218] In a general sense, the nanofibers of the current invention
often (but not exclusively) comprise long thin protuberances (e.g.,
fibers, nanowires, nanotubules, etc.) grown from a solid,
optionally planar, substrate. Of course, in some embodiments herein
the nanofibers are deposited onto their ultimate substrates, e.g.,
the fibers are detached from the substrate on which they are grown
and attached to a second substrate. The second substrate need not
be planar and, in fact, can comprise a myriad of three-dimensional
conformations, as can the substrate on which the nanofibers were
grown originally. In some embodiments herein, the substrates are
flexible. Also, as explained in greater detail below, nanofibers of
the invention can be grown/constructed in, or upon, variously
configured surfaces, e.g., within capillary tubes, shunts, etc.
See, infra.
[0219] In various embodiments herein, the nanofibers involved are
optionally grown on a first substrate and then subsequently
transferred to a second substrate which is to have the enhanced
surface area. Such embodiments are particularly useful in
situations wherein the substrate desired needs to be flexible or
conforming to a particular three dimensional shape that is not
readily subjected to direct application or growth of nanofibers
thereon. For example, nanofibers can be grown on such rigid
surfaces as, e.g., silicon wafers or other similar substrates. The
nanofibers thus grown can then optionally be transferred to a
flexible backing such as, e.g., rubber or the like. Again, it will
be appreciated, however, that the invention is not limited to
particular nanofiber or substrate compositions. For example,
nanofibers are optionally gown on any of a variety of different
surfaces, including, e.g., flexible foils such as aluminum or the
like. Additionally, for high temperature growth processes, any
metal, ceramic or other thermally stable material is optionally
used as a substrate on which to grow nanofibers of the invention.
Furthermore, low temperature synthesis methods such as solution
phase methods can be utilized in conjunction with an even wider
variety of substrates on which to grow nanofibers. For example,
flexible polymer substrates and other similar substances are
optionally used as substrates for nanofiber growth/attachment.
[0220] As one example, the growth of nanofibers on a surface using
a gold catalyst has been demonstrated in the literature.
Applications targeted for such fibers are based on harvesting them
from the substrate and then assembling them into devices. However,
in many other embodiments herein, the nanofibers involved in
enhanced surface areas are grown in place. Available methods, such
as growing nanofibers from gold colloids deposited on surfaces are,
thus, optionally used herein. The end product which results is the
substrate upon which the fibers are grown (i.e., with an enhanced
surface area due to the nanofibers). As will be appreciated,
specific embodiments and uses herein, unless stated otherwise, can
optionally comprise nanofibers grown in the place of their use
and/or through nanofibers grown elsewhere, which are harvested and
transferred to the place of their use. For example, many
embodiments herein relate to leaving the fibers intact on the
growth substrate and taking advantage of the unique properties the
fibers impart on the substrate. Other embodiments relate to growth
of fibers on a first substrate and transfer of the fibers to a
second substrate to take advantage of the unique properties that
the fibers impart on the second substrate.
[0221] For example, if nanofibers of the invention were grown on,
e.g., a non-flexible substrate (e.g., such as some types of silicon
wafers) they could be transferred from such non-flexible substrate
to a flexible substrate (e.g., such as rubber or a woven layer
material). Again, as will be apparent to those of skill in the art,
the nanofibers herein could optionally be grown on a flexible
substrate to start with, but different desired parameters may
influence such decisions.
[0222] A variety of methods may be employed in transferring
nanofibers from a surface upon which they are fabricated to another
surface. For example, nanofibers may be harvested into a liquid
suspension, e.g., ethanol, which is then coated onto another
surface. Additionally, nanofibers from a first surface (e.g., ones
grown on the first surface or which have been transferred to the
first surface) can optionally be "harvested" by applying a sticky
coating or material to the nanofibers and then peeling such
coating/material away from the first surface. The sticky
coating/material is then optionally placed against a second surface
to deposit the nanofibers. Examples of sticky coatings/materials
which are optionally used for such transfer include, but are not
limited to, e.g., tape (e.g., 3M Scotch.RTM. tape), magnetic
strips, curing adhesives (e.g., epoxies, rubber cement, etc.), etc.
The nanofibers could be removed from the growth substrate, mixed
into a plastic, and then surface of such plastic could be ablated
or etched away to expose the fibers.
[0223] The actual nanofiber constructions of the invention are
optionally complex. The nanofibers can form a complex
three-dimensional pattern. The interlacing and variable heights,
curves, bends, etc. form a surface which greatly increases the
surface area per unit substrate (e.g., as compared with a surface
without nanofibers). Of course, in other embodiments herein, it
should be apparent that the nanofibers need not be as complex.
Thus, in many embodiments herein, the nanofibers are "straight" and
do not tend to bend, curve, or curl. However, such straight
nanofibers are still encompassed within the current invention. In
either case, the nanofibers present a non-tortuous, greatly
enhanced surface area.
[0224] B) Functionalization
[0225] Some embodiments of the invention comprise nanofiber and
nanofiber enhanced area surfaces in which the fibers include one or
more functional moiety (e.g., a chemically reactive group) attached
to them. Functionalized nanofibers are optionally used in many
different embodiments, e.g., to confer specificity for desired
analytes in reactions such as separations or bio-assays, etc.
Beneficially, typical embodiments of enhanced surface areas herein
are comprised of silicon oxides, which are conveniently modified
with a large variety of moieties. Of course, other embodiments
herein are comprised of other nanofiber compositions (e.g.,
polymers, ceramics, metals that are coated by CVD or sol-gel
sputtering, etc.) which are also optionally functionalized for
specific purposes. Those of skill in the art will be familiar with
numerous functionalizations and functionalization techniques which
are optionally used herein.
[0226] For example, details regarding relevant moiety and other
chemistries, as well as methods for construction/use of such, can
be found, e.g., in Hermanson Bioconjugate Techniques Academic Press
(1996), Kirk-Othmer Concise Encyclopedia of Chemical Technology
(1999) Fourth Edition by Grayson et al. (ed.) John Wiley &
Sons, Inc., New York and in Kirk-Othmer Encyclopedia of Chemical
Technology Fourth Edition (1998 and 2000) by Grayson et al. (ed.)
Wiley Interscience (print edition)/John Wiley & Sons, Inc.
(e-format). Further relevant information can be found in CRC
Handbook of Chemistry and Physics (2003) 83.sup.rd edition by CRC
Press. Details on conductive and other coatings, which can also be
incorporated onto nanofibers of the invention by plasma methods and
the like can be found in H. S. Nalwa (ed.), Handbook of Organic
Conductive Molecules and Polymers, John Wiley & Sons 1997. See
also, ORGANIC SPECIES THAT FACILITATE CHARGE TRANSFER TO/FROM
NANOCRYSTALS U.S. Ser. No. 60/452,232 filed Mar. 4, 2003 by
Whiteford et al. Details regarding organic chemistry, relevant for,
e.g., coupling of additional moieties to a functionalized surface
of nanofibers can be found, e.g., in Greene (1981) Protective
Groups in Organic Synthesis, John Wiley and Sons, New York, as well
as in Schmidt (1996) Organic Chemistry Mosby, St Louis, Mo., and
March's Advanced Organic Chemistry Reactions, Mechanisms and
Structure, Fifth Edition (2000) Smith and March, Wiley Interscience
New York ISBN 0471-58589-0. Those of skill in the art will be
familiar with many other related references and techniques amenable
for functionalization of NFS herein.
[0227] Thus, again as will be appreciated, the substrates involved,
the nanofibers involved (e.g., attached to, or deposited upon, the
substrates), and any optional functionalization of the nanofibers
and/or substrates, and the like can be varied. For example, the
length, diameter, conformation and density of the fibers can be
varied, as can the composition of the fibers and their surface
chemistry.
[0228] C) Density and Related Issues
[0229] In terms of density, it will be appreciated that by
including more nanofibers emanating from a surface, one
automatically increases the amount of surface area that is extended
from the basic underlying substrate. This, thus, increases the
amount of intimate contact area between the surface and any
analyte, etc. coming into contact with the nanofiber surfaces. As
explained in more detail below, the embodiments herein optionally
comprise a density of nanofibers on a surface of from about 0.1 to
about 1000 or more nanofibers per micrometer.sup.2 of the substrate
surface. Again, here too, it will be appreciated that such density
depends upon factors such as the diameter of the individual
nanofibers, etc. See, below. The nanowire density influences the
enhanced surface area, since a greater number of nanofibers will
tend to increase the overall amount of area of the surface.
Therefore, the density of the nanofibers herein typically has a
bearing on the intended use of the enhanced surface area materials
because such density is a factor in the overall area of the
surface.
