Open pore biodegradable matrices

Details Open pore biodegradable matrices Open pore biodegradable matrices

2000-06-06

2001-08-28

Cooney, Jr., John M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Cellular products or processes of preparing a cellular...

C521S061000, C521S063000, C521S123000, C521S149000, C521S182000, C521S183000, C521S189000

Reexamination Certificate

active

06281256

ABSTRACT:

The invention is directed to a process for preparing porous polymer materials by a combination of gas foaming and particulate leaching steps. The invention is also directed to porous polymer material prepared by the process, particularly having a characteristic interconnected pore structure, and to methods for using such porous polymer material, particularly for tissue engineering.
The lack of autologous and allogeneic tissue suitable for transplantation has driven the development of the tissue engineering field, in which new tissues are created from cultured cells and biomaterials. This is advantageous because these cells can be expanded in vitro and cultured for use by multiple patients. The biomaterial serves as a vehicle to localize the cells of interest, a physical spacer to create potential space for tissue development, and as a template guiding tissue regeneration. Biodegradable homopolymers and copolymers of lactic and glycolic acid are attractive candidates for fabricating tissue engineering matrices due to their flexible and well defined physical properties and relative biocompatability. Additionally, the degradation product of these polymers are natural metabolites and are readily removed from the body.
Several techniques have been used to fabricate polymers into porous matrices for tissue engineering applications, including solvent-casting/particulate leaching (SC/PL) (A. G. Mikos, A. J. Thorsen, L. A. Czerwonka, Y. Bao, and R. Langer, “Preparation and characterization of poly(L-lactic acid) foams,” Polymer, 35, 1068-1077 (1994)); phase separation (H. Lo, M. S. Ponticiello, and K. W. Leong, “Fabrication of controlled release biodegradable foams by phase separation,” Tissue Engineering, 1, 15-28 (1995)); fiber extrusion and fabric forming processing (J. F. Cavallaso, P. D. Kemp and K. H. Kraus, “Collagen Fabrics as Biomaterials,” Biotechnology and Bioengineering, 43, p. 781-791 (1994)); and gas foaming. (D. J. Mooney, D. F. Baldwin, N. P. Suh, J. P. Vacanti, and R. Langer, “Novel approach to fabricate porous sponges of poly(D,L-lactic-co-glycolic acid) without the use of organic solvents,” Biomaterials, 17, 1417-1422 (1996).) The solvent-casting/particulate leaching and phase separation approaches require the use of organic solvents. Residues of organic solvents which can remain in these polymers after processing may damage transplanted cells and nearby tissue, and inactivate many biologically active factors (e.g., growth factors) one might wish to incorporate into the polymer matrix for controlled release. Fiber forming typically requires high temperatures (above the transition temperature of polymer), and is not amenable to processing amorphous polymers. The high temperatures used in this process would likely denature any biologically active molecules one might wish to incorporate into the matrix.
The gas foaming method (for example, of Mooney et al., cited above) provides a technique to fabricate highly porous matrices from poly(lactic-co-glycolic acid) (PLGA) using a high pressure gas that avoids the use of organic solvents and high temperatures. However, the technique typically yields a closed pore structure, which is disadvantageous in many applications of cell transplantation. In addition, a solid skin of polymer results on the exterior surface of the foamed matrix and this may lead to mass transport limitations.
An object of this invention is to provide a new process for preparing porous polymer materials which are useful for tissue engineering and other applications wherein the pore structure is particularly advantageous. For example, the polymers of the invention may have two types of porosity, the first formed by gas-foaming processing and the second formed by the action of particulate leaching. The combination of these two porosity types can be regulated by the processing conditions and materials used to provide porous polymer materials with a range of advantageous properties. In a preferred embodiment, the porosity from particulate leaching results in interconnected pore structure materials having an open pore structure. Other objects of the invention include the porous polymer materials prepared by the process and methods using such materials for tissue engineering, for example.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
According to the process of the invention, a mixture of polymer particles and a leachable particulate material molded, optionally with compression, to a desired size and shape are subject to a high pressure gas atmosphere so that the gas dissolves in the polymer; then a thermodynamic instability is created, for example by reduction of the pressure, so that the dissolved gas nucleates and forms gas pores within the polymer; this causes expansion of the polymer particles, and as they expand they fuse, creating a continuous polymer matrix containing the particulate material; finally, the particulate material is leached from the polymer with a leaching agent creating a further porosity. The process thus provides a novel combination of the processes of gas foaming (GF) to form pores and particulate leaching (PL) to form another type of porosity. Hence, the process can be termed as a GF/PL process as opposed to the known solvent-casting/particulate leaching (SC/PL) processes.
The novel materials prepared by the process are characterized by having pores formed from gas foaming and pores formed by particulate leaching, the particulate leaching pores also being termed macropores. Preferably, the porosity resulting from the particulate leaching, which can be controlled by the amount and size of the particulate among other factors, is such that it results in interconnections and, thus, an open pore structure. Typically, matrices prepared by the GF/PL method of the invention will have an interconnecting or open pore structure akin to the structure demonstrated in the photomicrographs generated according to Example 1 and discussed therein. In one embodiment providing a mixture of polymer and leachable particulate wherein the amount of leachable particulate is at least 50% by volume will result in a partially interconnecting or open pore structure. A higher amount of leachable particulate can be used to obtain a fully interconnected structure.
While materials prepared by an SC/PL process can also provide some extent of an interconnected pore matrix, the inventors have discovered that the materials prepared by the inventive GF/PL process exhibit a distinct pore structure and significantly advantageous mechanical properties over SC/PL prepared materials. This advantage is in addition to the advantage of the absence of necessity for organic solvents and/or high temperatures in preparation of the material and the absence of organic solvent residue in the prepared materials, which advantages make the materials even more useful for the applications described below. For example, the materials of the invention exhibit much higher strength properties, e.g. tensile strength. For instance, the materials according to the invention can be prepared to maximize the tensile strength to provide materials with a tensile modulus of, for example, 850 kPa, particularly 1100 kPa, or higher. Although, such high strength materials may not be required for all applications and materials with a tensile modulus as low as 100 kPa, for example, have been found to be useful. Further, the materials exhibit improved compression resistance. For instance, the materials according to the invention can be prepared to maximize the compression resistance to provide materials with a compression modulus of, for example, 250 kPa, particularly 289 kPa, or higher. Comparative SC/PL prepared materials exhibit a tensile modulus of about 334±52 kPa and a compression modulus of about 159±130 kPa.
While not intending to be bound by this theory, it is reasonably hypothesized that the improved mechanical properties and stronger matrix of the materials prepared by the inv

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