U.S. patent application number 10/903384 was filed with the patent office on 2005-01-06 for method of producing structures using centrifugal forces.
This patent application is currently assigned to matRegen Corp.. Invention is credited to Dalton, Paul D., Shoichet, Molly S..
Application Number | 20050003127 10/903384 |
Document ID | / |
Family ID | 22755799 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050003127 |
Kind Code |
A1 |
Dalton, Paul D. ; et
al. |
January 6, 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 was induced within a filled mold as it was
being rotated about one of its axis. As phase-separation occurs
within this rotating mold, the increase in density of one phase
results in sediment at the periphery under centrifugal forces.
After or during sedimentation, gelation of the phase-separated
particles fixes the tube morphology and the solvent remains in the
center of the mold. The solvent is removed from the mold resulting
in a 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.; (Toronto,
CA) ; Shoichet, Molly S.; (Toronto, CA) |
Correspondence
Address: |
DOWELL & DOWELL PC
2111 Eisenhower Ave.
Suite 406
Alexandria
VA
22314
US
|
Assignee: |
matRegen Corp.
Toronto
CA
|
Family ID: |
22755799 |
Appl. No.: |
10/903384 |
Filed: |
August 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10903384 |
Aug 2, 2004 |
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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: |
428/36.9 |
Current CPC
Class: |
B29C 41/042 20130101;
B29C 39/08 20130101; Y10T 428/1352 20150115; B29C 39/006 20130101;
Y10T 428/139 20150115; B29L 2023/00 20130101; A61B 17/1128
20130101; A61K 9/0092 20130101; B29K 2105/04 20130101; B29C 37/006
20130101; B29C 41/50 20130101; B29L 2031/753 20130101; B29K
2105/0014 20130101 |
Class at
Publication: |
428/036.9 |
International
Class: |
B32B 001/08 |
Claims
1.-21. (cancelled)
22. A product produced by a method comprising the steps of: filling
an interior of a mold with a solution so that substantially all air
is displaced therefrom, the solution 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
solution at an effective rotational velocity in the presence of
said phase separation agent to induce phase separation between said
at least two components into at least two phases 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.
23. The product according to claim 22 including removing said
product from said mold.
24. The product according to claim 22 wherein said hollow mold is a
cylindrical tube so that said product is a tube.
25. The product according to claim 22 wherein said at least two
components includes at least one monomer and at least one solvent,
and wherein said solution is a substantially homogenous solution,
wherein said at least one of the phases that deposits onto the
inner surface includes at least the monomer, and wherein the step
of stabilizing said deposited phase includes gelation of the
monomer by polymerization thereof, wherein said product is a
polymeric product.
26. The product according to claim 22 wherein said at least two
components includes at least one polymer dissolved in at least one
solvent, and wherein said solution is a substantially homogenous
solution, 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,
wherein said product is a polymeric product.
27. The product according to claim 25 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
28. The product according to claim 25 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.
29. The product according to claim 22 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.
30. The product according to claim 25 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.
31. The product according to claim 25 wherein the solution contains
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.
32. The product according to claim 23 wherein said hollow mold is a
cylindrical tube so that said product is a tube.
33. The product according to claim 24 wherein said tube has an
internal diameter in a range from about 10 .mu.m to about 100
cm.
34. The product according to claim 32 wherein said tube has an
internal diameter in a range from about 10 .mu.m to about 100
cm.
35. The product according to claim 23 wherein said at least two
components includes at least one monomer and at least one solvent,
and wherein said solution is a substantially homogenous solution,
wherein said at least one of the phases that deposits onto the
inner surface includes at least the monomer, and wherein the step
of stabilizing said deposited phase includes gelation of the
monomer by polymerization thereof, wherein said product is a
polymeric product.
36. The product according to claim 24 wherein said at least two
components includes at least one monomer and at least one solvent,
and wherein said solution is a substantially homogenous solution,
wherein said at least one of the phases that deposits onto the
inner surface includes at least the monomer, and wherein the step
of stabilizing said deposited phase includes gelation of the
monomer by polymerization thereof, wherein said product is a
polymeric product.
37. The product according to claim 23 wherein said at least two
components includes at least one polymer dissolved in at least one
solvent, and wherein said solution is a substantially homogenous
solution, 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,
wherein said product is a polymeric product.
38. The product according to claim 24 wherein said at least two
components includes at least one polymer dissolved in at least one
solvent, and wherein said solution is a substantially homogenous
solution, 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,
wherein said product is a polymeric product.
