Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-05-31
2004-02-24
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S093700, C435S001100, C435S177000, C435S395000
Reexamination Certificate
active
06696074
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of tissue engineering, and in particular to a method of processing animal tissue including, particularly, fetal or neo-natal tissue to produce a biopolymer scaffold material named EB Matrix (“EBM”). EBM has broad applications for tissue repair and regeneration. It can serve as a remodelable scaffold for repair or replacement of human tissues and organs. It can be enriched with signaling molecules and cells before implantation, or with or without signaling molecules, it can attract host vessels and vascular cells as well as host parenchymal cells and immune systems cells to populate it after implantation. Also, it can serve as a delivery device for signaling factors, cells or drugs.
2. Description of the Related Art
Rebuilding the human body is a significant industry. Human tissue banks and synthetic polymers do not meet the need for repair or replacement of body parts. High on the list of alternative sources of material used to meet this need are animal tissues prepared in new ways that reduce their immunogenicity and maximize their usefulness and efficacy.
In the field of tissue engineering, the following three components are used alone or in combination to repair or create new tissue and organ substitutes. 1) scaffolds made of naturally-occurring polymers (e.g. collagens), man-made polymers, (e.g. PTFE, Dacron, PET or polyethylene) or self-degrading, man-made polymers (e.g. PLA or PGA); 2) signaling molecules that give developmental instructions to cells; and 3) cells having specific or multiple tissue building potential, often referred to as “stem cells”. Here we describe biopolymer matrices, produced by novel methods, from animal tissues including fetal and neo-natal tissues to be used as tissue engineering scaffolds.
Man-made implant materials such as synthetic polymers, plastics, and surface-coated metals may have different degrees of immunogenicity and suffer from significant limitations that prohibit their broad applications. A major limitation is that cells cannot remodel them after implantation. They are highly susceptible to microbial infection, and some undergo calcification. Synthetic vascular conduits have a high incidence of occlusion after peripheral vascular bypass procedures.
There is a long history of the use of biopolymer matrices made from processed human or animal tissues. Several methods of preserving collagen-based matrices from animal tissues have been developed (U.S. Pat. Nos. 4,801,299, 5,336,616, 5,756,678, 5,916,265 and 5,997,895). All the methods include a chemical step that either kills or eliminates cells. Since tissues from post-natal animals or humans are the principal materials processed, a fixation step using glutaraldehyde or a similar agent may be used to mask antigenic determinants, eliminate the microbial burden and increase strength. However, aldehydic processing effectively destroys any biological activity, such as cell binding sites, associated with the original tissue and greatly reduces or eliminates the ability of cells to attach to it. It also eliminates binding sites for cell-synthesized products which attach to cells or to intermediates able to bind to cells and cell products that make up the extracellular matrix by cells.
Collagen-based devices that are animal-derived and fixed with glutaraldehyde or a similar agent can not be remodeled since they are highly resistant to metalloproteinase enzymes. Glutaraldehyde-treated devices are known to undergo gradual calcification. Heart valves made from fixed animal tissues can require replacement in 5-7 years or sooner due to calcification. The methods suggested in U.S. Pat. Nos. 4,801,299 and 5,916,265 include the use of glutaraldehyde or a similar agent for the fixation of tissue derived from a post-natal animal source. The resulting products can not be faithfully remodeled.
While detergents or sodium hydroxide may be used to process post-natal animal tissue (U.S. Pat. Nos. 4,801,299, 5,336,616, 5,756,678, 5,916,265, 5,997,895), they have not been used to process fetal or neo-natal animal tissue. For example, U.S. Pat. No. 5,997,895, filed on Apr. 30, 1998, provides a certified collagen dural substitute derived from post-natal animal tissue that undergoes an alkaline/salt treatment involving sodium hydroxide and sodium sulfate (preferably in an aqueous solution of 5% sodium hydroxide and 20% sodium sulfate). A method for processing collagen containing materials which uses 1.0 N sodium hydroxide was disclosed in a journal article in 1989 by Diringer H. and Braig H. R. (Diringer H. and Braig H. R., 1989, Infectivity of unconventional viruses in dura mater. The Lancet, 439-440). This reference was cited in the FDA's
Guide for
510(
k
)
Review of Process Dura Mater
(1990, 2).
The product of this invention, EBM, is unlike the other products cited above which in general are not bioremodelable. EBM is processed in a way that preserves its binding sites for cells and cell-secreted products that make up the extracellular matrix surrounding cells that occupy the scaffold. EBM is also distinguished by the fact that undesirable tissue components, such as DNA, are expressed mechanically from the tissue and that delipidyzing organic solvents are used to reduce the presence of cell and nuclear membranes. EBM does not calcify, making it safe for use in the human body for repair of soft tissues. In addition to its use for soft tissues, EBM can be used as a scaffold for bone repair if treated with an appropriate growth factor, if seeded with bone precursor cells or if occupied by bone forming cells when implanted.
EBM can be used as a tissue-building component with or without cells or signaling complexes for creating human body replacements. It can be used after the addition of signaling molecules, which will further promote tissue repair. It can also be implanted after stem or differentiated cells are seeded into or onto it.
BRIEF SUMMARY OF THE INVENTION
By processing animal tissue, including fetal or neo-natal tissue, by the method embodying the invention, tissue strength is preserved without reducing its intrinsic biological properties or compromising the ability of cells that occupy the tissue to remodel it. In addition to chemical processing, a step of mechanically expressing undesirable tissue components from the tissue is a significant innovation. Additionally, the uniqueness of this invention is that it includes the use of fetal or neo-natal tissue that, depending on age, is much less antigenic than adult tissue. The present invention overcomes the difficulties inherent in the approach to animal tissue use based on glutaraldehyde treatment.
DETAILED DESCRIPTION OF THE INVENTION
For convenience, certain terms used in the specification, examples, and appended claims are collected here alphabetically.
The term “bioremodelable” or “bioremodelability” refers to a material that lends itself to the breakdown by cells that occupy it and use it as a template for creating a replacement made up mainly of newly synthesized components secreted by the cells.
The terms “delipidizing” or “delipidized” refers to the removal of lipids from the tissue.
The term “DHT” refers to a dehydrothermal process, wherein the tissue is cross-linked and dehydrated at a high temperature.
The term “drapability” includes the capacity of the material to mold to irregular, curved surfaces or surfaces of other geometries.
The terms “inactivating” or inactivated” refers to the reduction of the concentrations of infective agents (e.g. bacteria, molds, viruses and prions) by 4, 6 or 8 logs consistent with the requirements needed to insure against infectivity.
The phrase “mechanically expressing” refers to mechanically applying pressure to express undesirable components from the tissue. With the aid of appropriate solvents, unwanted components from the product that are potentially antigenic, such as DNA, RNA or other molecules released by reagents, such as NaOH, are removed.
The term “suturable” includes the ability to suture the materia
Bell Eugene
Dai Jianwu
Russakovsky Vladimir
Fish & Richardson P.C.
Naff David M.
TEI Biosciences, Inc.
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