Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-05-03
2003-11-04
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S124000, C514S002600, C514S054000
Reexamination Certificate
active
06642363
ABSTRACT:
This application is a 371 of PCT/US97/16890, filed Sep. 19, 1997.
The invention relates to materials which contain polysaccharide chains, particularly alginate or modified alginate chains. The polysaccharide, particularly alginate or modified alginate, chains may be included as side chains or auxiliary chains from a backbone polymer chain, which may also be a polysaccharide. Further, the polysaccharide chains may be crosslinked between side chains, auxiliary chains and/or backbone chains. These materials are advantageously modified by covalent bonding thereto of a biologically active molecule for cell adhesion or other cellular interaction. The materials are particularly useful to provide polymeric matrices for many applications, such as in tissue engineering applications for bone or soft tissue replacement. For example, the loss of bony tissue is a central feature of many aspects of clinical dentistry (e.g. periodontal disease, caries, osteotomy for repair of trauma) and matrices from the materials described herein can be useful for repair or replenishment of lost bony tissue. The materials are also useful for drug delivery applications when the biologically active molecule is attached by a degradeable bond.
Unmodified alginate, a polysaccharide, has been previously utilized as a tissue engineering matrix in cell encapsulation and transplantation studies. It provides a useful matrix because cells can be immobilized within alginate with little cell trauma and alginate/cell mixtures can be transplanted in a minimally invasive manner. However, cells exhibit little or no adhesion or interaction with unmodified alginate. One aspect of this invention is to provide a matrix which combines specific cell adhesion ligands in the matrix such that high control over cell-matrix interactions, due to cell adhesion and matrix interactions, is attained.
One embodiment of the invention is directed to polymers containing a polymer backbone to which is linked polysaccharide groups, particularly of alginates or modified alginates, which preferably are polymerized D-mannuronate and/or L-guluronate monomers. The polysaccharide, particularly alginate, groups are present as side chains on the polymer backbone which is intended to include side chains at the terminal end of the backbone, thus being a continuation of the main chain. The polymers provide synthetic modified polysaccharides and alginates exhibiting controllable properties depending upon the ultimate use thereof. Further, the invention is directed to processes for preparing such polymers and to the use of such polymers, for example, as cell transplantation matrices, preformed hydrogels for cell transplantation, non-degradable matrices for immunoisolated cell transplantation, vehicles for drug delivery, wound dressings and replacements for industrially applied alginates.
Another embodiment of the invention is directed to polysaccharides, particularly alginates, which are modified by being crosslinked. The alginates may further be modified by covalent bonding thereto of a biologically active molecule for cell adhesion or other cellular interaction. Crosslinking of the alginate can particularly provide aloinate materials with controlled mechanical properties and shape memory properties which greatly expand their range of use, for example, to tissue engineering applications where size and shape of the matrix is of importance. The modification of the crosslinked alginates with the biologically active molecules can provide a further three-dimensional environment which is particularly advantageous for cell adhesion, thus making such alginates further useful as cell transplantation matrices. Further, the invention is directed to processes for preparing such crosslinked alginates and to their use, for example, for forming materials for tissue engineering and/or having cell adhesion properties particularly for cell transplantation matrices, such as injectable cell transplantation solutions and preformed materials for cell transplantation.
Another embodiment of the invention is directed to modified alginates, such as alginate backbone (i.e. unmodified alginate) or the above described side chain alginates or crosslinked alginates, modified by covalent bonding thereto of a biologically active molecule for cell adhesion or other cellular interaction, which is particularly advantageous for maintenance, viability and directed expression of desirable patterns of gene expression. The modified alginate polymers provide a three-dimensional environment which is particularly advantageous for cell adhesion. Further, the invention is directed to processes for preparing such polymers and to the use of such polymers, for example, for forming gels or highly viscous liquids having cell adhesion properties particularly for cell transplantation matrices, such as injectable cell transplantation solutions and preformed hydrogels for cell transplantation.
Further aspects of the invention may be determined by one of ordinary skill in the art from the following description.
BACKGROUND OF THE INVENTION
Organ or tissue failure remains a frequent, costly, and serious problem in health care despite advances in medical technology. Available treatments now include transplantation of organs from one individual to another, performing surgical reconstructing, use of mechanical devices (e.g., kidney dialyzer) and drug therapy. However, these treatments are not perfect solutions. Transplantation of organs is limited by the lack of organ donors, possible rejection and other complications. Mechanical devices cannot perform all functions of an organ, e.g., kidney dialysis can only help remove some metabolic wastes from the body. Likewise, drug levels comparable to the control systems of the body is difficult to achieve. This is partially due to difficulties in controlling the drug level in vivo. Financially, the cost of surgical procedures is very high. Advances in medical, biological and physical sciences have enabled the emergency of the field of tissue engineering. “Tissue engineering” is the application of the principles and methods of engineering and the life sciences toward the fundamental understanding of structure/function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore, maintain or improve function. It thus involves the development of methods to build biological substitutes as supplements or alternatives to whole organ or tissue transplantation . The use of living cells and/or extracellular matrix (ECM) components in the development of implantable parts or devices is an attractive approach to restore or to replace function. The advantage of this approach over whole organ/tissue transplantation is that only the cells of interest are implanted, and they potentially can be multiplied in vitro. Thus, a small biopsy can be grown into a large tissue mass and, potentially, could be used to treat many patients. The increased tissue supply may reduce the cost of the therapy because early intervention is possible during the disease, and this may prevent the long-term hospitalization which results as tissue failure progresses. The use of immunosuppression may also be avoided in some applications by using the patient's own cells.
Alginate is a linear polysaccharide, isolated, for example, from brown sea algae, which forms a stable hydrogel in the presence of divalent cations (e.g., Ba
++
, Ca
++
) (Smidsrod et al (1990): Alginate as immobilization matrix for cells.
TIBTECH
, 8:71-78.) Alginate is currently being used for the in vitro culture of some cells types, as an injectable cell delivery matrix, for immunoisolation based therapies, and as an enzyme immobilization substrate (Atala et al., 1993: Injectable alginate seeded with chondrocytes as a potential treatment for vesicoureteral reflux.
J. Urology
, 150:745:747; Levesque et al., 1992: Maintenance of long-term secretory function by microencapsulated islets of Langerhans.
Endocrinology
, 130:644-650; Dominguez et al., 1988: Carbodiimide coup
Bouhadir Kamal H.
Mooney David J.
Rowley Jon A.
Wong Wai Kung
Millen White Zelano & Branigan P.C.
The Regents of the University of Michigan
White Everett
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