[0230] For example, a typical flat planar substrate, e.g., a
silicon oxide chip or a glass slide, can typically comprise 10,000
possible binding sites for an analyte or 10,000 possible
functionalization sites, etc. per square micron (i.e., within a
square micron footprint). However, if such a substrate surface were
coated with nanofibers, then the available surface area would be
much greater. In some embodiments herein each nanofiber on a
surface comprises about 1 square micron in surface area (i.e., the
sides and tip of each nanofiber present that much surface area). If
a comparable square micron of substrate comprised from 10 to about
100 nanofibers per square micron, the available surface area is
thus 10 to 100 times greater than a plain flat surface. Therefore,
in the current illustration, an enhanced surface area would have
100,000 to 10,000,000 possible binding sites, functionalization
sites, etc. per square micron footprint. It will be appreciated
that the density of nanofibers on a substrate is influenced by,
e.g., the diameter of the nanofibers and any functionalization of
such fibers, etc.
[0231] Different embodiments of the invention comprise a range of
such different densities (i.e., number of nanofibers per unit area
of a substrate to which nanofibers are attached). The number of
nanofibers per unit area can optionally range from about 1
nanofiber per 10 micron.sup.2 up to about 200 or more nanofibers
per micro.sup.2; from about 1 nanofiber per micron.sup.2 up to
about 150 or more nanofibers per micron.sup.2; from about 10
nanofibers per micron.sup.2 up to about 100 or more nanofibers per
micron.sup.2; or from about 25 nanofibers per micron.sup.2 up to
about 75 or more nanofibers per micron. In yet other embodiments,
the density can optionally range from about 1 to 3 nanowires per
square micron to up to approximately 2,500 or more nanowires per
square micron.
[0232] In terms of individual fiber dimensions, it will be
appreciated that by increasing the thickness or diameter of each
individual fiber, one will again, automatically increase the
overall area of the fiber and, thus, the overall area of the
substrate. The diameter of nanofibers herein can be controlled
through, e.g., choice of compositions and growth conditions of the
nanofibers, addition of moieties, coatings or the like, etc.
Preferred fiber thicknesses are optionally between from about 5 nm
up to about 1 micron or more (e.g., 5 microns); from about 10 nm to
about 750 nanometers or more; from about 25 nm to about 500
nanometers or more; from about 50 nm to about 250 nanometers or
more, or from about 75 nm to about 100 nanometers or more. In some
embodiments, the nanofibers comprise a diameter of approximately 40
nm.
[0233] In addition to diameter, surface area of nanofibers (and
therefore surface area of a substrate to which the nanofibers are
attached) also is influenced by length of the nanofibers. Of
course, it will also be understood that for some fiber materials,
increasing length may yield increasing fragility. Accordingly,
preferred fiber lengths will typically be between about 2 microns
(e.g., 0.5 microns) up to about 1 mm or more; from about 10 microns
to about 500 micrometers or more; from about 25 microns to about
250 microns or more; or from about 50 microns to about 100 microns
or more. Some embodiments comprise nanofibers of approximately 50
microns in length. Some embodiments herein comprise nanofibers of
approximately 40 nm in diameter and approximately 50 microns in
length.
[0234] Nanofibers herein can present a variety of aspect ratios.
Thus, nanofiber diameter can comprise, e.g., from about 5 nm up to
about 1 micron or more (e.g., 5 microns); from about 10 nm to about
750 nanometers or more; from about 25 nm to about 500 nanometers or
more; from about 50 nm to about 250 nanometers or more, or from
about 75 nm to about 100 nanometers or more, while the lengths of
such nanofibers can comprise, e.g., from about 2 microns (e.g., 0.5
microns) up to about 1 mm or more; from about 10 microns to about
500 micrometers or more; from about 25 microns to about 250 microns
or more; or from about 50 microns to about 100 microns or more
[0235] Fibers that are, at least in part, elevated above a surface
are often preferred, e.g., where at least a portion of the fibers
in the fiber surface are elevated at least 10 nm, or even at least
100 nm above a surface, in order to provide enhanced surface area
available for contact with, e.g., an analyte, etc.
[0236] The nanofibers optionally form a complex three-dimensional
structure. The degree of such complexity depends in part upon,
e.g., the length of the nanofibers, the diameter of the nanofibers,
the length:diameter aspect ratio of the nanofibers, moieties (if
any) attached to the nanofibers, and the growth conditions of the
nanofibers, etc. The bending, interlacing, etc. of nanofibers,
which help affect the degree of enhanced surface area available,
are optionally manipulated through, e.g., control of the number of
nanofibers per unit area as well as through the diameter of the
nanofibers, the length and the composition of the nanofibers, etc.
Thus, it will be appreciated that enhanced surface area of
nanofiber substrates herein is optionally controlled through
manipulation of these and other parameters.
[0237] Also, in some, but not all, embodiments herein, the
nanofibers of the invention comprise bent, curved, or even curled
forms. As can be appreciated, if a single nanofiber snakes or coils
over a surface (but is still just a single fiber per unit area
bound to a first surface), the fiber can still provide an enhanced
surface area due to its length, etc.
[0238] D) Nanofiber Construction
[0239] As will be appreciated, the current invention is not limited
by the means of construction of the nanofibers herein. For example,
while some of the nanofibers herein are composed of silicon, the
use of silicon should not be construed as limiting. The formation
of nanofibers is possible through a number of different approaches
that are well known to those of skill in the art, all of which are
amenable to embodiments of the current invention.
[0240] Typical embodiments herein can be used with existing methods
of nanostructure fabrication, as will be known by those skilled in
the art, as well as methods mentioned or described herein. Typical,
but not all, embodiments herein comprise substances that are chosen
to be non-harmful (e.g., non-reactive, non-allergenic, etc.) in
medical settings. In other words, a variety of methods for making
nanofibers and nanofiber containing structures have been described
and can be adapted for use in various of the methods, systems and
devices of the invention.
[0241] The nanofibers can be fabricated of essentially any
convenient material (e.g., a semiconducting material, a
ferroelectric material, a metal, ceramic, polymers, etc.) and can
comprise essentially a single material or can be heterostructures.
For example, the nanofibers can comprise a semiconducting material,
for example a material comprising a first element selected from
group 2 or from group 12 of the periodic table and a second element
selected from group 16 (e.g., ZnS, ZnO, ZnSe, ZnTe, CdS, CdSe,
CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe,
SrTe, BaS, BaSe, BaTe, and like materials); a material comprising a
first element selected from group 13 and a second element selected
from group 15 (e.g., GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb,
and like materials); a material comprising a group 14 element (Ge,
Si, and like materials); a material such as PbS, PbSe, PbTe, AlS,
AlP, and AlSb; or an alloy or a mixture thereof.
[0242] In some embodiments herein, the nanofibers are optionally
comprised of silicon or a silicon oxide. It will be understood by
one of skill in the art that the term "silicon oxide" as used
herein can be understood to refer to silicon at any level of
oxidation. Thus, the term silicon oxide can refer to the chemical
structure SiO.sub.x, wherein x is between 0 and 2 inclusive. In
other embodiments, the nanofibers can comprise, e.g., silicon,
glass, quartz, plastic, metal, polymers, TiO, ZnO, ZnS, ZnSe, ZnTe,
CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe,
SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InN, InP,
InAs, InSb, PbS, PbSe, PbTe, AlS, AlP, AlSb, SiO.sub.1, SiO.sub.2,
silicon carbide, silicon nitride, polyacrylonitrile (PAN),
polyetherketone, polyimide, aromatic polymers, or aliphatic
polymers.
[0243] It will be appreciated that in some embodiments, the
nanofibers can comprise the same material as one or more substrate
surface (i.e., a surface to which the nanofibers are attached or
associated), while in other embodiments, the nanofibers comprise a
different material than the substrate surface. Additionally, the
substrate surfaces can optionally comprise any one or more of the
same materials or types of materials as do the nanofibers (e.g.,
such as the materials illustrated herein).
[0244] As previously stated, some, but by no means all, embodiments
herein comprise silicon nanofibers. Common methods for making
silicon nanofibers include vapor liquid solid growth (VLS), laser
ablation (laser catalytic growth) and thermal evaporation. See, for
example, Morales et al. (1998) "A Laser Ablation Method for the
Synthesis of Crystalline Semiconductor Nanowires" Science 279,
208-211 (1998). In one example approach, a hybrid pulsed laser
ablation/chemical vapor deposition (PLA-CVD) process for the
synthesis of semiconductor nanofibers with longitudinally ordered
heterostructures, and variations thereof, can be used. See, Wu et
al. (2002) "Block-by-Block Growth of Single-Crystalline Si/SiGe
Superlattice Nanowires," Nano Letters Vol. 0, No. 0.
[0245] In general, multiple methods of making nanofibers have been
described and can be applied in the methods, systems and devices
herein. In addition to Morales et al. and Wu et al. (above), see,
for example, Lieber et al. (2001) "Carbide Nanomaterials" U.S. Pat.
