WO2003033580A2

WO2003033580A2 - Non-degradable and degradable porous materials with high surface areas

Info

Publication number: WO2003033580A2
Application number: PCT/US2002/033000
Authority: WO
Inventors: Peter X. Ma
Original assignee: The Regents Of The University Of Michigan
Priority date: 2001-10-17
Filing date: 2002-10-16
Publication date: 2003-04-24
Also published as: WO2003033580A3

Abstract

A method for preparing a highly porous, high surface area material comprises steps of mixing a non-degradable polymer with a solvent; gelling the mixture; and treating the gel to form a substantially solvent free porous structure having a porosity greater than about 80 %. The resultant material is mechanically strong and has an architecture selected from nanofibrous, microfibrous, non-fibrous, complex porous structure with nanofibrous architecture, or mixtures thereof. A method for preparing a highly porous, high surface area material comprises steps of mixing a degradable or partially degradable polymer with a solvent mixture comprising a first and second solvent in a first to second solvent ratio higher than 1:1; gelling the mixture; and treating the gel to form a solvent free, mechanically strong, porous structure having a porosity greater than 80 % and having a complex porous structure with nanofibrous architecture.

Description

NON-DEGRADABLE AND DEGRADABLE POROUS MATERIALS WITH HIGH SURFACE AREAS

BACKGROUND OF THE INVENTION

The present invention relates generally to porous materials having high surface areas, and more particularly to such materials which are non-degradable, degradable or partially degradable, and methods for fabricating the same.

Membranes have been typically used for filtration (microfiltration, ultrafiltration, nanofiltration), reverse osmosis (hyperfiltration), dialysis, pervaporation, and gas separation applications. See Scott, K. and R. Hughes, Industrial Membrane Separation Technology, 1996, London: Blackie Academic & Professional; Baker, R.W., Membrane technology and applications, McGraw-Hill professional engineering, 2000, New York: McGraw-Hill; and Cardew, P.T., M.S. Le, and Royal Society of Chemistry, Process Technology Group, Membrane processes : a technology guide, 1998, Cambridge: Royal Society of Chemistry.

A solid membrane can be made of synthetic polymers, natural macromolecules, inorganic compounds, ceramic, or metallic materials. These membrane materials are generally fabricated through sintering, stretching, extrusion, phase inversion and etching, or casting. See Scott, K. and R. Hughes, Industrial Membrane Separation Technology, 1996, London: Blackie Academic & Professional; and Pinnau, I. and B.D. Freeman, Membrane formation and modification, ACS symposium series, 744, 2000, Washington, DC [New York]: American Chemical Society, Distributed by Oxford University Press.

Porous membranes are advantageous in their low resistance to mass transfer of solutes in solution due to the increased permeation rate resulting from the pores. Therefore, porous membranes have been employed for separation of mixtures of proteins and macromolecules, salt concentration, sterilization, etc. They can also serve as 3-D matrices for chemical and biochemical mass exchange or reactions to take place, or for cells or other living organisms (e.g., bacteria, viruses, fungi) to grow. Therefore, they can be used as matrices in diagnostic systems, catalysis systems, culture systems, drug delivery systems, wound dressings, etc. U.S. Patent No. 6,146,892 discloses a method for producing nanofibrillar matrices utilizing degradable polymers, such as for example, poly(L- lactic acid) (PLLA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), and the like. The disclosed nanofibrillar matrices are highly porous and work well for various applications. However, the pores sizes are very small (on the order of 2 μm to 3 μm), which may in some instances render it more difficult for cells to enter. Further, small pore sizes may render it more difficult for material transport, especially materials which are particulate or contain particles. Yet further, the disclosed non-fibrillar structure (a platelet structure) was not as mechanically strong as may be desirable in some instances.

SUMMARY OF THE INVENTION The present invention comprises a method for preparing a highly porous, high surface area material, comprising the steps of mixing a non-degradable polymer with a solvent or mixture of solvents; gelling the mixture; and treating the gel under conditions whereby a substantially solvent free porous structure is created having a porosity greater than about 80%; wherein the material is mechanically strong and has an architecture comprising at least one of nano fibrous, micro fibrous, non fibrous, complex porous structure with nano fibrous architecture, and mixtures thereof. The present invention further comprises a method for preparing a highly porous, high surface area material, comprising the steps of mixing a degradable or partially degradable polymer with a mixed solvent comprising a first solvent and a second solvent, wherein the mixed solvent comprises a ratio higher than 1:1, first solvent to second solvent; gelling the mixture; and treating the gel under conditions whereby a substantially solvent free porous structure is created having a porosity greater than about 80%; wherein the material is mechanically strong and has a complex porous structure with nano fibrous architecture. BRIEF DESCRIPTION OF THE DRAWINGS Objects, features and advantages of the present invention will become apparent by reference to the following detailed description and drawings, in which: Figure la is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of acetic acid/water (80/20) at the following gelation temperature: room temperature;

Figure lb is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of acetic acid/water (80/20) at the following gelation temperature: -20 °C;

Figure lc is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of acetic acid/water (80/20) at the following gelation temperature: -70 °C; Figure Id is a SEM micrograph of PA-6,6 foam prepared from a 10%

