U.S. patent application number 11/753896 was filed with the patent office on 2012-07-12 for implantable article, method of forming same and method for reducing thrombogenicity.
This patent application is currently assigned to Nanyang Technological University. Invention is credited to Yin Chiang BOEY, Subramanian VENKATRAMAN.
Application Number | 20120179242 11/753896 |
Document ID | / |
Family ID | 38779381 |
Filed Date | 2012-07-12 |
United States Patent
Application |
20120179242 |
Kind Code |
A9 |
VENKATRAMAN; Subramanian ;
et al. |
July 12, 2012 |
IMPLANTABLE ARTICLE, METHOD OF FORMING SAME AND METHOD FOR REDUCING
THROMBOGENICITY
Abstract
Endothelialization of a bodily fluid or tissue-contacting,
particularly blood-contacting, surface may be accomplished to
render that surface substantially non-thrombogenic. Thrombosis may
also be mitigated or eliminated by providing an eroding layer on
the surface that results in the removal of any thrombus formation
as the layer erodes. An implantable device may utilize at least one
surface having a plurality of nano-craters thereon that enhance or
promote endothelialization. Additionally, an implantable device may
have at least one first degradable layer for contacting bodily
fluid or tissue and disposed about a central core, and at least one
second degradable layer between the first degradable layer and the
central core. The first degradable layer has a first degradation
rate and the second degradable layer has a second degradation rate
which degrades more slowly than the first degradable layer on
contact with bodily fluid or tissue.
Inventors: |
VENKATRAMAN; Subramanian;
(Singapore, SG) ; BOEY; Yin Chiang; (Singapore,
SG) |
Assignee: |
Nanyang Technological
University
Singapore
SG
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20070299510 A1 |
December 27, 2007 |
|
|
Family ID: |
38779381 |
Appl. No.: |
11/753896 |
Filed: |
May 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10867617 |
Jun 15, 2004 |
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11753896 |
May 25, 2007 |
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60808558 |
May 26, 2006 |
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Current U.S.
Class: |
623/1.44 ;
604/6.16; 623/11.11; 623/2.42 |
Current CPC
Class: |
A61F 2210/0004 20130101;
A61L 27/56 20130101; A61L 27/58 20130101; A61L 33/0011 20130101;
A61L 31/08 20130101; A61L 27/50 20130101; A61L 2420/08 20130101;
A61L 2400/18 20130101; A61L 27/18 20130101; A61L 29/08 20130101;
A61L 27/34 20130101; A61L 31/10 20130101; A61L 27/18 20130101; A61F
2/06 20130101; A61F 2/0077 20130101; C08L 67/04 20130101; A61L
2420/06 20130101 |
Class at
Publication: |
623/001.44 ;
604/006.16; 623/011.11; 623/002.42 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. An implantable device comprising: at least one first degradable
layer providing at least one surface of the implantable device for
contacting bodily fluid or tissue and disposed about a central
core; and at least one second degradable layer between said first
degradable layer and the central core, wherein said first
degradable layer has a first degradation rate and said second
degradable layer has a second degradation rate such that said at
least one first degradable layer degrades more rapidly then said at
least one second degradable layer on contact with bodily fluid or
tissue.
2. The implantable device of claim 1, wherein the first degradable
layer comprises a different material than the second degradable
layer.
3. The implantable device of claim 1, wherein the second degradable
layer comprises PLA and the first degradable layer comprises
PLGA.
4. The implantable device of claim 1, wherein the first degradable
layer comprises a polymer selected from the group consisting of
PLGA 80/20, PLGA 75/25, and PLGA 53/47.
5. The implantable device of claim 1, further comprising: at least
one third degradable layer between the at least one second
degradable layer and the central core and having a third
degradation rate slower than the second degradation rate; and at
least one fourth degradable layer between the at least one third
degradable layer and the central core and having a fourth
degradation rate slower than the third degradation rate.
6. The implantable device of claim 5, wherein the first degradable
layer comprises PLGA 53/47, the second degradable layer comprises
PLGA 75/25, the third degradable layer comprises PLGA 80/20, and
the fourth degradable layer comprises PLA.
7. The implantable device of claim 1, wherein the implantable
device is selected from the group consisting of a stent, a graft, a
conduit, and a valve or dialysis tubing.
8. A method of reducing thrombogenicity of an implantable device
having at least one surface for contacting bodily fluid or tissue,
comprising: providing at least one first degradable layer which
provides said at least one surface and which is disposed about a
central core, and at least one second degradable layer between said
first degradable layer and the central core, wherein said first
degradable layer has a first degradation rate and said second
degradable layer has a second degradation rate such that said at
least one first degradable layer degrades more rapidly than said at
least one second degradable layer on contact with bodily fluid or
tissue.
9. The method of claim 8, wherein the implantable device is
selected from the group consisting of a stent, a graft, a conduit,
a valve, and dialysis tubing.
10. The method of claim 8, wherein providing comprises providing
the first degradable layer having a different material than the
second degradable layer.
11. The method of claim 8, wherein providing comprises providing
the first degradable layer made from a polymer selected from the
group consisting of PGA, PLA and PGLA.
12. The method of claim 8, wherein providing comprises providing
the first degradable layer made from PLA and the second degradable
layer made from PLGA.
13. The method of claim 8, wherein providing comprises providing
the second material made from a polymer selected from the group
consisting of PLGA 80/20, PLGA 75/25, and PLGA 53/47.
14. The method of claim 8, wherein the device further comprises: at
least one third degradable layer between the at least one second
degradable layer and the central core and having a third
degradation rate slower than the second degradation rate; and at
least one fourth degradable layer between the at least one third
degradable layer and the central core and having a fourth
degradation rate slower than the third degradation rate.
15. The method of claim 14, wherein the first degradable layer
comprises PLDA 53/47, the second degradable layer comprises PLGA
75/25, the third degradable layer comprises PLGA 80/20 and the
fourth degradable layer comprises PLA.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application Ser. No. 60/808,558 filed May 26,
2006, which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to implantable
devices, such as implantable medical devices, and methods for the
manufacture thereof. The invention also relates to methods for
enhancing and promoting endothelialization and for minimizing
thrombus formation on the surface of the implantable device.
BACKGROUND OF THE INVENTION
[0003] In recent years there has been growing interest in the use
of artificial materials, particularly materials formed from
polymers, for use in implantable devices that come into contact
with bodily tissues or fluids particularly blood. Some examples of
such devices are artificial heart valves, stents and vascular
prosthesis. Progress in this area has, however, been hampered
somewhat by the thrombogenicity of many polymer materials.
