U.S. patent application number 11/206019 was filed with the patent office on 2005-12-29 for method of producing structures using centrifugal forces.
This patent application is currently assigned to matRegen Corp.. Invention is credited to Dalton, Paul D., Levesque, Stephane G., Shoichet, Molly S..
Application Number | 20050287320 11/206019 |
Document ID | / |
Family ID | 32867989 |
Filed Date | 2005-12-29 |
United States Patent
Application |
20050287320 |
Kind Code |
A1 |
Dalton, Paul D. ; et
al. |
December 29, 2005 |
Method of producing structures using centrifugal forces
Abstract
A variety of hollow structures with unique morphologies were
manufactured with a rotational spinning technique. Phase separation
of soluble solutions or emulsions was induced within a filled mold
as it was being rotated about one of its axis. The density
difference between phases results in sediment at the inner lumen of
the mold under centrifugal forces. After or during sedimentation,
gelation of the phase-separated particles fixes the hollow
structure morphology and the solvent remains in the center of the
mold. The solvent is removed from the mold resulting in a coating
or tube. By controlling the rotational speed and the formulation
chemistry, the tube dimensions and wall morphology can be
manipulated. This technique offers a new approach to the
manufacture of polymeric tubes. It requires small quantities of
starting material, permits multi-layering of tubes, is applicable
to diverse polymers and can result in highly diffusive hollow
structures while maintaining good mechanical strength.
Inventors: |
Dalton, Paul D.;
(Dusseldorf, DE) ; Shoichet, Molly S.; (Toronto,
CA) ; Levesque, Stephane G.; (Toronto, CA) |
Correspondence
Address: |
Ralph A. Dowell of DOWELL & DOWELL P.C.
2111 Eisenhower Ave.
Suite 406
Alexandria
VA
22314
US
|
Assignee: |
matRegen Corp.
Toronto
CA
|
Family ID: |
32867989 |
Appl. No.: |
11/206019 |
Filed: |
August 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11206019 |
Aug 18, 2005 |
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10365532 |
Feb 13, 2003 |
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10365532 |
Feb 13, 2003 |
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10169948 |
Jul 11, 2002 |
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6787090 |
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10169948 |
Jul 11, 2002 |
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PCT/CA01/00680 |
May 11, 2001 |
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60203910 |
May 12, 2000 |
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Current U.S.
Class: |
428/34.1 |
Current CPC
Class: |
B29C 41/003 20130101;
B29C 39/08 20130101; B29K 2105/04 20130101; A61K 9/0092 20130101;
B29C 41/50 20130101; B29C 39/006 20130101; B29K 2105/0014 20130101;
B29C 67/02 20130101; A61K 9/70 20130101; B29L 2031/753 20130101;
B29C 37/006 20130101; Y10T 428/13 20150115; A61K 9/1647 20130101;
B29C 41/042 20130101; Y10T 428/139 20150115; B29L 2023/00 20130101;
A61B 17/1128 20130101 |
Class at
Publication: |
428/034.1 |
International
Class: |
B32B 001/08 |
Claims
1-30. (canceled)
31. A product produced by a method comprising the steps of: filling
an interior of a mold with a mixture so that substantially all gas
bubbles are displaced therefrom, the mixture comprising at least
two components which can be phase separated by a phase separation
agent into at least two phases; rotating said mold containing said
mixture at an effective rotational velocity so that under rotation
at least one of the phases deposits onto an inner surface of the
mold; and forming said product by stabilizing said at least one of
the phases deposited onto the inner surface of the mold.
32. The product according to claim 31 including removing said
product from said mold.
33. The product according to claim 31 wherein said hollow mold is a
cylindrical tube so that said product is a tube.
34. The product according to claim 31 wherein of said at least two
components at least one is selected from the group consisting of
the group of monomers and macromers and the other is at least one
solvent, wherein said at least one of the phases that deposits onto
the inner surface includes at least one of the monomer and
macromer, and wherein the step of stabilizing said deposited phase
includes gelation of the at least one of the monomer and macromer
by polymerization thereof.
35. The product according to claim 34 wherein said phase separation
agent is selected from the group consisting of solution
immiscibility, polymer immiscibility, light, pH, initiation agents,
change in temperature, creation of a chemical product within the
mold, changes in cationic and/or anionic concentrations, electric
and magnetic fields.
36. The product according to claim 35 wherein said initiation agent
is selected from the group consisting of free radical initiators,
thermal and photo initiators, redox initiators, anionic, cationic
or ring-opening initiators.
37. The product according to claim 34 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
38. The product according to claim 34 wherein the product has a
wall morphology that includes a predominantly gel morphology with
porous channels running from a periphery to a lumenal side,
resulting in spotting on an outer wall surface.
39. The product according to claim 31 wherein said at least two
components includes at least one polymer dissolved in at least one
solvent, and wherein said mixture is composed of at least two
solutions, wherein said at least one of the phases that deposits on
the inner surface includes at least the polymer, and wherein the
step of stabilizing said deposited phase includes gelation
thereof.
40. The product according to claim 39 wherein said phase separation
agent is selected from the group consisting of solution
immiscibility, light, change in pH, change in temperature, creation
of a chemical product within the mold, changes in cationic and/or
anionic concentrations, electric and magnetic fields.
41. The product according to claim 39 wherein gelation is achieved
by exposure to an agent selected from the group consisting of
light, change in pH, change in temperature, creation of a chemical
product within the mold, changes in cationic and/or anionic
concentrations, electric and magnetic fields.
42. The product according to claim 39 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
43. The product according to claim 39 wherein the product has a
wall morphology that includes a predominantly gel morphology with
porous channels running from a periphery to a lumenal side,
resulting in spotting on an outer wall surface.
44. The product according to claim 31 wherein said product is a
multi-layered product produced by repeating steps a), b) and c), at
least once to produce a multi-layered product.
45. The product according to claim 34 wherein the wall structure is
used as a reservoir for the delivery of drugs, therapeutics, cells,
cell products, genes, viral vectors, proteins, peptides, hormones,
carbohydrates, growth factors, enzymes.
46. The product according to claim 39 wherein the wall structure is
used as a reservoir for the delivery of drugs, therapeutics, cells,
cell products, genes, viral vectors, proteins, peptides, hormones,
carbohydrates, growth factors, enzymes.
47. The product according to claim 39 wherein the solution contains
particles containing pre-selected constituents, and wherein the
product includes said particles are distributed either uniformly or
in a gradient within the wall structure of the product.
48. The product according to claim 39 wherein the particles are
microspheres or nanospheres and said pre-selected constituents
include enzymes, proteins, peptides, genes, vectors, growth
factors, hormones, nucleotides, carbohydrates, drugs, therapeutics,
or cells.
49. The product according to claim 39 wherein the cells include
neurons, stem cells, stem cell derived cells, olfactory ensheathing
cells, Schwann cells, astrocyte cells, microglia cells, or
oligodendrocyte cells, endothelial cells, epithelial cells,
fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone
marrow-derived cells, hematopoetic cells, glial cells, inflammatory
cells, and immune system cells.
50. The product according to claim 39 wherein the particles are
microspheres or nanospheres and said pre-selected constituents
include enzymes, proteins, peptides, genes, vectors, growth
factors, hormones, oligonucleotides, or cells.
51. The product according to claim 50 wherein the cells include
neurons, stem cells, stem cell derived cells, olfactory ensheathing
cells, Schwann cells, astrocyte cells, microglia cells, or
oligodendrocyte cells, endothelial cells, epithelial cells,
fibroblasts, keratinocytes, smooth muscle cells, hepatocytes, bone
marrow-derived cells, hematopoetic cells, glial cells, inflammatory
cells, and immune system cells.
52. The product according to claim 50 wherein the particles are
degradable particles thereby releasing said constituents over
time.
53-56. (canceled)
57. The product according to claim 31 wherein the process includes
a step of inserting an object into the mold to be coated with
wherein said product includes said object being coated with said at
least one of the phases and which is stabilized on said object.
58-59. (canceled)
60. The product produced in accordance with claim 31 for use as a
coronary artery bypass graft, vascular graft, artificial fallopian
tubes, a drainage implant for glaucoma, a drainage implant for the
lachrymal duct, artificial tissues such as intestines, ligaments,
tendons, nerve guidance channels, ureter and urethra replacements,
aural drainage tubes, abdominal/gastrointestinal structural
replacements, stents for aortic aneurysms, esophageal scaffolds,
composite catheters, shunts, delivery matrices, coatings applied to
pacemaker leads, implantable sensor wire leads, wires for
interventional cardiology, and biosensors.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of United States
utility patent application Ser. No. 10/169,948 filed on Jul. 11,
2002, which is a National Phase application claiming the benefit of
PCT/CA01/00680 filed May 11, 2001 published in English, which
further claims priority benefit from United States provisional
patent application 60/203,910 filed May 12, 2000.
FIELD OF INVENTION
[0002] This invention relates to a method of manufacturing
structures and particularly polymeric tubular structures and
coatings with complex and unique morphologies in the walls, and on
the inner and outer surfaces of the structures.
BACKGROUND OF THE INVENTION
[0003] Tubular structures and coatings have been prepared by a
number of techniques, each of which has limitations for each
application. For biomedical applications, a limitation is the
abundant material required to prepare structures of limited size
and shape, which can prove costly. For porous polymeric tubes, also
known as hollow fiber membranes (HFMs), tubes with wall thicknesses
on the order of hundreds of microns are prepared. There is no
suitable method to prepare concentric, long HFMs, with thin walls,
whether by dip-coating, spinning, or centrifugal casting, among
others. As will be described in more detail, the invention
comprises a process to prepare HFMs, coatings or any hollow
structure, with a broad range of wall and surface morphologies,
dimensions and shapes. Such wall morphologies allow HFMs to be
manufactured with considerably different transport properties while
maintaining similar mechanical properties.
[0004] HFMs are commonly prepared by phase inversion through an
annular die (or spinneret) where the solvent/non-solvent system
controls many of the resulting properties, such as morphology of
the wall structure. The dimensions are controlled by the spinneret,
which must be finely tuned for concentricity. While the spinning
technique has a proven record commercially, it requires abundant
material and requires a certain amount of art to prepare
reproducible HFMs.
[0005] Centrifugal casting is a process used to make a wide number
of structures, both tubular and non-concentric (U.S. Pat. Nos.
5,266,325; 5,292,515). For manufacturing tubular shapes, a
cylindrical mold is partially filled with a monomer, polymer melt,
or monomer solution, and with air present inside the mold, coats
the periphery of the mold under centrifugal action. The material
spun to the outer portion of the mold is then held in place using
temperature changes (cooling), polymerization or evaporation of the
solvent. For this process, two phases are present inside the mold
(gas and liquid) before rotation; phase separation is not necessary
for tubular formation. Wall morphologies are only attained by the
addition of a porogen (salt, ethylene glycol etc.) that is leached
out post-polymerization. Since a gas is required in the mold to
form a tube (compared to a rod), attaining small diameter tubes
with a small inner diameter on the micron scale cannot be achieved.
Surface tension between the liquid and the gas inside the mold
prevents miniaturization of the inner diameters for tens of
centimeter length tubes.
[0006] For dip-coating, tubes are formed around a mandrel that is
sequentially dipped in a polymer solution and non-solvent system,
thereby coating the mandrel with the polymer via a phase inversion
process. Alternately, the mandrel may be dipped in a polymer
solution and the solvent left to evaporate. By these methods, the
uniformity of the tube wall along the length of the tube is not
well controlled.
[0007] It would therefore be very advantageous to manufacture tubes
within a size regime, concentricity and with a multi-layering
capability that is not presently achievable with the aforementioned
methods. Furthermore, it would be desirable to have composite
structures that were manufactured within a size regime,
concentricity and multi-layering not presently available with the
aforementioned methods. For example, composite structures allow
soft tissue moduli to be matched with soft (low moduli) materials,
yet to have a design that provides strength and patency, which is
important to device utility.
[0008] Current coatings technologies have limitations in terms of
the uniformity of the coating, thickness of the coating and coating
porous materials. For example, dip-coating provides uneven coatings
and the coating infiltrates the porous material. Spray-coating
achieves a conformal coating that inherently coats the each
pore.
[0009] It would be desirable to provide a method of producing
tubular or non-tubular structures which can be used in a variety of
physiological or other applications which can be produced using a
wide variety of materials and which can include composites of
biological materials.
SUMMARY OF INVENTION
[0010] It is an object of the present invention to provide
structures, preferably tubular structures and coatings, comprising
polymers and/or a combination of synthetic and naturally occurring
polymers (both organic and inorganic), ceramics, metals and
biological cells, tissue, matrix, proteins, in a variety of shapes
including wires, fibers, particles, among others.
[0011] The present invention allows composite structures to be
produced with one or a combination of synthetic and naturally
occurring polymers (both organic and inorganic), ceramics, metals
and biological cells, tissue, matrix, proteins, in a variety of
shapes including wires, fibers, particles, among others.