PA-6,6 solution in a mixed solvent of acetic acid/water (80/20) at the following gelation temperature: in liquid nitrogen;

Figure 2a is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: room temperature;

Figure 2b is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -20 °C;

Figure 2c is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -70°C, at x500 magnification;

Figure 2d is a SEM micrograph of PA-6,6 foam prepared from a 10% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -70 °C, at x4000 magnification; Figure 3 a is a SEM micrograph of PA-6,6 foam prepared from 10%

PA-6,6 solutions in a mixed solvent of formic acid/water (70/30) quenched in liquid nitrogen, at x500 magnification;

Figure 3b is a SEM micrograph of PA-6,6 foam prepared from 10% PA-6,6 solutions in a mixed solvent of formic acid/water (70/30) quenched in liquid nitrogen, at x2000 magnification; Figure 3c is a SEM micrograph of PA-6,6 foam prepared from 10% PA-6,6 solutions in a mixed solvent of formic acid/water (80/20) quenched in liquid nitrogen, at x500 magnification;

Figure 3d is a SEM micrograph of PA-6,6 foam prepared from 10% PA-6,6 solutions in a mixed solvent of formic acid/water (80/20) quenched in liquid nitrogen, at x4000 magnification;

Figure 4a is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: room temperature; Figure 4b is a SEM micrograph of PA-6,6 foam prepared from a 5%

PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -20°C;

Figure 4c is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -70°C;

Figure 4d is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: in liquid nitrogen;

Figure 5a is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature (dioxane instead of water was used for solvent exchange): room temperature;

Figure 5b is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature (dioxane instead of water was used for solvent exchange): - 20°C;

Figure 5c is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature (dioxane instead of water was used for solvent exchange): - 70°C; Figure 5d is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature (dioxane instead of water was used for solvent exchange): in liquid nitrogen; Figure 6a is a SEM micrograph of PA-6,6 foam prepared from a 5%

PA-6,6 solution in a mixed solvent of formic acid/THF (40/60) at the following gelation temperature: room temperature;

Figure 6b is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/THF (40/60) at the following gelation temperature: -20 °C;

Figure 6c is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/THF (40/60) at the following gelation temperature: -70 °C;

Figure 6d is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/THF (40/60) at the following gelation temperature: in liquid nitrogen;

Figure 7a is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/acetic acid/water (64/16/20) at the following gelation temperature: -20°C; Figure 7b is a SEM micrograph of PA-6,6 foam prepared from a 5%

PA-6,6 solution in a mixed solvent of formic acid/acetic acid/water (64/16/20) at the following gelation temperature: -70 °C;

Figure 7c is a SEM micrograph of PA-6,6 foam prepared from a 5% PA-6,6 solution in a mixed solvent of formic acid/acetic acid/water (64/16/20) at the following gelation temperature: in liquid nitrogen;

Figure 8a is a SEM micrograph of PA-6,6 PA-6 (50/50) polymer blend foam prepared from a 5% PA-6,6/PA-6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -20 °C;

Figure 8b is a SEM micrograph of PA-6,6/PA-6 (50/50) polymer blend foam prepared from a 5% PA-6,6/PA-6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: -70 °C; Figure 8c is a SEM micrograph of PA-6,6/PA-6 (50/50) polymer blend foam prepared from a 5% PA-6,6/PA-6 solution in a mixed solvent of formic acid/water (70/30) at the following gelation temperature: in liquid nitrogen;

Figure 9a is a SEM micrograph of PA-6 foam prepared from a 5% PA-6 solution in a mixed solvent of acetic acid/water (60/40) at the following gelation temperature: -20°C;

Figure 9b is a SEM micrograph of PA-6 foam prepared from a 5% PA-6 solution in a mixed solvent of acetic acid/water (60/40) at the following gelation temperature: in liquid nitrogen, at x500 magnification; Figure 9c is a SEM micrograph of PA-6 foam prepared from a 5%

PA-6 solution in a mixed solvent of acetic acid/water (60/40) at the following gelation temperature: in liquid nitrogen, at x2000 magnification;

Figure 9d is a SEM micrograph of PA-6 foam prepared from a 5% PA-6 solution in a mixed solvent of acetic acid/water (60/40) at the following gelation temperature: in liquid nitrogen, at x2000 magnification;

Figure 10a is a SEM micrograph of porous PVDF material prepared with PVDF solution in DMSO, phase-separation temperature of -18°C, low magnification;

Figure 10b is a SEM micrograph of porous PVDF material prepared with PVDF solution in DMSO, phase-separation temperature of - 18 ° C, intermediate magnification;

Figure 10c is a SEM micrograph of porous PVDF material prepared with PVDF solution in DMSO, phase-separation temperature of -18°C, high magnification; Figure lOd is a SEM micrograph of porous PVDF material prepared with PVDF solution in DMSO, phase-separation temperature of -70°C, low magnification;

Figure lOe is a SEM micrograph of porous PVDF material prepared with PVDF solution in DMSO, phase-separation in liquid nitrogen, low magnification; Figure 1 la is a SEM micrograph of porous PLLA material generated with PLLA solution in dioxane/pyridine mixed solvent with a ratio higher than 1:1, specifically, 7.5% PLLA in 2:1 dioxane/pyridine, at lOOx magnification;