Reference is made to M. Szycher, J. Biomat Appln (1998) 12:321 in
that regard.
[0004] Efforts to overcome the problems associated with
thrombogenicity of polymer materials used in the production of
implantable devices have not met with a great deal of success to
date. Some examples of approaches that have bee attempted include
heparinization (S. W. Kim, C. D. Ebert, J. Y. Lin, J. C. McRea Am
Soc Artif Internal Organs (1983) 6:76), physical modification of
the surface (K. Webb, W. Hlady, P. A Tresco, J. Biomed Mat Res
(1998) 41: 421-430; E. W. Merrill, Ann NY Acad Sci (1977) 6:
283-290) and increasing surface hydrophilicity (S. J. Sofia, E. W.
Merrill, in "Polyethylene Glycol; Chemistry and Biological
Applications", J. M. Harris and S. Zalipsky (eds.), American
Chemical Society (1997) Ch. 22). Although these methods have met
with some commercial viability, they are mainly useful for
short-term applications, such as in catheter or in dialysis tubing.
This is because many of the chemical and physical modifications of
the device surfaces have limited shelf-life, both ex vivo and in
vivo. Moreover, the methods involved in the production of
implantable devices using these approaches are both elaborate and
intricate.
[0005] Attempts have also been made to minimize thrombus formation
by promoting endothelialization of the surface of an implantable
device that contacts bodily fluids or tissues in use as described,
for example, in U.S. Pat. No. 5,744,515, which relates to
modification of a porous material with adhesion molecules, and U.S.
Pat. No. 6,379,383, which relates to deposition of the material
used to form the device so as to control surface
heterogenities.
SUMMARY OF THE INVENTION
[0006] Thrombus formation is a very complex process involving
inter-dependent interactions between a surface of an implantable
device, platelets and coagulation proteins. The present invention
addresses the problem of thrombosis by endothelialization of a
bodily fluid or tissue-contacting, particularly blood-contacting,
surface to render that surface substantially non-thrombogenic. The
invention also addresses the problem of thrombosis by providing an
eroding layer on the surface that results in the removal of any
thrombus formation as the layer erodes.
[0007] According to one aspect of the invention, there is provided
an implantable device having at least one surface for contacting
bodily fluid or tissue, said at least one surface comprising a
plurality of nano-craters thereon that enhance or promote
endothelialization of said at last one surface.
[0008] According to one aspect of the invention, there is provided
an implantable device having at least one first degradable layer
providing at least one surface of the implantable device for
contacting bodily fluid or tissue and disposed about a central
core, and at least one second degradable layer between said first
degradable layer and the central core, wherein said first
degradable layer has a first degradation rate and said second
degradable layer has a second degradation rate such that said at
least one first degradable layer degrades more rapidly than said at
least one second degradable layer on contact with bodily fluid or
tissue.
[0009] The material of the implantable device is not particularly
limited. Furthermore, the nano-craters may be formed in the
material that constitutes the body of the implantable device, or
may be formed in a layer that is applied to a support substrate
forming the implantable device. Generally, the nano-craters will be
formed in a surface layer of suitable biocompatible material
applied to a support structure for the implantable device. The
options for the biocompatible material forming the outer layer of
the implantable device are generally known and are discussed
hereafter.
[0010] The form of the implantable device is similarly not
particularly limited. This may include any device that is intended
to come into contact with bodily fluids or tissues, be that during
in vivo applications or in vitro applications. Examples of
particular devices will be provided hereafter.
[0011] According to further aspect of the invention, there is
provided a method of Manufacturing an implantable device having at
least one surface for contacting bodily fluid or tissue comprising:
providing on said at least one surface a plurality of nano-craters
that enhance or promote endothelialization of said at least one
surface.
[0012] According to a further aspect of the invention, there is
provided a method of reducing thrombogenicity of an implantable
device having at least one surface for contacting bodily fluid or
tissue, or promoting or enhancing endothelialization of an
implantable device having at least one surface for contacting
bodily fluid or tissue, comprising: providing on said at least one
surface a plurality of nano-craters that enhance or promote
endothelialization of said at least one surface.
[0013] According to another aspect of the invention, there is
provided a method of manufacturing an implantable device having at
least one surface for contacting bodily fluid or tissue,
comprising: providing at least one first degradable layer which
provides said at least one surface and which is disposed about a
central core, and at least one second degradable layer between said
first degradable layer and the central core, wherein said first
degradable layer has a first degradation rate and second degradable
layer has a second degradation rate such that said at least one
first degradable layer degrades more rapidly than said at least one
second degradable layer on contact with bodily fluid or tissue.
[0014] According to still another aspect of the invention, there is
provided a method of reducing thrombogenicity of an implantable
device having at least one surface for contacting bodily fluid or
tissue, comprising: providing at least one first degradable layer
which provides said at least one surface and which is disposed
about a central core, and at least one second degradable layer
between said first degradable layer and the central core, wherein
said first degradable layer has a first degradation rate and said
second degradable layer has a second degradation rate such that
said at least one first degradable layer degrades more rapidly than
said at least one second degradable layer on contact with bodily
fluid or tissue.
[0015] Other aspects and features of the present invention will
become apparent to those of ordinary skill in the art upon review
of the following description of specific embodiments of the
invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In the figures, which illustrate, by way of example only,
embodiments of the present invention,
[0017] FIG. 1 is a schematic representation of an implantable
device having nano-craters on the surface of the device; and
[0018] FIG. 2 is a Schematic diagram of a process to form
nano-craters in a surface using a mask and etching techniques;
[0019] FIG. 3 is a schematic representation of an implantable
device having two degradable layers.
[0020] FIG. 4 illustrates some of the results of the number of
cells correlated to pore size in a PLLA polymer.
[0021] FIG. 5 also illustrates some of the results of the number of
cells correlated to pore size in a PLGA polymer sample.
[0022] FIG. 6 illustrates results correlating inter-pore distance
to cell attachment and growth of the endothelial cells.
DETAILED DESCRIPTION OF THE INVENTION
[0023] When a bodily fluids-contacting or tissue-contacting,
particularly blood-contacting, surface is coated with endothelial
cells, it is rendered substantially non-thrombogenic. Thus, in one
aspect, the reduced thrombogenicity of an implantable device is
achieved by enhancing and/or promoting endothelialization of the
surface of the implantable device that contacts bodily fluid or
tissue.