[0012] In one aspect of the invention there is provided a process
of producing a product, comprising:
[0013] a) filling an interior of a mold with a mixture so that
substantially all gas bubbles are displaced therefrom, the mixture
comprising at least two components which can be phase separated by
a phase separation agent into at least two phases;
[0014] b) rotating said mold containing said mixture at an
effective rotational velocity so that under rotation at least one
of the phases deposits onto an inner surface of the mold; and
[0015] c) forming said product by stabilizing said at least one of
the phases deposited onto the inner surface of the mold.
[0016] In another aspect of the invention there is provided a
product produced by a method comprising the steps of:
[0017] filling an interior of a mold with a mixture so that
substantially all gas bubbles are displaced therefrom, the mixture
comprising at least two components which can be phase separated by
a phase separation agent into at least two phases;
[0018] rotating said mold containing said mixture at an effective
rotational velocity so that under rotation at least one of the
phases deposits onto an inner surface of the mold; and
[0019] forming said product by stabilizing said at least one of the
phases deposited onto the inner surface of the mold.
[0020] The product formed by this process may be removed from the
mold, or alternatively remain in the mold where the product and the
mold are used for various applications. The product may be a
polymeric material, in which case the mixture includes either
monomers or polymers or both.
[0021] The product may have a wall morphology that includes a
porous structure, a gel structure or overlapping regions of
porous/gel structure. The polymeric product may have a wall
morphology that includes a predominantly gel morphology with porous
channels running from a periphery to a lumenal side, resulting in
spotting on an outer wall surface.
[0022] The product may be a composite structure comprised of:
several polymers (synthetic, naturally-occurring, organic and
inorganic); polymers and metals; polymers and -ceramics; polymers
and particles (inorganic, cells, microspheres, nanospheres,
proteins, polysaccharides, glycosaminoglycans); polymers and fibers
(carbon, glass, polymeric, biological, etc.).
[0023] The polymeric product may be degradable and result in
soluble materials with exposure to specific conditions. The product
may be degradable by hydrolytic degradation, or by non-specific
(i.e. free radicals) or specific molecules, such as enzymes, which
may be entrapped within the polymeric product. The polymeric
product may degrade through breaking of crosslinks or the polymeric
backbone.
[0024] The polymeric product may be a multi-layered product
produced by repeating steps a), b) and c), at least once to produce
a multi-layered product. The polymeric product may contain
particulates within one or more of these steps; the position of
which is influenced by the density of said particulates. These
particulates may be a source of therapeutic drugs and may be
inorganic, or organic in nature, be degradable, or non-degradable.
These particulate may be living entities, or components of
entities, such as cells. The polymeric product may be used as a
reservoir for the delivery of enzymes, drugs, therapeutics, cells,
cell products, genes, viral vectors, proteins, peptides, hormones,
carbohydrates, growth factors or metals.
[0025] The polymeric product may contain microspheres containing
preselected constituents, and wherein the product includes said
microspheres distributed either uniformly or in a gradient within
the wall structure of the product.
[0026] The polymeric product may contain a predetermined structure,
which was inserted into the mold before said product fabrication,
such as a wire, stent or mesh. The polymeric product would coat the
predetermined structure, and may enhance the designed application
of the said structure by releasing therapeutic agents or reducing
the surface friction of said structure.
[0027] The polymeric product may be a coating on the inner wall of
another tubular structure.
[0028] BRIEF DESCRIPTION OF DRAWINGS The following is a
description, by way of example only, of the method of producing
tubes or coatings in accordance with the present invention,
reference being had to the accompanying drawings, in which:
[0029] FIG. 1a is a cross section of a cylindrical mold used to
manufacture tubes according to the present invention;
[0030] FIG. 1b is a cross section of an alternative embodiment of a
cylindrical mold;
[0031] FIG. 1c is a cross section of another alternative embodiment
of a cylindrical mold;
[0032] FIG. 1d is a cross section of another alternative embodiment
of a cylindrical mold;
[0033] FIG. 2a is a cross section of an embodiment of a cylindrical
mold with surface features along the length of the interior surface
of the mold;
[0034] FIG. 2b is a cross section of an alternative embodiment of a
cylindrical mold with surface features along the length of the
interior surface of the mold;
[0035] FIG. 2c is a cross section of another alternative embodiment
of a cylindrical mold with surface features along the length of the
interior surface of the mold;
[0036] FIG. 2d is a cross section of another alternative embodiment
of a cylindrical mold with surface features along the length of the
interior surface of the mold;
[0037] FIGS. 3a to 3c shows the steps of filling a cylindrical mold
with a liquid, FIG. 3a shows the puncturing needle (D) is used to
allow exit of air from the mold, while a syringe filled with
solution (E) is injected through a needle (C) that punctures the
lower injection port; FIG. 3b shows the filling of the mold with
the liquid solution, air exits needle (D) as the solution fills the
mold, and FIG. 3c shows the mold completely filled with solution
with the visible air all displaced;
[0038] FIG. 4a shows a method of rotating the cylindrical mold in
which the filled mold (A) is inserted into a drill chuck (F) and
rotation of the mold is commenced;
[0039] FIG. 4b shows another method of rotating the cylindrical
mold in which the filled mold (A) is attached to the two ends of a
lathe (G) and rotation of the mold is commenced;
[0040] FIG. 4c shows another method of rotating the cylindrical
mold in which the filled mold (A) is inserted into an adapter (H)
so it can be placed into a drill chuck (F) and rotation of the mold
is commenced and wherein O-rings (I) maintain position of mold (A)
inside the adapter (H);
[0041] FIG. 5a is a perspective view showing a mold (A) filled with
a liquid mixture (E) rotated about an axis at a suitable speed to
centrifuge the phase that will eventually separate;
[0042] FIG. 5b shows the mixture (E) of FIG. 5a beginning to
phase-separate during rotation, the dense phase (J) is centrifuged
to the periphery of the mold where it adopts the shape of the inner
surface of the mold (K);
[0043] FIG. 6 shows an environmental scanning electron microscope
(ESEM) micrograph of a gel-like coating on the inside of a glass
mold, produced with the mixture formulation of 1% HEMA, 99% water,
0.01% APS, 0.01% SMBS, 4000 rpm (also listed in Table 1 as example
1);
[0044] FIG. 7a shows a scanning electron microscope (SEM)
micrograph of the outer surface of a porous coating applied to the
inside of a glass mold, produced with the mixture formulation of
1.9% HEMA, 0.1% PEGMA, 98% water, 0.02% APS, 0.02% SMBS, 2700 rpm
(also listed in Table 1 as example 2);
[0045] FIG. 7b shows the inner surface of a porous coating applied
to the inside of a glass mold, produced with the mixture
formulation of 1.9% HEMA, 0.1% PEGMA, 98% water, 0.02% APS, 0.02%
SMBS, 2700 rpm (also listed in Table 1 as example 2);
[0046] FIG. 8a shows a porous plug (L) is included within the mold
of FIG. 5a prior to the injection of a liquid mixture; after phase
separation and gelation, the outer surface of the porous material
is coated with a phase-separated mixture without any affect on the
inner porosity;
[0047] FIG. 8b shows a SEM micrograph of a coating applied to a
porous poly(lactic-co-glycoloic acid [75:25] material that was
included within the mold of FIG. 8a prior to phase separation
produced with the mixture formulation of 7% HEMA, 93% water, 0.05%
APS, 0.04% SMBS, 4000 rpm (also listed in Table 1 as example
3).
[0048] FIG. 9a shows a SEM micrograph of a cross-section of the
wall of a cell-invasive, porous tube produced with the mixture
formulation of 15.75% HEMA, 2.25% MMA, 82% water, 0.02% EDMA, 0.08%
APS, 0.06% SMBS, 2700 rpm (also listed in Table 1 as example
4);
[0049] FIG. 9b is an ESEM micrograph of a cross-section of the wall
of a cell-invasive, porous tube produced with the mixture
formulation of 20% HEMA, 80% water, 0.02% EDMA, 0.1% APS, 0.04%
TEMED, 2700 rpm (also listed in Table 1 as example 5);
[0050] FIG. 10a shows an ESEM micrograph of a cross-section of the
wall of a predominantly gel-like tube produced with the mixture
formulation of 20% HEMA, 80% water, 0.02% EDMA, 0.1% APS, 0.06%
SMBS, 10 000 rpm (also listed in Table 1 as example 6);
[0051] FIG. 10b shows an ESEM micrograph of a cross-section of the
wall of a predominantly gel-like tube produced with the mixture
formulation of 23.25% HEMA, 1.75% MMA, 75% water, 0.025% EDMA,
0.125% APS, 0.1% SMBS, 2500 rpm (also listed in Table 1 as example
7);
[0052] FIG. 11a shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 28.3% HEMA, 58.3% water, 5.3% MMA, 8.3% ethylene
glycol, 0.125% APS, 0.1% SMBS, 2700 rpm (also listed in Table 1 as
example 8);
[0053] FIG. 11b is a SEM micrograph of a cross-section of the wall
of a mixed porous/gel-like tube, produced with the mixture
formulation of 27% HEMA, 3% MMA, 70% water, 0.1% APS, 0.075% SMBS,
4000 rpm (also listed in Table 1 as example 9);
[0054] FIG. 12a is an optical micrograph of a cross-section of the
wall of a mixed porous/gel-like tube with radial pores made in a
glass mold with the mixture formulation of 27% HEMA, 3% MMA, 70%
water, 0.15% APS, 0.12% SMBS, 2700 rpm (also listed in Table 1 as
example 10);
[0055] FIG. 12b shows an ESEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube with radial pores made in a
glass mold with the mixture formulation of 27% HEMA, 3% MMA, 70%
water, 0.15% APS, 0.12% SMBS, 2700 rpm (also listed in Table 1 as
example 10);
[0056] FIG. 12c shows an optical micrograph of the outer
longitudinal view of a mixed porous/gel-like tube with radial pores
made in a glass mold with the mixture formulation of 27% HEMA, 3%
MMA, 70% water, 0.15% APS, 0.12% SMBS, 2700 rpm (also listed in
Table 1 as example 10);
[0057] FIG. 12d shows an optical micrograph of of the outer
longitudinal view of a mixed porous/gel-like tube with no radial
pores made in a silane-treated glass mold with the mixture
formulation of 27% HEMA, 3% MMA, 70% water, 0.15% APS, 0.12% SMBS,
2700 rpm (also listed in Table 1 as example 10). The hollow
structure was synthesized with the same formulation as in 12a-c,
but spun in a silane-treated glass mold;
[0058] FIG. 13a shows an ESEM micrograph of a cross-section of a
predominantly gel-like wall with radial pores produced with the
mixture formulation of 20% HEMA, 80% water, 0.1% APS, 0.04% SMBS,
2700 rpm (also listed in Table 1 as example 11);
[0059] FIG. 13b shows a SEM micrograph of a cross-section of a
predominantly porous wall with radial fibers produced with the
mixture formulation of 2% HEMA, 98% water, 0.02% APS, 0.02% SMBS,
30 rpm (also listed in Table 1 as example 12);
[0060] FIG. 14 shows a SEM micrograph of a cross-section of the
wall of a multilayered tube produced with the mixture formulation
of (1.sup.st (outer) layer 1.8% HEMA, 0.2% PEGDMA, 98% water,
0.002% APS, 0.002% SMBS, 2700 rpm; 2.sup.nd (inner) layer 27% HEMA,
3% MMA, 70% water, 0.12% APS, 0.09% SMBS, 4000 rpm.) (also listed
in Table 1 as example 13);
[0061] FIG. 15 shows an ESEM micrograph of the inner lumen of a
tube with a smooth inner surface produced with the mixture
formulation of 20% HEMA, 80% water, 0.02% EDMA, 0.1% APS, 0.04%
SMBS, 2700 rpm (also listed in Table 1 as example 14);
[0062] FIG. 16a shows a SEM micrograph of the inner lumen of a tube
with a rough inner surface produced with the mixture formulation of
28.3% HEMA, 58.3% water, 5.3% MMA, 8.3% ethylene glycol, 0.15% APS,
0.12% SMBS, 2700 rpm (also listed in Table 1 as example 15);
[0063] FIG. 16b shows a SEM micrograph of a lateral cross-section
of the wall of the tube shown in FIG. 16a near the mold/polymer
interface showing a gel-like/porous wall morphology and a
dimpled/rough inner surface;
[0064] FIG. 17a shows a SEM micrograph of a lateral cross-section
of the wall of the tube near the mold/polymer interface showing a
gel-like/porous wall morphology and a unique cell-like surface
pattern on the inner surface produced with a formulation of 27.3%
HEMA, 2.7% MMA, 70% water, 0.03% EDMA, 0.12% APS, 0.09% SMBS, 4000
rpm (also listed in Table 1 as example 16);
[0065] FIG. 17b shows a SEM micrograph of cell-like surface
patterns on the inner surface of a tube shown in FIG. 17a;
[0066] FIG. 18 shows a SEM micrograph of very small diameter
micro-tubes manufactured with the mixture formulation of 22.5%
HEMA, 2.5% MMA, 75% water, 0.125% APS, 0.1% SMBS, 4000 rpm (also
listed in Table 1 as example 17), made in small diameter capillary
tubing with an internal diameter of 450 .mu.m;
[0067] FIG. 19 is an optical micrograph of a non-uniformly shaped
structure manufactured with the mixture formulation of 23.25%,
HEMA, 1.75% MMA, 75% water, 0.125% APS, 0.1% SMBS, 2500 rpm (also