Figure 1 lb is a SEM micrograph of porous PLLA material generated with PLLA solution in dioxane/pyridine mixed solvent with a ratio higher than 1:1, specifically, 7.5% PLLA in 2:1 dioxane/pyridine, at lOOOx magnification;

Figure 1 lc is a SEM micrograph of porous PLLA material generated with PLLA solution in dioxane/pyridine mixed solvent with a ratio higher than 1:1, specifically, 7.5% PLLA in 3:1 dioxane/pyridine, at 400x magnification; and Figure 1 Id is a SEM micrograph of porous PLLA material generated with PLLA solution in dioxane/pyridine mixed solvent with a ratio higher than 1:1, specifically, 7.5% PLLA in 3:1 dioxane/pyridine, at 7000x magnification. DETAILED DESCRIPTION OF THE EMBODIMENTS It would be desirable to provide highly porous structures having large pore sizes and high specific surface areas. It would further be desirable to provide such structures which are mechanically strong. Still further, it would be desirable to provide a variety of architectures, including but not limited to nano fibrous, micro fibrous, non fibrous, complex porous structure with nano fibrous architecture, and the like. The present invention is predicated upon the unexpected and fortuitous discovery that a recently discovered phase separation technique may be utilized to render highly porous, mechanically strong, high surface areas materials having varied architectures (eg. nano fibrous, micro fibrous, non fibrous, complex porous structure with nano fibrous architecture) by using non-degradable polymers. The novel materials of the present invention may have pore sizes ranging between about 30 μm and about 300 μm, with similarly sized connections, hi contrast, it had been expected that, whatever polymer were used, if the process as disclosed in U.S. Patent No. 6,146,892 were followed, it would render primarily nanofibrous structures. Further, it had been expected that if a non-nanofibrous structure were created, it may not be as mechanically strong as desirable for certain applications.

Still further, it had been expected that, whatever solvent/solvent system were used, if the process as disclosed in U.S. Patent No. 6,146,892 were followed, it would render primarily relatively simple (non-complex), uniformly nanofibrous structures having relatively small pores (eg. pore sizes on the order of 2 μm to 3 μm).

High surface areas are very desirable in that, if a material has a very high surface area, less of the material (compared to a low surface area material) may be used in order to render the same result; ie. the reaction is more efficient.

Without being bound to any theory, it is believed that the ladder like structure contained within the nanofibrous structure of an embodiment of the present invention (Figures 11) leads to the very high pore sizes disclosed therein. These large pore sizes promote and facilitate cell growth, mass transport processes, cell seeding, etc.

Some exemplary polymers suitable for the present invention comprise at least one of natural or synthetic hydrophilic polymers, natural or synthetic hydrophobic polymers, natural or synthetic amphiphilic polymers, degradable polymers, partially degradable polymers, and mixtures thereof.

Some exemplary, non-limitative non-degradable water soluble (hydrophilic) polymers include polyvinyl alcohol, polyethylene oxide, polymethacrylic acid (PMAA), polyacrylic acid, polyethylene glycol, alginate, collagen, gelatin, hyaluronic acid, and mixtures thereof. It is to be understood that the natural macromolecules such as alginate, collagen, gelatin and hyaluronic acid are generally not degradable unless treated with appropriate enzymes.

Some exemplary, non-limitative non-degradable water insoluble (hydrophobic) polymers include polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyamides (PA, Nylons), polyethylenes (PE), polysulfones, polyethersulphone, polypropylenes (PP), silicon rubbers, polystyrenes, polycarbonates, polyesters, polyacrylonitrile (PAN), polyimides, polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), polyvinylacetate (PVAc), polyphenylene oxide, cellulose and its derivatives, polypropylene oxide (PPO), polyvinylidene fluoride (PVDF), polybutylene, and mixtures thereof. Some degradable polymers of choice comprise at least one of poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), poly(L-lactic acid) (PLLA), poly(D,L-lactic acid) (PDLLA), polyglycolic acid (PGA), polyanhydrides, poly(ortho ethers), and mixtures thereof.

Further exemplary, non-limitative degradable polymers (which may or may not be water soluble) include polyamino acids, engineered artificial proteins, natural proteins, biopolymers, and mixtures thereof.

Partially degradable polymers may be formed through the block copolymerization of a degradable polymer with a non-degradable polymer. Examples of non-degradable polymers are disclosed hereinabove. A few non- limitative examples of partially degradable polymers include a block copolymer of PMMA PLA; and a block copolymer of polyethylene oxide/PLA.

It is to be understood that any suitable solvents may be used in embodiments of the present invention pertaining to non-degradable porous materials, providing the solvent(s) performs suitably within the context of the present inventive method. In an embodiment of the present invention, the solvent comprises at least one of water, acetic acid, formic acid, tetrahydiOfuran (THF), dimethylsulfoxide

(DMSO), dioxane, benzene, and mixtures thereof.

