Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/20—Polysaccharides
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B31/00—Preparation of derivatives of starch
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
  • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
  • C08L5/04—Alginic acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J2300/00—Characterised by the use of unspecified polymers
  • C08J2300/14—Water soluble or water swellable polymers, e.g. aqueous gels

Definitions

• the present invention includes hydrogel compositions and methods for the fabrication and use thereof.
• 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.
• 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 ⁇ -D-mannronic acid and ⁇ -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).
• tissue engineering is directed towards creating biological tissue rather than rely on scarce transplantable organs.
• ECM extracellular matrix
• a wide variety of ECM structures have been identified, and ECM has been implicated in tissue formation.
• 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.
• hydrogels used 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.
• 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.
• hydrogel degradation is a function of cross-linking density
• hydrogels characterized by high cross-linking density.
• 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.
• 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.
• 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.
• the lower mechanical stiffness is not coupled with a corresponding loss of stability to degradation.
• 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.
• 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
• 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.
• the hydrogel polymer is a polysaccharide comprising a synthetic or naturally derived alginate polymer having aldehyde groups
• the cross-linking agent is one having at least two hydrazide groups, such as adipic acid ⁇
• 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.
• the hydrogel polymer is preferably an oxidized polysaccharide, particularly an alginate.
• 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 preferably the cross-linker comprises AAD. Further exemplification of useful polymers and cross-linkers for the hydrogel is provided by reference to WO 98/12228 published March 26, 1998.
• the hydrogel polymer and cross-linking agent are admixed in amounts providing an excess of cross-linker so that dangling cross-linkers result and block a high-density extent of cross-linking.
• the hydrogels have a cross-linking efficiency for single-end dangling cross-linkers of from 20-90%, more preferably in the range of 20-80%, 20-70% or 30-50%o.
• the creation of significant dangling cross-linkers is facilitated by the use of an excess amount of cross-linker.
• hydrogel formation be conducted in a salt solution.
• Such solution preferably contains 0.01-20 g/1 (more preferably 2.0-10.0 g/1) of NaCl and may optionally additionally contain one or more of: 0.01 - 1.0 (pref. 0.1-0.5) g/L of CaCl 2 ; 0.01 - 2.0 (pref. 0.2-1.0) g/L of KC1;
• the hydrogel polymer is preferably of low molecular weight (Mw) so as to be suited for biomedical applications. However, applications using hydrogels with molecular weight up to 50,000 Daltons are possible. Hydrogels with molecular weight (Mw) from 1,000 to 30,000 or 1,000 to 10,000 are more preferred. Molecular weight can be modified by means such as acid hydrolysis and oxidation, as necessary. According to the illustrated example, an alginate material is hydrolyzed under acidic conditions to yield sodium poly(guluronate) (PG) of relatively low molecular weight (e.g. Mw about 7,000). The PG precipitate is then oxidized by sodium periodate to form the alginate polymer, PAG (e.g. Mw about 5,700).
• PG sodium poly(guluronate)
• This PAG intermediate is subsequently cross-linked with a suitable cross-linker, such as AAD, in the manner discussed above to form hydrogels with dangling cross-linkers.
• a suitable cross-linker such as AAD
• the resultant PAG hydrogels exhibited a higher degree of swelling (Q) and lower shear modulus (G) than PAG hydrogels with a higher cross-linking density (e.g., those on the order of 16.0 x 10 5 mol/cm 3 or higher).
• the preferred degree of swelling (Q) is from 1 to 200, more preferably 5 to 100.
• the preferred shear modulus (G) is from 0.005 to 200 kPa, more preferably 0.05 to 100 kPa.
• the hydrogels are further characterized by increased stability over time; that is, slower degradation.
• Hydrogels having this characteristic retarded degradation imparted by reversibly cross-linking dangling cross-linkers are well suited to numerous applications, including biomedical applications such as tissue engineering cell transplantation and drug delivery. Further discussion of useful applications is provided by reference to WO 98/12228 published March 26, 1998.
• the present invention relates to polymer hydrogel compositions and methods of making and using the same, and particularly to hydrogels characterized by a cross-linker having at least two functional groups able to reversibly cross-link the polymer.
• the hydrogels are further characterized by an extent of cross-linking such that some potentially cross-linkable sites are not cross-linked because two dangling cross-linkers are occupying sites which are cross-linkable by a single cross-linker.
• Such hydrogels display improved mechanical properties and retarded degradation as compared to conventional hydrogel systems.