listed in Table 1 as example 17) wherein the mold size does not
have a uniform internal diameter;
[0068] FIG. 20 is a diagram of a holding device to contain a
cylindrical mold so it is rotated about an axis other than its long
axis used to manufacture tubes according to the present
invention;
[0069] FIG. 21a is a diagram of a holding device with the centre of
gravity not on the axis of rotation so the molds, when inserted
into the holding device, have an axis of rotation that is parralell
to the axis of rotation of the rotating device;
[0070] FIG. 22 shows a SEM micrograph of degradable microspheres
situated in the outer lumen of a coating with the mixture
formulation of 1% polycaprolactone microspheres, 19.77% HEMA, 0.02%
EDMA, 79.04% water, 0.1% APS, 0.04% SMBS, 2500 rpm (also listed in
Table 2 as Example 25) wherein the microspheres were added to the
monomer formulation;
[0071] FIG. 23 shows a SEM micrograph of glass fibers situated in
the outer lumen of the coatings with the mixture formulation of 2%
glass fibers, 28.05% HEMA, 4.95% MMA, 67% water, 0.165% APS, 0.132%
SMBS, 2500 rpm (also listed in Table 2 as Example 29) wherein the
glass fibers were added to the monomer formulation;
[0072] FIG. 24a shows a SEM micrograph of a cross-section of the
wall of a multilayered tube containing degradable microspheres
situated near the inner lumen of the tube produced with the mixture
formulation of (1.sup.st (outer) layer 23% HEMA, 2% MMA, 75% water,
0.125% APS, 0.1% SMBS, 6000 rpm; 2.sup.nd (inner) layer 2% HEMA,
98% water, 1% polycaprolactone microspheres, 0.1% APS, 0.04% SMBS,
6000 rpm) (also listed in Table 2 as example 30) wherein the
microspheres were added to the monomer formulation;
[0073] FIG. 24b shows a SEM micrograph of the microspheres coated
in the inner surface;
[0074] FIG. 25(a) is an end view of an alternative embodiment of a
mold having a non-symmetrical cross section;
[0075] FIG. 25(b) is a cross section taken along the line BB of the
mold of FIG. 25(a);
[0076] FIG. 25(c) is a cross section taken along the line AA of the
mold of FIG. 25(a);
[0077] FIG. 26 shows a SEM micrograph of the lateral cross-section
of a tube produced with the mixture formulation of 25% HEMA, 72.5%
water, 2.5% MMA, 0.1% APS, 0.075% SMBS, 4000 rpm (also listed in
Table 2 as Example 32), with the monomer solution permitted to
phase separate before introduction into the mold;
[0078] FIG. 27 shows a SEM micrograph of the lateral cross-section
of a tube produced with the mixture formulation of 21.3% HEMA,
74.4% water, 2.1% MMA, 0.12% APS, 0.1% SMBS, 4000 rpm (also listed
in Table 2 as Example 33), with the monomer solution permitted to
phase separate inside the mold, but before rotation;
[0079] FIG. 28 shows a SEM micrograph of the length of a tube
produced with the mixture formulation of 22.5% HEMA, 75% water,
2.5% MMA, 0.2% APS, 0.15% SMBS, 6000 rpm (also listed in Table 2 as
Example 34), with the tube formed with a stent positioned inside
the mold, this may also be considered as a coating;
[0080] FIG. 29 shows a SEM micrograph of the length of a tube
produced with the mixture formulation of 28.05% HEMA, 67% water,
4.95% MMA, 0.165% APS, 0.132% SMBS, 2500 rpm (also listed in Table
2 as Example 35), with the tube formed with a coiled manganese wire
positioned inside the mold;
[0081] FIG. 30a shows a SEM micrograph of a cross-section of a
mixed porous/gel-like tube made in a cleaned glass mold with the
mixture formulation of 28.05% HEMA, 4.95% MMA, 67% water, 0.165%
APS, 0.162% SMBS, 2500 rpm (also listed in Table 2 as Example
36);
[0082] FIG. 30b shows a SEM micrograph of a cross-section of a
mixed porous/gel-like tube made in a mold with the mixture
formulation of 28.05% HEMA, 4.95% MMA, 67% water, 0.165% APS,
0.162% SMBS, 2500 rpm (also listed in Table 2 as Example 36), the
hollow structure was synthesized with the same formulation as in
FIG. 30a, but spun in a glass mold surface modified with
2-Methoxy(polyethyleneoxy) propyl trimethoxysilane;
[0083] FIG. 30c shows a SEM micrograph of a cross-section of a
mixed porous/gel-like tube made in a mold with the mixture
formulation of 28.05% HEMA, 4.95% MMA, 67% water, 0.165% APS,
0.162% SMBS, 2500 rpm (also listed in Table 2 as example 36), the
hollow structure was synthesized with the same formulation as in
FIG. 30a, but spun in a glass mold surface modified with
N-(2-aminoethyl)-3-aminopropyl trimethoxysilane;
[0084] FIG. 31 shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 10% dex-GMA, 40,000 g/mol, degree of substitution
10%, 10% PEG, 10 000 g/mol, 80% water, 0.14% APS, 0.018% SMBS, 6000
rpm (also listed in Table 1 as Example 38);
[0085] FIG. 32 shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 10% dex-GMA, 40,000 g/mol, degree of substitution
10%, 20% PEG, 10 000 g/mol, 70% water, 0.14% APS, 0.018% SMBS, 6000
rpm (also listed in Table 1 as Example 39);
[0086] FIG. 33 shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 20% dex-GMA, 40,000 g/mol, degree of substitution
10%, 10% PEG, 10 000 g/mol, 70% water, 0.28% APS, 0.035% SMBS, 6000
rpm (also listed in Table 1 as Example 40);
[0087] FIG. 34 shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 20% dex-GMA, 6,000 g/mol, degree of substitution
10%, 10% PEG, 10 000 g/mol, 70% water, 0.28% APS, 0.035% SMBS, 6000
rpm (also listed in Table 1 as Example 42); and
[0088] FIG. 35 shows an SEM micrograph of a cross-section of the
wall of a mixed porous/gel-like tube produced with the mixture
formulation of 30% dex-GMA, 6,000 g/mol, degree of substitution
10%, 10% PEG, 10 000 g/mol, 60% water, 0.42% APS, 0.053% SMBS, 6000
rpm (also listed in Table 1 as Example 44).
DETAILED DESCRIPTION OF THE INVENTION
[0089] The forces that generate the coatings and tubular structures
in this novel process are inertial forces associated with rotating
a mold. A mold is filled with a mixture containing at least two
liquid phase components (that are to be phase separated to produce
the final product) thereby displacing substantially all of the
visible gas bubbles (such as for example air) inside the mold. The
mold is then rotated at some pre-determined speed, for example by
being inserted into a rotating device, such as a drill chuck or
lathe. The process of completely filling the interior of the mold
with the liquid mixture is to ensure that all visible gas bubbles
are removed from the mold. However, it will be understood that
small or minute amounts of dissolved gases may still be present in
the liquid mixture. The presence of these minute amounts of gas may
be desirable in producing certain types of structures in that the
gas may be a reactive gas serving some purpose in the phase
separation process.
[0090] The phase separation process may begin immediately upon
producing the mixture with separation continuing during rotation of
the mold which would be the case when the phase separation is a
part of the mixture. Alternatively, the phase separation process
may be initiated after the mixture is formed by exposing the
mixture to the phase separation agent when desired. Phase
separation may be completed prior to rotation whereupon rotation
simply serves to move the one phase to the inner surface of the
mold or phase separation may be going on while the mold is
rotating.
[0091] The rotation of the mold will send one phase to the inner
surface of the mold, which will adopt the shape of the inner
surface of the mold and then be stabilized to produce the product.
Specifically, this separated phase must be stabilized at the
surface of the mold and generally the method of stabilization will
depend on the nature of the material in the separated phase. It
will be understood that the phase which is driven out to the inner
surface of the mold does not necessary adhere to the surface and in
fact adherence is generally undesirable particularly when the
product is to be removed from the mold after it is stabilized. To
this end, it may be desirable to treat the inner surface of the
mold to preferentially avoid adherence if this phase being
separated is typically prone to forming an adhering layer. The
materials from which the mold is produced may be selected to
minimize adherence depending on the material of the separated
phase. This would be for example when the product is to be removed
from the mold after stabilization, and/or when another object is
inserted into the mold onto which the phase is to be formed and
stabilized. Alternatively if the intent of the process is to
stabilize the product on the interior surface of the mold and use
both together instead of removing the product from the mold, it may
be desirable to enhance the adherence of the product on the
interior surface of the mold which may be accomplished by additives
added to the mixture itself which act to modify the surface or by
modifying the inner surface of the mold prior to deposition. In
this case the mold with product coated thereon is used in the
particular application at hand.
[0092] When the products are polymeric, the components of the
solution may contain monomers, macromers or polymers or any
combination of two or three of these components. The phase
separation process may result from changes in solubility as induced
by changes in polymer chain length, changes in temperature, newly
formed chemical reactants, changes in pH, exposure to light (UV,
visible, IR, laser), introduction of immiscible liquids,
polymer-polymer immiscibility in aqueous solutions, electric or
magnetic fields. The greater density of one of the phase-separated
phases results in that particular phase adopting the shape of the
inner surface of the mold. It will be understood that the phase
separation process may start upon mixture of the liquid components
or upon filling the mold with the mixture and the phase separation
process may continue during rotation of the mold or it may be
complete prior to rotation of the mold.
[0093] Gelation of the separated phase may be used to fix or
stabilize the morphology of the formed product and the solvent
phase remains in the center of the mold. For certain types of
materials, gelation of the deposited phase-separated phase can be
achieved using a number of methods, including but not restricted
to, continued polymerization in the separated phase (where the
deposited phase comprise monomers), cooling or heating of the mold,
creation of a chemical reaction product within the mold, changing
the pH of the phase-separated mixture and shining a certain
frequency or frequencies of light at the phase-separated mixture.
By controlling rotational speed, formulation chemistry, surface
chemistry and dimensions of the mold, the morphology, mechanical
and porosity properties, of the resulting product can be
manipulated. It will be understood that other methods of
stabilizing the denser phase may include more broadly
polymerization (of which gelation is but one example), changes in
temperature (either increase or decrease depending on the
composition of the denser phase), light, change in pH, creation of
a chemical product within the mold, changes in cationic and/or
anionic concentrations, electric and magnetic fields.
[0094] Hollow structures made using the invention were synthesized
in custom-built disposable molds, are shown in FIGS. 1a to 4c.
Referring to FIG. 1a, the mold, which may be a glass tubing A with
an inside diameter (ID) between 0.01 and 100 mm, was cut to a
desired length in the order of tens of centimeters. A septum B,
currently made of rubber, was slipped over each end of the glass
tube to serve as an injection port. Referring to FIGS. 3a to 3c,
the tubing A is filled using a needle D pushed through the upper
injection port to permit the exit of gas during liquid injection.
The desired mixture was injected via needle C through septum B at
the lower end of the mold, displacing all of the visible gas within
the mold. Withdrawing the needles D, then C results in a sealed,
liquid filled mold. For concentricity and a uniform hollow
structure along the length, the sealed mold was placed into the
chuck of a drill that had been mounted horizontally, using a spirit
level.
[0095] FIGS. 1b, 1c and 1d show alternative embodiments of
differently shaped molds that may be used to produce differently
shaped tubes. For example, FIG. 1d shows a mold with multiple
variations in diameter along the length of the mold used to
manufacture tubes with the same shape.
[0096] FIG. 2a shows a cylindrical mold containing inner surface
features such as rectangular fins on the inner surface used to
manufacture tubes with rectangular indentations in the outer wall
of the tubes. FIG. 2b shows a cylindrical mold containing inner
surface features such as convex spherical lumps on the inner
surface used to manufacture tubes with concave spherical
indentations in the outer wall. FIG. 2c shows a cylindrical mold
containing inner surface features such as pointed dimples on the
inner surface used to manufacture tubes with dimples in the outer
wall of the tube. FIG. 2d shows a cylindrical mold containing inner
surface features such as concave spherical lumps on the inner
surface used to manufacture tubes with these features embedded in
the wall of the resulting tubes. FIGS. 25a, b and c show a mold 60
that results in a non-concentric hollow structure that is
corrigated on one side, and smooth on the other, and contains
spherical dimples along the length of the structure. In all these
embodiments the surface features can be of a symmetrical or
non-symmetrical order, and different surface features can be used
in any combination.