[0024] This aspect of the invention is based on the surprising
discovery that the inclusion of nano-craters on a surface of an
implantable device that is intended to come into contact with
bodily fluids or tissues, such as blood, advantageously improves
endothelial cell attachment to the surface. The inclusion of the
nano-craters therefore assists in the propagation of endothelial
cells on the surface of the device. It is believed that the
improved attachment and propagation of endothelial cells on the
surface is a result of the nano-craters on the surface acting as
foci for endothelial cell attachment. This aspect of the invention
is particularly suited for manufacture of implantable devices that
are intended to be in long-term contact with bodily fluids or
tissues, particularly in long-term contact with blood.
[0025] In another aspect, the reduced thrombogenicity is achieved
by providing a surface layer that degrades in a controlled fashion,
such that any thrombus that is formed at the surface is removed as
the surface layer degrades. This aspect of the invention is based
on the discovery that by providing the surface with layers having
different degradation rates, it is possible to remove any thrombus
formed on the surface in a controlled fashion, by degradation of
each successive layer. This aspect of the invention is particularly
suited for manufacture of implantable devices that are intended to
be in short-term contact with bodily fluids or tissues,
particularly blood.
[0026] The implantable device described herein may be any device
that would benefit from the reduced thrombogenicity of a surface,
including by enhancement of the endothelialization of a surface or
by degradation of surface that comes in contact with bodily fluid
or tissue, as described below, so as to reduce or remove thrombus
formation on such a surface, particularly where such a surface is a
blood-contacting surface, when the device is in use.
[0027] As used herein, the term "implantable device", which may
also be referred to as a "device" or a "medical device", refers to
any device having at least one surface that comes in contact with
bodily tissue or fluid, including blood, and includes a device for
implanting in a subject's body, permanently or temporarily,
long-term or short-term. The term, as used herein, also refers to
any device that forms a part of an article.
[0028] It is envisaged that the device is useful not only for in
vivo applications, but also in vitro applications. As such, the
device is not particularly limited, but should be considered to
include any device that is intended for contact with bodily fluids
or tissues, particularly blood, including conduits, grafts, valves,
dialysis tubing and stents. As used herein the term "bodily fluids
or tissues" includes biologically derived fluids and tissues as
well as synthetic substitutes, for example artificial blood.
[0029] As used herein, the term "endothelialization" refers to the
growth and/or proliferation of endothelial cells on a surface, such
as the blood-contacting surface, or an implantable device.
Promoting or enhancing endothelialization of a surface refers to
promoting, enhancing, facilitation or increasing the attachment of,
and growth of, endothelial cells on the surface.
[0030] As would be appreciated by a skilled person, the surface of
a device for implantation into a subject is preferably
biocompatible. The term "biocompatible" means that a substance is
minimally toxic or irritating to biological tissue, such as to be
sufficiently tolerated in the body without adverse effect. The
surface may be formed of a material, which is different from the
material that forms the surface and which is used as a support.
Alternatively, the device and surface may be formed of the same
material.
[0031] Suitable materials for forming the surface include biostable
polymers, for example, polyethylene, polyurethane, polyolefin, or
polyethylene terephthalate and degradable polymers, including
degradable by chemical means or by exposure to radiation, for
example, poly-lactide (PLA) including poly-L-lactide (PLLA),
poly-glycolide (P GA), poly(lactide-co-glycolide) (PLGA) or
polycaprolactone. In certain other embodiments, the degradable
polymer may be biodegradable, meaning that the substance will
readily degrade in an environment that is, or that is equivalent
to, the body of a subject, for example when in contact with bodily
fluid or tissue.
[0032] Other suitable materials that can be used to form an
implantable device, or to provide the surface of an implantable
device, are generally known in the art and examples of such
materials are outlined in U.S. Pat. No. 5,744,515, which is herein
incorporated by reference. For example, preferred materials include
synthetic polymers, including oligomers, homopolymers, and
copolymers resulting from either addition or condensation
polymerization. Examples of suitable addition polymers include, but
are not limited to, acrylics such as those polymerized from methyl
cerylate, methyl methacrylate, acrylic acid, methacrylic acid,
acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate,
glyceryl scrylate, glyceryl methacrylate, methacrylamide and
methacrylamide; vinyls such as styrene, vinyl chloride, binaly
pyrrolidone, polyvinyl alcohol, and vinyls acetate; polymers formed
of ethylene, propylene, and tetrafluoroethylene. Examples of
condensation polymers include, but are not limited to, nylons such
as polycaprolactam, polylauryl lactam, polyhexamethylene adipamide,
and polyhexamethylene dodecanediamide, and also polyurethanes,
polycarbonates, polyamides, polysulfones, poly(ethylene
terephthalate), polylactic acid, polyglycolic acid,
polydimethylsiloxanes, and polyetherketones.
[0033] Other suitable materials include metals and ceramics. The
materials include, but are not limited to, nickel, titanium,
nickel-titanium alloys such as Nitinol, stainless steel, cobalt and
chromium. The ceramics include, but are not limited to, silicon
nitride, silicon carbide, zirconia, and alumina, as well as glass
and silica, ePTFE (Expanded polytetrafluoroethylene) is a preferred
substrate material for use in fabricating implantable devices of
the present invention, and particularly for fabricating vascular
grafts. Suitable ePTFE is available in the form of vascular grafts
from such sources as IMPRA, Inc., Tempe, Ariz. Commercially
available grafts are constructed of ePTFE and supplied in sterile
form in a variety of configurations, including straight, tapered
and stepped configurations.
[0034] Referring to FIG. 1, in the depicted embodiment, device 100
is stent, with an exterior surface 102a and an interior surface
102b which lines the lumen of the stent, both of which have reduced
thrombogenicity meaning that they have a reduced tendency to
promote, induce or facilitate formation of thrombi when in contact
with bodily fluid or tissue. In the case of a coronary stent, since
surface 102b contacts blood, including platelets, it is
particularly important that surface 102b be rendered less
thrombogenic, as described herein.
[0035] Device 100, in one particular variation, may comprise a
polymeric stent fabricated as disclosed in U.S. patent application
Ser. No. 10/867,617 filed Jun. 15, 2004 (U.S. Pat. Pub.
2005/0021131 A1), which is incorporated herein by reference in its
entirety. The stent, as shown and described, may comprise a polymer
that is at least partially amorphous and which undergoes a
transition from a pliable, elastic state at a first higher
temperature to a brittle glass-like state at a second lower
temperature as it transitions through a particular glass transition
temperature. This particular stent may be comprised of at least a
first layer and a second layer where the first layer includes a
first polymer that is at least partially amorphous and a second
layer that is also at least partially amorphous. The stent may be
formed to have a first shape at a relatively lower temperature and
a second shape at a relatively higher temperature. The inner and/or
outer layer of the stent 100 may be processed to have nano-crater
104 as described herein.
