Low swell tissue adhesive and sealant formulations

Abstract

A hydrogel tissue adhesive formed by reacting an aldehyde-functionalized dextran containing pendant aldehyde groups with a multi-arm polyethylene glycol amine is described. The hydrogel exhibits little to no swell upon exposure to physiological conditions. The hydrogel may be useful as a tissue adhesive or sealant for medical applications that require a low swell hydrogel to inhibit complications, such as fibrosis, including scar formation or surgical adhesions.

What is claimed is: 
     
         1 . A kit for forming a low swell hydrogel comprising:
 (a) a first aqueous solution or dispersion comprising one or more aldehyde-functionalized dextrans containing pendant aldehyde groups, said aldehyde-functionalized dextrans having a weight-average molecular weight of about 10,000 to about 20,000 Daltons and an equivalent weight per aldehyde group of about 226 to about 170; and   (b) a second aqueous solution or dispersion comprising one or more polyethylene glycols having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycols have a number-average molecular weight of about 9,000 to about 11,000 Daltons;
 wherein 
 (i) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 20 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 18 wt %; or 
 (ii) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 20 wt %. 
   
     
     
         2 . The kit of  claim 1 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185. 
     
     
         3 . The kit of  claim 1 , wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 10 wt % to about 18 wt %. 
     
     
         4 . The kit of  claim 1 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 13,000 to about 17,000 Daltons. 
     
     
         5 . The kit of  claim 1 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 222 to about 189. 
     
     
         6 . The kit of  claim 1 , wherein the polyethylene glycols have a number-average molecular weight of about 9,500 to about 10,500 Daltons. 
     
     
         7 . The kit of  claim 1 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Daltons and an equivalent weight per aldehyde group of about 177, wherein the polyethylene glycols have a number-average molecular weight of about 10,000 Daltons, and wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 10 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 15 wt %. 
     
     
         8 . The kit of  claim 1 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Daltons and an equivalent weight per aldehyde group of about 177, wherein the polyethylene glycols has a number-average molecular weight of about 10,000 Daltons, and wherein the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the first aqueous solution or dispersion is about 15 wt % and the total concentration of the polyethylene glycols in the second aqueous solution or dispersion is about 15 wt %. 
     
     
         9 . A dried hydrogel formed by a process comprising the steps of:
 combining in a solvent (a) one or more aldehyde-functionalized dextrans containing pendant aldehyde groups, said aldehyde-functionalized dextrans having a weight-average molecular weight of about 10,000 to about 20,000 Daltons and an equivalent weight per aldehyde group of about 226 to about 170, and (b) one or more polyethylene glycols having eight arms, substantially each arm of the which is terminated with at least one primary amine group, said polyethylene glycols having a number-average molecular weight of about 9,000 to about 11,000 Daltons, to form a low swell hydrogel;
 wherein 
 (i) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the solvent is about 5 wt % to about 20 wt % and the total concentration of the polyethylene glycols in the solvent is about 10 wt % to about 18 wt %; or 
 (ii) the total concentration of the aldehyde-functionalized dextrans containing pendant aldehyde groups in the solvent is about 5 wt % to about 10 wt % and the total concentration of the polyethylene glycols in the solvent is about 10 wt % to about 20 wt %; and 
   treating said hydrogel to remove at least a portion of said solvent to form the dried hydrogel.   
     
     
         10 . The dried hydrogel of  claim 9 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185. 
     
     
         11 . The dried hydrogel of  claim 9  wherein said dried hydrogel is in the form of a film. 
     