[0097] The inner surface of the mold 60 can be modified using a
surface treatment, physical or chemical, that affects the
morphology of the wall of the hollow structure. For example, as the
separated phase can be liquid-like in nature, it can be induced to
bead, and form droplets on the inner surface, thereby influencing
the wall morphology. Similarly, the desired surface treatment can
allow the separated phase to spread across the inner surface, also
influencing the wall morphology. Similarly the surface treatment
can control the ratio of porous to gel-like material in the wall
morphology.
[0098] FIGS. 4a, 4b and 4c show various schemes for rotation of the
filled mold (A). In FIG. 4a the mold A is inserted into a drill
chuck (F) and rotation of mold is commenced. In FIG. 4b the filled
mold (A) is attached to the two ends of a lathe (G) and rotation of
the mold is commenced. In FIG. 4c the filled mold (A) is inserted
into an adapter (H) so it can be placed into a drill chuck (F) and
rotation of the mold is commenced. O-rings (I) maintain position of
mold (A) inside the adapter (H).
[0099] FIGS. 5a and 5b show the process of phase separation during
rotation of the mold. In FIG. 5a the mold (A) filled with a mixture
(E) is rotated about an axis at a suitable speed to centrifuge the
phase that will eventually separate. FIG. 5b shows the mixture
beginning to phase-separate during rotation. The dense phase (J) is
centrifuged to the periphery of the mold where it adopts the shape
of the mold (K).
[0100] It will be understood by those skilled in the art that the
present method is not restricted to cylindrical molds or producing
tubes therefrom. Any hollow structure may be used as a mold as long
as it can be rotated about some axis to utilize centrifugal
forces.
[0101] With the rotating mold containing the separated phases, the
more dense phase(s) are forced to the inner surface of the mold.
Phase separation may result in either liquid-liquid or viscoelastic
solid-liquid interfaces within the mold, while the mold is static
or rotating. Phase separation can be induced using a range of
different techniques and environmental changes. The addition of a
propagating radical to a monomer solution can induce phase
separation, as can changes in temperature, pH, exposure of the mold
to light, introduction of immiscible liquids, electric and magnetic
fields.
[0102] One or more of the phases will be forced to the periphery if
the densities of the phases are different. The phase-separated
particles then gel together, through covalent or physical bonding,
to form a three-dimensional network between the separated phase(s).
The gelation of particles may commence at a finite time after the
onset of phase separation within the process of the invention.
[0103] A porous material can have an outer coating applied to it
using this technology. Prior to the injection of a mixture into the
mold, a plug of porous material is inserted into the mold (FIG.
8a). After insertion of the porous structure into the mold, a
mixture is injected into the mold and rotated at the desired speed.
The phase-separated phase is centrifuged through the pores of the
inserted plug, and form a structure on the outer surface of the
porous plug, therefore sealing the material, without blocking the
internal pores. A porous material may also be a hollow structure,
and the polymeric material coats the hollow structure (FIG. 28)
discussed hereinafter.
[0104] In a preferred embodiment of the present invention the
mixture includes at least two or more phases, one being a monomer,
macromer or polymer, and the other a solvent.
[0105] For mixtures containing monomer to be initiated, the
initiation agent may be free radical initiators, thermal or UV
initiators and redox initiators or ionic initiators. Examples of
initiators include ammonium persulfate or potassium persulfate with
sodium metabisulfite, or tetramethylethylene diamine or ascorbic
acid, azonitriles and derivatives thereof, alkyl peroxides and
derivatives thereof, acyl peroxides and derivatives thereof,
hydroperoxides and derivatives thereof; ketone peroxides and
derivatives thereof, peresters and derivatives thereof and peroxy
carbonates and derivatives thereof.
[0106] The mixture could also include a cross-linking agent
depending on the structure of the final product that is desired and
the polymer material that is formed. The crosslinking agent may be
a multifunctional molecule with at least two reactive
functionalities and includes multi-functional methacrylates or
multi-functional acrylates, multi-functional acrylamides or
multi-funtional methacrylamides, or multi-functional star polymers
of polyethylene glycol and preferably, but not limited to, one of
ethylene glycol dimethacrylate (EDMA), hexamethylene dimethacrylate
(HDMA), poly(ethylene glycol) dimethacrylate,
1,5-hexadiene-3,4-diol (DVG), 2,3-dihydroxybutanediol
1,4-dimethacrylate (BHDMA), 1,4-butanediol dimethacrylate (BDMA),
1,5-hexadiene (HD), methylene bisacrylamide (MBAm) multi-functional
star polymers of poly(ethylene oxide), oligopeptidic crosslinkers,
multifunctional proteins and derivatives thereof; or combinations
thereof.
[0107] An exemplary, non-limiting list of monomers that may be in
the mixture includes any one of acrylates, methacrylates, and
derivatives thereof such as, but not limited to, 2-hydroxyethyl
methacrylate, methyl methacrylate, 2-polyethylene glycol ethyl
methacrylate, ethyl acrylate, 2-hydroxyethyl acrylate, acrylic
acid, methacrylic acid, 2-chloroethyl methacrylate, butyl
methacrylate, glycidyl methacrylate, hydroxypropyl methacrylate;
acrylamides and derivatives thereof such as, but not limited to,
methacrylamide, hydroxypropyl methacrylamide, N,N-diethyl
acrylamide, N,N-dimethyl acrylamide, 2-chloroethyl acrylamide,
2-nitrobutyl acrylamide, N-vinyl pyrrolidone, acenaphthalene,
N-vinyl acetamide, phenyl-acetylene, acrolein, methyl acrolein,
N-vinyl pyridine, vinyl acetate, vinyl chloride, vinyl fluoride,
vinyl methyl ketone, vinylidene chloride, styrene and derivatives
thereof, propene, acrylonitrile, methacrylonitrile, acryloyl
chloride, allyl acetate, allyl chloride, allylbenzene, butadiene
and derivatives thereof, N-vinyl caprolactam, N-vinyl carbazole,
cinnamates and derivatives thereof, citraconimide and derivatives
thereof, crotonic acid, diallyl phthalate, ethylene and derivatives
thereof such as, but not limited to 1,1 diphenyl-ethylene,
chlorotrifluoro-ethylene, dichloroethylene, tetrachloro-ethylene;
fumarates and derivatives thereof, hexene and derivatives thereof,
isoprene and derivatives thereof such as, but not limited to
isopropenyl acetate, isopropenyl methyl ketone,
isopropenylisocyanate; itaconate and derivatives thereof;
itaconamide and derivatives thereof; diethyl maleate,
2-(acryloyloxy)ethyl diethyl phosphate, vinyl phosphonates and
derivatives thereof, maleic anhydride, maleimide, silicone
polymers, and derivatives thereof; polysaccharides and derivatives
thereof; carbohydrates and derivatives thereof; peptides and
protein fragments and derivatives thereof; chitosan and derivatives
thereof; alginate and derivatives thereof; and any combination
thereof.
[0108] An exemplary, non-limiting list of polymers that may be in
the mixture includes any of polyacrylates, polysaccharides and
derivatives thereof, such as, but not limited to glycidyl
methacrylated derivatized dextran, 2-hydroxyethyl
methacrylate-derivatized dextrans, dextran methacrylate, dextran
acrylates, carbohydrates and derivatives thereof, polysulfone,
peptide sequences, proteins, oligopeptides, collagen, fibronectin,
laminin, polymethacrylates such as but not limited to poly(methyl
methacrylate), poly(ethoxyethyl methacrylate),
poly(hydroxyethylmethacrylate; polyvinyl acetates polyacetates,
polyesters, polyamides, polycarbonates, polyanhydrides, polyamino
acids, such as but not limited to poly(N-vinyl pyrrolidinone),
poly(vinyl actetate), poly(vinyl alcohol, poly(hydroxypropyl
methacrylamide), poly(caprolactone), poly(dioxanone) polyglycolic
acid, polylactic acid, copolymers of lactic and glycolic acids, and
polytrimethylene carbonates, poly(butadiene), polystyrene,
polyacrylonitrile, poly(chloroprene), neoprene, poly(isobutene),
poly(isoprene), polypropylene, polytetrafluoroethylene,
poly(vinylidene fluoride), poly(chlorotrifluoroethylene),
poly(vinyl chloride), poly(oxymethylene), poly(ethylene
terephthalate), poly(oxyethylene) poly(oxyterephthaloyl),
polyamides such as but not limited to,
poly[imino(1-oxohexamethylene)],
poly(iminoadipoyl-iminohexamethalene),
poly(iminohexamethylene-iminosebac- oyl),
poly[imino(1-oxododecamethylene)], cellulose, polysulfones,
hyalonic acid, sodium hyaluronate, alginate, agarose, chitosan,
chitin, and mixtures thereof.
[0109] A non-limiting exemplary list of solvents in the mixture for
the monomer and/or polymers includes any one of water, a
neucleophilic or electrophilic molecule including, but not
necessarily restricted to an alcohol and preferably ethylene
glycol, ethanol, acetone, poly(ethylene glycol), dimethyl
sulfoxide, dimethyl formamide, alkanes and derivatives thereof,
acetonitrile, acetic acid, benzene, acetic anhydride, benzyl
acetate, carbon tetrachloride, chlorobenzene, n-butanol,
2-chloroethanol, chloroform, cyclohexane, cyclohexanol,
dichloromethane, diethyl ether, di(ethylene glycol), di(ethylene
glycol) monomethyl ether, 1,4 dioxane, N,N, dimethyl acetamide,
N,N, dimethyl formamide, ethyl acetate, formaldehyde, n-heptane,
hexachloroethane, hexane, isobutanol, isopropanol, methanol, methyl
ethyl ketone, nitrobenzene, n-octane, n-pentanol, propyl acetate,
propylene glycol, pyridene, tetrahydrofuran, toluene,
trichloroethylene, o-xylene and p-xylene, or aforementioned
monomers or crosslinking agents, or mixtures thereof.
[0110] The solvent can be chosen to solubilize the monomer but not
a polymer or crosslinked polymer formed from the monomer. One of
the components may include a polymer dissolved in a solvent. The
two phase-mixture may also be an emulsion.
[0111] In another embodiment an aqueous two-phase system is formed
from two water soluble polymers, the two water soluble polymers
being incompatible in solution and at least one of these polymers
being crosslinkable; the crosslinkable polymer phase being
emulsified in the other polymer phase. Crosslinking can be achieved
chemically, with free radical or redox initiation, acid/base
catalysis, heat, electrophilic or nucleophilic attack, or
radiation. An advantage of this latter crosslinking is that in one
step sterile hollow structures can be obtained. Further,
crosslinking by UV radiation and physical crosslinking using
hydrophobic tails coupled to a polymer are possible techniques.
This aqueous polymer immiscibility occurs with many combinations of
water-soluble polymers (e.g. combinations of dextran, poly(ethylene
glycol) (PEG), poly(vinyl alcohol), poly(vinylpyrrolidone),
gelatin, soluble starch or ficoll). The polymers stay in solution,
but separate in two aqueous phases above a certain concentration.
After emulsification, the polymer in the dispersed phase can be
crosslinked under centrifugal forces to form a tube with hydrogel
character. Examples of emulsion systems suitable for hollow
structures includes but is not limited to: glycidyl methacrylated
derivatized dextran(dex-GMA)/poly(ethylene glycol) (PEG);
2-hydroxyethyl methacrylate-derivatized dextrans (dex-HEMA)/PEG;
dex-lactate-HEMA/PEG; dex-GMA/Pluronic F68; PEG-dimethacrylate
(PEG-MA.sub.2)/dextran with or without salt, such as MgSO.sub.4;
PEG-MA.sub.2/cloud point agent such as MgSO.sub.4;
Gelatin/Poly(vinylpyrrolidone); Gelatin/dextran, among others.
[0112] In another embodiment, macromers may be used, comprising
hydrophilic oligomers having biodegradable monomeric or oligomeric
extensions or side chains, which biodegradable segments are
terminated on the free end thereof with end cap monomers or
oligomers capable of polymerization and cross linking.
Biodegradation occurs at the backbone or at the crosslinks and
results in fragments which are non-toxic and easily digested or
excreted by the body. For example, macromers include modified
dextran-oligopeptide-methacrylate or PEG-oligopeptides-acrylates
where the peptide sequence may be recognized by enzymes, resulting
in biodegradable segments.
[0113] In another embodiment a tapered hollow structure with
changing dimensions along its length can be manufactured where the
sealed mold is rotated at a predetermined angle between 0 and
90.degree. from the horizontal plane.
[0114] In another embodiment a tapered hollow structure with
changing dimensions along its length can be manufactured using a
holding device such as shown in FIGS. 20a to d, which holds the
sealed mold at a predetermined angle between 0 and 90.degree. from
the axis of rotation. The holder of FIGS. 20a, b, c holds a
cylindrical mold 70 (shown in FIG. 20d, so it is rotated about an
axis other than its long axis for producing tubes. The holding
device (A) is preferably made of aluminium and has a stem (B) which
is held in the rotating device. A hole drilled though the holding
device at an angle (theta) from the axis of rotation permits the
insertion of the mold (C). The mold is held in place by two rubber
o-rings (E) and capped with two rubber septa (E). The angle of
rotation will result in non-uniform wall thickness dimensions along
the length of the mold.