It is to be understood that any suitable solvents may be used in embodiments of the present invention pertaining to degradable or partially degradable porous materials, provided that the solvent(s) performs suitably within the context of the present inventive method. In an embodiment, a mixed solvent is used at a ratio of higher than 1:1, first solvent to second solvent. In an embodiment, the first solvent comprises dioxane, benzene, and mixtures thereof; and the second solvent comprises pyridine, tetrahydrofuran (THF), and mixtures thereof. It is to be understood that dioxane may be mixed with pyridine and/or THF; and that benzene may be mixed with pyridine and/or THF. In an embodiment, the ratio of first solvent to second solvent is 2:1; and in an alternate embodiment, the ratio of first solvent to second solvent is 3:1.

The dissolution/precipitation process is one of the most frequently used techniques to manufacture membrane materials. See, Young, T.H., L.P. Cheng, D.J. Lin, L. Fane, and W.Y. Chuang, Mechanisms of PVDF membrane formation by immersion-precipitation in soft (1-octanol) and harsh (water) nonsolvents, Polymer, 1999, 40(19): p. 5315-5323. In that technique, a polymer is first dissolved in a good solvent and cast on a substrate. The cast material is then immersed in a non-solvent' or poor solvent for the polymer to induce polymer precipitation from the solution. Industrial membranes fabricated with such techniques have a specific surface area typically lower than 5 m²/g (see Meier-Haack, J., W. Lenk, S. Berwald, T. Rieser, and K. Lunkwitz, Influence of thermal treatment on the pervaporation separation properties ofpolyamide-6 membranes, Separation and Purification Technology, 2000. 19(3): p. 199-207), and typically with an intermediate or low porosity (70% or lower). The inventor of the present invention has recently developed a novel phase-separation technique to generate porous polymeric materials (porosity is typically higher than 80 or 90%) with a unique nano fibrous structure (an average fiber diameter ranging from 50 nm to 500 nm). See Ma, P.X. and R. Zhang, Fibrillar Matrices, in United States Patent 6,146,892, 2000, which Patent is incorporated by reference herein in its entirety; Zhang, R. and P.X. Ma, Synthetic nanofibrillar extracellular matrices with predesigned macroporous architectures, J Biomed Mater Res, 2000, 52(2): p. 430-438; and Zhang, R. and P.X. Ma, Fabrication of polymer scaffolds: Phase separation, in Methods of Tissue Engineering, A. Atala and R. Lanza, Editors, 2001, Academic Press: San Diego, CA (in press). With the new techniques, dissolution/gelation (phase- separation)/solvent exchange (may be optional) /freezing/freeze-drying are some illustrative sequences to create the porous nano fibrous structure.

In contrast, as stated hereinabove, the present invention has unexpectedly and fortuitously discovered new porous polymeric materials with a variety of porous architectures (e.g., nano fibrous, micro fibrous, or non fibrous, or complex porous structure with nano fibrous architecture) and very high surface areas, which are fabricated with the new techniques. Their structures and properties generally depend on either the polymer/solvent systems and/or the phase-separation conditions; such as type of polymer(s), type of solvent(s), mixture ratio of two or more types of polymer(s) and/or solvent(s), polymer concentration, phase-separation temperature and so forth. This invention discloses polymeric (or substantially polymeric) materials with very high surface areas, such as >5 m²/g, >10 m²/g, >20 m²/g, >50 m²/g, or much higher, and having high porosity such as 70%, 80%, 90% or even higher, using the new fabrication techniques. hi an embodiment, the novel materials of the present invention have a specific surface area ranging between about 5 m²/g and about 1000 m²/g. In an alternate embodiment, the materials have a specific surface area ranging between about 10 m²/g and about 500 m²/g. h yet another alternate embodiment, the materials have a specific surface area ranging between about 20 m²/g and about 200 m²/g.

The novel materials of the present invention may have pore sizes ranging between about 30 μm and about 300 μm, with similarly sized connections. In an alternate embodiment, the novel materials of the present invention may have pore sizes ranging between about 50 μm and about 100 μm, with similarly sized connections.

The polymers may be synthetic or natural. They may be homopolymers (with one structural unit) or copolymers (with two or more structural units). The copolymers maybe random copolymers, block copolymers, graft copolymers, and/or mixtures thereof. They may be one single polymer type or polymer blends. The materials may also be a composite of polymeric and non- polymeric materials. Further, it is to be understood that chemically or biologically active or inert materials may be involved as additives or as major components. These polymers may be physically, chemically, and/or biologically modified to improve certain properties or function. It is to be yet further understood that such modification may be carried out before fabrication (raw materials) or after fabrication of the porous materials. Fabrication Techniques 1. Polymer solution preparation

Accurately weighed polymer(s) was added into a flask, and calculated amount of solvent(s) was added into the flask to make a polymer solution of a desired concentration. In an embodiment, the polymer solution (polymer/solvent mixture) contains between about 1% and about 20% polymer. Typically, the polymers were dissolved for two hours or longer to ensure a homogeneous solution when stirred with a magnetic stirrer at either room temperature or an elevated temperature (at or higher than room temperature, for example, 20°C, 40°C, 50°C, 60°C, 70°C and so forth).