No. 6,190,634 B1; Lieber et al. (2000) "Nanometer Scale Microscopy
Probes" U.S. Pat. No. 6,159,742; Lieber et al. (2000) "Method of
Producing Metal Oxide Nanorods" U.S. Pat. No. 6,036,774; Lieber et
al. (1999) "Metal Oxide Nanorods" U.S. Pat. No. 5,897,945; Lieber
et al. (1999) "Preparation of Carbide Nanorods" U.S. Pat. No.
5,997,832; Lieber et al. (1998) "Covalent Carbon Nitride Material
Comprising C.sub.2N and Formation Method" U.S. Pat. No. 5,840,435;
Thess, et al. (1996) "Crystalline Ropes of Metallic Carbon
Nanotubes" Science 273:483-486; Lieber et al. (1993) "Method of
Making a Superconducting Fullerene Composition By Reacting a
Fullerene with an Alloy Containing Alkali Metal" U.S. Pat. No.
5,196,396; and Lieber et al. (1993) "Machining Oxide Thin Films
with an Atomic Force Microscope: Pattern and Object Formation on
the Nanometer Scale" U.S. Pat. No. 5,252,835. Recently, one
dimensional semiconductor heterostructure nanocrystals, have been
described. See, e.g., Bjork et al. (2002) "One-dimensional
Steeplechase for Electrons Realized" Nano Letters Vol. 0, No.
0.
[0246] It should be noted that some references herein, while not
specific to nanofibers, are optionally still applicable to the
invention. For example, background issues of construction
conditions and the like are applicable between nanofibers and other
nanostructures (e.g., nanocrystals, etc.).
[0247] In another approach which is optionally used to construct
nanofibers of the invention, synthetic procedures to prepare
individual nanofibers on surfaces and in bulk are described, for
example, by Kong, et al. (1998) "Synthesis of Individual
Single-Walled Carbon Nanotubes on Patterned Silicon Wafers," Nature
395:878-881, and Kong, et al. (1998) "Chemical Vapor Deposition of
Methane for Single-Walled Carbon Nanotubes," Chem. Phys. Lett.
292:567-574.
[0248] In yet another approach, substrates and self assembling
monolayer (SAM) forming materials can be used, e.g., along with
microcontact printing techniques to make nanofibers, such as those
described by Schon, Meng, and Bao, "Self-assembled monolayer
organic field-effect transistors," Nature 413:713 (2001); Zhou et
al. (1997) "Nanoscale Metal/Self-Assembled Monolayer/Metal
Heterostructures," Appilied Physics Letters 71:611; and WO 96/29629
(Whitesides, et al., published Jun. 26, 1996).
[0249] In some embodiments herein, nanofibers (e.g., nanowires) can
be synthesized using a metallic catalyst. A benefit of such
embodiments allows use of unique materials suitable for surface
modifications to create enhanced properties. A unique property of
such nanofibers is that they are capped at one end with a catalyst,
typically gold. This catalyst end can optionally be functionalized
using, e.g., thiol chemistry without affecting the rest of the
wire, thus, making it capable of bonding to an appropriate surface.
In such embodiments, the result of such functionalization, etc., is
to make a surface with end-linked nanofibers. These resulting
"fuzzy" surfaces, therefore, have increased surface areas (i.e., in
relation to the surfaces without the nanofibers) and other unique
properties. In some such embodiments, the surface of the nanowire
and/or the target substrate surface is optionally chemically
modified (typically, but not necessarily, without affecting the
gold tip) in order to give a wide range of properties useful in
many applications.
[0250] In other embodiments, to slightly increase or enhance a
surface area, the nanofibers are optionally laid "flat" (i.e.,
substantially parallel to the substrate surface) by chemical or
electrostatic interaction on surfaces, instead of end-linking the
nanofibers to the substrate. In yet other embodiments herein,
techniques involve coating the base surface with functional groups
which repel the polarity on the nanofiber so that the fibers do not
lay on the surface but are end-linked.
[0251] Synthesis of nanostructures, e.g., nanocrystals, of various
composition is described in, e.g., Peng et al. (2000) "Shape
control of CdSe nanocrystals" Nature 404:59-61; Puntes et al.
(2001) "Colloidal nanocrystal shape and size control: The case of
cobalt" Science 291:2115-2117; U.S. Pat. No. 6,306,736 to
Alivisatos et al. (Oct. 23, 2001) entitled "Process for forming
shaped group III-V semiconductor nanocrystals, and product formed
using process"; U.S. Pat. No. 6,225,198 to Alivisatos et al. (May
1, 2001) entitled "Process for forming shaped group II-VI
semiconductor nanocrystals, and product formed using process"; U.S.
Pat. No. 5,505,928 to Alivisatos et al. (Apr. 9, 1996) entitled
"Preparation of III-V semiconductor nanocrystals"; U.S. Pat. No.
5,751,018 to Alivisatos et al. (May 12, 1998) entitled
"Semiconductor nanocrystals covalently bound to solid inorganic
surfaces using self-assembled monolayers"; U.S. Pat. No. 6,048,616
to Gallagher et al. (Apr. 11, 2000) entitled "Encapsulated quantum
sized doped semiconductor particles and method of manufacturing
same"; and U.S. Pat. No. 5,990,479 to Weiss et al. (Nov. 23, 1999)
entitled "Organo luminescent semiconductor nanocrystal probes for
biological applications and process for making and using such
probes."
[0252] Additional information on growth of nanofibers, such as
nanowires, having various aspect ratios, including nanofibers with
controlled diameters, is described in, e.g., Gudiksen et al. (2000)
"Diameter-selective synthesis of semiconductor nanowires" J. Am.
Chem. Soc. 122:8801-8802; Cui et al. (2001) "Diameter-controlled
synthesis of single-crystal silicon nanowires" Appl. Phys. Lett.
78:2214-2216; Gudiksen et al. (2001) "Synthetic control of the
diameter and length of single crystal semiconductor nanowires" J.
Phys. Chem. B 105:4062-4064; Morales et al. (1998) "A laser
ablation method for the synthesis of crystalline semiconductor
nanowires" Science 279:208-211; Duan et al. (2000) "General
synthesis of compound semiconductor nanowires" Adv. Mater.
12:298-302; Cui et al. (2000) "Doping and electrical transport in
silicon nanowires" J. Phys. Chem. B 104:5213-5216; Peng et al.
(2000), supra; Puntes et al. (2001), supra; U.S. Pat. No. 6,225,198
to Alivisatos et al., supra; U.S. Pat. No. 6,036,774 to Lieber et
al. (Mar. 14, 2000) entitled "Method of producing metal oxide
nanorods"; U.S. Pat. No. 5,897,945 to Lieber et al. (Apr. 27, 1999)
entitled "Metal oxide nanorods"; U.S. Pat. No. 5,997,832 to Lieber
et al. (Dec. 7, 1999) "Preparation of carbide nanorods"; Urbau et
al. (2002) "Synthesis of single-crystalline perovskite nanowires
composed of barium titanate and strontium titanate" J. Am. Chem.
Soc., 124:1186; Yun et al. (2002) "Ferroelectric Properties of
Individual Barium Titanate Nanowires Investigated by Scanned Probe
Microscopy" Nano Letters 2, 447; and published PCT application nos.
WO 02/17362, and WO 02/080280.
[0253] Growth of branched nanofibers (e.g., nanotetrapods, tripods,
bipods, and branched tetrapods) is described in, e.g., Jun et al.
(2001) "Controlled synthesis of multi-armed CdS nanorod
architectures using monosurfactant system" J. Am. Chem. Soc.
123:5150-5151; and Manna et al. (2000) "Synthesis of Soluble and
Processable Rod-, Arrow-, Teardrop-, and Tetrapod-Shaped CdSe
Nanocrystals" J. Am. Chem. Soc. 122:12700-12706. Synthesis of
nanoparticles is described in, e.g., U.S. Pat. No. 5,690,807 to
Clark Jr. et al. (Nov. 25, 1997) entitled "Method for producing
semiconductor particles"; U.S. Pat. No. 6,136,156 to El-Shall, et
al. (Oct. 24, 2000) entitled "Nanoparticles of silicon oxide
alloys"; U.S. Pat. No. 6,413,489 to Ying et al. (Jul. 2, 2002)
entitled "Synthesis of nanometer-sized particles by reverse micelle
mediated techniques"; and Liu et al. (2001) "Sol-Gel Synthesis of
Free-Standing Ferroelectric Lead Zirconate Titanate Nanoparticles"
J. Am. Chem. Soc. 123:4344. Synthesis of nanoparticles is also
described in the above citations for growth of nanocrystals, and
nanofibers such as nanowires, branched nanowires, etc.
[0254] Synthesis of core-shell nanofibers, e.g., nanostructure
heterostructures, is described in, e.g., Peng et al. (1997)
"Epitaxial growth of highly luminescent CdSe/CdS core/shell
nanocrystals with photostability and electronic accessibility" J.
