Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Solid support and method of culturing cells on said solid...
Reexamination Certificate
2001-01-16
2002-04-30
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Solid support and method of culturing cells on said solid...
C435S366000, C435S399000, C435S400000, C435S402000
Reexamination Certificate
active
06379963
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention concerns a process for producing a three-dimensional bioartificial tissue having viable cells in or on a matrix, and by which cells and matrix can be cultivated into a tissue or a precursor of a tissue, a vascularized tissue of biological materials, obtained by this process, and an experimental reactor for scientific purposes and for producing clinically usable tissues and organs.
2. Background Description
Bioartificial tissues are understood to be tissues produced in vitro from natural biological materials, which are, therefore, not natural tissues, but tissues which as nearly as possible simulate natural tissues.
The process according to the invention and the matching reactor are particularly suitable for producing a bioartificial heart muscle tissue.
Morbidity and mortality in the Western population are largely related to loss of heart function and heart tissue (cardiac failure). This is a problem of great socioeconomic relevance. Bypass surgery or heart transplants are increasingly necessary as ultimate therapeutic measures. Transplants, though, involve problems such as lack of suitable donor organs or the stress on transplant patients by lifelong treatment to suppress rejection reactions.
The problems of transplantation affect not only hearts, but also other organs which are no longer functional and which must be replaced. Because of these problems, major attempts have been made in medical research in the areas of “tissue retention” and “tissue and organ replacement”. Research endeavors on “tissue and organ replacement” comprise use and better adaptation of xenogeneic organs as well as the culture of three-dimensional tissues from natural starting materials so as to be able to replace at least parts of organs.
In the past, early cellular forms (e. g., embryonal stem cells or infant heart cells) have been injected into recipient myocardium (individually and as clumps of cells).
Prototypes of rat heart muscles in collagen, enriched with nutrients and growth factors have been made to produce, or, initially, to simulate, heart muscle from simple biological basic materials. Contractions have already been demonstrated with them. However, these experiments have not dealt with functional three-dimensional tissue which would be suitable for transplantation and which could replace damaged organ tissue (R. L. Carrier et al., “Cardiac Tissue Engineering: Cell Seeding, Cultivation Parameters and Tissue Construct Characterization”, Biotechn. Bioengin. 64 (5), 580-90, 1999).
The artificial pieces of heart tissue so obtained were only a few millimeters thick and never survived longer than a few weeks. After implantation, they were unable to integrate themselves into the recipient tissue so as significantly to improve the strength of beating (B. S. Kim et al., “Optimizing Seeding and Culture Methods to Engineer Smooth Muscle Tissue on Biodegradable Polymer Matrices”, Biotechn. Bioengin. 57 (1), 1998; R. K. Li et al., “In vivo Survival and Function of Transplanted Rat Cardiomyocytes”, Circ. Res. 1996; 78: 283-288). Thus the objective of the invention is to provide a process for producing an improved three-dimensional bioartificial tissue. In particular, vascularization of the tissue is attempted, so that it can be supplied and thus maintained in a viable state.
SUMMARY OF THE INVENTION
To achieve that objective, the generic concept of the process is designed so that at least one vessel is inserted in the tissue at the beginning of its production. The vessel is supplied from the outside, so that vascular propagation occurs in the course of tissue cultivation and a three-dimensional, vascularized bioartificial tissue is obtained.
Because the tissue is permeated by a vessel even during its cultivation, it can develop three-dimensionally as in nature. The main vessel branches, leading to a vascularized tissue. The vascularized tissue produced can, on transplantation, be connected to the vascular system, so that it remains nourished and viable. There is a more natural modeling of the tissue conditions even during the tissue culture itself. Culturing over longer periods is possible because the supply to alls cells, even those in the interior of the cell assembly, can be better assured. A longer culture can be advantageous, for instance, if a better degree of cell differentiation is to be attained. Culture in the experimental reactor, which is described in more detail below, also allows provision of a physiological environment for organogenesis (e. g., atmospheric pressure or vacuum, defined gas concentrations (partial pressures), biochemical environment, etc.).
A bioartificial tissue in the sense of the invention is understood to be a tissue not taken, as such, from an organism, as by surgery, but rather simulated artificially using biological materials. That is generally done by assembling certain cells into a cell assembly, applying them to a stabilizing substrate, or putting them in a matrix. The substrate or matrix can itself be of synthetic or, alternatively, biological origin. Polymers, especially biodegradable polymers, may be considered as synthetic matrices. They can also be in the form of layers or networks. Collagen in particular is also considered as a matrix material. A segment of tissue, removed from a human or animal, generally acellularized by chemical and/or mechanical methods, can also be used as the source of the collagen matrix.
The bioartificial tissue should contain viable cells so that they can form a three-dimensional biological tissue which has the longest possible stability and viability.
In one simple embodiment, collagen and viable cells can be mixed, and further cultivated (i. e., supplied with a nutrient solution renewed continuously or at intervals). Various simulated tissues have already been recommended and used. The detailed structure of this tissue depends on the nature of the tissue or organ.
The principal problem with tissues comprising biodegradable matrices and cells, especially artificially simulated heart tissue, is their limited dimensions and survivability, because for a long time it has been impossible to nourish them by blood or nutrient medium in a natural manner (see N. Bursac et al., “Cardiac Muscle Tissue Engineering: Toward an in vitro and in vivo model for electrophysiological studies”, Am. J. Physiol. 277 (2), HH433-H444, August 1999; R. K. Li et al., “Survival and Function of Bioengineered Cardiac Grafts”, Circulation 1999, 100 [Suppl. II]; II-63 to II-69).
The invention is, then, based on the recognition that the ability of a tissue to survive and develop its function is critically dependent on its vascularization (the occurrence of vessels within the tissue). Therefore the process of the invention provides that at least one vessel, which is supplied from the outside, is inserted into the artificial biological tissue at the beginning of its production. By supplying the vessel with a suitable nutrient solution or blood, vessels propagate naturally in the course of the cultivation.
The vessel can be inserted into the matrix, such as an acellularized collagen matrix, before it is inoculated with the cells desired for the artificial biological tissue; or, if the production of the artificial tissue involved only mixing of cells and matrix material, the vessel can be inserted into that mixture at the beginning of the culture.
A vessel of natural origin from a human or animal can be used as the vessel, for instance, rat aortas, especially for scientific experiments. But it can also be an artificial vessel, particularly one of a biologically compatible polymer. It is also possible to use the entire vascular structure of an organ to be supplied.
Preferably, a native vessel with a large lumen, as nearly as possible specific for the species, is used. The extended vessel lumen can have lateral openings or branches. The openings are produced in the simplest case by cutting off side branches from the main branch of a native vessel. On culture of the artificial tissue, vascular d
Haverich Axel
Kofidis Theo
Guttman Harry J.
Weber Jon P.
Whitham, Curtis & Christofferson
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