Chemistry: molecular biology and microbiology – Apparatus – Bioreactor
Reexamination Certificate
1999-09-15
2001-08-28
Beisner, William H. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Bioreactor
C435S395000, C435S399000
Reexamination Certificate
active
06281007
ABSTRACT:
BACKGROUND OF THE INVENTION
This application relates to the preparation of grafts, implants, prostheses or other tissue constructs, typically for use as replacements for damaged or diseased bodily tissue. More particularly, this application relates to apparatus and methods for maturing or conditioning biopolymer tissue constructs prior to implantation of the construct in the body.
Tissue constructs are often used as grafts, implants or prostheses to replace diseased or damaged bodily tissue. Tissue needing replacement can include, for example, cartilage, tendon and ligament tissue. A fully functional replacement tissue should withstand at least the stresses and strains imposed by normal bodily activity on the type of tissue the construct is to replace. Furthermore, the construct should be biocompatible and integrable, in vivo, i.e., the construct should resemble a natural tissue so as to attract and interact with specific cells present in the body. The attracted cells further organize the construct and secrete specific biosynthetic products, such as extracellular matrix proteins and/or growth factors, that bind to the replacement construct, enabling it to degrade, remodel and regenerate as a fully functional replacement tissue. Such integration strengthens and conditions the construct to better perform as a replacement tissue.
Synthetic materials such as polyester fibers (Dacron™) or polytetrafluorlethylene (PTFE) (Teflon™) have been used extensively as replacements for bodily tissue, with some success. However, due to the poor biocompatibility of such synthetic materials, they often initiate persistent inflammatory reactions. Additionally, they do not readily breakdown and are not readily integrated with the body via remodeling by tissue cells.
It is also known to fabricate replacement constructs from structural biopolymer matrix components, such as collagen, that are extracted, purified and combined with specialized cells. The cells can organize, condense, and otherwise interact with the matrix proteins to create a tissue-like construct that can more closely resemble a natural tissue, and hence more readily integrate with the body than implants, grafts or prostheses based on synthetic materials. However, available biopolymer implants do not always have, or develop in vivo, the matrix complexity characteristic of the tissue they are to replace so as to become fully-functional replacements.
Therefore, there is a need for improved replacement tissue constructs that are stronger and more readily integrable with the bodily environment. Accordingly, one object of the invention is to provide methods and apparatus for producing improved replacement tissue constructs.
Another object of the invention is to provide replacement tissue constructs that are stronger and more capable of withstanding the stresses and strains imposed thereon by the rigors of bodily activity.
A further object of the invention is to provide apparatus for maturing and conditioning prostheses, grafts and implants to be more readily accepted by and integrable with the natural bodily environment.
Another object of the invention is to provide prostheses, grafts and implants that more readily resemble the tissues they are intended to replace.
Other general and more specific objects of the present invention will in part by obvious and will in part appear from the drawings and description which follow.
SUMMARY OF THE INVENTION
The present invention attains the foregoing and other objects by providing methods and apparatus for exposing elongate biopolymer tissue constructs to selected conditions, i.e., to a selected maturation fluid and to selected forces and/or stresses, for maturing the replacement tissue prior to insertion of the tissue into the body. Typically the elongate tissue construct is intended for use as a replacement ligament tissue. The elongate biopolymer tissue constructs described herein typically includes biopolymer fibers. Methods and apparatus for fabricating biopolymer fibers are known to those of ordinary skill in the art as disclosed in U.S. Pat. No. 5,562,946, entitled “Apparatus and Method for Spinning and Processing Collagen Fiber,” issued Oct. 8, 1996, the disclosure of which is herein incorporated by reference.
As used herein, maturing a tissue refers to conditioning a tissue such that it is more readily integrable with the bodily environment. An integrable tissue is a tissue that more readily remodels, degrades and regenerates within the body to create a stronger and more durable functional replacement tissue. Maturing a tissue construct can also refer to increasing the mechanical strength of the tissue such that it more readily withstands the stresses and strains of bodily activity.
As used herein, a biopolymer is a polymer suitable for introduction into a living organism, e.g., a human. The biopolymer is usually non-toxic and bioabsorbable when introduced into the living organism, and any degradation products of the biopolymer are also non-toxic to the organism. The biopolymer can be formed into biocompatible constructs that include, for example, biopolymer foams, e.g., single or double density foams, and/or biopolymer fibers. A typical biopolymer is collagen.
Typically, a biopolymer tissue construct to be matured using the apparatus and methods of the present invention is seeded with cells, such as connective tissue cells obtained from a biopsy of human or animal tissue. Exposing the replacement tissue to maturation fluid and subjecting the tissue to selected forces is believed to provide an environment that, similar to the natural bodily environment, provides biological signals to the seed cells for producing an integrable replacement tissue more readily accepted by the body. For example, the biological signals provided by the methods and apparatus of the present invention may promote, in addition to other beneficial effects, the secretion of extracellular matrix material, the generation of cell binding sites that attract specific cells from the body, or cell differentiation.
The maturation and seeding fluid is typically a fluid that resembles the naturally occurring fluid present in the bodily environment in which the tissue is to be used. The present invention is intended to be particularly useful in maturing replacement ligament tissue. For example, the maturation fluid can be a tissue culture media with suitable biological supplements. The maturation fluid can have several functions, which can include at least one of the following: delivering seed cells to the replacement tissue, delivering nutrients to the seed cells to promote expansion of the seed cell population, delivering growth factors to the replacement tissue to promote the generation of extracellular matrix material, as well as other functions that those of ordinary skill in the art, in light of the disclosure herein, can appreciate. The invention is intended to be particularly useful for the maturation of replacement ligament tissue.
According to one aspect, the invention provides apparatus that includes an element for extending the elongate biopolymer tissue construct along a longitudinal axis, an element for introducing a maturation fluid to the elongate tissue to promote tissue maturation, and an element for applying a selected force to the tissue construct to promote tissue maturation. The extending element can include first and second mounting elements for coupling to first and second ends, respectively, of the elongate biopolymer tissue, thereby mounting the tissue so as to extend between the mounting first and second mounting elements. In one aspect of the invention, the mounting elements can include a weight for coupling to one end of the elongate tissue construct. In another aspect of the invention, the mounting elements include a piston disposed in a longitudinal bore in which the tissue construct can be disposed.
In yet a further aspect of the invention, the fluid element includes a housing having a bore therethrough for confining maturation fluid and for mounting the elongate tissue therein. In another aspect
Bell Eugene
Fofonoff Timothy W.
Beisner William H.
Lahive & Cockfield LLP
TEI Biosciences, Inc.
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