2. Porous polymer material fabrication

Typically, four processing steps were taken to prepare a porous polymer material from a polymer solution: (A) Polymer solution (typically pre- warmed to a temperature at or higher than room temperature, for example, 20 °C, 40°C, 50°C, 60°C, 70°C, 100°C and so forth) was added into a mold or container (e.g., Teflon vial). The mold containing the polymer solution was then rapidly transferred into a cooling device (e.g. a refrigerator or freezer) at a preset temperature to induce gelation. The cooling device is maintained at a predetermined temperature between about room temperature and about liquid nitrogen. The gelation time depended on temperature, solvent(s) and the polymer concentration of the solution. After gelation, the gel was kept at the gelling temperature for typically 2 hours or longer. (B) The mold containing the gel was immersed in a liquid (poor or non- solvent for the polymer) such as distilled water for solvent exchange. The water (or other liquid) was changed three times a day for two days. (C) The gel was removed from the water (or other liquid) and blotted by a piece of filter paper, and then was placed in a device set at a desired freezing temperature, the freezing temperature ranging between about room temperature and about liquid nitrogen. In an embodiment, the freezing temperature ranges between about room temperature and about -20 °C. h an alternate embodiment, the freezing temperature ranges between about room temperature and about -70 °C. The gel was frozen for typically 2 hours or longer. (D) The frozen gel was taken into a freeze-drying vessel, and was freeze- dried under a predetermined vacuum and at a predetermined temperature. It is to be understood that any suitable vacuum and temperature may be used; however, in an embodiment, a vacuum lower than 0.5 mmHg was used at a temperature ranging between about -5 °C and about -10°C. The frozen gel was freeze dried in an ice/salt bath for one week. The dried porous polymer material was then kept in a desiccator until characterization. Ch ar acterization

The morphologies of the porous materials were examined with scamiing electron microscopy (SEM) (S-3200N, Hitachi, Japan) at 15 kV. The samples were coated with gold using a sputter coater (Desk-II, Denton Vacuum hie.) for 200 seconds with a gas pressure of lower than about 50 mtorr and a current of about 40 mA.

The compressive mechanical properties of the scaffolds were measured with an MTS mechanical tester (Model: Synergie 200, MTS Systems

Corporation, Cary, NC). Cubic specimens with a side length of 5 mm were compressed with a cross-head speed of 0.5 mm/min. The compressive modulus was determined from the initial linear region of the stress-strain curve, and the yield strength was determined from the cross point of the two tangents on the stress-strain curve around the yield point. At least six specimens were tested for each sample, and the averages and standard deviations were calculated.

To further illustrate the present invention, the following examples are given. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present invention. EXAMPLES

1. PA-6,6 in acetic acid and water:

PA-6,6 was completely dissolved in pure acetic acid or acetic acid/water mixture with water content ranging from 10 to 30%. The gelation of the solution was observed when water content was higher than 20%. The gelation occurred when the temperature was from room temperature to liquid nitrogen. The typical morphologies of the resulting porous foams are shown in Figures la - Id. Figures la and lb are partially nano fibrous; and Figures lc and Id are non fibrous.

2. PA-6.6 in formic acid and water:

PA-6,6 was completely dissolved in pure formic acid or a mixture of formic acid and water with water content ranging from 0% to 35%. When the concentration of the polymer was higher than 10%, gelation was observed when the water content of the solvent was higher than 20% and the temperature was lower than -20 °C. For the polymer concentration lower than 5%, gelation was observed when water content was higher than 30%. The gelation was observed in a temperature range from -20°C to liquid nitrogen. The liquid used for solvent exchange was either water or tetrahydrofuran (THF). The typical morphologies of the foams are shown in

Figures 2a through 5d. Figures 2a and 2b are partially nano fibrous. Figures 2c and 2d have morphologies including several different structures. Figures 3a and 3b are non fibrous. Figures 3c and 3d are partially nano fibrous. Figures 4a, 4b and 4c are complex porous structure with nano fibrous architecture. Figure 4d is a spherical structure. Figures 5a - 5d are non fibrous.

3. PA-6,6 in formic acid and tetrahydrofuran ( HF^'):

PA-6,6 was completely dissolved in formic acid/THF co-solvent with THF content ranging from 5% to 60%. Gelation was observed when THF content was 60%. The gelation temperature range was from room temperature to liquid nitrogen. The typical morphologies of the foams are shown in Figures 6a - 6d.

Figures 6a - 6d are partially nano fibrous with interconnect structure and high surface area.

4. PA-6,6 in formic acid/acetic acid (80/20 and water:

PA-6,6 was completely dissolved in formic acid/acetic acid (80/20)/water co-solvent with water content ranging from 0% to 30%. Gelation of the solution was observed when the water content was higher than 20%. The gelation temperature was from room temperature to liquid nitrogen. The typical morphologies of the foams are shown in Figures 7a - 7c. Figure 7b is non fibrous. Figure 7c is partially nano fibrous. 5. PA-6,6 and PA-6 blends in formic acid and water:

The gelation was observed for the solution of PA-6,6/PA-6 (50/50) with a mixed solvent of formic acid and water (70/30). The gelation temperature ranged from room temperature to liquid nitrogen. The moφhologies of the foams are shown in Figures 8a - 8c. Figures 8a - 8c are complex porous structure with nano fibrous architecture. 6. PA-6 in acetic acid and water:

PA-6 was completely dissolved in acetic acid/water co-solvent with water content ranging from 0 to 40%. Gelation of the solution was observed when water content was higher than 30%. The gelation temperature was from room temperature to liquid nitrogen. The typical morphologies of the foam are shown in Figure 9. Figures 9a - 9d are complex porous structure with nano fibrous architecture.