[0115] FIG. 21a is a diagram of a holding device with the centre of
gravity not on the axis of rotation so the molds, when inserted
into the holding device, have an axis of rotation that is parallel
to the axis of rotation of the rotating device. The resultant
hollow structures retrieved from such molds have non-uniform wall
thicknesses as demonstrated in FIG. 21c. Alternatively the mold may
have a centre of gravity not on the axis of rotation (FIG. 21b).
This will also result in a hollow structure formed similar to FIG.
21c.
[0116] In another embodiment controlling the viscoelastic
properties of the separated phase and/or the rotation speed can
create cell-invasive hollow structures. If the separated phase has
substantial elastic properties, they will not coalesce, and after
gelation, the porous network between the phases is large enough for
the penetration of cells into the construct.
[0117] In another embodiment multi-layered structures can be formed
by repeating the process as many times as desired. After forming
the first layer, the solvent can be tipped out and another mixture
injected into the mold. The first layer coating the mold,
effectively becomes the mold for the next coating and the second
formation may penetrate into the first coating, binding them
together after gelation. The multi-layered hollow structures can be
manufactured using any or all of the types of tubes described in
the examples, made from any material, similar or different
materials, in any order required, as many times as required. A
layered wall structure (ie. gel-like and porous) can be made by
multiple formulations and multiple rotations or in one
formulation/one rotation. The layers may result in composite
polymer walls comprising polymers, polymer blends of biopolymers
(such as collagen, matrix molecules, glycosaminoglycans), or any
type of biodegradable material, and may contain polymer beads or
spheres, colloids, drugs, living cells and other mixtures
concentrically arranged in the wall radius.
[0118] Various shaped structures can be manufactured with the same
methodology as Example 1 but prepared using a mold shape that is
non-symmetrical along any axis. FIGS. 25a, 25b and 25c show an
example of such a mold that results in a hollow structure that is
corrugated on one side, and smooth on the other, and contains
spherical dimples along the internal length of the structure. Any
example formulation can be used to create this shape of hollow
structure, in a mold with a variable diameter.
[0119] In another embodiment, composite hollow structures can be
formed with another structure, such as but not limited to a mesh,
scaffold, stent, coil and/or fiber(s) that occupies the periphery
of the mold. The formulation is added to this mold as described
above, resulting in composite hollow structure consisting of the
hollow structure that coats the structure. Examples 34 and 35
discussed hereinafter describe such structures which are shown in
FIGS. 28 and 29.
[0120] Manufacture of both physically and chemically crosslinked
hollow structures are possible using this technique, as is the
manufacture of both degradable and non-degradable polymer tubes.
Those skilled in the art will appreciate the many applications for
which the structures produced with the present method may be used.
The ability to control the morphology, porosity and wall thickness
of these tubes permits their use as drug delivery vehicles, when
the structures are composed of physiologically acceptable
materials. Drugs can also be incorporated in other materials that
are incorporated into the tube, or in the tube wall itself. For
example, the tube can be filled with a material, such as, but not
limited to, a hydrogel, in which drugs are dispersed.
Alternatively, the wall structure can serve as a reservoir for the
drug or other constituent, which may be incorporated directly into
the wall structure either during production of the product by
including the drug or other constituent in the mixture or they can
be incorporated after production by soaking the product in a
solution containing the drug or constituent which is then taken up
into the product (especially in the case of porous products).
Alternatively, the drug or other constituent may be incorporated
into another material/drug reservoir, such as microspheres or
nanospheres designed to release the drug or other constituent. By
multilayering with materials incorporated within each of the
stages, a tube can be made with delivery of drugs to a specific
location within the tube wall. FIGS. 24a and 24b shows a tube with
microspheres which were included in a second layer formulation with
small quantities of monomer. The drug may be delivered uniformly or
in a gradient. By tuning the set-up, a gradient can be established.
The drug may include, but is not limited to, enzymes, proteins,
peptides, genes, vectors, growth factors, hormones,
oligonucleotides, or cells.
[0121] It is also possible to produce hollow structures that allow
molecules to diffuse across the wall structure. Also hollow
structures can be produced that selectively allow the diffusion of
molecules based on size and/or shape to diffuse across the wall
structure and to allow preferential directional drug delivery. The
invention can also provide hollow structures with the appropriate
mechanical properties for their end use, for example to match the
mechanical properties of the tissue in which they are to be
implanted.
[0122] The present method can be used to produce hollow structures
that have an outer gel phase and an inner porous phase. The present
method can also be used to provide a hollow structure with
overlapping regions of porous phase/gel phase.
[0123] A significant advantage of the present method can be used to
make hollow structures of various dimensions with internal
diameters from 10 .mu.m to 100 cm. Another advantage of the present
method is that it can be used to make composite hollow structures
with various materials and shapes as well as thin coatings on the
inner surface of other hollow structures.
[0124] The present invention will now be illustrated with several
non-limiting examples. The first examples relate to 2-hydroxyethyl
methacrylate polymers and copolymers that are synthesized (and
crosslinked) in a rotating mold, resulting in a tube due to
centrifugal forces. Such morphologies given as examples of
2-hydroxyethyl methacrylate and its copolymers are also relevant to
any monomeric or polymeric system that can be induced to phase
separate in a liquid-filled rotating mold. Additional examples
relate to crosslinked dextran tubes and composite tubes containing
microspheres, cells, particulates, spheres, coils, stents,
mesh.
[0125] Applications and Utility
[0126] The product produced according to the present method may be
used for a variety of applications including but not limited to
aural drainage tubes, abdominal/gastrointestinal structural
replacements, stents for aortic aneurysms, esophageal scaffolds, in
advanced wound dressings for draining edematous fluid while
releasing therapeutic agents, such as growth factors, antibiotics.
Additional applications that take advantage of a tubular shape
include composite catheters useful for wound care as drains, shunts
and delivery matrices. Coatings applications apply to pacemaker
leads, implantable sensor wire leads, wires for interventional
cardiology.
[0127] More particularly, the product may be a coating on a
pre-existing hollow structure. The pre-existing hollow structure is
either inserted into the mold and coated with the product, or the
pre-existing hollow structure is used as the mold itself. The
product can contain therapeutic drugs, cells, in a gradient along
length or uniformly distributed. In addition therapeutic drugs can
be incorporated directly into the wall the wall of the product or
they may be incorporated into microparticles (microspheres) or
nanoparticles (nanospheres) which are themselves incorporated into
the wall of the products. Such particles may be degradable, or
non-degradable materials, and the cells may be genetically
modified, or not genetically modified cells, including but not
limited to olfactory ensheathing cells, fibroblasts, or
oligodendrocytes, neurons, stem cells, stem cell derived cells,
olfactory ensheathing cells, Schwann cells, astrocyte cells,
microglia cells, or oligodendrocyte cells, endothelial cells,
epithelial cells, keratinocytes, smooth muscle cells, hepatocytes,
bone marrow-derived cells, hematopoetic cells, glial cells,
inflammatory cells, and immune system cells to mention just a few
examples. Cells encapsulated in the product can secrete molecules
useful in therapeutic applications.
[0128] The product may be made of a physiologically compatible
material so that it can be used as a nerve guidance channel. The
nerve guidance channel can contain cell invasive scaffolds, or
therapeutic drugs, cells, in a gradient along its length or
uniformly distributed. In addition therapeutic drugs may be present
in the wall of the product or within particles incorporated into
the walls. Such particles may be degradable, or non-degradable
materials, containing cells as disclosed above.
[0129] Alternatively, the mold itself may be made of a
physiologically compatible material suitable as a nerve guidance
channel and the product coats the inside surface of the mold. The
product is effectively a coating on the inner lumen of an existing
nerve guidance channel, can contain cell invasive scaffolds, or
drugs, cells, in a gradient along length or not in a gradient. As
mentioned above, the nerve guidance channel can contain cell
invasive scaffolds, or therapuetic drugs, cells as listed above, in
a gradient along its length or uniformly distributed. In addition
therapeutic drugs, may be present in the wall of the product or
within particles incorporated into the walls. Such particles may be
made of degradable, or non-degradable materials.
[0130] The product may be used for encapsulated cell therapy
applications containing genetically modified, or not genetically
modified cells as discussed above. Cells encapsulated in the
product can secrete molecules useful in therapeutic applications.
These cells could also be used in bioreactors produced using the
method of the present invention.
[0131] The product may be used as a coronary artery bypass graft or
vascular graft, including those in the brain, for abdominal aortic
aneurysms, and endovascular grafts. In addition therapeutic drugs,
either alone embedded in the wall of the product or encapsulated
within a time release drug delivery particle present in the wall of
the product. Such particles may be made of degradable or
non-degradable materials.
[0132] The product may be produced using materials which are
physiologically compatible as replacement or artificial fallopian
tubes which can contain cells, drugs and the like. The product may
be used as a drainage implant for glaucoma or as a drainage implant
for the lachrymal duct. These drainage implants can be produced
with diameters suitable for regulating the intraocular pressure of
the eye. In addition therapeutic drugs, present within particles or
not, can be present in the wall of the product. The drainage
implant may be used as part of a device, so as to regulate the
intraocular pressure of the eye. The product may also be used as
ureter and urethra replacements.
[0133] The product may also be a bioreactor for the manufacture of
cell products or artificial tissues, such as intestines. The
product, which may or may not be a multi-layered structure, may
contain cells and remains in the mold and effectively becomes a
sealed vessel where nutrients for cell growth, viability and
differentiation are introduced and waste removed accordingly. The
product may be a coating on a porous membrane inside the mold, and
nutrients can be exposed to both sides of the product. The product
can contain cell invasive scaffolds, or drugs, cells, in a gradient
along length or not in a gradient. In addition therapeutic drugs,
present within particles or not, can be present in the wall of the
product. Such particles may be degradable, or non-degradable
materials, genetically modified, or not genetically modified cells,
including but not limited to the list of cells given. The
bioreactor may contain degradable materials so that after a
pre-determined period of time, the resultant bioreactor contains
solely living cells and their extracellular matrix, and the cells
may or may not have organized into a structure that can be used as
an intestinal replacement.
[0134] The product may be a coating on a preexisting hollow
structure and is used as a biosensor. The pre-existing hollow
structure is either inserted into the mold and coated with the
product, or the pre-existing hollow structure is the mold itself.
The product can have a high surface area, and improve signal to
noise ratios for the application of a biosensor. The coating may
have well defined surface chemistry for improvements in biosensor
reproducibility.
EXAMPLE 1
[0135] 2-hydroxyethyl methacrylate (HEMA) was polymerized in the
presence of excess water, with a crosslinking agent, preferably,
but not limited to ethylene dimethacrylate (EDMA), using a free
radical initiating system and preferably an ammonium persulfate
(APS)/sodium metabisulfite (SMBS) redox initiating system. A
homogeneous mixture, with components detailed in Table 1, was
injected into a cylindrical glass mold as described for the process
involving 2-hydroxyethyl methacrylate. The homogeneous mixture was
made by adding the relevant quantities of HEMA, and water into a
glass vial, and mixing in the glass vial. Mixing of the solution
was repeated after the appropriate amount of 10% APS solution
listed in Table 1 was added. The appropriate volume of 10% SMBS
solution was added to this mixture, which was mixed for an
additional 30 seconds. The homogeneous monomer mixture was then
drawn into a Luer-lok syringe using a 20-gauge needle. The needle
was removed from the syringe and, using a new 20-gauge needle and a
0.8 .mu.m filter, the monomer mixture was injected into the
polymerization molds.
[0136] The sealed mold was placed in the chuck of a RZR-1 dual
range, variable speed stirring drill (Heidolph, Germany) that had
been mounted horizontally, using a spirit level. The rotational
speed was 2700 rpm as listed in Table 1. The resulting gel-like
coating on the inner surface of the mold is shown in FIG. 6 and is
approximately 10.+-.3 .mu.m thick. FIG. 6 shows an environmental
scanning electron microscope (ESEM) micrograph of a gel-like
coating on the inside of a glass mold, in which the mixture
formulation was 1% HEMA, 99% water, 0.01% APS, 0.01% SMBS, 4000
rpm.
EXAMPLE 2
[0137] A coating with both gel-like and porous morphologies was
prepared with the same methodology as Example 1; the monomer
mixture used also included poly(ethylene glycol) methacrylate as a
comonomer. The monomer mixture and rotation conditions used in
Example 2 are listed in Table 1. The resulting porous
material/gel-like hybrid coating on the inner surface of the mold
is shown in FIGS. 7a and 7b with the outer gel-like coating (the
surface that is against the inside of the mold) facing forward in
FIG. 7a and the inner porous structure (the one against the water)
facing forward in FIG. 7b. The thickness of the coating is
approximately 30.+-.5 .mu.m thick. The micrograph in FIGS. 7a and
7b were taken after removing the coating from the glass mold. More
specifically, FIG. 7a shows a scanning electron microscope (SEM)
micrograph of the outer surface of a porous coating applied to the
inside of a glass mold, in which the mixture is 1.9% HEMA, 0.1%
PEGMA, 98% water, 0.02% APS, 0.02% SMBS, 2700 rpm. FIG. 7b shows
the inner surface of a porous coating applied to the inside of a
glass mold, in which the mixture formulation is 1.9% HEMA, 0.1%
PEGMA, 98% water, 0.02% APS, 0.02% SMBS, 2700 rpm.