• hydrogel refers to a three-dimensional network of cross- linked hydrophilic polymers comprising water. Hydrogels are preferably, though not necessarily, limited to gels. Hydrogels may have a net positive or negative charge, or may be neutral.
• cross-linking and formatives thereof, as used herein refers to an attachment of two chains of polymer molecules by bridges, composed of either an element, a group, or a compound, that join certain atoms of the chains by chemical bonds. Cross-linking can be effected naturally and artificially. Internal cross-linking between two sites on a single polymer molecular is also possible.
• cross-linker or "cross-linking agent”, as used herein, refers to the element, group, or compound that effects cross-linking between polymer chains.
• cross-linkers or “dangler” refers to cross-linkers having at least one site bonded to the hydrogel polymer and at least one site remaining free and capable of subsequent bonding to the polymer
• reversibly cross-linking refers to the phenomenon of degradation and reformation of cross-links over time in a degradable hydrogel system.
• Fig. 1 is a plot of the characteristic infrared absorption bands for PAG and for a PAG hydrogel cross-linked with 150mM AAD over time.
• Fig. 2 is a plot of weight loss (%) over time for exemplary PAG gels prepared with
• AAD cross-linker in concentrations of lOOmM(o), 150mM (D), and 200mM ( ⁇ ).
• Fig. 3 is a plot of shear modulus change (G/G 0 ) over time for exemplary PAG hydrogels prepared with AAD cross-linker in concentrations of lOOmM (o), 150mM (D), and 200mM ( ⁇ ).
• Fig. 4 is a plot of change in degree of swelling (Q/Qo) over time for exemplary PAG hydrogels prepared with AAD cross-linker in concentrations of lOOmM (o), 150mM (D), and
• Fig. 5 is a plot of change in cross-linking density (VX(V ⁇ o) over time for exemplary PAG hydrogels prepared with AAD cross-linker in concentrations of lOOmM (o), 150mM
• Fig. 6 is a plot of shear modulus (G) versus degree of swelling (Q) for exemplary AG.
• the exemplary hydrogel of the present invention is prepared by cross-linking a hydrogel polymer, preferably an oxidized polysacharide such as an alginate polymer, with a cross-linking agent having at least two functional groups, the cross-linking agent capable of reversibly cross-linking the polymer and provided in an amount to result in the discussed dangling cross-linkers.
• the hydrogel polymer is an alginate cross-linked with a cross-linker having two hydrazide functional groups, the polymer and cross-linker admixed in relative amounts such that the resultant hydrogel is characterized by the presence of a significant amount of dangling cross-linkers.
• the hydrogel preferably has a relatively low cross-linking density, as determined by the Flory-Rehner equation.
• the preferred cross-linking density (Ve) is less than 16.0 x 10 5 mol/cm 3 , and most preferably less than approximately 12.3 x 10 5 mol/cm 3 .
• polymer hydrogels were generally prepared by hydrolyzing an alginate under acidic conditions, isolating and subsequently oxidizing poly guluronate (PG) therefrom to prepare poly(aldehyde guluronate) (PAG), and cross- linking the PAG (20% wt solution) with a cross-linker having at least two hydrazide groups, for example adipic acid dihydrazide (AAD), to form hydrogels.
• PG poly(aldehyde guluronate)
• AAD adipic acid dihydrazide
• the concentration of cross-linker was varied from 50 mM to 250mM.
• the hydrogel polymer preferably comprises an oxidized polysaccharide, for example an alginate such as the commercially available sodium alginate (PROTANAL LF 20/60) obtained from PRONOVA (Drammen, Normay).
• alginate is characterized by a high guluronate content, since the guluronate units provide sites for ionic cross-linking through divalent cations to gel the polymer.
• alginates may serve for the present invention.
• Alginate refers to any of a number of derivatives of alginic acid (e.g., calcium, sodium, or potassium salts or propylene glycol alginate). These compounds may be synthetic or naturally derived. Both natural and synthetic alginates are commercially available or may be prepared, and may be substituted in preparation of the present inventive hydrogel according to this disclosure.
• Natural source alginates may be derived from seaweed or bacteria according to conventional methods. See Biomaterials: Novel Materials from Biological Sources, ed. Byrum, Alginates chapter (ed. Sutherland), p. 309-331 (1991). Both naturally derived and synthetically o prepared alginates can be fabricated, according to known methods, to provide side chains with a desired mannuronate and guluronate proportion. It is not intended that the present invention be limited to alginate or any particular polymer, or a particular method of making the same.
• any of a number of polysaccharides may be substituted for the alginate of the exemplary disclosure.