Am. Chem. Soc. 119:7019-7029; Dabbousi et al. (1997) "(CdSe)ZnS
core-shell quantum dots: Synthesis and characterization of a size
series of highly luminescent nanocrystallites" J. Phys. Chem. B
101:9463-9475; Manna et al. (2002) "Epitaxial growth and
photochemical annealing of graded CdS/ZnS shells on colloidal CdSe
nanorods" J. Am. Chem. Soc. 124:7136-7145; and Cao et al. (2000)
"Growth and properties of semiconductor core/shell nanocrystals
with InAs cores" J. Am. Chem. Soc. 122:9692-9702. Similar
approaches can be applied to growth of other core-shell
nanostructures. See, for example, U.S. Pat. No. 6,207,229 (Mar. 27,
2001) and U.S. Pat. No. 6,322,901 (Nov. 27, 2001) to Bawendi et al.
entitled "Highly luminescent color-selective materials."
[0255] Growth of homogeneous populations of nanofibers, including
nanofibers heterostructures in which different materials are
distributed at different locations along the long axis of the
nanofibers is described in, e.g., published PCT application nos. WO
02/17362, and WO 02/080280; Gudiksen et al. (2002) "Growth of
nanowire superlattice structures for nanoscale photonics and
electronics" Nature 415:617-620; Bjork et al. (2002)
"One-dimensional steeplechase for electrons realized" Nano Letters
2:86-90; Wu et al. (2002) "Block-by-block growth of
single-crystalline Si/SiGe superlattice nanowires" Nano Letters 2,
83-86; and U.S. patent application Ser. No. 60/370,095 (Apr. 2,
2002) to Empedocles entitled "Nanowire heterostructures for
encoding information." Similar approaches can be applied to growth
of other heterostructures and applied to the various methods and
systems herein.
[0256] In some embodiments the nanofibers used to create enhanced
surface areas can be comprised of nitride (e.g., AlN, GaN, SiN, BN)
or carbide (e.g., SiC, TiC, Tungsten carbide, boron carbide) in
order to create nanofibers with high strength and durability.
Alternatively, such nitrides/carbides (and other materials as well
such as silica, A1203 etc.) are used as hard coatings on lower
strength (e.g., silicon or ZnO) nanofibers. While the dimensions of
silicon nanofibers are excellent for many applications requiring
enhanced surface area (e.g., see, throughout and "Structures,
Systems and Methods for Joining Articles and Materials and Uses
Therefore," filed Apr. 17, 2003, U.S. Ser. No. 60/463,766, etc.)
other applications require nanofibers that are less brittle and
which break less easily. Therefore, some embodiments herein take
advantage of materials such as nitrides and carbides which have
higher bond strengths than, e.g., Si, SiO.sub.2 or ZnO. The
nitrides and carbides are optionally used as coatings to strengthen
the weaker nanofibers or even as nanofibers themselves. The
nanofibers may also be coated with any other biologically
compatible material (e.g., a silicon nanowire with an ALD coating
of TiO such as TiO2) suitable for use with a medical device
according to the teachings of the present invention, including any
other organic, inorganic or hybrid organic/inorganic material.
[0257] Carbides and nitrides can be applied as coatings to low
strength fibers by deposition techniques such as sputtering, atomic
layer deposition and plasma processes. In some embodiments, to
achieve high strength nanocoatings of carbide and nitride coatings,
a random grain orientation and/or amorphous phase are grown to
avoid crack propagation. Optimum conformal coating of the
nanofibers can optionally be achieved if the fibers are growing
perpendicular to a substrate surface. The hard coating for fibers
in such orientation also acts to enhance the adhesion of the fibers
to the substrate. For fibers that are randomly oriented, the
coating is preferential to the upper layer of fibers.
[0258] Low temperature processes for creation of silicon nanofibers
are achieved by the decomposition of silane at about 400.degree. C.
in the presence of a gold catalyst. However, as previously stated,
silicon nanofibers are too brittle for some applications to form a
durable nanofiber matrix (i.e., an enhanced surface area). Thus,
formation and use of, e.g., SiN is optionally utilized in some
embodiments herein. In those embodiments, NH.sub.3, which has
decomposition at about 300.degree. C., is used to combine with
silane to form SiN nanofibers (also by using a gold catalyst).
Other catalytic surfaces to form such nanofibers can include, e.g.,
Ti, Fe, etc.
[0259] Forming carbide and nitride nanofibers directly from a melt
can sometimes be challenging since the temperature of the liquid
phase is typically greater than 1000.degree. C. However, a
nanofiber can be grown by combining the metal component with the
vapor phase. For example, GaN and SiC nanofibers have been grown
(see, e.g., Peidong, Lieber, supra) by exposing Ga melt to NH.sub.3
(for GaN) and graphite with silane (SiC). Similar concepts are
optionally used to form other types of carbide and nitride
nanofibers by combing metal-organic vapor species, e.g., tungsten
carbolic [W(CO)6] on a carbon surface to form tungsten carbide
(WC), or titanium dimethoxy dineodecanoate on a carbon surface to
form TiC. It will be appreciated that in such embodiments, the
temperature, pressure, power of the sputtering and the CVD process
are all optionally varied depending upon, e.g., the specific
parameters desired in the end nanofibers. Additionally, several
types of metal organic precursors and catalytic surfaces used to
form the nanofibers, as well as, the core materials for the
nanofibers (e.g., Si, ZnO, etc.) and the substrates containing the
nanofibers, are all also variable from one embodiment to another
depending upon, e.g., the specific enhanced nanofiber surface area
to be constructed.
[0260] The present invention can be used with structures that may
fall outside of the size range of typical nanostructures. For
example, Haraguchi et al. (U.S. Pat. No. 5,332,910) describes
nanowhiskers which are optionally used herein. Semi-conductor
whiskers are also described by Haraguchi et al. (1994)
"Polarization Dependence of Light Emitted from GaAs p-n junctions
in quantum wire crystals" J. Appl. Phys. 75(8):4220-4225; Hiruma et
al. (1993) "GaAs Free Standing Quantum Sized Wires," J. Appl. Phys.
74(5):3162-3171; Haraguchi et al. (1996) "Self Organized
Fabrication of Planar GaAs Nanowhisker Arrays"; and Yazawa (1993)
"Semiconductor Nanowhiskers" Adv. Mater. 5(78):577-579. Such
nanowhiskers are optionally nanofibers of the invention. While the
above references (and other references herein) are optionally used
for construction and determination of parameters of nanofibers of
the invention, those of sill in the art will be familiar with other
methods of nanofiber construction/design, etc. which can also be
amenable to the methods and devices herein.
[0261] Some embodiments herein comprise repetitive cycling of
nanowire synthesis and gold fill deposition to make "nano-trees" as
well as the co-evaporation of material that will not form a silicon
eutectic, thus, disrupting nucleation and causing smaller wire
formation
[0262] Such methods are utilized in the creation of ultra-high
capacity surface based structures through nanofiber growth
technology for, e.g., adhesion promotion between surfaces,
non-fouling surfaces, etc.). Use of single-step metal film type
process in creation of nanofibers limits the ability to control the
starting metal film thickness, surface roughness, etc., and, thus,
the ability of control nucleation from the surface. The present
methods address these issues
[0263] In some embodiments of nanofiber enhanced surfaces it can be
desirable to produce multibranched nanofibers. Such multibranched
nanofibers could allow an even greater increase in surface area
than would occur with non-branched nanofiber surfaces. To produce
multibranched nanofibers gold film is optionally deposited onto a
nanofiber surface (i.e., one that has already grown nanofibers).
When placed in a furnace, fibers perpendicular to the original
growth direction can result, thus, generating branches on the
original nanofibers. Colloidal metal particles can optionally be
used instead of gold film to give greater control of the nucleation
and branch formation. The cycle of branching optionally could be
repeated multiple times, e.g., with different film thicknesses,
different colloid sizes, or different synthesis times, to generate
additional branches having varied dimensions. Eventually, the
branches between adjacent nanofibers could optionally touch and
generate an interconnected network. Sintering is optionally used to
improve the binding of the fine branches.
[0264] In yet other embodiments, it is desirable to form finer
nanofibers (e.g., nanowires). To accomplish this, some embodiments
herein optionally use a non-alloy forming material during gold or
other alloy forming metal evaporation. Such material, when
introduced in a small percentage can optionally disrupt the metal
film to allow it to form smaller droplets during wire growth and,
thus, correspondingly finer wires.
[0265] Such approaches can allow improved control of nanofiber
formation and allow generation of finer and more numerous
nanofibers from a slightly thicker initial metal film layer. In
applications such as nanoarrays, etc., the improved control can
optionally improve the signal ratio from the nanofibers to the
planar surface or just add a greater degree of control. Possible
materials for use in finer nanofiber construction include, e.g.,
Ti, Al.sub.2O.sub.3 and SiO.sub.2.
[0266] In yet other embodiments, post processing steps such as
vapor deposition of glass can allow for greater anchoring or
mechanical adhesion and interconnection between nanofibers, thus,
improving mechanical robustness in applications requiring
additional strength as well as increasing the overall surface to
volume of the nanostructure surface.