[0036] A substantially uniform layer of nano-craters 104 are
distributed on surface 102a and 102b, meaning that nano-craters 104
of substantially similar depth are distributed on the surfaces 102a
and 102b to form a discernible layer having such nano-craters. It
has advantageously been found that the provision of such
nano-craters 104 enhances endothelialization of surface 102a and
102b, resulting in reduced thrombogenicity. The stent 100 is
suitable for long-term implantation in the body of a subject.
[0037] As used herein, the term "nano-crater" means indentations or
depressions provided on a surface. Generally the indentations are
on the nanometer scale. In different embodiments, the nano-craters
have an average diameter of between about 30 nm and about 150
nm.
[0038] The stent 100 has nano-craters 104 sufficiently distributed
over surfaces 102a and 102b to promote or enhance
endothelialization, preferably over the entirety of surface 102a
and 102b. The nano-craters 104 may be regularly or irregularly
distributed over surfaces 102a and 102b. In some embodiments,
adjacent craters may be spaced about 200 nm or greater apart.
[0039] Such nano-craters 104 may be suitably shaped, having a
regular or irregular shape, provide that endothelialization of the
surfaces 102a and 102b having the nano-craters 104 is enhanced
and/or promoted. For example, the nano-craters 104 may be
hemi-spherical, hemi-cylindrical or elliptical.
[0040] The size and shape of the nano-craters 104 can be controlled
to provide a unique surface morphology. By varying this surface
morphology, the range of sizes that selectively promote endothelial
cell attachment while not being reception to platelet attachment,
can be readily ascertained.
[0041] Optionally, surfaces 102a and 102b of the stent 100 can be
chemically modified so as to further enhance or promote
endothelialization, for example when implanted in a subject's
body.
[0042] By way of background, it is noted that there are two ways by
which an implanted device or surface can be covered with
endothelial cells. In the first, called the transmural or capillary
endothelialization, endothelial cells migrate into the device from
tissue that is external to (usually above or below) the implanted
device. For this sort of endothelialization to occur, the device
itself must be sufficiently porous to permit the endothelial cells
to migrate into it. A coronary stent such as the Palmaz stent (U.S.
Pat. No. 6,379,383) is an example of such a device. This type of
endothelialization may be achieved by coating an implantable device
with a radiation-sensitive bioerodible polymer followed by
irradiation with an electron beam to generate the nano-craters, as
it set out below.
[0043] The second method of endothelialization involves migration
of endothelial cells longitudinally into the device (e.g., in the
lumen of a stent implanted in a blood vessel) from tissue adjacent
to the device. In this case, porosity of the implantable device is
not required, as endothelial cell attachment occurs from within a
lumen or cavity of the device. However, the number of endothelial
cells that are capable of this type of attachment is lower than
those that can be achieved by transmural endothelialization.
[0044] Hence, it is envisaged that while the nano-cratered surfaces
will enhance selective endothelial cell attachment on non-porous
devices, the production and attachment of these endothelial cells
in vivo may be enhanced using certain growth-stimulating molecules
and adhesion-promoting molecules.
[0045] As used herein, the term "growth-stimulating molecule"
refers to a molecule that stimulates or induces the
differentiation, growth and proliferation of endothelial cells.
Growth-stimulating molecules include peptides, proteins and
glycoproteins, including hormones, capable of inducing an
endothelial cell to grow and divide.
[0046] As used herein, the term "adhesion-promoting molecule"
refers to a molecule that promotes or encourages adhesion or
attachment of an endothelial cell to a surface. Adhesion-promoting
molecules include peptides, proteins and glycoproteins capable of
binding a cell to a substrate or to an adjacent cell.
[0047] As such, according to certain embodiments, surfaces 102a and
102b of the stent 100 include growth-stimulating molecules and/or
adhesion-promoting molecules dispersed therein, which facilitate
enhanced production of endothelial cells and their attachment to
the nano-cratered surfaces 102a and 102b.
[0048] Suitable growth-stimulating molecules include granulocyte
colony stimulating factor (gCSF), platelet-derived endothelial cell
growth factor (PD-ECGF), fibroblast-derived endothelial cell growth
factor alpha, endothelial cell growth factor beta, endothelial cell
growth factor 2a and endothelial call growth factor 2b.
[0049] Suitable adhesion molecules are described in U.S. Pat. No.
5,774,515, which is herein incorporated by references. They are
typically large, naturally occurring proteins or carbohydrates,
with molecular weights above 100,000 daltons. In vivo, adhesion
molecules are typically able to bind to specific cell surface
receptors, and mechanically attached cells to the substrate or to
adjacent cells. In addition to promoting cell attachment, suitable
adhesion molecules can promote other cell responses including cell
migration and cell differentiation (which in turn can include the
formation of capillary tubes by endothelial cells).
[0050] Preferred adhesion molecules include substrate adhesion
molecules (SAM's) such as the proteins laminin, fibronectin,
collagen, vitronectin, and tenascin, and adhesion peptides or
functional synthetic analogs derived from SAM's. Other suitable
adhesion molecules include cell-to-cell adhesion molecules (CAM's)
such as N-cadherin and P-cadherin.
[0051] Parent (i.e., native) adhesion proteins typically have one
or more active peptide domains that bind to cell surface receptors
and which domains produce the cell attachment, migration, and
differentiation effects of the parent adhesion proteins. These
domains consist of specific amino acid sequences, several of which
have been synthesized and reported to promote the adhesion of
endothelial cells. These domains and functional analogs of these
domains are termed "adhesion peptides". In different embodiments,
adhesion molecules are adhesion peptides and desirably, adhesion
peptides have about 3 to about 30 amino acid residues in their
amino acid sequences.
[0052] Adhesion peptides from fibronectin include, but are not
limited to, RGD (arg-gly-asp) [SEQ ID NO.:1], REDV
(arg-glu-asp-val) [SEQ ID NO.:2], and C/H--V (WQPPRARI or
trp-gln-pro-pro-arg-ala-arg-ile) [SEQ ID NO.:3]. Adhesion peptides
from laminin include, but are not limited to, YIGSR
(tyr-ile-gly-ser-arg) [SEQ ID NO.:4] and SIKVAV
(ser-ile-lys-val-ala-val) [SEQ ID NO.:5] and F-9
(RYVVLPRPVCFEKGMNYTVR or
arg-tyr-val-val-leu-pro-arg-pro-val-cys-phe-glu-lys-gly-met-asn-tyr-thr-v-
al-arg) [SEQ ID NO.:6]. Adhesion peptides from type IV collagen
include, but are not limited to, Hep-III (GEFYFDLRLKGDK or
gly-glu-phe-tyr-phe-asp-leu-arg-leu-lys-gly-asp-lys) [SEQ ID
NO.:7].