39. The product according to claim 26 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
40. The product according to claim 35 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
41. The product according to claim 36 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
42. The product according to claim 37 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 38 wherein the product has a
wall morphology that includes a porous structure, a gel structure
or overlapping regions of porous/gel structure.
44. The product according to claim 26 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.
45. The product according to claim 35 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.
46. The product according to claim 36 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.
47. The product according to claim 37 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.
48. The product according to claim 38 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.
49. The product according to claim 26 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.
50. The product according to claim 35 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.
51. The product according to claim 36 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.
52. The product according to claim 37 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.
53. The product according to claim 38 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.
54. The product according to claim 26 wherein the solution contains
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.
55. The product according to claim 35 wherein the solution contains
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.
56. The product according to claim 36 wherein the solution contains
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.
57. The product according to claim 37 wherein the solution contains
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.
58. The product according to claim 38 wherein the solution contains
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.
59. The product according to claim 22 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.
60. The product according to claim 23 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.
61. The product according to claim 24 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.
62. The product according to claim 25 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.
63. The product according to claim 26 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.
Description
FIELD OF INVENTION
[0001] This invention relates to a method of manufacturing
structures and particularly polymeric tubular structures with
complex and unique morphologies in the walls, and on the inner and
outer surfaces of the structures.
BACKGROUND OF THE INVENTION
[0002] Tubular structures 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, 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.
[0003] 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.
[0004] 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
(air 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 air 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.
[0005] 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.
[0006] 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.
SUMMARY OF INVENTION
[0007] The present invention provides a process of producing a
product, comprising:
[0008] a) filling an interior of a mold with a solution so that
substantially all air is displaced therefrom, the solution
comprising at least two components which can be phase separated by
a phase separation agent into at least two phases;
[0009] b) rotating said mold containing said solution at an
effective rotational velocity in the presence of said phase
separation agent to induce phase separation between said at least
two components into at least two phases so that under rotation at
least one of the phases deposits onto an inner surface of the mold;
and
[0010] c) forming said product by stabilizing said at least one of
the phases deposited onto the inner surface of the mold.
[0011] The present invention provides a product produced by the
method, comprising:
[0012] a) filling an interior of a mold with a solution so that
substantially all air is displaced therefrom, the solution
comprising at least two components which can be phase separated by
a phase separation agent into at least two phases;
[0013] b) rotating said mold containing said solution at an
effective rotational velocity in the presence of said phase
separation agent to induce phase separation between said at least
two components into at least two phases so that under rotation at
least one of the phases deposits onto an inner surface of the mold;
and
[0014] c) forming said product by stabilizing said at least one of
the phases deposited onto the inner surface of the mold.
[0015] 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 solution includes either
monomers or polymers or both.
[0016] 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.
[0017] 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.
[0018] The polymeric product may be used as a reservoir for the
delivery of drugs, therapeutics, cells, cell products, genes, viral
vectors, proteins, peptides, hormones, carbohydrates, growth
factors.
[0019] 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.
BRIEF DESCRIPTION OF DRAWINGS
[0020] The following is a description, by way of example only, of
the method of producing tubes in accordance with the present
invention, reference being had to the accompanying drawings, in
which:
[0021] FIG. 1a is a cross section of a cylindrical mold used to
manufacture tubes according to the present invention;
[0022] FIG. 1b is a cross section of an alternative embodiment of a
cylindrical mold;
[0023] FIG. 1c is a cross section of another alternative embodiment
of a cylindrical mold;
[0024] FIG. 1d is a cross section of another alternative embodiment
of a cylindrical mold;
[0025] 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;
[0026] 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;
[0027] 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;
[0028] 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;
[0029] 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;
[0030] 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;
[0031] 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;
[0032] 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);
[0033] 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;
[0034] 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);
[0035] 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);
[0036] 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);
[0037] FIG. 7b shows a SEM micrograph of 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);
[0038] 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;
[0039] 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).
[0040] 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);
[0041] 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);
[0042] 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);
[0043] 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);
[0044] 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);
[0045] 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);
[0046] 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
example10);
[0047] 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);
[0048] 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);
[0049] FIG. 12d shows an optical micrograph 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 12(a-c),
but spun in a silane-treated glass mold;
[0050] 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);
[0051] 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);
[0052] FIG. 14 shows a SEM micrograph of a cross-section of the
wall of a multi-layered 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);
[0053] 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);
[0054] 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);
[0055] 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;
[0056] 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);
[0057] FIG. 17b shows a SEM micrograph of cell-like surface
patterns on the inner surface of a tube shown in FIG. 17a;
[0058] 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; and
[0059] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0060] The forces that generate the tubular structures in this
novel process are inertial forces associated with spinning a mold.
