Chemistry: molecular biology and microbiology – Carrier-bound or immobilized enzyme or microbial cell;...
Reexamination Certificate
2000-06-27
2002-01-08
Foelak, Morton (Department: 1711)
Chemistry: molecular biology and microbiology
Carrier-bound or immobilized enzyme or microbial cell;...
C435S177000, C435S180000, C435S182000, C521S084100
Reexamination Certificate
active
06337198
ABSTRACT:
TECHNICAL FIELD
The present invention relates to biodegradable porous polymer scaffolds useful for tissue engineering and tissue guided regeneration. In particular, the present invention relates to biodegradable porous polymer scaffolds with a bimodal distribution of open pore sizes providing a high degree of interconnectivity, high internal surface area, and linearly aligned pores along the walls of the larger pores. The present invention further relates to methods for preparing the scaffolds to obtain the orderly bimodal pore distribution.
BACKGROUND ART
Synthetic degradable polymer scaffolds have been proposed as a new means of tissue reconstruction and repair. The scaffold serves as both physical support and adhesive substrate for isolated cells during in vitro culturing and subsequent in vivo implantation. Scaffolds are utilized to deliver cells to desired sites in the body, to define a potential space for engineered tissue, and to guide the process of tissue development. Cell transplantation on scaffolds has been explored for the regeneration of skin, nerve, liver, pancreas, cartilage and bone tissue using various biological and synthetic materials.
In an alternate approach, degradable polymeric scaffolds are implanted directly into a patient without prior culturing of cells in vitro. In this case, the initially cell-free scaffold needs to be designed in such a way that cells from the surrounding living tissue can attach to the scaffold and migrate into it, forming functional tissue within the interior of the scaffold.
A variety of synthetic biodegradable polymers can be utilized to fabricate tissue engineering scaffolds. Poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and their copolymers are the most commonly used synthetic polymers in tissue engineering. However, in principle, any biodegradable polymer that produces non-toxic degradation products can be used. The potential utility of a polymer as a tissue engineering substrate is primarily dependent upon whether it can be readily fabricated into a three-dimensional scaffold. Therefore, the development of processing techniques to prepare porous scaffolds with highly interconnected pore networks has become an important area of research.
Solvent casting is one of the most widely used processes for fabricating scaffolds of degradable polymers (see Mikos et al.,
Polymer,
35, 1068-77, (1994); de Groot et al.,
Colloid Polym. Sci.,
268, 1073-81 (1991); Laurencin et al.,
J. Biomed. Mater. Res.,
30, 133-8 (1996)). U.S. Pat. No. 5,514,378 discloses the basic procedure in which a polymer solution is poured over a bed of salt crystals. The salt crystals are subsequently dissolved away by water in a leaching process. De Groot et al. disclose a modified leaching technique in which the addition of a co-solvent induces a phase separation of the system upon cooling through liquid-liquid demixing. While this separation mechanism leads to the formation of round pores embedded within the polymer matrix, most of the pores are of insufficient size to form a highly interconnected network between the larger pores formed by leaching.
The existing processing methods produce poor scaffolds with a low interconnectivity, especially when a basic leaching method, such as the method disclosed in U.S. Pat. No. 5,514,378, is used. Particles, when dispersed in a polymer solution, are totally covered by the solution, limiting the interconnectivity of the pores within the scaffolds.
U.S. Pat. No. 5,686,091 discloses a method in which biodegradable porous polymer scaffolds are prepared by molding a solvent solution of the polymer under conditions permitting spinodal decomposition, followed by quenching of the polymer solution in the mold and sublimation of the solvent from the solution. A uniform pore distribution is disclosed. A biomodal pore distribution would increase the degree of pore interconnectivity by creating additional channels between the pores, thereby increasing total porosity and surface area.
U.S. Pat. No. 5,723,508 discloses a method in which biodegradable porous polymer scaffolds are prepared by forming an emulsion of the polymer, a first solvent in which the polymer is soluble, and a second polymer that is immiscible with the first solvent, and then freeze-drying the emulsion under conditions that do not break the emulsion or throw the polymer out of solution. This process, however, also produces a more uniform pore size distribution, with the majority of the pores ranging from 9 to 35 microns in diameter.
There remains a need for biodegradable porous polymer scaffolds for tissue engineering having a bimodal pore size distribution providing a highly interconnected pore network, as well as methods by which such scaffolds may be made. Based on a more advanced scientific rationale, polymeric scaffolds with a bimodal pore size distribution may have significant advantages. Pores in the size range of 50 to 500 micron diameter provide sufficiently open space for the formation of functional tissue within the scaffold while the presence of a large number of smaller pores forming channels between the larger pores would increase cell-cell contact, diffusion of nutrients and oxygen to the cells, removal of metabolic waste away from the cells, and surface patterning to guide the cells. This new design concept for degradable polymeric scaffolds requires the presence of a bimodal pore size distribution with larger pores of 50 to 500 micron diameter and smaller pores creating channels between the larger pores.
SUMMARY OF THE INVENTION
This need is met by the present invention. A process is provided that allows fabrication of polymer scaffolds with novel architectures for tissue engineering through a combination of phase separation and leaching techniques.
According to one aspect of the present invention, a biodegradable and biocompatible porous scaffold is provided having a substantially continuous polymer phase with a highly interconnected bimodal distribution of rounded large and small open pore sizes, in which the large pores have a diameter between about 50 and about 500 microns, and the small pores have a diameter less than 20 microns, wherein the small pores are aligned in an orderly linear fashion within the walls of the large pores. The pore interconnectivity is greatly enhanced by the presence of the small pores, which form channels between the large pores. This results in a porosity greater than about 90% and a high specific pore surface area in excess of 10 m
2
/g.
The network of small pores is created in the walls of the large pores, and is unexpectedly well oriented in a linear array. This provides surface patterning for guiding cell growth throughout the scaffold. This specific architecture also provides a large surface area and internal volume that is ideal for cell seeding, cell growth and the production of extra-cellular matrices. Furthermore, the high interconnectivity of the pores allows for distribution of pores throughout the scaffold, transmission of cell-cell signaling molecules across the scaffolds, diffusion of nutrients throughout the structure, and the patterning of the surface to guide cell growth. Pore diameter and interconnecting structure are essential to vascularization and tissue ingrowth.
The open porosity of the three-dimensional structure maximizes diffusion and permits vascular ingrowth into the implanted scaffold. Ideally, the polymer is completely resorbed over time, leaving only the newly-formed tissue.
The polymer scaffolds of the present invention are prepared from homogenous solutions of biodegradable polymers in a mixture of a first solvent in which the polymer is soluble, and a second solvent in which the polymer is insoluble, but which is miscible with the first solvent. The homogenous solutions are cast on water-soluble particles that are between about 50 and about 500 microns in diameter, and then phase separated by quenching at a low temperature and freeze-drying, followed by leaching. The bimodal distribution of pore diameters results from the larger pores being created by leaching and the smal
Kohn Joachim B
Levene Howard B.
Lhommeau Christelle M.
Foelak Morton
Rutgers The State University
Synnestvedt & Lechner LLP
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