     
         12 . A composition comprising the reaction product of:
 a) at least one aldehyde-functionalized dextran containing pendant aldehyde groups, wherein the aldehyde-functionalized dextran has a weight-average molecular weight of about 10,000 to about 20,000 Daltons and an equivalent weight per aldehyde group of about 226 to about 170, and   b) at least one polyethylene glycol having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycol has a number-average molecular weight of about 9,000 to about 11,000 Daltons;
 wherein 
 (i) the composition contains about 5 wt % to about 20 wt % of the aldehyde-functionalized dextran and about 10 wt % to about 18 wt % of the polyethylene glycol; or 
 (ii) the composition contains about 5 wt % to about 10 wt % of the aldehyde-functionalized dextran and about 10 wt % to about 20 wt % of the polyethylene glycol. 
   
     
     
         13 . The composition of  claim 12 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185. 
     
     
         14 . A crosslinked hydrogel composition comprising:
 a) at least one aldehyde-functionalized dextran containing pendant aldehyde groups, wherein the aldehyde-functionalized dextran has a weight-average molecular weight of about 10,000 to about 20,000 Daltons and an equivalent weight per aldehyde group of about 226 to about 170, and   b) at least one polyethylene glycol having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycol has a number-average molecular weight of about 9,000 to about 11,000 Daltons;
 wherein 
 (i) the composition contains about 5 wt % to about 20 wt % of the aldehyde-functionalized dextran and about 10 wt % to about 18 wt % of the polyethylene glycol; or 
 (ii) the composition contains about 5 wt % to about 10 wt % of the aldehyde-functionalized dextran and about 10 wt % to about 20 wt % of the polyethylene glycol; and 
   wherein said aldehyde-functionalized dextran and said polyethylene glycol are crosslinked through covalent bonds formed between the pendant aldehyde groups of the dextran and the primary amine groups of the polyethylene glycol.   
     
     
         15 . The crosslinked hydrogel composition of  claim 14 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185. 
     
     
         16 . A method for applying a low swell coating to an anatomical site on tissue of a living organism comprising the steps of:
 applying to the site (a) aldehyde-functionalized dextrans containing pendant aldehyde groups, wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 10,000 to about 20,000 Daltons and an equivalent weight per aldehyde group of about 226 to about 170; followed by   (b) polyethylene glycols having eight arms, substantially each arm of which is terminated with at least one primary amine group, wherein the polyethylene glycols have a number-average molecular weight of about 9,000 to about 11,000 Daltons,   or (b) followed by (a), or premixing (a) and (b) and applying the resulting mixture to the site before the resulting mixture completely cures; and   wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 2:1 to about 1:4.   
     
     
         17 . The method of  claim 16 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 226 to about 185. 
     
     
         18 . The method of  claim 16 , wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:1 to about 5:18. 
     
     
         19 . The method of  claim 16 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 13,000 to about 17,000 Daltons. 
     
     
         20 . The method of  claim 16 , wherein the aldehyde-functionalized dextrans have an equivalent weight per aldehyde group of about 222 to about 189. 
     
     
         21 . The method of  claim 16 , wherein the polyethylene glycols have a number-average molecular weight of about 9,500 to about 10,500 Daltons. 
     
     
         22 . The method of  claim 16 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Daltons and a degree of aldehyde substitution of about 108%, wherein the polyethylene glycols have a number-average molecular weight of about 10,000 Daltons, and wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:1.5. 
     
     
         23 . The method of  claim 16 , wherein the aldehyde-functionalized dextrans have a weight-average molecular weight of about 15,000 Daltons and a degree of aldehyde substitution of about 108%, wherein the polyethylene glycols has a number-average molecular weight of about 10,000 Daltons, and wherein the weight percent ratio of aldehyde-functionalized dextrans to polyethylene glycols is about 1:1. 
     
     
         24 . The method of  claim 16 , wherein the site is tissue involved in or affected by a surgical procedure. 
     
     
         25 . The method of  claim 24 , wherein the surgical procedure is lumbar laminectomy, laminotomy, discectomy, flexor tendon surgery, spinal fusion, joint replacement or repair, abdominal procedures, gynecological procedures, musculoskeletal surgeries, thoracic surgeries, cranial surgeries, ocular surgeries, oral surgeries or implants.