EXAMPLE 3
[0138] A porous material can have an outer coating applied to it
using this technology. The coating that can be either gel-like or
have porous morphology or both was prepared with similar
methodology as in Example 1. Prior to the injection of a
homogeneous mixture into the mold, a plug of porous material is
inserted into the mold (FIG. 8a). Porous PLGA is manufactured using
techniques previously described (Holy et al, Biomaterials, 20,
1177-1185, 1999), however the porous material may be made of any
material, including polymers, ceramics, metals, composites, or
combinations thereof. After insertion of the porous structure into
the mold, the homogeneous mixture listed in Table 1 as Example 3 is
injected into the mold and the mold rotated at the speed listed in
Table 1. The resulting coated porous material removed from the mold
is shown in FIG. 8b. There was no coating or blocked pores on the
inside of the porous material; the only coating visible was on the
outside. This example demonstrates the successful outer coating
(and sealing) of a porous material without affecting the morphology
of the said porous material.
EXAMPLE 4-5
[0139] A porous, cell-invasive tube can be manufactured with the
same methodology as Example 1, except the monomer mixture used may
include methyl methacrylate (MMA) as a comonomer. Example 5 also
substitutes TEMED for SMBS as the second component in the
initiating system. The monomer mixture and rotation conditions used
in Examples 4-5 are listed in Table 1, and both result in cell
invasive, porous tubes. In this particular instance, the use of a
faster initiating system, such as, but not limited to the APS/TEMED
redox system, or increased concentrations of initiator in the
homogeneous mixture is beneficial to achieve the porous structure.
FIGS. 9a and 9b show a porous wall morphology of Examples 4 and 5.
Formation is due to sudden phase separation, in addition to
viscoelastic particles separating, that do not coalesce.
EXAMPLES 6-7
[0140] A semi-porous, cell-impermeable tube can be manufactured
with the same methodology as Example 1, except the monomer mixture
used may include methyl methacrylate (MMA) as a comonomer. The
monomer mixture and rotation conditions used in Examples 6-7 are
listed in Table 1, and both result in semi-permeable non-cell
invasive, tubes. In example 6, the rotation speed is at 10,000 rpm;
the high rotation speed compacts the phase separating structure
against the tube wall, resulting in gel-like wall morphology with
closed cell pores that affect diffusion across the wall membrane
(FIG. 10a).
[0141] In the instance of example 7, the initiating system as a
phase separating agent may be in a lower concentration, as slower
phase separation is beneficial to achieve the non-porous, gel-like
structure at lower rotation speeds (FIG. 10b).
EXAMPLES 8-9
[0142] A mixed porous/gel-like tube can be manufactured with the
same methodology as Example 1, except the monomer mixture used may
include MMA and/or ethylene glycol EG) which affects phase
separation. The monomer mixture and rotation conditions used in
Examples 8-9 are listed in Table 1, and both result in mixed porous
and gel-like tubes manufactured with one polymerization. The
bi-layer morphology of the cross-section of Example 8, seen in FIG.
11a, is due to the precipitation of a liquid-like phase at the
start of the phase separation followed by a viscoelastic
precipitate towards the end of the phase separation. Co-solvents
other than water, such as EG, are therefore useful for delaying or
accelerating phase separation, and therefore control the bi-layered
morphology of the wall.
[0143] For Example 9, a porous/gel-like tube can be manufactured
with the same methodology as Example 1, except faster speeds in
combination with slower phase separation can induce the morphology
in FIG. 11b.
EXAMPLE 10
[0144] A mixed porous/gel-like tube with radial porosity can be
manufactured with the same methodology as Example 1, when the
denser separating phase can be beaded as droplets on the inner
surface of the rigid mold. The contact angle of the separating
phase can be influenced by surface modification of the rigid mold,
or changing the material of the inside of the mold. The wall
morphology can therefore be influenced by the surface chemistry of
the mold. The monomer mixture and rotation conditions used in
Example 10 are listed in Table 1, may include co-solvents such as
methyl methacrylate or ethylene glycol to influence the solubility
of the separated phase. FIGS. 12a and 12b are micrographs of the
porous/gel-like tube with radial porosity cross-section, with FIG.
12c showing the outer longitudinal morphology of the same
formulation. The hollow structure shown in the optical micrograph
in FIG. 12d was synthesized with the same formulation as Example
10, but was formed in a silane-treated glass mold. The silanating
agent was Sigmacote from Sigma-Aldrich. The Sigmacote solution was
drawn up into glass molds and then dried in an oven to evaporate
the solvent. Contact angle studies on glass slides showed the water
contact angle changed from 44.7.+-.3.degree./11.6.+-.1.8.degree. to
47.+-.0.3.degree./44.+-.0.4.degr- ee. after surface modification.
The glass mold was then used with the formulation listed as Example
10 in Table 1. The hollow fiber membranes had equilibrium water
contents between 42% and 57%; elastic moduli between 22 kPa and 400
kPa, and diffusive permeabilities between 10.sup.-7 and 10.sup.-9
cm.sup.2s.sup.-1 for vitamin B12 and dextran 10 kD. Similar
mechanical strengths of the tube walls could be achieved with
significantly different permeabilities, reflecting their intrinsic
microstructures. The beading described in Example 10 permits highly
diffusive hollow structures while maintaining good mechanical
strength.
EXAMPLE 11
[0145] A porous tube with pores that are radial in nature can be
manufactured with the same methodology as Example 1, with a monomer
formulation mixture and rotation conditions listed in Table 1 as
Example 11. The wall morphology is predominantly gel, with channels
or pores that penetrate in a radial manner that does not require
beading as in Example 10. An example of this morphology is shown in
FIG. 13a.
EXAMPLE 12
[0146] A porous tube with fibers that are radial can be
manufactured with the same methodology as Example 1, with a monomer
formulation mixture and rotation conditions listed in Table 1 for
Example 12. The wall morphology is predominantly space, with fibers
that penetrate in a radial manner. The inner lumen of the formed
hollow structure is small relative to the wall thickness and an
example of this morphology is shown in FIG. 13b. In this example,
the prevention of sedimentation of low concentrations was achieved
with a slow rotation rate. This surprising result demonstrates the
profound effect of rotation rate on the wall morphology, especially
compared to Example 2 (FIGS. 7a and 7b) which has the similar
monomer concentrations, but significantly different rotation
rates.
EXAMPLE 13
[0147] Morphology of a cross-section of the wall of a multi-layered
tube with the mixture formulation listed in Table 1 as example 13.
These multi-layered tubes are can be manufactured with the same
methodology as Example 1, repeated as many times as required.
Example 13 in Table 1 refers to the first, outer, layer formed (o)
and the second, inner formed layer (i). Multi-layered hollow
structures are possible by forming one layer and using the formed
hollow structure as the surface coating of the mold and the hollow
structure process repeated as many times as desired. The
multi-layered hollow structures can be manufactured using any or
all of the types of tubes described in the examples, made from any
material, similar or different materials, in any order required, as
many times as required. An example is shown in FIG. 14.
EXAMPLE 14
[0148] Smooth surface morphology the inner layer of a tube with the
mixture formulation listed in Table 1 as Example 14 can be
manufactured with the same methodology as Example 1. A tube with a
smooth inner surface is shown in FIG. 15.
EXAMPLE 15
[0149] Dimpled/rough surface morphology on the inner layer of a
tube, which can be made using the mixture formulation listed in
Table 1 as example 15, can be manufactured with the same
methodology as Example 1. A tube with a dimpled/rough inner surface
is shown in FIG. 16a. A lateral cross-section of the tube showing a
gel-like/porous wall morphology and a dimpled/rough inner surface
is shown in FIG. 16b.
EXAMPLE 16
[0150] Unique surface morphology of the inner lumen of a tube with
unique cell-like surface patterns can be made using the mixture
formulation listed in Table 1 as example 16 manufactured with the
same methodology as Example 1. Surface morphologies such as those
seen in FIG. 17a are created using this process. FIG. 17b shows
such cell-like surface patterns on the inner lumen of a tube with a
gel-like/porous wall morphology.
EXAMPLE 17
[0151] Very small diameter micro-tubes can be manufactured with the
same methodology as Example 1, except the mold size is very narrow.
FIG. 18 is a tube that was manufactured from a mixture formulation
listed in Table 1 as example 17 in small diameter capillary tubing
with an internal diameter of 450 .mu.m. Smaller tubing can be
created by using molds with an internal diameter of 10 .mu.m and
larger.
EXAMPLE 18
[0152] Various shaped structures can be manufactured with the same
methodology as Example 1, except the mold size is neither
cylindrical nor has a uniform internal diameter. FIG. 19 is a tube
that was manufactured from a mixture formulation listed in Table 1
as example 18, in a mold with a variable diameter. Any example
formulation can be used to create this shape of hollow
structure.
EXAMPLE 19
[0153] A tapered hollow structure with changing dimensions along it
length can be manufactured with the same methodology as example 1,
except the sealed mold was placed into the chuck of a drill that
had been mounted at a predetermined angle between 0 and 90.degree.
from the horizontal plane.
EXAMPLE 20
[0154] A hollow structure with variable wall thickness or holes
along the length can be manufactured with the same methodology as
example 1, except the sealed mold has some inner surface
morphologies, such as in. FIG. 2a-d. Any example formulation can be
used to create this shape of hollow structure.
EXAMPLE 21
[0155] Hollow structures can be manufactured from the liquid-liquid
phase separation of a polymer solution using temperature as the
phase separating agent. Poly(lactic-co-glycolic acid) was dissolved
in a 87:13 (wt %) dioxane/water mixture at 60.degree. C. to create
a solution that is injected into pre-heated glass molds. After
injecting in a sealed glass mold, removing all air from the mold,
it was placed in the chuck of a drill at room temperature and spun
at 4000 rpm. The mold was allowed to cool to room temperature,
which induced liquid-liquid phase separation and gelation. The mold
was then frozen and the dioxane/water mixture removed by placing in
a freeze-dryer. The formed tube is then removed from the mold.
EXAMPLE 22
[0156] N-2-(hydroxypropyl) methacrylamide (HPMA) (30 vol %) was
polymerized in the presence of excess acetone/dimethyl sulfoxide
(DMSO) (93:7 v/v), with a crosslinking agent, preferably, but not
limited to methylene bisacrylamide (1 mol %), using
azobisisobutyronitrile (AIBN) as an initiating system. A monomeric
sugar may or may not be also added to the polymerization mixture.
The mixture was fully mixed, and injected into a cylindrical glass
mold as described for Example 1 using the mixture formulation
listed in Table 1 as example 22.
[0157] The sealed mold was placed in the chuck of a stirring drill
that had been mounted horizontally, using a spirit level and
rotated at 4000 rpm at 50.degree. C. for 24 hours. The resulting
hollow structure on the inner surface of the mold is removed from
the mold.
EXAMPLE 23
[0158] A coating with non-uniform dimensions along the length
prepared with the same methodology as Example 1, except the molds
were rotated about an axis other than its long axis. Holding
devices as shown in FIG. 20 were fabricated from aluminium and are
designed to fit into the chuck of a drill and hold the
polymerization mold at an angle from. Molds can be rotated an axis
other than its long axis determined by the holding device created.
The resultant coatings have tapered, non-uniform dimensions along
their long axis. Any example formulation can be used to create this
shape of hollow structure.
EXAMPLE 24
[0159] A coating with non-uniform dimensions was prepared with the
same methodology as Example 1, except the polymerization molds were
rotated in a holding device with the centre of gravity not on the
axis of rotation. The polymerization molds listed in Example 1 were
placed into a cylindrical aluminium holding device with an offset
centre (FIG. 21a or FIG. 21b) from the axis of rotation. The
holding device was then inserted into the chuck of the drill and
rotation commenced. The resultant coating is non-uniform in its
lateral cross-section as shown in FIG. 21c. Any example formulation
can be used to create this shape of hollow structure.
EXAMPLE 25
[0160] A coating with degradable microspheres situated in the outer
lumen of the coating can be prepared with the same methodology as
Example 1, except a particulate material that has greater density
than the phase separated monomer component was included within the
homogeneous monomer mixture. Upon rotation of the polmerization
mold, the dense particulates are forced to the inner surface of the
mold. When the dense, polymeric phase is gelled within the mold, a
coating is formed that is shown in lateral cross-section in FIG.
22. Polycaprolactone (PCL) microspheres of average diameter 20
microns were manufactured as described in Cao et al; Biomaterials,
20, 329-339, 1999, and were added to the filtered monomer mixture
in quantities outlined in Table 2. Filtering the solution was not
done after the microspheres were added. Such particulate-containing
tubes can be made using any material for the tube that is conducive
to this manufacturing process, and using microspheres made from any
biodegradable or non-biodegradable polymer that is compatable with
the formulation mixture.
