Degradable cross-linking agents and cross-linked network polymers formed therewith

Abstract

Degradable cross-linkers which are used to form polymer networks which degrade under aqueous conditions are described. These cross-linkers comprise a central polyacid, monomeric or oligomeric degradable regions and an optional water soluble regions. These monomers are preferably polymerized using free radical or condensation polymerization. Degradation occurs at the ester linkages after cross-linking polymer filaments, and results in soluble polymer filaments which may be cleared from the body. Preferred applications of these materials include, for example, controlled release of drugs and cosmetics, tissue engineering, wound healing, hazardous waste remediation, metal chelation, swellable devices for absorbing liquids and the prevention of surgical adhesions.

What is claimed:  
     
         1 . A monomeric or oligomeric cross-linker comprising a polyacid core with at least two acidic groups being connected to reactive groups usable to cross-link polymer filaments wherein between at least one reactive group and the polyacid core is a region degradable under aqueous conditions; the cross-linker being usable to form cross-linked polymer filaments.  
     
     
         2 . A monomeric or oligomeric cross-linker comprising a polyacid core with at least two acidic groups connected to a region degradable under aqueous conditions and having a covalently attached reactive group usable to form cross-linked polymer filaments.  
     
     
         3 . The cross-linker of  claim 1  or  2  where the polyacid is a polycarboxylic acid.  
     
     
         4 . The cross-linker of  claim 3  described further as containing a water soluble region between at least one carboxyl group and its associated reactive group.  
     
     
         5 . The cross-linker of  claim 1  or  2  wherein the polymer is a hydrogel.  
     
     
         6 . The cross-linker of  claim 1  or  2  wherein the polymer is hydrophobic.  
     
     
         7 . The cross-linker of  claim 1  or  2  wherein the polyacid core comprises at least one acidic group attached to a water soluble region that is linked to a biodegradable region having a reactive group attached thereto.  
     
     
         8 . The cross-linker of  claim 1  or  2  where the polyacid core is a diacid.  
     
     
         9 . The cross-linker of  claim 1  or  2  where the polyacid core is a triacid.  
     
     
         10 . The cross-linker of  claim 1  or  2  where the polyacid is a pentaacid or tetraacid.  
     
     
         11 . The cross-linker of  claim 1  where the polyacid is succinic acid, adipic acid, fumaric acid, maleic acid, sebacic acid, malonic acid, tartaric acid, or citric acid.  
     
     
         12 . The cross-linker of  claim 1  or  2  where the polyacid is citric acid, ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA).  
     
     
         13 . The cross-linker of  claim 1  or  2  wherein cross-linked polymer filaments are separated by at least two degradable regions.  
     
     
         14 . The cross-linker of  claim 1  or  2  wherein cross-linked polymer filaments are separated by one degradable region.  
     
     
         15 . The cross-linker of  claim 1  or  2  where the degradable region comprises a hydroxyalkyl acid ester.  
     
     
         16 . The cross-linker of  claim 1  or  2  where the degradable region comprises an alpha hydroxy acid ester.  
     
     
         17 . The cross-linker of  claim 1  or  2  wherein the degradable region comprises a peptide.  
     
     
         18 . The cross-linker of  claim 1  or  2  wherein the degradable region comprises an glycolic polyester, a DL lactic acid polyester, a L lactic acid ester, or combinations thereof.  
     
     
         19 . The cross-linker of  claim 1  or  2  where the degradable region comprises at least one anhydride, orthoester or phosphoester or combinations thereof, optionally attached to one or more hydroxyalkyl acid esters.  
     
     
         20 . The cross-linker of  claim 1  or  2  wherein the degradable region comprises at least one amide functionality.  
     
     
         21 . The cross-linker of  claim 1  or  2  defined further as comprising at least one of an ethylene glycol oligomer, poly(ethylene) glycol, poly(ethylene) oxide, poly(vinylpyrolidone), poly(ethylene) oxide, co-poly(propylene) oxide), and poly (ethyloxazoline).  
     
     
         22 . The cross-linker of  claim 1  or  2  where the reactive group contains a carbon-carbon double bond.  
     
     
         23 . The cross-linker of  claim 1  or  2  where the reactive group is an end group.  
     
     
         24 . The cross-linker of  claim 1  or  2  where the reactive group contains a carbonate, carbamate, hydrazone, hydrazino, cyclic ether, acid halide, acyl azide, succinimidyl ester, imidazolide or amino functionality.  
     
     
         25 . The cross-linker of  claim 1  or  2  wherein networks of polymer filaments are formed by thermal, catalytic or photochemical initiation.  
     
     
         26 . The cross-linker of  claim 1  or  2  wherein networks of polymer filaments are formed by pH change.  
     
     
         27 . The cross-linker of  claim 1  or  2  wherein networks of polymer filaments are formed by free radical addition or Michael addition.  
     
     
         28 . The cross-linker of  claim 1  or  2  where the aqueous conditions are physiological conditions.  
     
     
         29 . A network of polymer filaments formed by precipitation, dispersion or emulsion polymerization and cross-linked by a monomeric or oligomeric cross-linker having a polyacid core with at least two acidic groups connected to a covalently attached reactive group used to cross-link polymer filaments and at least one acidic group having a region degradable under aqueous conditions between the acidic group and the reactive group.  
     
     
         30 . A network of polymer filaments formed via condensation reaction of preformed polymer filaments of polynucleic acids, polypeptides, proteins or carbohydrates and cross-linked by a monomeric or oligomeric cross-linker comprising a polyacid core with at least two acidic groups connected to at least one region degradable under in vivo conditions, and having a covalently attached reactive group cross-linking the polymer filaments.  
     
     
         31 . The network of  claim 29  or  30  further comprising biologically active molecules.  
     
     
         32 . A network of polymer filaments cross-linked by a monomeric or oligomeric cross-linker comprising a polyacid core with at least two acidic groups connected to at least one region degradable under in vivo conditions, and both acidic groups connected to a covalently attached reactive group and defined further as comprising an organic molecule, inorganic molecule, protein, carbohydrate, poly(nucleic acid), cell, tissue or tissue aggregate.  
     
     
         33 . A network of polymer filaments cross-linked by monomeric or oligomeric cross-linker comprising a central polyacid core with at least two acidic groups connected to at least one region degradable under in vivo conditions, and terminated by a covalently attached reactive end group usable to cross-link polymer filaments, the network comprising an organic radioisotope, inorganic radioisotope or nuclear magnetic resonance relaxation reagent.  
     
     
         34 . The cross-linker monomer or macromer of  claim 1  or network of  claim 26  wherein the polyacid core has a molecular weight between 60 and 400 Da; the degradable region has a molecular weight between 70 and 500 Da and the reactive group has a molecular weight between 10 and 300 Da.  
     
     
         35 . A microparticle or nanoparticle polymer composition containing a monomeric or oligomeric cross-linker comprising a polyacid core with at least two acidic groups connected to at least one region degradable under in vivo conditions, and having a covalently attached reactive group usable to cross-link polymer filaments.