[0267] D) Interaction of Biomaterials and Nanofiber Enhanced
Surface Area Substrates
[0268] In typical embodiments, the nanofiber enhanced surface area
substrates of the invention are used in various medical product
applications. For example, coatings on medical products for drug
release, lubricity, cell adhesion, low bio-adsorption, electrical
contact, etc. See above. For example, the application of surface
texture (e.g., as with the present invention) to the surfaces of
polymer implants has been shown to result in significant increases
in cellular attachment. See, e.g., Zhang et al. "Nanostructured
Hydroxyapatite Coatings for Improved Adhesion and Corrosion
Resistance for Medical Implants" Symposium V: Nanophase and
Nanocomposite Materials IV, Kormareni et al. (eds.) 2001, MRS
Proceedings, vol. 703. Other medical applications of the current
embodiments include, e.g., slow-release drug delivery. For example,
drugs can be incorporated into various pharmaceutically acceptable
carriers which allow slow release over time in physiological
environments (e.g., within a patient). Drugs, etc. incorporated
into such carriers (e.g., polymer layers, etc.) are shielded, at
least partially, from direct exposure to body fluids due to
incorporation into the carrier layer (e.g., present interstitially
between the nanofibers). Drugs, etc. at the interface between the
body fluids and the carrier layer (at the top of the nanofiber
layer) diffuse out fairly quickly, while drugs deeper within the
carrier layer diffuse out slowly (e.g., once body fluid diffuses
into the carrier layer and then diffuses back out with the drug).
Such carriers are well known to those of skill in the art and can
be deposited or wicked onto the surface of a nanofiber substrate
(i.e., amongst the nanofibers).
[0269] Biofilm formation and infection on indwelling catheters,
orthopedic implants, pacemakers and other medical devices
represents a persistent patient health danger. Therefore, some
embodiments herein comprise novel surfaces which minimize bacterial
colonization, as well as the colonization of viruses, viral spores,
etc., due to their advantageous morphology. In contrast, yet other
embodiments herein utilize the unique surface morphology of
nanofiber enhanced surface area substrates to foster cell growth
under desired conditions or in desired locations. The high surface
area/non-tortuous aspect of the current invention allows greater
attachment area and accessibility (in certain embodiments) for
nutrients/fluids, etc. and initial attachment benefits over porous
surfaces where growth, etc. is limited by space (both in terms of
surface area and space within the pores for the cells to grow
out).
[0270] The substrates of the invention, because of their high
surface areas and ready accessibility (e.g., non-tortuous paths),
are extremely useful as bioscaffolds, e.g., in cell culture,
implantation, and controlled drug or chemical release applications.
In particular, the high surface area of the materials of the
invention provide very large areas for attachment of desirable
biological cells in, e.g., cell culture or for attachment to
implants. Further, because nutrients can readily access these
cells, the invention provides a better scaffold or matrix for these
applications. This latter issue is a particular concern for
implanted materials, which typically employ porous or roughened
surfaces in order to provide tissue attachment. In particular, such
small, inaccessible pores, while providing for initial attachment,
do not readily permit continued maintenance of the attached cells,
which subsequently deteriorate and die, reducing the effectiveness
of the attachment. Another advantage of the materials of the
invention is that they are inherently non-biofouling, e.g., they
are resistant to the formation of biofilms from, e.g., bacterial
species that typically cause infection for implants, etc.
[0271] Without being bound to a particular theory or method of
action, the unique morphology of a nanofiber surface can reduce the
colonization rate of bacterial species such as, e.g., S.
epidermidis, as well as viruses, viral spores, etc., by about ten
fold. For example, embodiments such as those comprising silicon
nanowires grown from the surface of a planar silicon oxide
substrate by chemical vapor deposition process, and which comprise
diameters of approximately 60 nanometers and lengths of about
50-100 microns show reduced bacterial colonization. See, below. It
will be appreciated that while specific bacterial species are
illustrated in examples herein, that the utility of the
embodiments, does not necessarily rest upon use against such
species. In other words, other bacterial species are also
optionally inhibited in colonization of the nanofiber surfaces
herein. Additionally, while examples herein utilize silicon oxide
nanowires on similar substrates, it will be appreciated other
embodiments are optionally equally utilized (e.g., other
configurations of nanofibers; nanofibers on non-silicon substrates
such as plastic, etc; patterns of nanofibers on substrates,
etc.).
[0272] It will be noticed that substrates herein that are covered
with high densities of nanofibers (e.g., silicon nanowires) resist
bacterial colonization and mammalian cell growth. For example,
approximately 10.times. less (or even less) bacterial growth occurs
on a nanowire covered substrate as compared to an identical planar
surface. In various embodiments herein, the physical and chemical
properties of the nanofiber enhanced surface area substrates are
varied in order to optimize and characterize their resistance to
bacterial colonization.
[0273] In contrast to prevention of bacterial colonization, other
embodiments herein comprise substrates that induce the attachment
of mammalian cells to the nanofiber surface by functionalization
with extra-cellular binding proteins, etc. or other moieties, thus,
achieving a novel surface with highly efficient tissue integration
properties.
[0274] In some embodiments herein where NFS substrates are to be
used in settings requiring, e.g., sterility, etc., the nanofibers
are optionally coated with, or composed of, titanium dioxide. Such
titanium dioxide confers self-sterilizing or oxidative properties
to such nanofibers. Nanofibers which comprise titanium dioxide,
thus, allow rapid sterilization and oxidation compared to
conventional planar TiO.sub.2 surfaces while maintaining rapid
diffusion to the surface.
[0275] In embodiments herein which involve nanowires comprising
titanium oxides (e.g., coated nanowires, etc.), such can optionally
be achieved though any of a number of methods. For example, in some
embodiments herein the nanowires can be designed and implemented
through an approach which involves analytical monitoring of
(SiO.sub.4),(TiO.sub.4).sub.y nanowires by coating and a molecular
precursor approach. The layer thickness and porosity are optionally
controlled through concentration of reagent, dip speed, and or
choice of precursor for dip coating such as tetraethoxytitanate or
tetrabutoxytitanate, gelation in air, air drying and calcinations.
Molecular precursors such as M[(OSi(O.sup.tBu)3)4, where M=Ti, Zi,
or other metal oxides, can be decomposed to release 12 equivalents
of isobutylene and 6 equivalents of water to form mesoporous
materials or nanowires. These precursors can also be used in
conjunction with CVD or detergents in nanocrystal syntheses (wet
chemistry) to produce dimetallic nanocrystals of desired size
distribution. Material can be made via wet chemistry standard
inorganic chemistry techniques and oxidative properties determined
by simple kinetics monitoring of epoxidation reactions (GC or GCMS)
using alkene substrates. Porosity can be monitored by standard BET
porosity analysis. Copolymer polyether templates can also be used
to control porosity as part of the wet chemistry process.
[0276] Titanium oxide materials are well known oxidation catalysts.
One of the keys to titanium oxide materials is control of porosity
and homogeneity of particle size or shape. Increased surface area
typically affords better catalytic turnover rates for the material
in oxidation processes. This has been difficult as the kinetics of
oxide formation (material morphology) can be difficult to control
in solution. 102401 As described, recent interest in TiO.sub.2 for
oxidative catalytic surfaces (self-cleaning surfaces) shows promise
for marketing "green chemistry" cleaning materials. However, the
self-cleaning efficiency of the material is dependent upon, e.g.,
the surface area and porosity. Nanowires have a much higher surface
areas than bulk materials (e.g., ones with a nanofiber enhanced
surface) that are currently used for self-cleaning materials. Thus,
the combination of silicon nanowire technology coated with
TiO.sub.2 or TiO.sub.2 nanowires or molecular precursors to form
wires can optionally provide access to previously unknown materials
that are useful in self-cleaning, sterilizing, orthopedic/dental
implants and/or non-biofouling surfaces.
[0277] In some embodiments, such sterilizing activity arises in
conjunction with exposure to UV light or other similar excitation.
Such factors are optionally important in applications such as,
e.g., sterile surfaces in medical settings or food processing
settings. The increased surface area due to the NFS of the
invention (e.g., increasing area 100-1000 times or the like),
therefore, could vastly increase the disinfection rate/ability of
such surfaces.
[0278] i] Current Means of Preventing Bacterial Contamination of
Medical Devices
[0279] A variety of methods have been used to combat surface
colonization of biomedical implants by bacteria and other
microorganisms as well as the resulting biofilm formed. Previous
methods have included varying the fundamental biomaterial used in
the devices, applying hydrophilic, hydrophobic or bioactive
coatings or creating porous or gel surfaces on the devices that
contain bioactive agents. The task of generating universal
biomaterial surfaces is complicated by species'specificity to
particular materials. For example S. epidermidis has been reported
to bind more readily to hydrophobic than to hydrophilic surfaces.
S. aureus has a greater affinity for metals than for polymers,
while S. epidermidis forms a film more rapidly on polymers than
metals.