[0053] While it is believed that nano-craters can selectively
promote endothelialization, it is possible that platelet attachment
to the nano-cratered surface may also be enhanced, leading to the
undesirable effect of clot formation. To minimize any such effect,
an anti-thrombotic molecule may be included on the surfaces 102a
and 102b of the stent 100 by any suitable means, in amounts
sufficient to minimize any platelet attachment during the process
of endothelialization.
[0054] As used herein, an "anti-thrombotic molecule" is a molecule
that reduces or prevents the formation of thrombi or clots on the
surface of an implantable device that contacts bodily fluid or
tissue, including when implanted in a subject's body.
Anti-thrombotic molecules include, without limitation, heparin, and
small molecules, such as benzamidine compounds, bicyclic pyrimidine
compounds, nitro compounds, thio acid compounds, and proteins and
peptides, including tissue-type plaminogen activator (t-PA),
protein S and protein C.
[0055] The implantable device may be formed entirely from a single
material and standard methods know in the art may be used to
fashion the device. For example, a mold may be used, and a liquid
polymer may be poured into the mold. This methods used will depend
on the particular material used and the particular medical device
that is to be formed.
[0056] In the case of the stent 100, the device may be formed by
rolling a sheet or film of material, or by winding a thin strip of
material into a helix, as is known in the art. In this way, the
nano-craters may be readily formed on each side of the sheet or
strip, as discussed below, prior to rolling or winding to form the
stent.
[0057] The implantable device may also be formed from a substrate
material and another material applied to the substrate material to
form a bodily fluid or tissue contracting surface by any suitable
means, for example, by spin-coating from a solution or suspension,
and the nano-craters are subsequently introduced into the surface.
This surface layer should have sufficient thickness to introduce
nano-craters having depth sufficient to enhance or promote
endothelialization.
[0058] Without intending to particularly limit the method by which
the nano-craters 104 are introduced to the surfaces 102a and 102b
of the stent 100, the following illustration of two possible
approaches for forming the nano-craters 104 are provided.
[0059] The nano-craters 104 may be introduced through controlled
degradation of the surfaces 102a and 102b of the stent 100, as
depicted in FIG. 2. According to this approach, discrete portions
of surfaces 102a and 102b, both of which are formed from a
degradable polymer, are etched using a degradative process, for
example, by exposing the polymer surface to electron beam radiation
or by treating with a chemical that will degrade the surface, for
example, strong alkali.
[0060] The technique of masking certain areas of the surface 102a
and 102b may be employed to define areas of degradation. A higher
density material, for example a silicon-based polymer or an acrylic
polymer, may be patterned over surface 102a and 102b in which the
nano-craters 104 are to be introduced, in a pattern that defines
the desired distribution and depth of the nano-craters. For
example, a focused ion beam may be used to form the desired pattern
in the mask material which is layered on the degradable surface
102a and 102b.
[0061] After exposure to the etching means that degrade the
unmasked regions of surface 102a and 102b, for example radiation or
chemical means, the surface material in the degraded areas may then
be leached out using water or solvent in which the degraded
portions of the surface material are soluble, but which will not
dissolve the non-degraded regions of the surface. The mask material
may then be subsequently removed, for example by dissolution in a
suitable solvent that dissolves the mask material but not the
polymer surface 102a and 102b.
[0062] To illustrate, in one example, PLGA, PLLA, PGA,
polycaprolactone or polyethylene may be employed to form the stent
100 or surfaces 102a and 102b of the stent 100, both of which
degrade in the dry state under electron-beam irradiation.
[0063] Thus, the degree of degradation may be controlled using the
well-known effects of attenuation with depths of an incident
electron beam. The depth of penetration of the incident electron
beam is generally proportional to the electron energy or the
accelerating voltage being used. This depth-dose distribution is
determined by the absorption mechanism of mono-energetic electron
beams having electron energy, eV, for a material of density p. The
higher the density of a given material, the grater the attenuation
effect on the electron beam. This attenuation effect will result in
a varying radiation dose across the thickness of the surface and
patterned higher density material, resulting in a variation of
molecular weight of the polymer across the thickness of the
surface.
[0064] An example of utilizing an incident electron beam for
patterning a surface of a polymeric sample may include use of
electron beam lithography, which is typically used in the
semiconductor electronics industry for patterning integrated
circuits and biosensors. Generally, a polymeric substrate having a
radiation-sensitive film or resist may be placed in a vacuum
chamber of a scanning-electron microscope and exposed by an
electron beam under digital control. Because the beam width may be
adjusted to range from a few picometers to several nanometers, an
etched pattern may be formed by the beam across the polymer
surface.
[0065] This variation of molecular weight across the thickness of
the surface will result in differing degradation rates at areas
masked with the higher density material than those not asked. When
these non-masked degraded sections are exposed to water (or another
suitable solvent), the leaching of low-molecular weight,
water-soluble oligomers from the water-insoluble not-degraded
regions of the surface will result in well-defined craters of known
lateral dimensions and depth. Thus, the size and shape of the
nano-craters 104 may be accurately controlled by this method, for
example by controlling the does of the radiation, and the density
of the material used to mask, as well as the pattern in which the
masking material is applied. This results in a unique surface
morphology, as discussed above, that selectively promotes
endothelial cell attachment, while not being receptive to platelet
attachment.
[0066] Alternatively, chemical means can be used with the
above-described masking method to produce nano-craters at the
surfaces 102a and 102b. For example, sodium hydroxide may be used
to dissolve PLA in regions that are not protected by the
alkali-resistant mask material, and the dissolved material may then
be rinsed away in water to form nano-craters 104. The mask may be
removed as described above.
[0067] The nano-craters 104 may alternatively be formed on the
surfaces 102a and 102b of the stent 100 by including nano-particles
that are leachable from the surfaces 102a and 102b.
[0068] A "nano-particle" is any granular or particulate material in
which the particulates have dimensions in the nano-metre range. The
nano-particles may be irregularly shaped, or may be of well-defined
size and shape, and may be leached from the surface leaving behind
nano-craters corresponding to the size and shape of the
nano-particles.
[0069] The nano-particles may be formed of any granular or
particulate material which can be embedded in the material used to
form surface 102a and 102b, which will not dissolve in or become
irreversibly bound to the material, and which can then be
subsequently leached from the material. For example, the
nano-particles can be formed from an inorganic salt, such as sodium
chloride, form gelatin, sugar, chitosan, or polyvinyl
pyrrolidone.