• other polymers may be used which are biocompatible, can provide hydrogels and are cross-linkable according to the invention.
• PAG was prepared for the exemplary hydrogels according to the method of Haug et al., reported in Acta. Chem. Scand., 20: p. 183-190 (1966), which disclosure is incorporated herein in its entirety.
• the alginate material underwent acid hydrolysis to break down the ⁇ -glycosidic linkages between mannuronate and guluronate residues, thereby providing a lowered molecular weight PG which is essentially lacking mannuronic acid units.
• SEC was performed on a triple detector system including a laser refractometer (LR40, VISCOTEK), a differential viscometer, and RALLS (T60, VISCOTEK), 0.1 M NaNO 3 buffer solution (pH 6.3) was used as a mobile phase with a flow rate of 0.7 ml/min.
• Two TSK-gel columns (G4000PW XL and G3000PW XL ) were used for separation.
• TNBS trinitrobenzene sulfonic acid
• the molecular weight of the hydrogel polymer material so prepared is at or below the renal threshold for clearance by the host, whether human or other, which reduction in molecular weight can be effected by the oxidation reaction described above with reference to the exemplary alginate polymer.
• the method of preparing the hydrogel polymer for the exemplary hydrogel of this disclosure is not intended to be limiting of the present invention, according to which a variety of polymers, including the preferred oxidized polysaccharides, prepared according to the above or other known methods, may be substituted in the hydrogel system.
• the PAG so obtained was cross-linked with varying amounts of AAD (ALDRICH, Milwaukee, WI), a bi-functional cross-linker.
• AAD ADRICH, Milwaukee, WI
• Cross-linking of the PAG and AAD occurs in the absence of a catalyst or additive, as aldehyde groups are known to be much more reactive towards hydrazide groups as compared to carboxyl groups.
• AAD is a preferred cross- linker for the exemplary hydrogel
• other preferred cross-linking agents include compounds with at least two functional groups capable of reversibly cross-linking the hydrogel polymer.
• Preferred functional groups are hydrazide groups, and any multi -hydrazide cross-linkers will be suited to this invention.
• the functional groups may vary according to such factors as the hydrogel polymer employed.
• the cross-linker may comprise amine groups, for example.
• the functional groups of the polymer and cross-linker may be reversed from the exemplary hydrogel; that is, the cross- linker may comprise aldehyde functional groups, while the hydrogel polymer comprises the hydrazide groups.
• a 20 wt% solution of PAG was admixed with AAD in concentrations of from 50mM to 250mM. All such solutions were prepared in Dulbecco's Modified Eagle's Medium (DMEM) (LIFE TECHNOLOGIES, Grand Island, NY) having an adjusted pH of 7.4 prior to mixing. The final concentration of PAG in the hydrogel was fixed at 6 wt%. The hydrogel solution was plated in tissue culture plates and incubated at room temperature for 4 hours to permit hydrogel formation.
• DMEM Dulbecco's Modified Eagle's Medium
• the PAG hydrogels formed with AAD concentrations varying from 1 OOmM to 200mM were tested for extent of effective cross-linking, degradation behavior and mechanical properties, the latter two over time.
• the cross-linked PAG hydrogel is characterized by an absorption band at 1658cm "1 corresponding to the hydrazone bond between the PAG aldehyde group and the AAD hydrazide group.
• the hydrazone linkages are hydrolyzed in the presence of aqueous media.
• Fig 1 is illustrative for PAG and a PAG hydrogel cross-linked with AAD at a concentration of 150mM; where the band at (a) is PAG, the band at (b) is the PAG hydrogel, the band at (c) is the PAG hydrogel after 5 days degradation, the band at (d) is the PAG hydrogel after 15 days degradation, and the band at (e) is the PAG hydrogel after 29 days degradation.
• the arrow in FIG. 1 indicates the hydrazone band at 1658 cm "1 .
• TNBS trinitrobenzene sulfonic acid solution
• the mechanical strength of the exemplary hydrogels formed according to the present invention was measured by compression testing with an MTS BIONIX 100 mechanical tester (MTS SYSTEMS, France) to obtain an elastic modulus in compression.
• the deformation rate was 0.5 mm/min and the indentor had a diameter of 3.15mm.
• the shear modulus (G) of the hydrogels was determined by the slope of ⁇ v. -( ⁇ - ⁇ 2 ), where ⁇ is the stress and ⁇ is the ratio of deformed length: undeformed length of the hydrogel (assuming an affine network model) as disclosed in Treloar, Physics of Rubber Elasticitv (Clarendon Press: Oxford, 1975), and Stainsby, Food Chemistry, 6: p. 3(1980), both of which disclosures are incorporated herein by reference in their entireties.