EXAMPLE 26
[0161] A coating with microspheres situated near the inner lumen of
the coating can be prepared with the same methodology as Example 1,
except a particulate material with a density between the solvent
and denser phase was included within the monomer mixture. Upon
rotation of the polmerization mold, the dense particulates move to
the interface between the solvent and the dense polymeric phase.
When the dense polymeric phase is gelled within the mold, a coating
is formed with particulates fixed near the inner lumen of the
coating. Such particulate-containing tubes can be made using any
material for the tube that is conducive to this manufacturing
process, and using microspheres made from any biodegradable or
non-biodegradable polymer that is compatible with the formulation
mixture.
EXAMPLE 27
[0162] A coating with degradable microspheres in a gradient along
the length of the axis of rotation can be prepared with the same
methodology as Example 1, except a particulate material that has
greater density than the phase separated monomer component was
included within the homogeneous monomer mixture and the sealed mold
was placed into the chuck of a drill that had been mounted at a
predetermined angle between 0 and 90.degree. from the horizontal
plane. The microspheres sediment due to gravity and upon rotation
of the mold, the particulates are forced to the inner surface of
the mold and then fixed in place due to the gelation of the dense
polymeric phase. Polycaprolactone (PCL) microspheres of average
diameter 20 microns were manufactured as described in Cao et al;
Biomaterials, 20, 329-339, 1999, and were added to the filtered
monomer mixture in quantities outlined in Table 2. Filtering the
solution was not done after the microspheres were added. Such
particulate-containing tubes can be made using any material for the
coating that is conducive to this manufacturing process, and using
microspheres made from any biodegradable or non-biodegradable
polymer that is compatible with the formulation mixture.
EXAMPLE 28
[0163] A coating with microspheres situated in the outer lumen of
the coating can be prepared with the same methodology as Example 1,
except a particulate material that contains a therapuetic drug was
included within the homogeneous monomer mixture. For example,
molecules, such as nerve growth factor (NGF) and ovalbumin (OVA)
can be encapsulated in PCL polymer microspheres using a solvent
evaporation technique described in Cao et al; Biomaterials, 20,
329-339, 1999. A mixture containing microspheres is therefore
injected into a sealed cylindrical glass mold as described in
Example 1, except the mixture is not passed through a filter.
Examples of therapeutic drugs include, but are not limited to NGF,
BDNF, NT-3, NT-4/5, FGF-1, FGF-2, IGF, VEGF, CNTF, GDNF, BMP
family; hormones, proteins, peptides, chemical drugs, such as
neuroprotective agents.
EXAMPLE 29
[0164] A coating with particulates within the coating can be
prepared with the same methodology as Example 1, except a
particulate material with non-spherical shapes was included within
the homogeneous monomer mixture. Glass fibers with an average
diameter of 50 microns and between 1 and 10 cm in length were were
added to the filtered monomer mixture as described in Table 2.
Filtering the solution was not done after the fibers were added.
Upon rotation of the mold, the dense particulates move to the inner
surface of the mold. When the dense polymeric phase is gelled
within the mold, a coating is formed that is shown in FIG. 23
removed from the mold. Such particulate-containing coatings can be
made using any material for the tube that is conducive to this
manufacturing process, and particulates that are fibers included,
but are not limited to; glass, carbon nanofibers, biodegradable
polymeric fibers, such as polyesters, poly carbonates,
polydioxanone, poly(hydroxybutyrate, polylactide, polyglycolide,
copolymers of lactide and glycolide that is compatible with the
formulation mixture.
EXAMPLE 30
[0165] Morphology of a cross-section of the wall of a multi-layered
tube with particulates situated near the inner lumen of the coating
the mixture formulation listed in Table 2 as example 30. These
multi-layered, particulate tubes are can be manufactured with the
same methodology as Example 1, repeated as many times as required.
Example 30 in Table 2 refers to the first, outer, layer formed (o)
and the second, inner formed layer which contains particulates (i).
Multi-layered hollow structures are possible by forming one layer
and using the formed hollow structure as the surface coating of the
mold and the hollow structure process repeated as many times as
desired, with particulates included at any stage of the process.
Following the first polymerization, the coating is not removed from
the glass mold but instead the remaining mixture is drained, the
mold is resealed, and a new formulation containing HEMA monomer,
cross-linker, initiator, and microspheres, is injected into the
mold containing the tube. The mold is inserted into a drill chuck
and spun for a second time. The multi-layered hollow structures can
be manufactured using any or all of the types of tubes described in
the examples, made from any material, similar or different
materials, in any order required, containing particluates in any or
all layers, as many times as required. An example is shown in FIG.
24. The gel-like coating on the inner surface of the mold contains
polycaprolactone microspheres embedded on the outer portion of the
inner coating. FIG. 24 shows a scanning electron microscope (SEM)
micrograph of a coating containing poly(caprolactone) microspheres,
in which microspheres are distributed uniformly along the length of
the coating, however a coating with non-uniformly distributed along
the length can be created using methodology outlined in Example
27.
EXAMPLE 31
[0166] Various shaped structures can be manufactured with the same
methodology as Example 1, except the mold shape is non-symmetrical
along any axis. FIG. 25 is an example of such a mold that results
in a hollow structure that is corrigated on one side, and smooth on
the other, and contains spherical dimples along the length of the
structure. Any example formulation can be used to create this shape
of hollow structure, in a mold with a variable diameter.
EXAMPLE 32
[0167] A coating with both gel-like and porous morphologies was
prepared with the same methodology as Example 1, except the
initiated monomer mixture was allowed to phase separate before it
was injected into the molds. The monomer mixture was permitted to
phase separate inside the injecting device, and the heterogeneous
solution was injected into the molds. The sealed mold was then
placed in the chuck of a drill as prevously described in Example 1.
The monomer mixture and rotation conditions used in Example 32 are
listed in Table 2. The resulting porous material/gel-like coating
after removal from the mold is shown in FIGS. 26a and 26b.
EXAMPLE 33
[0168] A coating with both gel-like and porous morphologies was
prepared with the same methodology as Example 1, except the
initiated monomer mixture was allowed to phase separate while it
was in the molds, before rotation. The monomer mixture and rotation
conditions used in Example 33 are listed in Table 2. The resulting
porous material/gel-like hybrid coating on the inner surface of the
mold is shown in FIG. 27.
EXAMPLES 34 & 35
[0169] A coating with both gel-like and porous morphologies was
prepared with the same methodology as Example 1, except the mold
contains an object predominantly made of wires. The coating that
can be either gel-like or have porous morphology or both was
prepared with similar methodology as in Example 1. Prior to the
injection of a mixture into the mold, an object predominantly made
of wires is inserted into the mold (FIGS. 28 & 29). Example 34
is a metallic stent that is placed inside a mold with the same
inner diameter as the outer diameter of the stent. After insertion
of the stent into the mold, the homogeneous mixture listed in Table
2 as Example 34 is injected into the mold and the mold rotated at
the speed listed in Table 2. The resulting coated stent is shown in
FIG. 28. Example 35 is a coiled wire that was shaped by winding the
wire around a metallic rod. After insertion of the coiled wire into
the mold, the homogeneous mixture listed in Table 2 as Example 34
is injected into the mold and the mold rotated at the speed listed
in Table 2. The resulting coating containing the manganese coiled
wire is removed from the mold and is shown in FIG. 29. The coiled
wire or stent could be composed of polymer, metal or ceramic
material.
EXAMPLES 36-37
[0170] A mixed porous/gel-like tube with radial porosity can be
manufactured with the same methodology as Example 1, with the ratio
of porous to gel-like component varied by the surface chemistry of
the polymerization mold. FIG. 30 shows three coatings, removed from
the mold, that were fabricated with a) clean glass mold, b) glass
mold modified with 2-Methoxy(polyethyleneoxy) propyl
trimethoxysilane (MPEOS--Example 36) and c) glass mold modified
with N-(2-aminoethyl)-3-aminopropyl trimethoxysilane
(AEAPS--Example 37). The glass molds were sonicated for 10 minutes
in Glass & Plastic Cleaner.TM. 100 solution, rinsed with
deionized water, and air dried for 30 minutes. The monomer mixture
and rotation conditions used in Examples 36 and 37 are listed in
Table 2. The resulting porous material/gel-like hybrid coating
removed from the mold is shown in FIG. 30a. For surface
modification of the glass mold with both MPEOS and AEAPS, the
cleaned glass was activated by dipping for 10 min in a solution of
9:1 v/v conc H.sub.2SO.sub.4/H.sub.2O.sub.2, and the rinsed with
plenty of water and air dried for 30 min. For Example 36, the glass
molds were immersed in a 2 wt % MPEOS solution in water:methanol
(5:95 wt %) solution with a pH of 2 only, adjusted by adding
concentrated HCl. The surface modification reaction took place for
15 min at 40.degree. C. The reaction was completed by drying the
silane-treated glass in air for 30 min at 110.degree. C. The
resulting porous material/gel-like hybrid coating removed from the
mold is shown in FIG. 30b with considerably higher proportion of
gel within the coating wall than the coating in FIG. 30a.
[0171] For Example 37, surface modification of the glass molds with
AEAPS was achieved by immersion in a 2 wt % AEAPS solution in
water:methanol (5:95 wt %) solution for 15 min at 40.degree. C. The
reaction was completed by drying the silane-treated glass in air
for 30 min at 110.degree. C. The resulting porous material/gel-like
hybrid coating removed from the mold is shown in FIG. 30c with
considerably higher proportion of porous material within the
coating wall than the coating in FIG. 30a. The coating shown in the
SEM micrograph in FIGS. 30b and 30c was synthesized with the same
formulation as FIG. 30a, but was formed in surface-modified
molds.
EXAMPLE 38
[0172] A mixed porous/gel-like coating with either non-degradable
or degradable properties can be manufactured with the same
methodology as Example 1, except the two phases always exist and
are and insoluble in each other. Glycidyl methacrylated derivatized
dextrans (dex-GMA) with varying degree of substitution (DS, the
number of methacrylate groups per 100 glucopyranose residues) were
synthesized by anchoring glycidyl methacrylate to dextran, with
molecular weight as described in Table 2 for Example 38, in
dimethylsulfoxide (DMSO) using N,N-dimethylaminopyridi- ne (DMAP)
as a catalyst, as adapted from the experimental methodology
proposed Van Dijk-Wolthuis et al. (Macromolecules 28, (1995)
6317-6322). Polyethylene glycol (PEG, Mw of 10,000 g/mol) was
dissolved in 0.22 M KCl to a concentration of 0.2 g/ml-0.4 g/ml.
Dex-GMA was dissolved in 0.22 M KCl to a concentration of 0.2
g/ml-0.4 g/ml. Both solutions and an additional volume of 0.22 M
KCl solution were filtered using syringe prefilters and then
degassed for 10 minutes. Different volumes of each solution were
mixed together to final composition as listed in Table 2 for
Example 38. The mixture was vortexed for 2 minutes resulting in a
water-in-water emulsion. Dex-GMA was polymerized preferably using,
but not limited to a free radical initiating system and preferably
an ammonium persulfate (APS)/sodium metabisulfite (SMBS) redox
initiating system. Short vortexing of the solution was repeated
after the appropriate amount of 0.1 g/ml APS solution, listed in
Table 2 for Example 38, was added. The appropriate volume of 0.015
g/ml SMBS solution, listed in Table 2 for Example 38, was added to
this mixture, which was briefly vortexed again. The mixture was
then injected into a glass mold as described for Example 1. The
mold was placed in the chuck of a drill that had been mounted
horizontally, using a spirit level. The rotational speed was 6000
rpm as listed in Table 2 for Example 38. A SEM micrograph of the
resulting degradable or non-degradable coating is shown in FIG. 31,
with gel-like morphology on the outer portion of the wall, and
porous morphology on the inner portion of the wall.
EXAMPLE 39
[0173] A mixed porous/gel-like coating with either non-degradable
or degradable properties and unique channels in the gel-like phase
can be manufactured with the same methodology as Example 38, except
the ratio of PEG to water is increased. Different volumes of each
solution were mixed together to final composition as listed in
Table 2 for Example 39. A SEM micrograph of the resulting
degradable or non-degradable coating is shown in FIG. 32.
EXAMPLE 40
[0174] A mixed porous/gel-like coating with either non-degradable
or degradable properties and sharp, defined separation of two wall
morphologies shown in FIG. 33 can be manufactured with the same
methodology as Example 38, except the percentage of dex-GMA in the
composition was increased. Different volumes of each solution were
mixed together to final composition as listed in Table 2 for
Example 40. A SEM micrograph of the resulting degradable or
non-degradable coating is shown in FIG. 33.
EXAMPLE 41
[0175] A mixed porous/gel-like coating with either non-degradable
or degradable properties can be manufactured with the same
methodology as Example 40, except the percentage of PEG in the
composition was increased and the percentage of water in the
composition decreased. Different volumes of each solution were
mixed together to final composition as listed in Table 2 for
Example 41.