[0070] The nano-particles may be suspended in a dilute solution of
a polymer being used to form the implantable device or more
preferably, the surface of the implantable device which may then be
spin-coated onto the substrate of the device at a desired
thickness. The thickness will usually be in the micrometer range.
By casting a very thin layer containing the nano-particles, it is
possible to form a layer of polymer on an implantable device that
has nano-craters only at the surface.
[0071] Subsequently, these particles on the surface are either
leached out upon exposure to water or another suitable solvent, or
are eroded once the device comes in contact with bodily fluid or
tissue, for example when stent 100 is implanted, leaving behind a
surface with well defined nano-craters 104 of know dimensions.
Advantageously, the dimensions of the nano-craters 104 may be
varied by varying the size and shape of the nano-particles
dispersed in the polymer.
[0072] If the bodily fluid-contacting or tissue-contacting surface
of the implantable device is to contain adhesion-promoting
molecules, the nano-craters may be created, for example by
irradiation, and concurrently the surface may be modified to
release adhesion-promoting molecules and/or growth-stimulating
molecules, for example into a lumen or cavity of the implantable
device. The adhesion-promoting molecules and/or growth-stimulating
molecules may be passed to a polymer used to form the implantable
device or the surface of the implantable device prior to coating
the polymer on the substrate of the implantable device, and forming
nano-craters.
[0073] However, adhesion-promoting molecules and growth-stimulating
molecules may typically be proteins, which are sensitive
biomolecules that may be denatured by addition to a liquid polymer,
or when subjected to high intensity radiation. Thus, the
adhesion-promoting molecules and/or growth-stimulating molecules
may first be encapsulated in nano-particles of well-defined size
and shape as it known in the art, for example, as described in U.S.
Pat. No. 6,589,562 which is herein fully incorporated by reference.
The nano-particles may be leached out as discussed above, leaving
behind the nano-craters and simultaneously releasing the
adhesion-promoting molecules and/or growth-stimulating molecules,
for example into a lumen. The nano-particles, when containing
adhesion-promoting molecules and/or growth-stimulating molecules
for delivery to bodily fluid or tissue comprise a material that is
soluble in bodily fluid or tissue, for example, gelatin.
[0074] An anti-thrombotic molecule may be included in the
nano-crated surface of an implantable device in a similar
manner.
[0075] In an alternative embodiment, an implantable device with
reduced thrombogenicity is achieved by providing the device with a
surface that will degrade in a layered fashion when it contacts
bodily fluid or tissue. This embodiment is useful for applications
in which the device will be in contact with bodily fluid or tissue
for a relatively short period of time, for example, a catheter or
dialysis tubing that is in such contact for less than 24 hours.
Preferably, the layers degrade relatively quickly, so as to prevent
the formation of thrombi. This means that the degradation time for
a given layer upon contacting bodily fluid or tissue may be, for
example, between about 5 minutes and about 1 hour.
[0076] Thus, with reference to FIG. 3, in an illustrative
embodiment, a stent 100' has first degradable layers 106a and 106b
disposed about a central core 110, and which layers provide
surfaces 102'a and 102'b that comes into contact with bodily fluid
or tissue, including blood, and second degradable layers 108a and
108b, between layers 106a and 106b, respectively, and the central
core 110 of stent 100'. In the depicted embodiment, the stent 100'
has a first surface 102'a, which forms the exterior surface of the
stent and an interior surface 102'b which defines the lumen of the
stent.
[0077] The second degradable layers 108a and 108b are the inner
layer relative to the outer surfaces 102a' and 102'b, respectively,
and have a slower degradation rate than the first degradable layers
106a and 106b. Therefore, on contact with bodily fluid or tissue,
there is a peeling effect resulting from successive degradation of
first degradable layers 106a and 106b followed by degradation of
the second degradable layers 108a and 108b, and any thrombus
formation on surface 102'a and 102'b is removed as the layers
erode.
[0078] As mentioned above, the stent 100' may also be configured
and comprised in the manner as shown and described in U.S. patent
application Ser. No. 10/867,617, which has been incorporated above
by reference in its entirety. In one variation, the stent 100'
configured as disclosed in U.S. patent application Ser. No.
10/867,617 may comprise the central core 110 having the multiple
degradable layers disposed thereon. In other variations, it may be
possible to have the multiple degradable layers correspond to the
multiple layers comprising the stent structure.
[0079] The degradable layers 106a and 106b and 108a and 108b may be
formed from any biodegradable polymers that are generally known in
the art and described above and hereafter. For example, suitable
polymers include polylactic acid (PLA) and polyglycolic acid (PGA)
and copolymers of PLA and PGA (PLGA). These polymers may be
amorphous or semi-crystalline.
[0080] For example, in one embodiment layers 106a and 106b may
comprise PLA and the layers 108a and 108b may comprise PLGA,
particularly PLDA 80/20; PLGA 75/25; or PLGA 53/47, wherein the
numbers in the copolymer represent the percentage of PLA and PGA by
weight, respectively, included in the copolymer.
[0081] Preferably, the thickness of each layers 106a and 106b and
108a and 108b is in the micrometer or sub-micrometer range, for
example about 0.5 .mu.m to about 10 .mu.m.
[0082] In stent 100', the central core 110 may comprise a different
material than layers 106a, 106b, 108a and 108b, and the material
comprising the respective layers may be applied to central core
110. Alternatively, stent 100' may be formed of a single polymeric
material but having first and second degradable layers of different
average molecular weights of the polymer than found in central core
110, so as to form the discrete layer 106a, 106b, 108a, and 108b
about central core 110, as described below.
[0083] Without intending to particularly limit the method by which
the degradable layers 106a and 106b and 108a and 108b having
varying degradation rates are provided on the central core 110, the
following illustration of two possible approaches for forming the
degradable layers are provided.
[0084] Polymers having different degradation rates can be selected
and applied successively such that the layers 108a and 108b
comprise a polymer with a slower degradation rate. A polymer with a
faster degradation rate is selected for layers 106a and 106b such
that layer 106a and 106b degrade more rapidly and remove any
thrombus that may have formed on the surfaces 102'a and 102'b,
respectively.
[0085] A skilled person will appreciate that a layered device
having first and second degradable layers may comprise additional
degradable layers, and that the degradation rate of each degradable
layer increases with each successively inward layer such that the
outer-most layer degrades more quickly and that the inner-most
layer degrades most slowly. For example, in one particular
embodiment, a layered device may comprise the following layers
disposed about a central core: PLA; PLGA 80/20; PLGA 75/25; and
PLGA 53/47 in the given order with PLGA 53/47 being the outer-most
layer.
