Porous constructs fabricated by gas induced phase inversion

Details Porous constructs fabricated by gas induced phase inversion Porous constructs fabricated by gas induced phase inversion

2001-04-17

2003-09-16

Fortuna, Ana (Department: 1723)

Plastic and nonmetallic article shaping or treating: processes

Pore forming in situ

C210S500270, C210S490000, C264S083000, C521S051000, C521S064000, C521S155000

Reexamination Certificate

active

06620356

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for fabricating open-pore polymeric matrices using gas induced phase inversion. The present invention also relates to matrices prepared via this process of varying thickness and shape with open-pore morphologies, and pore sizes and densities ranging from, but not limited, about 10-500 &mgr;m in diameter and about 0.1 to 0.3 g/cm
3
. In the case of biodegradable and biocompatible polymers, matrices prepared via this process with these characteristics are useful in tissue engineering/regeneration applications including, but not limited to, medical implant devices to promote bone healing, cartilage repair, cellular infiltration and tissue ingrowth. Constructs prepared from commodity, engineering, or other thermoplastic polymers may be useful for such applications as filtration and separation aids and porous supports.
BACKGROUND OF THE INVENTION
A variety of techniques have been developed for fabricating open pore biodegradable polymer scaffolds for tissue engineering applications. The most common methods have been adapted from the polymer membrane industry and include such techniques as phase separation of polymer solutions induced either by thermal instability (Nam et al. J. Biomed. Mater. Res. 1999 47:8-18) or solvent (solubility) instabilities (Nunes, S. TRIP 1997 5(6):187-192; Cohen, J. et. al. Polymer Bulletin 1999 42:345-352), and particulate leaching (Freed et al. J. Biomed. Mater. Res. 193 27:11-23).
Porous polymer constructs produced using thermally induced phase separation (TIPS) have open-pore structures; however, the pore size is typically limited to approximately 10 to 20 &mgr;m in diameter. Recently, porous devices with larger pore sizes and morphologies different from the typical ladder-like structures have been fabricated using TIPS as described in Nam et al. J. Biomed. Mater. Res. 1999 47:8-18, which is incorporated herein by reference. This was achieved by varying the quench depth and the coarsening times for morphology development.
Larger pores can be generated using solvent induced phase separation (SIPS), but asymmetric membranes with a dense skin layer are generally produced. Membranes fabricated by the SIPS technique are cast on a fabric support since the membranes themselves are only a few hundred microns thick. Typically, the membranes will have an asymmetric pore distribution and in some instances, finger like structures are produced. One of the disadvantages associated with SIPS processes is the cost of solvents and their disposal or purification.
A modified SIPS technique can also be applied in the fabrication of thicker and larger porous constructs of varying shape. However, development times required to produce these constructs are on the order of days to weeks. In the case of biodegradable polymers, long development times can be detrimental to the structural integrity of the construct as premature degradation can occur.
In order to achieve sufficient porosity and interconnectivity using leaching techniques, high poragen contents are required. This high poragen loading often leads to mechanically fragile matrices. In the case of low poragen loadings, complete removal of the poragen can be complicated by the presence of closed pores.
Recent efforts have been made in adapting microcellular foaming techniques to produce foams with open pore architecture. Typically, microcellular foaming processes yield closed-cell foams that have pores on the order of about 10 &mgr;m and a pore density of >10
8
pores/cm
3
. In order to generate sufficient interconnectivity, biodegradable polymer compression molded with NaCl particles have been foamed using CO
2
microcellular techniques (Harris et. al., Biomed. Mater. Res. 1998 42:396-402). Once foamed, the salt is leached out to create the interconnected pores.
Various methods for production of microcellular foams via the use of supercritical fluid antisolvents (or nonsolvents) have been described. See, for example, U.S. Pat. No. 5,066,684, U.S. Pat. No. 5,116,883, and U.S. Pat. No. 5,158,986. Use of supercritical fluid antisolvents has also been described for production of small particles and coatings of medicaments (U.S. Pat. No. 5,833,891), aerogels (U.S. Pat. No. 5,864,923), membranes (Matsuyama et al. J. of Appl. Polymer Sci. 1999 74:171-178), and in recrystallization of solid materials such as RDX, the explosive cyclotrimethylenetrinitramine (U.S. Pat. No. 5,360,478 and U.S. Pat. No. 5,389,263).
U.S. Pat. No. 5,422,377 discloses a process for producing thin microporous polymeric films for numerous uses including high energy physics targets, biomedical structures for tissue ingrowth, filters, low dielectric films for electronic devices, and asymmetric membranes. In this process, a polymer solution film, comprised of polymer dissolved in a non-volatile solvent, is subjected to a dense or pressurized gas that is not a solvent for the polymer but is soluble in the solvent. The dense gas diffuses into the film, and since the dense gas is soluble in the solvent of the film, but is a non-solvent for the polymer, phase separation occurs and two phases are formed. Simultaneous with the dense gas diffusing into the film is the diffusion of the solvent from the film out into the dense gas. Eventually little solvent remains in the film and the polymer will either glass or crystallize so that the phase separated morphology is locked in. When the pressure of the system is released, the dense gas leaves the film taking with it any remaining solvent while leaving behind a dry microporous polymer film with a cell morphology dependent upon the relationship that existed between the first and second phase.
Many studies have been performed to separate polymers from solution using a supercritical fluid (SCF; Gucke, T. et. al. U.S. Pat. No. 4946940; Mc Clellan A. et. al. Polym. Eng. Sci. 1985 25(17):1088-1092) but their emphasis has mainly been to purify the polymer. Kojima, J. et. al. (Macromol. 1999 32:1809-1815) have examined the early stages of spinodal decomposition in polymer solution under high pressure using light scattering techniques. Poly(vinylidene fluoride) membranes have been synthesized by using water vapor to induce nonsolvent phase separation (Matsuyama H. et. al. J. Appl. Polym. Sci. 1999 74:171-178).
Fabricating matrices which can be varied in thickness, shape and size, and contain interconnected pores of sufficient size, to be useful for the tissue engineering and medical device industries has been problematic.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for producing open-pore polymeric matrices which comprises preparing a homogeneous polymer solution comprising one or more polymers and one or more solvents; treating the solution with a gas or supercritical fluid under selected conditions of pressure and temperature so that the gas or supercritical fluid is a nonsolvent or is sparingly soluble for the polymer; allowing the polymer solution to phase separate so that the polymer gels and precipitates from the solution, thus solidifying to form the matrix; if necessary, lowering the temperature of the solution to prevent the polymer from redissolving and help lock-in the pore morphology; and removing the residual solvent preferably via lyophilization. Typically the temperature is lowered near or below the freezing temperature of the solvent or near or below the plasticized glass transition temperature of the polymer/solvent/gas system so that further changes in morphology are minimized upon depressurization.
Another object of the present invention is to provide open-pore polymer matrices prepared via this process of gas induced phase inversion.
Yet another object of the present invention is to provide devices comprising open-pore polymer matrices prepared via this process. Devices which can be prepared include, but are not limited to, medical implant devices comprising open-pore biodegradable matrices and filtration/separation aids and porous supports from commodity, engineering and other thermoplastic polymer

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