• the hydrogels so prepared were also measured for swelling. As indicated, all of the hydrogels were immersed in DMEM (pH 7.4) for 24 hours at 37 ° C, following which excess water was removed and the hydrogels weighed.
• p p is the polymer density (0.87555 g/cm for sodium alginate)
• p s is the density of water (0.9971 g/cm 3 at 25 °C)
• Q m is the swelling ratio, defined as the mass ratio of absorbed water and the dried hydrogel. See DeRossie et al., Polymer Gels Fundamentals and Biomedical Applications (Plenum Press, New York 1991).
• V e fln(l-v 2 ) + v 2 + Xtv jfVjfo 3 -2v 2 / ⁇ y 1
• X is the interaction parameter,/is the cross-linking functionality
• v is the molar volume of water (18.062 cm 3 /mol)
• v 2 is the volume fraction of polymer in the hydrogel when it reaches the equilibrium swelling state.
• X is assumed to be 0.35 on the basis of previous modeling of similar interactions.
• f is assumed to be 4. Higher cross- linking density corresponds to stiffer mechanical properties and a lower degree of swelling in hydrogels.
• Table 1 provides characteristics data for exemplary PAG hydrogels including AAD in concentrations from lOOmM to 200mM. Data include cross-linking efficiency, shear moduli (G), swelling ratio (Q m ), degree of swelling (Q), and cross-linking density (V e ), all as defined above.
• the PAG hydrogels with initially higher cross-linking density (V e ) i.e., hydrogels cross-linked with lOOmM and 150mM AAD
• V e cross-linking density
• the PAG hydrogels with a higher percentage of single-end dangling cross-linkers exhibited less stiff initial mechanical properties.
• the exemplary hydrogels of the present invention formed with an AAD concentration of 200mM, and thus characterized by cross-linking densities of less than 16.0 x 10 5 mol/cm 3 , but a higher portion of dangling cross-linkers exhibited slower degradation than comparative hydrogels having lOOmM or 150mM AAD concentrations, despite having these lower cross-linking densities as determined by the Flory-Rehner equation.
• FIG. 3 shows the change over time in shear modulus (G/Go) of comparative PAG hydrogel examples cross-linked with lOOmM (O) and 150mM (D) AAD, and PAG hydrogels prepared with 200mM ( ⁇ ) concentration of AAD. All of the hydrogels were incubated in DMEM (pH 7.4) at 37°C. As shown, mechanical strength was rapidly lost for the lOOmM and 150mM AAD hydrogels, while the 200mM AAD hydrogel of the present invention, despite the low cross-linking density (TABLE 1), displayed significantly less reduction in mechanical strength over the duration of the evaluation period.
• FIG.4 shows the change in degree of swelling (Q/Qo) over time for PAG hydrogels cross-linked with AAD in concentrations of lOOmM (O), 150mM (D), and 200mM ( ⁇ ). All of the hydrogels were incubated in DMEM (pH 7.4) at 37°C. These data reflect the relative stability of low cross-linking density hydrogels prepared according to the present invention. Particularly, the hydrogels of the comparative examples, cross-linked with lOOmM and 150mM AAD, exhibited increased swelling over the course of degradation, while hydrogels cross-linked with 200mM AAD showed no significant change.
• FIG.5 shows the change in cross-linking density (VX(V ⁇ o) over time for PAG hydrogels cross-linked with AAD in concentrations of lOOmM (0), 150mM (D), and 200mM ( ⁇ ).
• V e cross-linking density
• FIG.5 shows the linear relationship between the shear modulus (G) and degree of swelling (Q) after degradation for hydrogels having AAD in each of the three concentrations, lOOmM (0), 150mM (D), and 200mM ( ⁇ ), which relationship suggests Gaussian elasticity justifying use of the Flory-Rhener equation.
• the improved degradation characteristics of the hydrogels of the present invention result from the relatively high concentration of dangling, single-end cross-linker molecules in the multi-hydrazide cross-linking agent, which molecules permit reversible-cross-linking with the hydrogel polymer following hydrolysis of the initial cross-linking bond to retain stability over time.
• the present invention surprisingly and unexpectedly provides a hydrogel and method of making the same wherein the mechanical and degradative properties of the hydrogel may be decoupled by the utilization of a cross-linking agent capable of reversibly cross-linking the polymer, resulting in a relatively mechanically "soft" hydrogel but with retarded degradation characteristics.

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