[0086] The suitable number of layers to be applied can be readily
determined and will depend on the degradation rates of the layers
and the particular type of device and its intended use, including
the intended duration of contact with bodily fluid or tissue.
[0087] Each of such layers may be spin-coated or solvent cast on to
a substrate material forming the implantable device, using a
solution or suspension containing, for example, about 10 to about
40% polymer by weight. As will be appreciated, other suitable means
of applying thin layers of a polymer to a substrate may also be
employed, for example, vapour deposition.
[0088] Alternatively, controlled degradation of a surface of an
implantable device may be effected, for example, using radiation
such as electron beam radiation. This method utilizes the
attenuation effect of electron beam radiation within an irradiated
material.
[0089] To illustrate, a single biodegradable material may be
applied to the surface of an implantable device as described above
and then irradiated to provide layers having different average
molecular weights of the biodegradable material, and therefore
varying degradation rates.
[0090] The suitable thickness of the material to be applied will
typically be in the micrometer range, for example about 1 micron to
about 20 microns, and can be readily determined. The desired
thickness will depend on the particular polymer used and on the
particular type of device and its intended use, including the
intended duration of contact with bodily fluid and tissue.
[0091] The mechanism of attenuation, as discussed above, can be
described as the loss of energy of the accelerating electrons. The
depth of penetration is proportional to the electron energy or the
accelerating voltage, and is attenuated in a manner proportional to
the density of the material being penetrated. This attenuation
effect will result in a varying radiation does through the depth of
the material as the beam is attenuated as it travels deeper into
the material, with the exterior surface receiving the strongest
does of radiation. This will result in a variation of molecular
weight in the surface material as a function of penetration depth
or material thickness. This variation of molecular weight through
the depth of the material will in turn result in different
degradation rates of the material coated on the device, thereby
providing the first degradable layer, which due to the higher
radiation does will have a lower molecular weight and will degrade
faster then the underlying second degradable layer. This will
result in a `layer peeling` effect across the thickness of the
polymer when in contact with bodily fluid or tissue.
[0092] The above-described devices can provide an implantable
device having reduced thrombogenicity on contact with bodily fluid
or tissue, for example when implanted, as compared to that
typically observed with implantable medical devices. Standard
surgical methods for implanting medical devices are known in the
art. The method of implantation and duration of implantation will
depend on the type of implantable device used, for example, a stent
or a valve, the purpose of implantation and the disorder or
condition that is to be treated with the implantable medical
device. Thus, a method for reducing thrombogenicity, and for
enhancing or promoting endothelialization, of an implantable device
having at least one surface for contacting bodily fluid or tissue
is contemplated.
[0093] The method comprises providing on the at least one surface a
plurality of nano-craters that enhance or promote
endothelialization of the at least one surface.
[0094] Alternatively the method comprises providing at least one
first degradable layer which provides said at least one surface and
which is disposed about a central core, and at least one second
degradable layer between said first degradable layer and the
central core, wherein said first degradable layer has a first
degradation rate and said second degradable layer has a second
degradation rate such that said at least one first degradable layer
degrades more rapidly then said at least one second degradable
layer so as to remove any thrombus that may be formed on said at
least one surface.
[0095] All documents referred to herein are fully incorporated by
reference.
[0096] Although various embodiments of the invention are disclosed
herein, many adaptations and modifications may be made within the
scope of the invention in accordance with the common general
knowledge of those skilled in this art. Such modifications include
the substitution of know equivalents for any aspect of the
invention in order to achieve the same result in substantially the
same way. All technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the
art of this invention, unless defined otherwise.
EXAMPLE 1
[0097] For the following examples, each polymer was first dissolved
in chloroform. Nano-sized salt particles were ground and sieved,
and then dispersed in the polymer solution with constant stirring
until the particles were visually uniformly dispersed. The polymer
concentration was chosen such that it had sufficiently high
viscosity to maintain a stable dispersion. The dispersion was then
cast as a film of required thickness using a coater. The film was
dried in an oven at 37.degree. C., and then left at room
temperature for several days in a dry environment. The dried films
were immersed in water for 14 days, with constant exchange of the
water. The salt nano-particles were thus leached out, and the
resulting film was dried again at 37.degree. C. and at room
temperature.
[0098] Control films were prepared as pure polymer films without
any surface modification.
[0099] PLLA and PLGL films having nano-craters in the surface were
obtained by leaching out incorporated nano-particles of NaCl, as
indicated in Table 1.
[0100] The best result were obtained with PLLA polymer surfaces
prepared by incorporation and leaching out of salt particles
(<90 Micron Diameter). Rapid endothelial cell attachment was
seen with these surfaces, with significant coverage of the surface
by cells.
[0101] Although early attachment of cells to the PLGA polymer film
was observed, the results obtained with PLGA did not result in
significant endothelialization of the polymer film. This is likely
due to the molecular weight of PLGA chosen, or the ratio of lactide
to glycolide in the copolymer, resulting in a polymer that degraded
under the conditions used to leach the salt particles, and confirms
that the degradation properties of the polymer and dissolution rate
of the leachable salt particle can affect the formation of
nano-craters. The resulting craters were therefore likely too large
and improperly formed to promote confluent growth and attachment of
the cells. This problem can be solved by varying the PLGA used to
select a more stable form of PLGA and to increase the rate of
leaching of salt particles, such that the PLGA is not degraded
during the leaching process. TABLE-US-00001 TABLE 1 Results of
Endothelialization of Nano-Cratered Surfaces. First endothrlial
Sample Surface Cell Seeding call Result at days Material
Preparation Treatment (cells/sq cm) attachment 4/5 Control PLLA
Polymer + Solvent NIL 20000 36 hours Day 5 PLLA approximately 20%
confluency Contold Polymer + Solvent NIL As Above 36 hours Day 5
PLGA PLGA approximately 80:20 40% confluency PLLA with Polymer +
Solvent Leached NaCl As Above 2 hours At Day 4 Nanocraters PLLA 99%
purity about 70% <90 Microns confluency 1% Seen. concentration
Leaching period 15 days. PLGA with Polymer + Solvent Leached NaCl
As Above 6 hours At Day 4 nanocraters PLGA 990% Purity about 5%
80:20 <90 microns confluency 1% Seen. concentration Leaching
period 15 days.
EXAMPLE 2
[0102] In another example of a method for modifying a surface of a
polymer for implantation within a patient body, porogen leaching of
surfaces may be utilized to yield a surface which enhances
endothelial cell growth over a defined range of surface features.