[0280] Antimicrobial agents, such as antibiotics and polyclonal
antibodies integrated into porous biomaterials have been shown to
actively prevent microbial adhesion at the implant site. However,
the effectiveness of such local-release therapies is often
compromised by the increasing resistance of bacteria to antibiotic
therapy and the specificity associated with antibodies. Recent in
vitro studies have also explored the use of biomaterials that
release small molecules such as nitrous oxide in order to
non-specifically eliminate bacteria at an implant surface. Nitrous
oxide release must, however, be localized to limit toxicity.
[0281] ii) Prevention of Biofilm Formation by Nanofiber Enhanced
Area Surfaces
[0282] Results of the inventors have shown that silicon nanowire
surfaces aggressively resist colonization by the bacteria S.
epidermidis as well as the growth of CHO, MDCK and NIH 3T3 cell
lines. This is found to be the case when the bacteria or cells were
cultured in contact with a native hydrophilic nanowire surface or
with a fluorinated hydrophobic nanowire surface. Since silicon
oxide flat control surfaces and polystyrene flat control surfaces
supported profuse growth of S. epidermidis and the three cell
lines, it is inferred that the nanowire morphology renders the
surface cytophobic. Of course, again, it will be realized that the
utility of the current invention is not limited by specific
theories or modes of action. However, surface morphology is thought
to be basis for the antimicrobial activity. The nanofibers on such
substrates are spaced tightly enough to prohibit the bacteria from
physically penetrating to the solid surface below. The amount of
presentable surface area available for attachment is typically less
then 1.0% of the underlying flat surface. In typical embodiments,
the nanofibers are approximately 40 nm in diameter and rise to a
height about 20 uM above the solid surface. Thus, unlike a typical
membrane surface that would be found on a medical device, the
nanowire surfaces herein are discontinuous and spiked and have no
regular structure to aid in cell attachment. In fact, the current
surfaces are almost the exact opposite of a conventional membrane;
rather than a solid surface with holes, they are open spiked
surfaces. It is thought that this unique morphology discourages
normal biofilm attachment irrespective of the hydrophobic or
hydrophilic nature of the nanofibers involved.
[0283] As detailed throughout, the nanofiber growth process can be
conducted on a wide variety of substrates that can have planar or
complex geometries. Thus, various substrates of the invention can
be completely covered, patterned or have nanofibers in specific
locations. For example, one arrangement for capturing nanofibers
involves forming surfaces that comprise regions that selectively
attract nanofibers such as hydrophobic and/or hydrophilic regions.
For example, --NH2 can be presented in a particular pattern at a
surface, and that pattern will attract nanofibers having surface
functionality attractive to amines. Surfaces can be patterned using
known techniques such as electron-beam patterning,
soft-lithography, or the like. See also, International Patent
Publication No. WO 96/29629, published Jul. 26, 1996, and U.S. Pat.
No. 5,512,131, issued Apr. 30, 1996. Patterned surfaces can in
certain instances enhance the interaction of a device with the body
into which it is inserted. For instance, different rows or patches
or stripes of hydrophobic and/or hydrophilic regions of nanofibers
may be useful to enhance cell integration in certain applications
such as orthopedic implants, tissue engineering and the like.
However, for ease of focus herein, silicon nanofibers on silicon
oxide or metallic substrates are discussed in most detail. Again,
however, nanofibers from a wide variety of materials are also
contemplated as is growing such on plastic, metal and ceramic
substrates. The versatility of the nanofiber production process
lends itself to the eventual scale-up and commercialization of a
wide variety of products with nanofiber surfaces for the
bio-medical field.
[0284] It is thought that, although absolute surface area is
increased on substrates growing nanofibers, the low solid surface
volume, lack of continuity and nanoscale aspect of the fibers
discourages cellular attachment. The nanowire surfaces used in
these illustrations herein was produced for an electronics
application and was not optimized for this use, yet, as will be
noted, such surfaces still reduced biofilm accumulation. The
silicon wires utilized were .about.40 nm in diameter and 50 to 100
um in length and were grown on a four inch silicon substrate. The
nanowire preparation method is described below. In the current
example, the nanowire pieces used in this experiment were about
0.25 cm.sup.2. Immediately before introduction into the culture
media they were soaked in 100% ethanol and blown dry with a stream
of nitrogen. Silicon wafer controls (i.e., without nanowires) were
also soaked in ethanol and blown dry. S. epidermidis was grown in
LB broth for 6 hours at 37.degree. C. with gentle shaking in 35 mm
Petri dishes. Wafer sections were then placed in the culture and
left for 24 hours at 37.degree. C. in the original media. The wafer
slices were removed after 24 hours incubation, washed briefly in
fresh media, rapidly immersed in water and then heat fixed for 30
seconds prior to staining in a 0.2% crystal violet solution. The
wafer segments were rinsed thoroughly in water. Any microbes
attached to the wafers were visualized by conventional brightfield
microscopy. Images were captured with a digital camera. The results
showed approximately a ten fold decrease in bacteria on the
nanowire substrate as compared to the silicon wafer control.
Quantitation was performed on the microscope by focusing through
the nanowires since the thickness of the nanowire layer was greater
than the depth of field of the microscope.
[0285] To illustrate the nanofiber surfaces' repulsion of mammalian
cells, CHO cells were maintained in culture in complete media (Hams
F12 media supplemented with 10% fetal bovine serum) at 37.degree.
C. in a 5% CO.sub.2 atmosphere. Wafer segments were placed in 35 mm
cell culture treated Petri dishes. CHO cells were seeded into the
dishes at a density of 10.sup.6 cell/ml in complete media after
trypsinization from confluent culture. The cells were allowed to
adhere overnight and were then observed microscopically every 24
hours. The surface of the 35 mm Petri dish was confluent at 48
hours when the first observation was made. No cell growth was
observed directly on the nanowire surface. Where the nanowires had
been removed by scratching the surface with a knife the cells
adhered and grew. Silicon wafer controls became confluent with
cells. In these experiments complete retardation of mammalian
cellular growth and approximately a 10.times. reduction in
bacterial growth was observed. The control surfaces were chemically
identical to the nanowires so it is thought that reduction in cell
and bacterial growth is due to the unique surface morphology of the
nanofiber enhanced surface area substrates.
[0286] S. epidermidis was used in the illustrations herein because
it is a representative bacteria involved in infections of medical
devices. Additionally, S. epidermidis has been widely used in the
evaluation of biomaterials and has been identified as a dominant
species in biomaterial centered infections. Other bacteria
implicated in biomaterial related infections such as S. aureus,
Pseudomonas aeruginosa and B-hemolytic streptococci are also
contemplated as being prohibited through use of current
embodiments. In addition to CHO cells illustrated herein, other
common tissue culture lines such as, e.g., MDCK, L-929 and HL60
cells are also contemplated as being prohibited through use of
current embodiments. Such cell lines represent a wide diversity of
cell types. The CHO and MDCK cells are representative of epithelial
cells, L-929 cells participate in the formation of connective
tissue and the HL60 line represents immune surveillance cells.
Thus, the nanofiber enhanced surface areas herein are contemplated
against these cell types and other common in vivo cell types. The
nanofibers used in the in vitro illustration herein were made of
silicon, and, as detailed throughout, several methods have been
reported in the literature for the synthesis of silicon nanowires.
For example, laser ablating metal-containing silicon targets, high
temperature vaporizing of Si/SiO.sub.2 mixture, and
vapor-liquid-solid (VLS) growth using gold as the catalyst. See,
above. While any method of construction is optionally used, the
approach to nanowire synthesis is typically VLS growth since this
method has been widely used for semiconductor nanowire growth.
Description of such method is provided elsewhere herein.
[0287] As mentioned previously, it is thought that the primary
means of biofilm prevention by nanofiber surfaces herein is due to
the unique morphology of the substrate, however, it is also
possible that such substrates comprise inherent cytophobicity
activity.
[0288] The effect of surface hydrophilicity or hydrophobicity on
growth is also optionally modified on the nanofiber substrates
herein to specifically tailor biofilm prevention in different
situations. Such functionalization goes along with variability in
wire length, diameter and density on the substrate. The silicon
oxide surface layer of the typical nanofiber substrates is quite
hydrophilic in its native state. Water readily wets the surface and
spreads out evenly. This is partially due to the wicking properties
of the surface. Functionalization of the surface is facilitated by
the layer of native oxide that forms on the surface of the wires.
This layer of SiO.sub.2 can be modified using standard silane
chemistry to present functional groups on the outside of the wire.
For example the surface can be treated with gaseous
hexamethyldisilane (HMDS) to make it extremely hydrophobic. See,
above. In addition, it is possible to use multi-component nanofiber
surfaces to tailor a medical device for a particular application.
