Reversibly cross-linked hydrogels

Details Reversibly cross-linked hydrogels Reversibly cross-linked hydrogels

2000-11-27

2004-09-14

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S059000, C514S060000, C536S003000, C536S102000, C536S105000, C536S112000, C524S916000, C424S093200, C435S397000

Reexamination Certificate

active

06790840

ABSTRACT:

FIELD OF THE INVENTION
The present invention includes hydrogel compositions and methods for the fabrication and use thereof.
BACKGROUND OF THE INVENTION
Water-containing hydrogels have numerous applications including as food additives, blood contact materials, bioadhesives, contact lenses, wound dressings, artificial organs, drug delivery, controlled release formulations, membranes, superabsorbents, cell encapsulation and immunoisolation materials, and delivery carriers for bioactive agents, including drugs. Their biocompatibility is likely related to their high water content and low interfacial tension with surrounding biological environment. One of the most recent applications of hydrogels is as delivery vehicles of cells for tissue engineering approaches. The aim of this approach is the reconstruction of tissues and organs using three-dimensionally designed synthetic matrices which mimic the function of the extracellular matrix, and offers an alternative to the patient who needs new tissues or organs. Hydrogels may be potent materials for soft tissue engineering applications due to their similarity to the highly hydrated macromolecular-based materials in the body. Critical properties of hydrogels utilized in these applications include their degradation time and mechanical properties. One typically desires to time the rate of hydrogel degradation to the rate of new tissue formation, and this time may vary significantly for different tissues. The mechanical properties of these materials are critical to their ability to create and maintain a space for new tissue formation in vivo, and the mechanical properties of the materials to which cells adhere can also regulate the gene expression of the cells. A number of synthetic and naturally derived materials may be used in the formation of hydrogels. One widely used material in hydrogel formation is alginate, a hydrophilic polysacchoride derived from seaweeds. Alginate comprises a family of natural copolymers of &bgr;-D-mannronic acid and &agr;-L-guluronic acid. See Martinsen et al., Biotechnology and Bioengineering, 33: p. 79-89 (1989); Draget et al., Carbohydrate Polymers, 14: p. 159-178 (1991).
One particularly promising application of hydrogels is in tissue engineering. Tissue engineering is directed towards creating biological tissue rather than rely on scarce transplantable organs. An extracellular matrix (ECM) of noncellular material has been identified in many multi-cellular organisms, including human beings. ECM molecules include specialized glycoproteins, proteoglycans, and complex carbohydrates. A wide variety of ECM structures have been identified, and ECM has been implicated in tissue formation. Simply put, the method of tissue engineering is tissue and organ reconstruction using synthetic (e.g., polymeric), three-dimensional matrices, also referred to as “scaffolds” which mimic a body's ECM to provide a space for new tissue formation in vivo. Because alginate exhibits a high degree of biocompatability, is abundant, and inexpensive, it is well suited to application in tissue engineering as well as other applications.
Use of hydrogels in tissue engineering applications particularly is dependent upon hydrogel degradation time and mechanical properties. While alginate is widely employed to fabricate hydrogels for various biomedical applications, ionically cross-linked alginate hydrogels have uncontrollable mechanical properties and disintegration behavior. Preferably, however, hydrogels used in tissue engineering, for example, persist as a tissue generation “scaffold” at least as long as required for new tissue formation. Additionally, the molecular weight of alginate as commonly used in such hydrogels is greater than the limit of renal clearance in humans, such that the disintegrated hydrogel cannot be processed by human kidneys.
Use of hydrogels in injectable form for the delivery of drugs and/or cells has also been of advantageous use. The ability to inject these materials minimizes the pain and cost of delivery to the patient.
Because it is conventionally considered that hydrogel degradation is a function of cross-linking density, one solution to the problem of rapid bydrogel degradation has been the creation of hydrogels characterized by high cross-linking density. However, highly cross-linked hydrogels display mechanical stiffness, an undesirable characteristic particularly in biomedical applications.
What is needed is a hydrogel composition with both desirable mechanical properties and degradation characteristics.
SUMMARY OF THE INVENTION
The hydrogel compositions of the invention are provided with excess reversible cross-linking agent(s) such that some binding sites on the cross-linking agent(s) are initially unbound to the polymer, but are capable of binding to other sites on the polymer as those sites become available through degradation of other cross-links. The cross-linkers which have at least one site bonded to the polymer and at least one site open for reversible bonding will be referred to as dangling cross-linkers or danglers. The conventional view in the art was that such dangling cross-linkers were disadvantageous and to be avoided because the danglers block the site of the polymer to which they are attached. The inventors have discovered, however, how to put this supposed disadvantage to advantageous use according to their invention. For the hydrogels of the invention, the provision of dangling cross-linkers advantageously results in a hydrogel with less mechanical stiffness because not all of the potentially cross-linked sites can be cross-linked due to blocking by the danglers.
It has surprisingly been discovered that the lower mechanical stiffness is not coupled with a corresponding loss of stability to degradation. As cross-linking sites degrade, the presence of the dangling cross-linkers allows formation of new cross-links, thus, compensating for and slowing the degradation rate. The invention therefore results in hydrogels where the mechanical stiffness properties do not have to correspond or be coupled with the degradation properties. In a particular embodiment, hydrogels with desired slow degradation but not with undesired high mechanical stiffness are provided. These hydrogels are particularly useful in drug delivery and tissue engineering applications where it is desirable that the hydrogel not be too stiff to manipulate, administer and/or implant, but which still is resistant to degradation until its function has been served.
The present invention thus relates to an improved polymeric hydrogel composition and method of making the same, and in particular to such a hydrogel composition comprising a hydrogel polymer, preferably an oxidized polysaccharide, and at least one cross-linker having two or more functional groups capable of reversibly cross-linking the polysaccharide in the hydrogel system. The cross-linker is provided as described above to have dangling cross-linkers. In an exemplary hydrogel, the hydrogel polymer is a polysaccharide comprising a synthetic or naturally derived alginate polymer having aldehyde groups, and the cross-linking agent is one having at least two hydrazide groups, such as adipic acid dihydrazide (AAD). Because the hydrogel has preferably many dangling cross-linkers capable of reversibly cross-linking the polymer, the inventive hydrogel compositions display surprisingly improved degradation characteristics and improved mechanical properties as compared with hydrogels having higher cross-linking densities, and/or no dangling cross-linkers.
As indicated, the hydrogel polymer is preferably an oxidized polysaccharide, particularly an alginate. Preferably, such alginate polymer comprises any of several derivatives of alginic acid, including calcium, sodium, or potassium salts or propylene glycol alginate, and most preferably comprises an alginate salt of high guluronate content. The cross-linking agent preferably comprises at least two functional groups which are capable of reversibly cross-linking the polymer, preferably at least two hydrazide groups, and most

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