7. PVDF in dimethylsulfoxide (DMSOV.

PVDF was easily dissolved in DMSO, and gelation occurred at a wide range of temperatures. With the new phase-separation and freeze-drying techniques, porous materials with complex architectures were formed. They had fibrous architecture, and the fibers are further composed of smaller features at the micrometer scale. Typical moφhologies are shown in Figures 10a - lOe. Figures 10a - lOe are micro fibrous. 8. PLLA in dioxane and pyridine:

PLLA was easily dissolved in a mixed solvent of dioxane and pyridine. We have previously found that PLLA solution could be used to fabricate nano fibrous PLLA foams with our fabrication techniques. See Ma, P.X. and R. Zhang, Fibrillar Matrices, in United States Patent 6,146,892, 2000; Ma, P.X. and R. Zhang, Synthetic nano-scale fibrous extracellular matrix, J Biomed Mater Res, 1999, 46(1): p. 60-72; and Zhu, S. and P.X. Ma, Development of phase structure during the processing ofpoly(l-lactic acid) scaffolds for tissue engineering, Polymer Preprints, 2000, 41(2): p. 1675-1676.

However, in the present invention, it has been unexpectedly and fortuitously found that if the solvent is a mixture of dioxane and pyridine with a ratio of dioxane/pyridine higher than 1:1, certain complex architectures can be generated with such techniques. In embodiments of the present invention, ratios of 2:1 and 3:1 dioxane to pyridine were used. However, it is to be understood that any ratio higher than 1 : 1 may be used to gain the advantages of the present invention. Some typical complex moφhologies, e.g. porous architecture at the micrometer scale (such as ladder-like) and fibrous architecture at the nanometer scale, are shown in Figures 11a

- l id.

9. PLGA in benzene and THF:

PLGA is dissolved in a mixed solvent of benzene and THF. Ratios of 2:1 and 3 : 1 benzene to THF are used. The polymer/solvent mixture contains between about 1% and about 20% PLGA. However, it is to be understood that any ratio higher than 1 : 1 may be used to gain the advantages of the present invention. The porous materials have complex moφhologies, e.g. porous architecture at the micrometer scale (such as ladder-like) and fibrous architecture at the nanometer scale.

Mechanical Properties and Specific Surface Area:

In the examples of the present invention described above, the generated highly porous materials have many interesting architectural features, which are novel. The porous materials generated in the present invention are believed to have excellent mechanical properties and higher specific surface areas than previously known porous materials. They have high potential to be used in a variety of biomedical, industrial and household applications. For many of these applications, a high specific surface area and the mechanical integrity are important.

For some of the porous materials generated (Figures 6), the specific surface area and mechanical properties are characterized. The compressive moduli are 5.22 ± 0.77 kPa and 7.36 ± 4.11 kPa for a PA-6,6 foam generated from 10% PA- 6,6 solution in formic acid/water (70/30) and a PA-6,6 foam generated from 5% PA- 6,6 solution in formic acid/THF (40/60) respectively. The mechanical properties for such highly porous materials are excellent. The specific surface area of a PA-6,6 foam prepared from 5% PA-6,6 solution in formic acid/THF (40/60) is 55 m²/g (BTE method), which is substantially higher than those currently on the market (typically lower than 5 m²/g).

As disclosed herein, the present invention comprises non-degradable porous materials having very high surface areas, and methods for fabricating the same. A variety of 3D architectures with features at the nanometer and or micrometer scales may advantageously be generated. The materials may be synthetic polymers, natural macromolecules, or their derivatives. They may be hydrophilic, hydrophobic, or amphiphilic. Further, the materials may be homo-polymers, copolymers, blends, mixtures, or composites of polymers. The novel porous materials may advantageously be used in a variety of applications including medical devices (eg. artificial kidney, dialysers), matrix materials for chemical reactors, bioreactors, controlled release devices, wound dressings, separation membranes, filters, catalysis systems, absorbents, packaging and insulating materials. Further, the porous materials may be desirable for use as tissue engineering scaffolds for a variety of applications, including implants. While preferred embodiments, forms and arrangements of parts of the invention have been described in detail, it will be apparent to those skilled in the art that the disclosed embodiments may be modified. Therefore, the description herein is to be considered exemplary rather than limiting, and the true scope of the invention is that defined in the following claims.

Claims

What is claimed is:

1. A method of preparing a porous material, comprising the steps of: mixing at least one non-degradable polymer with a solvent to provide a polymer/solvent mixture; gelling the mixture; and treating the gel under predetermined conditions whereby a substantially solvent free porous material is created having a porosity greater than about 80%, wherein the resultant porous material is mechanically strong, has a high specific surface area, and has an architecture comprising at least one of nano fibrous, micro fibrous, non fibrous, complex porous structure with nano fibrous architecture, and mixtures thereof.