For example, a hydrophobic (or hydrophilic) nanofiber surface which
resists cellular attachment (and thus biofilm formation) as
described above can also be specifically tailored to allow one or
more specific types of cells such as endothelial cells,
osteoblasts, etc to grow on some (or all) portions of the surface
(e.g., where cellular integration and proliferation is needed),
e.g., by modifying the hydrophobic (or hydrophilic) nanofiber
surface with functional groups (e.g., fibronectin, collagen, RGD
containing peptides, extracellular matrix proteins, chemoattracts,
and other cell binding motifs)--which promote cellular attachment
and integration. The hydrophobic layer may diminish over time as
the desired cells integrate. Thus, medical devices such as
catheters, implants and the like can be engineered to resist
biofilm formation over portions of or their entire surface by
rendering the nanofiber surface hydrophobic as described above and
in co-pending U.S. Ser. No. 10/833,944, filed Apr. 27, 2004, the
entire contents of which are incorporated by reference herein, and
then the surface coverage of one or more functional groups on the
hydrophobic surface can be precisely controlled to encourage
cellular attachment in specific areas where tissue integration is
most desirable (e.g., where grafting or bonding is to occur).
Examples of multicomponent films are demonstrated and described,
for example, in T. M. Herne et al., Characterization of DNA Probes
Immobilized on Gold Surfaces, J. Am. Chem. Soc. 1997, 119,
8916-8920 (e.g., FIG. 4), the entire contents of which are
incorporated by reference herein."
[0289] iii) Attachment of Extra-Cellular Proteins onto Nanofiber
Surfaces
[0290] As shown herein, nanofiber surfaces do not readily support
the growth of mammalian cells or bacteria. Yet, in other instances,
the growth of mammalian cell lines on surfaces is advantageous.
Thus, embodiments of the current invention, by attaching
extra-cellular proteins or other moieties to nanofibers encourages
such cell growth. The deposition of the proteins on the nanofibers
can be through simple nonspecific adsorption. Other embodiments
contemplate covalent attachment of cells/proteins to a nanofiber
surface. Proteins with known extra-cellular binding functions such
as Collagen, Fibronectin, Vitronectin and Laminin are contemplated
in use. In embodiments where grafting and/or bonding of nanofiber
substrates and, e.g., biological material such as bone or medical
devices such as metal bone pins, etc. is to occur, different
embodiments can have different patterns of nanofibers upon the
substrate. Thus, for example, nanofibers can optionally only exist
on an area of a medical implant where grafting or bonding is to
occur. Further, a medical device may be covered by two or more
different nanostructured surfaces to impart different properties to
different portions of the device as described above. For example,
one portion of a device can include nanofibers (e.g., hydrophilic
wires) which promote adhesion to tissue surfaces (such as where
grafting or bonding is to occur), e.g., through increased
interactivity with endothelial cells, osteoblasts, etc., while
another portion of the device may be coated with nanofibers that
are tailored (e.g., through hydrophobic functionalization) to
resist biofouling. Again, standard protein attachment methods can
be used to make the covalent linkage to the nanofibers.
[0291] Additionally various sol-gel coatings can be deposited upon
nanofiber surfaces herein to encourage bio-compatibility and/or
bio-integration applications. Previous work on devices concerned
with bone integration has used porous materials on titanium
implants to encourage bone growth. In some embodiments herein, the
current invention utilizes addition of similar materials in
conjunction with the nanofiber surfaces herein. For example,
hydroxyapatite, a common calcium based mineral, can optionally be
deposited on nanofiber surfaces to facilitate bone integration
into/with the nanofiber surface. Common sol-gel techniques can
optionally be used to produce the hydroxyapatite deposition. Such
hydroxyapatite coated nanofiber surfaces optionally could have the
benefit of both promoting bone integration and displaying
anti-biofouling properties, thus, resulting in a greater likelihood
that proper bone growth/healing will occur.
[0292] In an alternative embodiment, the nanowires, by virtue of
being crystalline in nature, can induce or hasten the
crystallization of hydroxyapatite directly in the vicinity of the
nanowires. Such results are not surprising in light of the fact
that bioactive glass has been utilized for many years as a
component of orthopedic materials and the osseointegration has been
shown to be superior. With the current invention, high surface area
bioactive glass can essentially be grown on the surface of an
orthopedic implant, creating a platform on the implant for both
control of surface topography as well as altering the biochemical
nature of the surface through chemical attachment, adsorption, and
other techniques detailed in this invention. 102541 Those of skill
in the art will readily appreciate that the current invention also
includes use of deposition of ceramic-type materials and the like
through sol-gel techniques to produce a wide range of, e.g.,
compatibility applications (i.e., in addition to those involving
hydroxyapatite and bone growth).
[0293] E) Kits/Systems
[0294] In some embodiments, the invention provides kits for
practice of the methods described herein and which optionally
comprise the substrates of the invention. In various embodiments,
such kits comprise one or more nanofiber enhanced surface area
substrate, e.g., one or more catheter, heat exchanger,
superhydrophobic surface or, one or more other device comprising a
nanofiber enhanced surface area substrate, etc.
[0295] The kit can also comprise any necessary reagents, devices,
apparatus, and materials additionally used to fabricate and/or use
a nanofiber enhanced surface area substrate, or any device
comprising such.
[0296] In addition, the kits can optionally include instructional
materials containing directions (i.e., protocols) for the synthesis
of a nanofiber enhanced surface area substrate and/or for adding
moieties to such nanofibers and/or use of such nanofiber
structures. Preferred instructional materials give protocols for
utilizing the kit contents.
[0297] In certain embodiments, the instructional materials teach
the use of the nanofiber substrates of the invention in the
construction of one or more devices (such as, e.g., medical
devices, etc.). The instructional materials optionally include
written instructions (e.g., on paper, on electronic media such as a
computer readable diskette, CD or DVD, or access to an internet
website giving such instructions) for construction and/or
utilization of the nanofiber enhanced surfaces of the
invention.
EXAMPLE 1
[0298] The following non-limiting Example presents data from a
study conducted at Boston University that illustrates how the use
of nanofiber (e.g., nanowire) surfaces as compared to control
(reference) surfaces (e.g., quartz) for bone biotemplating
applications helps in faster cell differentiation which can be
expected to result in faster bone in-growth.
[0299] Osteoblast Culture
[0300] Human fetal osteoblasts, designated hFOB 1.19 (American Type
Culture Collection (ATCC), Manassas, Va.), were used for cell
adhesion studies. This cell line was obtained from a spontaneous
miscarriage and transfected with a temperature-sensitive mutant
gene of SV40 large T antigen. The cells were programmed to
proliferate at 34.degree. C. and differentiate only when the
temperature is raised to 39.degree. C. Cells with passage 10 were
used in all experiments. The medium used for growing osteoblasts
consisted of 1:1 ratio of DMEM:F12 (Invitrogen Corp.) with 10%
fetal bovine serum (Sigma-Aldrich) and 0.3 mg/mL of G418 sulfate
powder (ATCC). The medium was changed every 2-3 days, and the
subculture was done at a ratio of 1:4.
[0301] Osteoblast Seeding
[0302] Different nanowire surfaces along with control (reference)
surfaces (e.g., quartz) were placed in wells of 12-well plates and
were placed under ultraviolet lights in a biological hood for 24
hours. They were then soaked in 70% ethanol for 30 minutes for
sterilization with final rinsing with PBS and cell culture media.
Osteoblasts were seeded at a density of about 100,000
cells/well.
[0303] Osteoblast Adhesion and Proliferation
[0304] Osteoblast adhesion and proliferation was investigated 1 and
4 days respectively after seeding them on the nanowire and quartz
(reference) surfaces. Cell adhesion and proliferation was
characterized by trypsinizing the adhered cells on the various
surfaces and counting them using a hemacytometer.
[0305] FIG. 7 shows the cell count on various surfaces obtained by
a hemacytometer for cell adhesion after 1 day and proliferation
after 4 days of seeding. To create the nanowire surfaces,
commercially available gold colloids were deposited on the
substrate surfaces and the substrates were placed in a CVD furnace
and silane gas was flowed in at 480.degree. C. for 10 minutes
(short wires) or 30 minutes (long wires). This process produced a
dense mat of silicon nanowires (with native oxide shells) at
locations where the gold catalysis material was deposited yielding
nanowires with dimensions of about 40 nm in diameter and between
approximately 1 to 30 um in length The high density long nanowire
surfaces shown in FIG. 7 comprised nanowires grown for 30 minutes
and having a length between about 20 to 30 microns and a density of
about 25 wires/micron.sup.2; the high density short nanowire
surfaces shown in FIG. 7 comprised nanowires grown for 10 minutes
and having a length between about 7 to 12 microns and a density of
about 25 wires/micron.sup.2; the low density long nanowire surfaces
shown in FIG. 7 comprised nanowires grown for 30 minutes having a
length between about 20 to 30 microns and a density of about 5 to
10 wires/micron.sup.2. As can be seen, nanowire surfaces supported
the highest osteoblast adhesion compared to quartz surfaces.