In this particular example, surface pores were created by filling
polymers such as Poly caprolactone (PCL), Poly L-lactide (PLLA),
Poly (lactide-co-glycolide), etc. (although any of the other
suitable polymers described herein may be utilized) with leaching
agents of sugar and gelatin.
[0103] The sugar and gelatin particles ranged in size from 20 to 90
microns in diameter (although particles as small as 5 microns may
also be utilized) where the average particle sizes typically ranged
from 20, 45, and 90 microns. The leaching agents were added in
concentrations ranging from 1 to 10% by weight in the polymer. More
particularly, the leaching agents were added in concentrations
ranging from 1%, 5%, and 10% by weight in the polymer.
[0104] The leaching agents were then leached out with water from
the polymer for a period of 10 to 12 days and the surface porosity
was characterized by a scanning electron microscope (SEM) for
crater dimensions and inter-crater spacing. With the physical
characteristics determined, the surfaces of the polymer were then
exposed to endothelial cells over an 11 day period, at the end of
which the cells attached to the surface were counted and correlated
to the surface features.
[0105] FIG. 4 illustrates some of the results of the number of
cells correlated to pore size in a PLLA polymer sample at day 9,
which is representative of the results. FIG. 5 also illustrates
some of the results of the number of cells correlated to pore size
in a PLGA polymer sample (specifically PLGA 80/20) also at day 9.
In both the PLLA and PLGA polymers, each sample was prepared
utilizing the methods described above. Generally, endothelial cell
growth appeared better on PLGA 80/20 samples than on PLLA samples.
Moreover, both gelatin and sugar pyrogens appear to act similarly
and regardless of the porogen used, cell growth appears inversely
dependent on pore size. However, gelatin appeared to be optimal for
use as a porogen in the size range of about 5 to 40 microns at
concentrations of about 5 to 10% in the starting solution. The PCL
samples, also prepared as described above, showed growth of
endothelial cells although the growth did not appear dependent on
pore size in the range studied.
[0106] Generally, endothelial cell attachment and proliferation is
higher at lower crater sizes (between about 5-10 microns) and
decreases with higher crater size up to about 90 microns; however,
compared to controls (no craters), all the samples showed enhanced
endothelial cell attachment.
[0107] By changing the concentration of the particles in the
polymer (prior to leaching), mentioned above as 1%, 5%, and 10%
concentrations, the inter-pore distances along the polymer surfaces
were varied from an average of about 50 microns to 250 microns. As
illustrated by the results in FIG. 6, an inter-pore distance
ranging from about 50 to 100 microns and more preferably between 50
to 80 microns appeared optimal for attachment and growth of the
endothelial cells.
[0108] Accordingly, endothelial cell growth appears to correlate
inversely to pore size on surfaces of PLLA and PLGA samples, but
not to PCL samples. As pore size is decreased (e.g., down to about
5 to 10 microns), endothelial cell growth is increased. However, at
all pore sizes, PCL showed good endothelial cell growth on its
surface.
EXAMPLE 3
[0109] As mentioned above, chemicals such as sodium hydroxide may
be used to dissolve PLA in regions unprotected by an
alkali-resistant mask material where the dissolved material may be
rinsed away in water to form nano-craters. In another example, the
polymer surface may be first irradiated prior to etching with the
sodium hydroxide to enhance the etching process.
[0110] In this example, samples of PLGA, PCL, and PLLA (other
suitable polymers described above may alternatively be utilized)
were first irradiated with an electron beam and then etched using
the sodium hydroxide, as described above, for a period of 16 hours
to create surface features. The average surface roughness of the
samples was measured using an atomic force microscope (AFM) and the
etched samples were then exposed to endothelial cells. Growth was
quantified over a period of 15 days and the irradiated and etched
samples were compared to control samples after 4 days, 8 days, and
15 days. Table 2 shows a comparison of the results for sample
roughness between the irradiated and control samples where the MTS
value is an indication of the number of active cells.
TABLE-US-00002 TABLE 2 Results of Comparison For Irradiated and
Control Samples With Respect to Sample Roughness and Cell Growth.
AFM Avg surface Static MTS Average MTS Average MTS Average
Roughness (Scan Contact Absorbance Absorbance Absorbance Size 50
.mu.m) Angle after 4 days after 8 days after 15 days PLGA Control
3.3 .+-. 1 73.2 .+-. 1 0.51 0.37 0.26 PLGA Modified 93 .+-. 3 57.4
.+-. 2 0.57 0.29 0.45 PLLA Control 646 .+-. 9 94.2 .+-. 2 0.40 0.29
0.40 PLLA Modified 333 .+-. 27 63.4 .+-. 1 0.51 0.17 0.27 PCL
Control 259 .+-. 20 80.2 .+-. 3 0.39 0.24 0.28 PCL Modified 390
.+-. 16 61.8 .+-. 1 0.53 0.38 0.39 *Modified = Ebeam with 2.5 Mrads
+ 16 hours 0.1N NaOH immersion
[0111] Generally, irradiating samples prior to etching with sodium
hydroxide gives surface features that are rougher than control
samples. Table 3 shows a comparison of the results for the
irradiated and control samples with respect to live cell growth and
total cell growth. TABLE-US-00003 TABLE 3 Results of Comparison For
Irradiated and Control Samples With Respect to Live Cell Growth and
Total Cell Growth. Hemocytometer Hemocytometer Hemocytometer
Hemocytometer Avg Hemocytometer Avg Hemocytometer Avg Avg Live
Cells Avg total Cells Avg Live Cells total Cells Count after Live
Cells Count after total Cells Count after Count after 4 day Count
after 4 day Count after 8 day 8 day 15 day 15 day PLGA Control 5400
9600 9300 15800 9400 22700 PLGA Modified 8800 12800 9700 17800
17800 31400 PLLA Control 5300 9000 3800 4900 13500 27700 PLLA
Modified 6500 8800 3300 4800 13600 27400 PCL Control 4400 9200 1530
3800 3060 12000 PCL Modified 4100 7600 9830 14200 5300 23400
*Modified = Ebeam with 2.5 Mrads + 16 hours 0.1N NaOH immersion
[0112] Generally, the surface-modified samples show enhanced
endothelial cell growth for PLGA and PCL samples except for PLLA
samples. The endothelial cell growth also appeared to correlate
well with overall surface roughness of PLGA and PCL samples where
endothelial cell growth increases as surface roughness
increases.
[0113] As can be understood by one skilled in the art, many
modifications to the exemplary embodiments described herein are
possible. The invention, rather, is intended to encompass all such
modification within its scope, as defined by the claims.
* * * * *