2. The method as defined in claim 1 wherein the solvent comprises at least one of water, acetic acid, formic acid, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dioxane, benzene, and mixtures thereof.

3. The method as defined in claim 2 wherein the solvent comprises a mixture of at least two solvents.

4. The method as defined in claim 3 wherein the solvent comprises a mixture of acetic acid and water.

5. The method as defined in claim 3 wherein the solvent comprises a mixture of formic acid and water.

6. The method as defined in claim 3 wherein the solvent comprises a mixture of formic acid and THF.

7. The method as defined in claim 3 wherein the solvent comprises a mixture of acetic acid, formic acid and water.

8. The method as defined in claim 2 wherein the solvent comprises DMSO.

9. The method as defined in claim 1 wherein the at least one non- degradable polymer comprises at least one of natural or synthetic hydrophilic polymers, natural or synthetic hydrophobic polymers, natural or synthetic amphiphilic polymers, and mixtures thereof.

10. The method as defined in claim 9 wherein the at least one non- degradable polymer is a hydrophilic polymer comprising at least one of polyvinyl alcohol, polyethylene oxide, polymethacrylic acid (PMAA), polyacrylic acid, polyethylene glycol, alginate, collagen, gelatin, hyaluronic acid, and mixtures thereof.

11. The method as defined in claim 9 wherein the at least one non- degradable polymer is a hydrophobic polymer comprising at least one of polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyamides (PA, Nylons), polyethylenes (PE), polysulfones, polyethersulphone, polypropylenes (PP), silicon rubbers, polystyrenes, polycarbonates, polyesters, polyacrylonitrile (PAN), polyimides, polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), polyvinylacetate (PVAc), polyphenylene oxide, cellulose and its derivatives, polypropylene oxide (PPO), polyvinylidene fluoride (PVDF), polybutylene, and mixtures thereof.

12. The method as defined in claim 1, further comprising the step of heating the mixture to a temperature ranging between about room temperature and above room temperature before gelling.

13. The method as defined in claim 12 wherein the temperature ranges between about room temperature and about 100°C.

14. The method as defined in claim 1 wherein the gelling step is accomplished by rapidly transferring the mixture to a cooling device maintained at a temperature between about room temperature and about liquid nitrogen.

15. The method as defined in claim 14, wherein the gel treating step comprises the steps of: immersing the gel in a liquid to cause solvent exchange, wherein the liquid is a poor or non-solvent for the non-degradable polymer; removing the gel from the liquid; freezing the gel at a predetermined temperature, the temperature ranging between about room temperature and about liquid nitrogen; and freeze drying the frozen gel under vacuum.

16. The method as defined in claim 1, wherein the porosity is greater than approximately 85%.

17. The method as defined in claim 1, wherein the porosity is greater than approximately 90%.

18. The method as defined in claim 1, wherein the porosity is approximately 98%.

19. The method as defined in claim 1 wherein the porous material has a specific surface area greater than about 5 m²/g.

20. The method as defined in claim 19 wherein the porous material has a specific surface area ranging between about 10 m²/g and about 500 m²/g.

21. The method as defined in claim 20 wherein the porous material has a specific surface area ranging between about 20 m²/g and about 200 m²/g.

22. The method as defined in claim 1 wherein the porous material comprises pores having a size and connections therebetween, wherein the pore sizes range between about 30 μm and about 300 μm, and wherein the connections range in size between about 30 μm and about 300 μm.

23. The method as defined in claim 22 wherein the porous material comprises pores having a size and connections therebetween, wherein the pore sizes range between about 50 μm and about 100 μm, and wherein the connections range in size between about 50 μm and about 100 μm.

24. The method as defined in claim 4 wherein the polymer/solvent mixture contains about 10% polyamide-6,6.

25. The method as defined in claim 6 wherein the polymer/solvent mixture contains about 5% polyamide-6,6.

26. The method as defined in claim 5 wherein the polymer/solvent mixture contains about 5% of a 1:1 blend of polyamide-6,6 and polyamide-6.

27. The method as defined in claim 8 wherein the polymer/solvent mixture contains between about 5% and about 10% polyvinylidene fluoride.

28. The method as defined in 25 wherein the compressive modulus of the porous material ranges between about 5.22 ± 0.77 kPa and about 7.36 ± 4.11 kPa.

29. A non-degradable porous material formed by the process of claim 1.

30. A method of preparing a porous material, comprising the steps of: mixing at least one degradable or partially degradable polymer with a mixed solvent to provide a polymer/solvent mixture, wherein the mixed solvent comprises a first solvent and a second solvent, and wherein the mixed solvent comprises a ratio higher than 1:1, first solvent to second solvent; gelling the mixture; and treating the gel under predetermined conditions whereby a substantially solvent free porous material is created having a porosity greater than about 80%), wherein the resultant porous material is mechanically strong, has a high specific surface area, and has a complex architecture comprising porous architecture at the micrometer and larger scale and fibrous architecture at the nanometer scale.