However, surfaces with high density long nanowires showed highest
adhesion and proliferation followed by high density short nanowires
and low density long nanowires. Without being bound to any
particular theory, it is believed that this is because high density
long nanowires provide high surface area at a nanolevel which
promotes osteoblast adhesion and eventually proliferation.
[0306] Because high density long nanowires provide the highest
osteoblast adhesion and proliferation, the remainder of this
Example describes the use of these nanowire surfaces for bone
biotemplating applications. Further, osteoblast adhesion and
proliferation on these nanowires was also investigated using
fluorescence microscopy. The adhered and proliferated cells were
stained using CMFDA (5-chloromethylfluorescein diacetate) and
HOESCHT. Both CMFDA and HEOESCHT will stain live cells. CMFDA will
stain the cytoplasm green and the HOESCHT will stain the nucleus
blue. FIGS. 8A-F show fluorescence microscope images of adhered and
proliferated cells on various nanowire surfaces after 1 day (FIG.
8B) and 4 days (FIGS. 8D and F) and on quartz surfaces after 1 day
(FIG. 8A) and 4 days (FIGS. 8C and E). Nanowire surfaces show
higher osteoblast adhesion compared to quartz surfaces. Further, no
nucleus staining was seen at Day 1 on nanowire and quartz
surfaces.
[0307] Osteoblast Differentiation
[0308] Osteoblasts were seeded on sterilized nanowire and control
surfaces and were allowed to adhere and proliferate for 4 days at
34.degree. C. The temperature was then raised to 39.degree. C. to
stimulate the cells to differentiate and begin producing matrix. In
order to investigate normal osteoblast behavior, total protein
content was determined after up to 4 weeks of incubation. In order
to release the intracellular protein, the adhered cells on the
surfaces were lysed using 2% Triton-X detergent solution. The
resulting lysate solution was then used for analysis. The total
protein content was determined by a BCA (bicinchoninic acid) assay
kit (Pierce Biotechnology, Inc.) and the absorbance of the solution
was measured using a spectrophotometer at a wavelength of 562 nm.
The absorbance was converted to protein content using an albumin
standard curve. The lysate was also used to measure the
concentration of alkaline phosphatase using colorimetric assay
(Teco Diagnostics) at 590 nm.
[0309] FIG. 9 shows the alkaline phosphatase activity for
osteoblasts for a 4 week period. The ALP activity was normalized
with corresponding total protein content to take into account
variations in number of cells present on the surface. It should be
noted that the adhered cells were not proliferating during this
period since they were incubated at 39.degree. C. Therefore, the
increase in ALP activity can be attributed to healthy functionality
of the cells. For week 1, there is no significant difference in ALP
activity for cells adhered to all the surfaces. However, for longer
time periods, cells on nanowire surfaces show higher ALP activity
suggesting improved performance (p<0.01). They also show more
activity compared to commercially available ANOPORE.TM. membranes
suggesting that nanowire surfaces are more favorable templates for
osteoblast culture.
[0310] The extracellular matrix deposited by osteoblasts can be
determined by measuring calcium deposited by osteoblasts on these
surfaces. The deposited calcium can be stripped by dissolving it in
HCl and measuring the concentration using colorimetric assay (Teco
Diagnostics) at 570 nm. Similar results to that of alkaline
phosphatase activity are observed for matrix composition (FIG. 10).
For week 1, there is no significant difference in calcium
concentration. However, for longer time periods, cells on nanowire
surfaces deposited more matrix (as suggested by calcium
concentration) suggesting improved performance (p<0.01). By week
4, the calcium concentration on nanowire surfaces increased by
3-fold. Calcium assay was not used on ANOPORE membranes since they
react with acid. Thus, as a secondary characterization, X-ray
photoelectron spectroscopy was used. XPS was used to detect
presence of calcium and phosphorous on the surfaces after cell
lysis. XPS is a sensitive surface characterization technique which
measures the surface elemental concentrations. FIG. 11 shows the
calcium and phosphorous concentrations obtained from XPS. Ca/Si(or
Al) and P/Si(or Al) ratios are highest for all four weeks for
nanowire surfaces compared to other surfaces suggesting more
extracellular matrix was deposited by osteoblasts on these surfaces
(p<0.01). Further, the amount of deposited matrix on surfaces
increases with time as suggested by higher Ca/Si(or Al) and P/Si
(or Al) ratios.
[0311] Osteoblast morphology after differentiation was investigated
using scanning electron microscopy. SEM was performed on surfaces
with osteoblasts after each week for a period of 4 weeks. FIGS.
12A-H show SEM images of osteoblasts adhered on quartz (reference)
surfaces after 1 week (FIGS. 12A-B), 2 weeks (FIGS. 12C-D), 3 weeks
(FIGS. 12E-F) and 4 weeks (FIGS. 12G-H). FIGS. 121-P show SEM
images of osteoblasts adhered on nanowire surfaces after 1 week
(FIGS. 12I-J), 2 weeks (FIGS. 12K-L), 3 weeks (FIGS. 12M-N) and 4
weeks (FIGS. 120-P). Osteoblasts show improved performance on
nanowire surfaces as shown by SEM images. Osteoblasts show early
signs of differentiation on nanowire surfaces compared to quartz
surfaces. By the end of week 1, osteoblasts start communicating
with each other which is not observed on quartz surfaces. By the
end of week 2, cells extend their processes towards each other
which are the first signs of cell communication and signaling. This
kind of behavior is absent on quartz surfaces. By the end of week
3, osteoblasts start clustering on nanowire surfaces and start
filling the surfaces with matrix around them. By the end of week 4,
many clusters of osteoblasts are seen on nanowire surfaces compared
to quartz surfaces. This suggests that osteoblasts perform better
on nanowire surfaces and the nanoarchitecture helps in faster
differentiation which is expected to result in faster bone
in-growth.
EXAMPLE 2
[0312] The following non-limiting Example presents data from a
Purdue University study that illustrates how the use of nanofiber
(e.g., nanowire) surfaces as compared to current orthopedic implant
materials leads to increased select osteoblast adhesion in a
competitive cell adhesive environment. Various cells important for
orthopedic applications were allowed to interact with: current
implant materials (i.e., commercially pure titanium (Ti),
Ti.sub.6Al.sub.4V, and CoCrMo), current implant materials with a
bioactive hydroxyapatite (HA) coating (i.e., Ti coated with HA and
Ti.sub.6Al.sub.4V coated with HA), HA used not as a coating but in
bulk, and nanowire surfaces. Cells that were allowed to interact
with the materials simultaneously to simulate in vivo conditions
were: osteoblasts (bone-forming cells), fibroblasts (fibrous, not
hard, tissue forming cells), endothelial cells, and smooth muscle
cells. Fibroblasts, endothelial cells, and smooth muscle cells are
considered competitive cells to osteoblasts. Data has been shown
that when the functions of these cells are greater than those of
osteoblasts, orthopedic implant failure occurs.
[0313] Materials and Methods:
[0314] Each cell type was obtained from rats and was used as
primary cells (used directly after isolation). Cells were seeded
simultaneously at 3,500 cell/cm.sup.2 onto the materials and were
cultured under standard conditions for 4 hours. The nanowire
surfaces used in this study were prepared by growing nanowires from
40 nm gold colloids deposited onto poly-1-lysine coated titanium
coupons (1 cm.sup.2) (Alfa Aesar, Ward Hill, Mass.) for 30 minutes
at 480 degrees C. The final grown nanowires were approximately 5-20
um long and 40 nm in diameter. Each cell type was fluorescently
stained prior to seeding to assist in distinguishing each cell type
after the adhesion experiment. After 4 hours, cells were then fixed
and counted. Each experiment was done in triplicate and repeated at
three separate times for statistical significance.
[0315] Results and Discussion:
[0316] The results of this competitive adhesion assay showed
significantly more competitive adhesion after 1 day (FIG. 13A) and
proliferation after 3 days (FIG. 13B) of osteoblasts (bone forming
cells) on the nanowire surfaces compared to current materials used
in orthopedic implant applications. The results were even greater
than the currently defined bioactive HA coatings. Equally as
important, the simultaneous adhesion of competitive cells was the
lowest on the nanowire surfaces compared to currently used
orthopedic implant materials. These results suggest that
competitive adhesion and proliferation of osteoblasts over
competitive cells would be enhanced on the nanowire surfaces
compared to even the best clinical materials used in orthopedics
today (such as HA). Thus, it is fully expected that competitive
long-term functions of osteoblasts will also be higher on the
nanowire surfaces compared to those currently used as bone
implants.
[0317] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, it will be clear
to one skilled in the art from a reading of this disclosure that
various changes in form and detail can be made without departing
from the true scope of the invention. For example, all the
techniques and apparatus described above can be used in various
combinations. All publications, patents, patent applications, or
other documents cited in this application are incorporated by
reference in their entirety for all purposes to the same extent as
if each individual publication, patent, patent application, or
other document were individually indicated to be incorporated by
reference for all purposes.
* * * * *