Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-01-28
2002-10-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S484000, C424S487000, C424S422000, C424S423000, C424S424000, C424S425000, C424S426000, C514S772300
Reexamination Certificate
active
06471993
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to porous polymer matrices.
Porous polymer media, such as membranes, macroporous solids, and cellular solids are used in a wide variety of applications. These materials are used as support structures for gas and solution phase catalysis; support structures for solid phase synthesis; immobilized beds in bioreactors; and thermal insulation.
Recent advances in the field of tissue engineering have led to new uses for these porous materials. Tissue engineering techniques provide alternatives to the prosthetic materials currently used in plastic and reconstructive surgery, and in joint repair and replacement; these techniques are also useful in the formation of organ equivalents to replace diseased, defective, or injured organs. Porous materials are used as scaffolds for the in vitro or in vivo growth and development of tissue. Because these materials are placed in the human body, they must often have structural and functional characteristics that differ from the requirements for materials used in non-therapeutic applications.
SUMMARY OF THE INVENTION
The invention features porous matrices that are useful in a variety of applications, including tissue engineering, electromagnetic shielding, and fuel cell applications.
In a first aspect, the invention features a matrix including a macrostructure having a semi-solid network and voids; the matrix further includes a microstructure, which preferably has voids; the microstructure is located within the semi-solid network. In a preferred matrix, the semi-solid network includes a polymer or a copolymer. The copolymer can have a carboxylic acid group or an amine group. Another preferred matrix includes a conductive polymer selected from the group consisting of polypyrrole, polyaniline, polyacetylene, and polythiophene.
In a preferred matrix, the semi-solid network consists essentially of a polymer or mixture of polymers. In another preferred matrix, the semi-solid network is substantially continuous.
The voids of the macrostructure can also be substantially continuous. The voids of the macrostructure and the voids of the microstructure can be connected or not connected. The voids of the macrostructure define openings. In a preferred matrix, the average diameter of the openings and the average diameter of the cross-sections of the semi-solid network have a ratio of from 2:1 to 10:1, and more preferably have a ratio of from 2:1 to 5:1.
In a preferred embodiment, a cubic matrix having dimensions of about 0.5 cm on all sides and having voids defining openings with an average diameter of 50-500 &mgr;m has a connectivity number of at least 10, and more preferably has a connectivity number of at least 20.
A ratio of the maximum diameter and the minimum diameter of a cross section of the semi-solid network of a preferred matrix is from 1:1 to 10:1, and more preferably is from 1:1 to 4:1, or from 1:1 to 2:1.
In another preferred matrix, at least 10% of the voids of the microstructure have a fractal dimension of at least 3; preferably, less than 10% of the voids of the macrostructure of this matrix have a fractal dimension higher than 1. A preferred matrix is three dimensional, and the exterior face of the matrix can be porous.
The matrix can include an additive, at least 5% of which is located within the microstructure; the preferred additive is selected from the group consisting of transition metal oxides, transition metal sulfates, transition metal carbonates, transition metal phosphates, transition metal nitrates, sodium carbonate, sodium phosphate, calcium carbonate, calcium phosphate, &bgr;-glycerophosphate, and hydroxyapatite having particle sizes of greater than 150 &mgr;m. The additive can also be selected from the group consisting of polyethylene fibers, polypropylene fibers, Teflon® (polytetrafluoroethylene) fibers, nylon fibers, and PGA fibers; it can also be selected from the group consisting of titanium fibers, titanium powder, and titanium dioxide; or from the group consisting of inorganic and organic reducing agents.
A preferred matrix has a porosity of at least about 20%, and more preferably has a porosity of at least about 40%, 70%, 90%, 92%, or 95%. A preferred matrix is biodegradable, bioerodible, or bioresorbable. The matrix can be permeable or impermeable to cells; it is preferably permeable to bodily fluids. A preferred matrix includes a living cell; preferably, the cell is selected from the group consisting of bone marrow cells, periosteal cells, chondrocytes, smooth muscle cells, endothelial cells, fibroblasts, epithelial cells, tenocytes, neuronal cells, Schwann cells, hepatocytes, Kupffer cells, fibroblasts, pancreatic islet cells, and cardiac myocytes. Another preferred matrix includes a bioactive agent, which is preferably contained in microspheres. The bioactive agent is selected from the group consisting of antibiotics, anesthetics, anti-inflammatory agents, contrast agents, and imaging agents.
A preferred matrix has a coating; less than 5% of the coating is contained in the voids of the microstructure. The coating may be attached to the matrix by electrostatic forces, by covalent bonding, or as a result of the shape of the coating. In this last case, the coating encases at least a portion of the matrix.
The matrix may be coated by any coating known to those skilled in the art to be appropriate, however, another preferred matrix is coated with a hydrophilic material selected from the group consisting of collagen, PEG, PEO, PVA, hydrogels, carboxylic acid-containing substances, fibronectin, vitronectin, laminin, and bone morphogenetic protein (BMP).
Yet another preferred matrix includes bioerodible fibers; the fibers preferably include PGA or therapeutic agents. Another preferred matrix includes a protein that is protected with a cyclodextrin.
A preferred matrix changes in size less than 50% when cells are added to the matrix; another preferred matrix has a compressive modulus which is higher than known polymer matrices having the same components in the same ratio. For example, a preferred matrix has a compressive modulus of at least 0.4 MPa at 4% strain. In addition, a preferred matrix is non-friable.
In a second aspect, the invention features a porous polymer matrix that changes in size less than 50% when cells are added to the matrix. A preferred matrix changes in size less than 25% when cells are added to the matrix, and more preferably changes in size less than 10%. In a preferred embodiment the change in matrix size is defined as that change which occurs over a limited time period, of over a period of less than ½ the time it takes for the matrix to degrade, preferably, less than {fraction (1/10)} the time it takes for the matrix to degrade, most preferably, the period of time during which the initial cells are added to the matrix if such time is less than {fraction (1/10)} the time it takes for the matrix to degrade.
A preferred matrix has a macrostructure having a semi-solid network and voids and a microstructure having voids; the microstructure is located within the semi-solid network. Preferably, the voids of the macrostructure are substantially continuous. A preferred matrix has a porosity of at least 90%, and more preferably has a porosity of at least 92%, or 95%. A preferred matrix is biodegradable, bioerodible or bioresorbable. A preferred matrix is permeable to bodily fluids. Another preferred matrix includes a living cell or a bioactive agent.
A preferred matrix has a coating; less than 5% of the coating is contained in the voids of the microstructure. The coating may be attached to the matrix by electrostatic forces, by covalent bonding, or as a result of the shape of the coating. In this last case, the coating encases at least a portion of the matrix.
The matrix may be coated with any suitable coating known to those skilled in the art, another preferred matrix is coated with a hydrophilic material selected from the group consisting of collagen, PEG, PEO, PVA, hydrogels, carboxylic acid-containing substances, fibronectin, vitronectin, laminin, and bo
Langer Robert S.
Martin Ivan
Seidel Joachim
Shastri Venkatram R.
Bieker-Brady Kristina
Clark & Elbing LLP
Di Nola-Baron Liliana
Massachusetts Institute of Technology
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