EXAMPLE 42
[0176] A predominantly gel-like coating with either non-degradable
or degradable properties can be manufactured with the same
methodology as Example 40, except the molecular weight of dex-GMA
used in the composition was significantly lower as listed in Table
2. Different volumes of each solution were mixed together to final
composition as listed in Table 2 for Example 42. A SEM micrograph
of the resulting degradable or non-degradable coating is shown in
FIG. 34 and reveals the compactness of the wall.
EXAMPLE 43
[0177] A mixed porous/gel-like coating with either non-degradable
or degradable properties can be manufactured with the same
methodology as Example 42, except the percentage of PEG in the
composition was increased and the percentage of water in the
composition decreased. Different volumes of each solution were
mixed together to final composition as listed in Table 2 for
Example 43.
EXAMPLE 44
[0178] A predominantly gel-like coating with either non-degradable
or degradable properties and a porous inner lumen can be
manufactured with the same methodology as Example 42, except the
percentage of dex-GMA in the composition was increased and the
percentage of water in the composition decreased as listed in Table
2. Different volumes of each solution were mixed together to final
composition as listed in Table 2 for Example 44. FIG. 35 shows the
compactness of the wall morphology and porous inner lumen for
Example 44.
EXAMPLE 45
[0179] A mixed porous/gel-like coating with degradable properties
can be manufactured with the same methodology as Example 37, except
the polymerizing polymer is 2-hydroxyethyl methacrylate-derivatized
dextrans (dex-HEMA). Different volumes of each solution were mixed
together to final composition as listed in Table 2 for Example
45.
EXAMPLE 46
[0180] A mixed porous/gel-like coating with degradable properties
can be manufactured with the same methodology as Example 45, except
the percentage of dex-HEMA in the composition was increased, the
percentage of water in the composition decreased. Different volumes
of each solution were mixed together to final composition as listed
in Table 2 for Example 46.
EXAMPLE 47
[0181] A mixed porous/gel-like coating with with either
non-degradable or degradable properties can be manufactured with
the same methodology as Example 38, except Pluronic F68 replaced
PEG to a final composition as listed in Table 2 for Example 47.
EXAMPLE 48
[0182] A mixed porous/gel-like coating containing microspheres can
be manufactured with the same methodology as Example 38, except an
enzyme degrading particulate was included in the mixture which
degrades the polymer backbone. Different quantities of dex-GMA,
PEG, dextranase containing PCL microspheres and water solution were
mixed together to a final composition as listed in Table 2 for
Example 48. The mixed porous/gel-like coating is non-degradable by
hydrolysis, but is susceptible to degradation in the presence of
enzymes. The PCL microspheres incorporated in the wall of the
coating degrade with hydrolysis and release the enzyme, which
degrades the coating by scission of the polymer backbone.
EXAMPLE 49
[0183] A mixed porous/gel-like coating with degradable properties
can be manufactured with the same methodology as Example 38, except
the polymerizing polymer is dex-oligopeptide-methacrylate.
Different quantities of dex-Lys-Pro-Leu-Gly-Ile-Ala-methacrylate,
PEG, and water solution were mixed together to a final composition
as listed in Table 2 for Example 49. The mixed porous/gel-like
coating is non-degradable by hydrolysis, but is susceptible to
degradation in the presence of cell-secreted enzyme, gelatinase A
(MMP2), which degrades the coating by scission of the oligopeptide
crosslink.
EXAMPLE 50
[0184] A mixed porous/gel-like coating containing microspheres can
be manufactured with the same methodology as Example 49, except an
enzyme degrading particulate was included in the mixture which
degrades the crosslinking agent.
[0185] Different quantities of
dex-Lys-Pro-Leu-Gly-Ile-Ala-methacrylate, PEG, MMP2 containing PCL
microspheres and water solution were mixed together to a final
composition as listed in Table 2 for Example 50. The mixed
porous/gel-like coating is non-degradable by hydrolysis, but is
susceptible to degradation in the presence of MMP2. The PCL
microspheres incorporated in the wall of the coating degrade with
hydrolysis and release the enzyme, which degrades the coating by
scission of the oligopeptide crosslink.
EXAMPLE 51
[0186] A mixed porous/gel-like coating with degradable properties
can be manufactured with the same methodology as Example 38, except
an enzyme, which was entrapped in the coating during
polymerization, was included in the mixture, which degrades the
polymer backbone. Different quantities of dex-GMA, PEG, dextranase
and water solution were mixed together to a final composition as
listed in Table 2 for Example 48. The mixed porous/gel-like coating
is non-degradable by hydrolysis, but is susceptible to degradation
of the polymer backbone in the presence of enzymes.
[0187] As used herein, the terms "comprises", "comprising",
"including" and "includes" are to be construed as being inclusive
and open ended, and not exclusive. Specifically, when used in this
specification including claims, the terms "comprises",
"comprising", "including" and "includes" and variations thereof
mean the specified features, steps or components are included.
These terms are not to be interpreted to exclude the presence of
other features, steps or components.
[0188] The foregoing description of the preferred embodiments of
the invention has been presented to illustrate the principles of
the invention and not to limit the invention to the particular
embodiment illustrated. It is intended that the scope of the
invention be defined by all of the embodiments encompassed within
the following claims and their equivalents.
1TABLE 1 Example Formulations Example # Monomer 1 Monomer 2 Monomer
3 Solvent 1 Solvent 2 Initiator 1 Accelerator Rotation Tube ID 1 1%
HEMA 99% water 0.01% APS 0.01% SMBS 4000 rpm 2.4 mm 2 1.9% HEMA
0.1% PEGMA 98% water 0.02% APS 0.02% SMBS 2700 rpm 3.2 mm 3 7% HEMA
93% water 0.05% APS 0.04% SMBS 4000 rpm 7.5 mm 4 15.75% HEMA 2.25%
MMA 0.02% EDMA 82% water 0.08% APS 0.06% SMBS 2700 rpm 3.2 mm 5 20%
HEMA 0.06% EDMA 80% water 0.1% APS 0.04% TEMED 2700 rpm 2.4 mm 6
20% HEMA 0.02% EDMA 80% water 0.1% APS 0.06% SMBS 10000 rpm 2.4 mm
7 23.25% HEMA 1.75% MMA 75% water 0.125% APS 0.1% SMBS 2500 rpm 3.2
mm 8 28.3% HEMA 5.3% MMA 58.3% water 8.3% EG 0.125% APS 0.1% SMBS
2700 rpm 1.8 mm 9 27% HEMA 3% MMA 70% water 0.1 APS 0.075% SMBS
4000 rpm 2.4 mm 10 27% HEMA 3% MMA 70% water 0.15% APS 0.12% SMBS
2700 rpm 2.4 mm 11 20% HEMA 80% water 0.1% APS 0.4% SMBS 2700 rpm
3.2 mm 12 2% HEMA 98% water 0.02% APS 0.02% SMBS 30 rpm 3.2 mm 13
(o) 1.8% HEMA 0.2% PEGMA 98% water 0.002% APS 0.002% SMBS 2700 rpm
3.2 mm 13 (i) 27% HEMA 3% MMA 70% water 0.12% APS 0.09% SMBS 4000
rpm 14 20% HEMA 0.02% EDMA 80% water 0.1% APS 0.04% SMBS 2700 rpm
2.4 mm 15 28.3% HEMA 5.3% MMA 58.3% water 8.3% EG 0.15% APS 0.12%
SMBS 2700 rpm 1.8 mm 16 27.3% HEMA 2.7% MMA 0.03% EDMA 70% water
0.12% APS 0.09% SMBS 4000 rpm 3.2 mm 17 22.5% HEMA 2.5% MMA 75%
water 0.125% APS 0.1% SMBS 4000 rpm 0.45 mm 18 23.25% HEMA 1.75%
MMA 75% water 0.125% APS 0.1% SMBS 2500 rpm 2.8 mm to 5.8 mm 22 30
vol % HPMA 1% MBAm 65% acetone 4.9% DMSO 1% AIBN 4000 rpm 3.2
mm
[0189]
2TABLE 2 Example Formulations Exam- Monomer ple # Monomer 1 Monomer
2 3 particulate Solvent 1 Solvent 2 Initiator accelerator Rotation
Tube ID 25 19.77% HEMA 0.02% 1% PCL 79.04% H.sub.2O 0.1% APS 0.04%
2700 rpm 2.4 mm EDMA microspheres SMBS 27 19.77% HEMA 0.02% 1% PCL
79.04% H.sub.2O 0.1% APS 0.04% 2700 rpm 2.4 mm EDMA microspheres
SMBS 28 2% HEMA -- 0.002% 1% PCL 98% H.sub.2O 0.1% APS 0.04% 6000
rpm EDMA microspheres SMBS with NGF & OVA 29 28.05% HEMA 4.95%
MMA 2% Glass 67% H.sub.2O 0.165% 0.132% 2500 rpm 2.4 mm fibers APS
SMBS 30 (o) 23% HEMA 2% MMA 0.02% 75% H.sub.2O 0.125% 0.1% 6000 rpm
4.2 mm EDMA APS SMBS 30 (i) 2% HEMA 0.002% 1% PCL 98% H.sub.2O 0.1%
APS 0.04% 6000 rpm EDMA microspheres SMBS with NGF & OVA 32 25%
HEMA 2.5% MMA 72.5% H.sub.2O 0.1% APS 0.075% 4000 rpm 4.2 mm SMBS
33 21.3% HEMA 2.1% MMA 74.4% H.sub.2O 0.12% APS 0.1% 4000 rpm 4.2
mm SMBS 34 22.5% HEMA 2.5% MMA stent 75% H.sub.2O 0.2% APS 0.15%
6000 rpm 2.2 mm SMBS 35 28.05% HEMA 4.95% MMA Coiled Mn 67%
H.sub.2O 0.165% 0.132% 2500 rpm 2.4 mm wire APS SMBS 36 28.05% HEMA
4.95% MMA 67% H.sub.2O 0.165% 0.132% 2500 rpm 2.4 mm APS SMBS 37
28.05% HEMA 4.95% MMA 67% H.sub.2O 0.165% 0.132% 2500 rpm 2.4 mm
APS SMBS 38 10% Dex-GMA, 10% PEG 80% H.sub.2O 0.14% APS 0.018% 6000
rpm 4.6 mm 40K MW, DS 10 10K g/mol SMBS 39 10% Dex-GMA, 20% PEG 70%
H.sub.2O 0.14% APS 0.018% 6000 rpm 4.8 mm 40K MW, DS 10 10K g/mol
SMBS 40 20% Dex-GMA, 10% PEG 70% H.sub.2O 0.28% APS 0.035% 6000 rpm
4.8 mm 40K MW, DS 10 10K g/mol SMBS 41 20% Dex-GMA, 20% PEG 60%
H.sub.2O 0.28% APS 0.035% 6000 rpm 4.8 mm 40K MW, DS 10 10K g/mol
SMBS 42 20% Dex-GMA, 10% PEG 70% H.sub.2O 0.28% APS 0.035% 6000 rpm
4.8 mm 6K MW, DS 10 10K g/mol SMBS 43 20% Dex-GMA, 20% PEG 60%
H.sub.2O 0.28% APS 0.035% 6000 rpm 4.3 mm 6K MW, DS 10 10K g/mol
SMBS 44 30% Dex-GMA, 10% PEG 60% H.sub.2O 0.42% APS 0.053% 6000 rpm
4.5 mm 6K MW, DS 10 10K g/mol SMBS 45 10% Dex-HEMA, 10% PEG 80%
H.sub.2O 0.14% APS 0.018% 6000 rpm 4.3 mm 40K MW, DS 10 10K g/mol
SMBS 46 20% Dex-HEMA, 20% PEG 60% H.sub.2O 0.28% APS 0.035% 6000
rpm 4.8 mm 40K MW, DS 10 10K g/mol SMBS 47 10% Dex-GMA, 10%
Pluronic 80% H.sub.2O 0.14% APS 0.018% 6000 rpm 4.6 mm 40K MW, DS
10 F68 SMBS 48 10% Dex-GMA, 1% PCL 10% PEG 80% H.sub.2O 0.14% APS
0.018% 6000 rpm 4.6 mm 40K MW, DS 10 microspheres 10K g/mol SMBS
with dextranase & OVA 49 10% Dex-Lys-Pro- 10% PEG 80% H.sub.2O
0.14% APS 0.018% 6000 rpm 4.6 mm Leu-Gly-Ile-Ala- 10K g/mol SMBS
methacrylate, 40K MW, DS 10 50 10% Dex-Lys-Pro- 1% PCL 10% PEG 80%
H.sub.2O 0.14% APS 0.018% 6000 rpm 4.6 mm Leu-Gly-Ile-Ala-
microspheres 10K g/mol SMBS methacrylate, 40K with MMP2 & MW,
DS 10 OVA 51 10% Dex-GMA, 2 Units/g 10% PEG 80% H.sub.2O 0.14% APS
0.018% 6000 rpm 4.6 mm 40K MW, DS 10 dextranase 10K g/mol SMBS
* * * * *