Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Miscellaneous
Reexamination Certificate
2000-02-23
2002-06-04
Isabella, David J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Miscellaneous
C623S901000, C424S422000
Reexamination Certificate
active
06398819
ABSTRACT:
BACKGROUND OF THE INVENTION
The use of synthetic materials, such as polyester fiber (Dacron™) or polytetraflurorethylene (PTFE) (Teflon™) as implants designed to replace diseased or damaged body parts, has been extensive. These materials have however, enjoyed limited success. This has been due to the poor biocompatibility of these materials which among other problems, frequently initiate persistent inflammatory reactions. Additionally, the failure of the body to integrate these materials, because they do not break down and do not lend themselves to remodeling by tissue cells that may come into contact with them, causes further problems.
Efforts to use animal or human materials have also been unsatisfactory when these materials are crosslinked by formaldehyde or glutaraldehyde, for example. The process of generalized aldehydic crosslinking renders biomaterials sufficiently unrecognizable to tissue cells so that normal remodeling and integration are not promoted. Similarly, other types of chemical processing of animal or human biomaterials, such as extraction with detergents, or hypertonic buffers or hypotonic buffers can alter them to the degree that they are toxic to tissue cells and ineffective in promoting angiogenesis and in stimulating repair and remodeling processes needed for the conversion of an implant into a functional substitute for the tissue or organ being replaced.
A third approach has been that of reconstituting tissue and organ equivalents from structural matrix components, such as collagen, for example, that have been extracted, purified and combined with specialized cells and gelled. The process depends upon interactions between the cells and collagen filaments in the gel that the cells condense and organize. While tissue-like constructs have been fabricated and been shown to somewhat resemble their natural counterparts, they do not readily develop the matrix complexity characteristic of the actual tissues they are meant to imitate. See, for example, U.S. Pat. Nos. 4,485,096 and 4,485,097, both issued to Eugene Bell on Nov. 27, 1984.
SUMMARY OF THE INVENTION
The present invention relates to a method for producing extracellular matrix particulates constituting a scaffold to which extracellular matrix particulates are bound and a fabric having tissue extracellular matrix particulates.
A tissue source having living cells is processed to derive an extracellular matrix, whereby the living cells are disrupted to form cell remnants. The tissue source is processed to remove the cell remnants from the extracellular matrix of the tissue source without removing growth factors necessary for cell growth, morphogenesis and differentiation to form a processed extracellular matrix. The processed extracellular matrix source is fragmented to produce tissue matrix particulates. Further, the extracellular matrix particulates can be combined with a biopolymer scaffold. The scaffold with extracellular matrix particulates can be seeded with cultivated cells under such conditions that the cells adhere to the scaffold and extracellular matrix particulates.
A biopolymer scaffold consists of a fabric, which is formed of a polymer by weaving, knitting, braiding or felting threads and to which the extracellular matrix particulates are applied. If the polymer is collagen, the scaffold is crosslinked before the particulates are applied to it.
An advantage of this invention is that the formed tissues include use as skin, blood vessels, glands, periodontal prostheses and others.
DETAILED DESCRIPTION OF THE INVENTION
The above features and other details of this invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.
The present invention embodies a new method for preparing animal tissues and material derived from them as transplants designed to substitute for tissues or organs that are damaged or diseased. This is accomplished in such a way that their native complexity is preserved and thus allows them to be remodeled and integrated by the specialized cells with which they are brought into contact. In other words, because the matrix particulates of the present invention contain cell growth and differentiation stimulatory molecules, they provide the biomolecular signals needed for in vivo tissue repair or for tissue formation in vitro in a model tissue system in which cells have been seeded. In contrast to methods previously described, the method of the present invention avoids the use of harsh reagents, such as high salt, or dilapidation reagents, such as butanol/ether or detergents. The use of such reagents in methods previously described is responsible for removing from the source tissue a great many factors whose presence is considered essential for stimulating repair and remodeling processes needed for the conversion of an implant into a functional substitute for the tissue or organ being replaced.
The invention includes a method of producing tissues for grafting or for use as model systems in vitro by obtaining extracellular matrix from fetal and other tissue sources; by processing it to remove associated cells without removing factors necessary for cell growth, morphogenesis and differentiation and by combining it with collagen scaffolding with or without cells to produce tissues.
A scaffold or scaffolding includes polymers, such as collagen in the form of a foam, thread, fabric or film. Also, the scaffold can be other biodegradable polymers. Further, the scaffold can be the micro particulates themselves.
To prepare the extracellular matrix, the fetuses or other animal materials can be flash-frozen at the slaughterhouse. Fetuses are frozen in utero with the ends of the uteri tied off before freezing to insure the sterility of fetuses in their amnions. The fetuses are thawed under class 100 clean room conditions and the tissues are dissected for processing.
In one embodiment, the tissue is minced, manually and mechanically without heating to rupture the structure and reduce it to particulates of sizes no greater than about two cubic millimeters. Particles are washed in buffer to remove blood and intracellular components. Particles are then freeze-dried, cryomilled and size-sorted. The range of sizes is in the range of between about 10 and 500 &mgr;m in diameter. In another embodiment, the tissue is freeze-dried after dissection and processed on demand.
The invention also includes methods of producing extracellular matrix for tissue building which comprise the above method with the additional steps, alone or in combination, of 1) again processing the cellular tissue particulates to remove the components without removing the factors necessary for cell growth, morphogenesis and differentiation; 2) combining the particulates with collagen scaffolding, and 3) seeding the scaffold to which extracellular matrix particulates are attached with cultivated cells under such conditions that the cells adhere to or populate the scaffold.
Advanced methods of in vitro cell cultivation permit expansion of small numbers of stem cells or of differentiated cells into large cell banks. Tissue matrix vehicles that can stimulate cell division and differentiation of these specialized cells for delivery to the human recipient in the clinic are needed. The present invention can be used to bring a disease, such as diabetes, under control by engineering and implanting reconstituted tissues or composites populated by cells with the appropriate functional capacity to overcome the problems caused by absent or insufficient insulin biosynthesis or its regulated delivery. For example, particulates of the present invention can be combined in vitro with cells from the islets of Langerhans, or with undissociated islets, first to stimulate division of the glandula
Isabella David J.
Leonnig Ellen
TEI Biosciences, Inc.
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