A mold is filled with a homogeneous solution containing at least
two components that can be phase separated thereby displacing
substantially all of the visible 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.
Phase separation of this homogeneous solution is induced by a phase
separating agent while the mold is spinning.
[0061] The spinning will only send one of the phases to the inner
surface of the mold, therefore broadly speaking this phase which
adopts the shape of the inner surface of the mold needs to be
stabilized to produce the product. Specifically, this separated
phase must be stabilized to prevent it from falling off the surface
of the mold and returning to the solution and generally the method
of stabilization will depend on the nature of the material in the
separated phase.
[0062] When the products are polymeric, the components of the
solution may contain monomers or polymers or both. The phase
separation process may result from changes in solubility as induced
by changes in polymer chain length, changes in temperature,
creation of a chemical product within the mold, changes in pH, or
exposure to light, electric or magnetic fields. The greater density
of one of the phase-separated phases results in the phase adopting
the shape of the inner surface of the mold.
[0063] Gelation of the separated phase fixes 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 frequency of the ultra-violet/visible light
at the phase-separated mixture. By controlling rotational speed,
formulation chemistry, surface chemistry and dimensions of the
mold, the resulting morphology, mechanical and porosity properties,
of the resulting product can be manipulated.
[0064] Tubes 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 0.02 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 air during liquid injection.
The desired homogeneous liquid was injected via needle C through
septum B at the lower end of the mold, displacing all of the air
within the mold. Withdrawing the needles D, then C, results in a
sealed, liquid filled mold. For concentricity and a uniform tube
along the length, the sealed mold was placed into the chuck of a
drill that had been mounted horizontally, using a spirit level.
[0065] 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.
[0066] 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. In all these embodiments the
surface features can be of symmetrical or non-symmetrical order,
and different surface features can be used in any combination.
[0067] The inner surface of the mold 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.
[0068] 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
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 mold is commenced. O-rings (I) maintain position of
mold (A) inside the adapter (H).
[0069] FIGS. 5a and 5b show the process of phase separation during
rotation of the mold. In FIG. 5a the mold (A) filled with a
homogeneous 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).
[0070] 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.
[0071] With the rotating mold containing the homogeneous liquid,
phase separation of the mixture was induced, creating at least two
phases from the liquid inside the mold. Phase separation may result
in either liquid-liquid or viscoelastic solid-liquid interfaces or
both within the mold. Phase separation can be induced using a range
of different techniques and environmental changes. The addition of
a propagating radical to a homogeneous monomer solution can induce
phase separation, as can changes in temperature, pH, exposure of
the mold to light, electric and magnetic fields.
[0072] After inducing different phases within the homogeneous
solution, 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 must commence at a finite time after the
onset of phase separation within the process of the invention.
[0073] A porous material can have an outer coating applied to it
using this technology. Prior to the injection of a homogeneous
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 homogeneous 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 forms a
structure on the outer surface of the porous plug, therefore
sealing the material, without blocking the internal pores.
[0074] In a preferred embodiment of the present invention the
homogenous solution includes at least two or more phases, one being
a monomer, or polymer, and the other a solvent.
[0075] For homogeneous solutions containing monomer to be
initiated, the initiation agent may be free radical initiators,
thermal initiators and redox initiators. Examples of initiators
includes 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.
[0076] The homogeneous solution 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) or combinations thereof.
[0077] An exemplary, non-limiting list of monomers that may be in
the homogeneous 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, and any combination thereof.
[0078] An exemplary, non-limiting list of polymers that may be in
the homogeneous mixture includes any of polyacrylates, 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-iminosebacoyl),
poly[imino(1-oxododecamethylene)]- , cellulose, polysulfones,
hyalonic acid, sodium hyaluronate, alginate, agarose, chitosan,
chitin, and mixtures thereof.
[0079] A non-limiting exemplary list of solvents in the homogeneous
mixture for the monomer and/or polymers includes any neucleophilic
or electrophilic molecule including, but not necessarily restricted
to water, alcohols, 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.
[0080] 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.