31. The method as defined in claim 30 wherein the porous architecture at the micrometer and larger scale comprises substantially ladder structure.

32. The method as defined in claim 30 wherein the at least one degradable or partially degradable polymer comprises at least one of natural or synthetic hydrophilic polymers, natural or synthetic hydrophobic polymers, natural or synthetic amphiphilic polymers, and mixtures thereof.

33. The method as defined in claim 32 wherein the at least one degradable or partially degradable polymer is a degradable polymer comprising at least one of poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), poly(L-lactic acid) (PLLA), ρoly(D,L-lactic acid) (PDLLA), polyglycolic acid (PGA), polyanhydrides, poly(ortho ethers), and mixtures thereof.

34. The method as defined in claim 33 wherein the degradable polymer comprises at least one of polyamino acids, engineered artificial proteins, natural proteins, biopolymers, and mixtures thereof.

35. The method as defined in claim 32 wherein the at least one degradable or partially degradable polymer is a partially degradable polymer comprising at least one degradable polymer block copolymerized with at least one non-degradable polymer; wherein a hydrophilic non-degradable polymer comprises at least one of polyvinyl alcohol, polyethylene oxide, polymethacryhc acid (PMAA), polyacryhc acid, polyethylene glycol, alginate, collagen, gelatin, hyaluronic acid, and mixtures thereof; and wherein a hydrophobic non-degradable polymer comprises at least one of polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyamides (PA, Nylons), polyethylenes (PE), polysulfones, polyethersulphone, polypropylenes (PP), silicon rubbers, polystyrenes, polycarbonates, polyesters, polyacrylonitrile (PAN), polyimides, polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), polyvinylacetate (PVAc), polyphenylene oxide, cellulose and its derivatives, polypropylene oxide (PPO), polyvinylidene fluoride (PVDF), polybutylene, and mixtures thereof.

36. The method as defined in claim 35 wherein the at least one degradable polymer comprises at least one of poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), poly(L-lactic acid) (PLLA), poly(D,L-lactic acid) (PDLLA), polyglycolic acid (PGA), polyanhydrides, poly(ortho ethers), polyamino acids, engineered artificial proteins, natural proteins, biopolymers, and mixtures thereof.

37. The method as defined in claim 36 wherein the partially degradable polymer comprises a block copolymer of PMMA and PLA.

38. The method as defined in claim 36 wherein the partially degradable polymer comprises a block copolymer of polyethylene oxide and PLA.

39. The method as defined in claim 30, further comprising the step of heating the mixture to a temperature ranging between about room temperature and above room temperature before gelling.

40. The method as defined in claim 39 wherein the temperature ranges between about room temperature and about 100°C.

41. The method as defined in claim 30 wherein the gelling step is accomplished by rapidly transferring the mixture to a cooling device maintained at a temperature between about room temperature and about liquid nitrogen.

42. The method as defined in claim 41, wherein the gel treating step comprises the steps of: immersing the gel in a liquid to cause solvent exchange, wherein the liquid is a poor or non-solvent for the non-degradable polymer; removing the gel from the liquid; freezing the gel at a predetermined temperature, the temperature ranging between about room temperature and about liquid nitrogen; and freeze drying the frozen gel under vacuum.

43. The method as defined in claim 30, wherein the porosity is greater than approximately 85%.

44. The method as defined in claim 30, wherein the porosity is greater than approximately 90%.

45. The method as defined in claim 30, wherein the porosity is approximately 98%.

46. The method as defined in claim 30 wherein the porous material has a specific surface area greater than about 5 m²/g.

47. The method as defined in claim 46 wherein the porous material has a specific surface area ranging between about 10 m²/g and about 500 m²/g.

48. The method as defined in claim 47 wherein the porous material has a specific surface area ranging between about 20 m²/g and about 200 m²/g.

49. The method as defined in claim 30 wherein the porous material comprises pores having a size and connections therebetween, wherein the pore sizes range between about 30 μm and about 300 μm, and wherein the connections range in size between about 30 μm and about 300 μm.

50. The method as defined in claim 49 wherein the porous material comprises pores having a size and connections therebetween, wherein the pore sizes range between about 50 μm and about 100 μm, and wherein the connections range in size between about 50 μm and about 100 μm.

51. The method as defined in claim 30 wherein the polymer/solvent mixture contains between about 1% and about 20% PLA.

52. The method as defined in claim 30 wherein the polymer/solvent mixture contains between about 1% and about 20% PLGA.

53. The method as defined in claim 30 wherein the polymer/solvent mixture contains between about 1% and about 20% polyanhydrides.

54. The method as defined in claim 30 wherein the first solvent comprises dioxane and the second solvent comprises pyridine.

55. The method as defined in claim 54 wherein the ratio of dioxane to pyridine is 2:1.

56. The method as defined in claim 54 wherein the ratio of dioxane to pyridine is 3:1.

57. The method as defined in claim 30 wherein the first solvent comprises benzene and the second solvent comprises THF.

58. The method as defined in claim 57 wherein the ratio of benzene to THF is 2:1.

59. The method as defined in claim 57 wherein the ratio of benzene to THF is 3:1.

60. A degradable or partially degradable porous material formed by the process of claim 30.