[0081] In another embodiment a tapered hollow structure with
changing dimensions along it length can be manufactured where the
sealed mold is rotated at a predetermined angle between 0 and
90.degree. from the horizontal plane.
[0082] 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 phase is large enough for
the penetration of cells into the construct.
[0083] 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 phase can be removed and another
homogeneous mixture injected into the mold. The first layer coating
the mold, effectively becomes the mold for the next coating and the
second formation penetrates 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.
[0084] Manufacture of both physically and chemically crosslinked
tubes 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, which may be incorporated in another material/drug reservoir,
such as microspheres releasing the drug. 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, proteins,
peptides, genes, vectors, growth factors, hormones,
oligonucleotides, cell products, or cells or combinations
thereof.
[0085] 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 tubular 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.
[0086] The present method can be used to produce tubular structures
that have an outer gel phase and an inner porous phase. The present
method can also be used to provide a tubular structure with
overlapping regions of porous phase/gel phase.
[0087] 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.
[0088] 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 where phase separation precedes
gelation of polymer networks formed, 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.
EXAMPLE 1
[0089] 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.
[0090] 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
[0091] 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
[0092] 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
[0093] 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.
EXAMPLE 6-7
[0094] 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).
[0095] 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).
EXAMPLE 8-9
[0096] 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.
[0097] 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
[0098] 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.+-.4.degree- . 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
[0099] 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
[0100] 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 (FIG. 7a and 7b) which has the similar
monomer concentrations, but significantly different rotation
rates.
EXAMPLE 13
[0101] 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
[0102] 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
[0103] 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
[0104] 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
[0105] 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
[0106] 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
[0107] 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
[0108] 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
[0109] 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
[0110] 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.
[0111] 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
[0112] 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 Fmulations Exam- ple Monomer Solvent Rota- Tube #
Monomer 1 Monomer 2 3 Solvent 1 2 Initiator 1 Accelerator tion ID 1
1% HEMA 99% water 0.01% APS 0.01% SMBS 4000 2.4 rpm mm 2 1.9% HEMA
0.1% PEGMA 98% water 0.02% APS 0.02% SMBS 2700 3.2 rpm mm 3 7% HEMA
93% water 0.05% APS 0.04% SMBS 4000 7.5 rpm mm 4 15.75% HEMA 2.25%
MMA 0.02% 82% water 0.08% APS 0.06% SMBS 2700 3.2 EDMA rpm mm 5 20%
HEMA 0.06% EDMA 80% water 0.1% APS 0.04% TEMED 2700 2.4 rpm mm 6
20% HEMA 0.02% 80% water 0.1% APS 0.06% SMBS 10000 2.4 EDMA rpm mm
7 23.25% HEMA 1.75% MMA 75% water 0.125% APS 0.1% SMBS 2500 3.2 rpm
mm 8 28.3% HEMA 5.3% MMA 58.3% water 8.3% 0.125% APS 0.1% SMBS 2700
1.8 EG rpm mm 9 27% HEMA 3% MMA 70% water 0.1 APS 0.075% SMBS 4000
2.4 rpm mm 10 27% HEMA 3% MMA 70% water 0.15% APS 0.12% SMBS 2700
2.4 rpm mm 11 20% HEMA 80% water 0.1% APS 0.4% SMBS 2700 3.2 rpm mm
12 2% HEMA 98% water 0.02% APS 0.02% SMBS 30 3.2 rpm mm 13 1.8%
HEMA 0.2% PEGMA 98% water 0.002% APS 0.002% SMBS 2700 3.2 (o) rpm
mm 13 27% HEMA 3% 70% water 0.12% APS 0.09% SMBS 4000 (i) MMA rpm
14 20% HEMA 0.02% 80% water 0.1% APS 0.04% SMBS 2700 2.4 EDMA rpm
mm 15 28.3% HEMA 5.3% MMA 58.3% water 8.3% 0.15% APS 0.12% SMBS
2700 1.8 EG rpm mm 16 27.3% HEMA 2.7% MMA 0.03% 70% water 0.12% APS
0.09% SMBS 4000 3.2 EDMA rpm mm 17 22.5% HEMA 2.5% MMA 75% water
0.125% APS 0.1% SMBS 4000 0.45 rpm mm 18 23.25% HEMA 1.75% MMA 75%
water 0.125% APS 0.1% SMBS 2500 2.8 rpm mm to 5.8 mm 22 30 vol %
HPMA 1% MBAm 65% acetone 4.9% 1% AIBN 4000 3.2 DMSO rpm mm
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