Biocompatible prosthetic tissue

Abstract

Crosslinked tissue is contacted with one or more toxicity reducing solutions to remove cytotoxicity associated with the crosslinking process. In particular, crosslinked tissue can be contacted with an inorganic sulfur-oxygen group to form chemical adducts of aldehydes and the inorganic sulfur-oxygen group. Preferably, the cytotoxicity reduced crosslinked tissue has no residual cytotoxicity. In preferred embodiments, a plurality of toxicity reducing agents are used to detoxify the tissue. Preferred toxicity reducing agents include, for example, inorganic sulfur-oxygen ions, such as bisulfate and thiosulfate, organic sulfates, amines, ammonia/ammonium, and surfactants.

What is claimed is:  
     
         1 . A prosthetic tissue comprising a chemically crosslinked protein matrix having no detectable cytotoxicity without any added growth factors.  
     
     
         2 . The prosthetic tissue of  claim 1  comprising adducts of aldehyde functional groups and sulfur-oxygen compounds.  
     
     
         3 . The prosthetic tissue of  claim 1  comprising adducts of aldehyde functional groups and amines.  
     
     
         4 . The prosthetic tissue of  claim 1  comprising adducts of aldehyde functional groups and ammonia/ammonium.  
     
     
         5 . The prosthetic tissue of  claim 1  comprising adducts of aldehyde functional groups and amino acids.  
     
     
         6 . The prosthetic tissue of  claim 1  further comprising a growth factor.  
     
     
         7 . The prosthetic tissue of  claim 6  wherein the growth factor is vascular endothelial growth factor.  
     
     
         8 . The prosthetic tissue of  claim 1  further comprising compounds that attract cell precursors.  
     
     
         9 . A heart valve prosthesis comprising the prosthetic tissue of  claim 1 .  
     
     
         10 . A vascular graft comprising the prosthetic tissue of  claim 1 .  
     
     
         11 . A prosthetic tissue comprising a protein matrix crosslinked with a multifunctional aldehyde having extractable residual aldehyde compound concentrations of no more than about 5×10 −4  moles of aldehyde per gram of dry tissue.  
     
     
         12 . The prosthetic tissue of  claim 11  wherein residual aldehyde concentration is no more than about 2×10 −4  moles of aldehyde per gram of dry tissue.  
     
     
         13 . The prosthetic tissue of  claim 11  having a residual multifunctional aldehyde concentration no more than about 6×10 −5  moles of multifunctional aldehyde per gram of dry tissue.  
     
     
         14 . The prosthetic tissue of  claim 11  having a residual multifunctional aldehyde concentration no more than about 1×10 −5  moles of multifunctional aldehyde per gram of dry tissue.  
     
     
         15 . The prosthetic tissue of  claim 11  having a residual formaldehyde concentration no more than about 1×10 −4  moles of formaldehyde per gram of dry tissue.  
     
     
         16 . The prosthetic tissue of  claim 11  having a residual formaldehyde concentration no more than about 2×10 −5  moles of formaldehyde per gram of dry tissue.  
     
     
         17 . The prosthetic tissue of  claim 11  having no detectable cytotoxicity without any added growth hormones.  
     
     
         18 . A prosthetic tissue comprising adducts of aldehyde groups and inorganic sulfur-oxygen groups.  
     
     
         19 . The prosthetic tissue of  claim 18  further comprising adducts of aldehyde groups and amines.  
     
     
         20 . The prosthetic tissue of  claim 18  further comprising adducts of aldehyde groups and ammonia/ammonium.  
     
     
         21 . The prosthetic tissue of  claim 18  wherein the amino acid comprises glycine.  
     
     
         22 . The prosthetic tissue of  claim 18  further comprising a surfactant.  
     
     
         23 . The prosthetic tissue of  claim 18  wherein the inorganic sulfur-oxygen compound comprises a bisulfate compound.  
     
     
         24 . The prosthetic tissue of  claim 18  wherein the inorganic sulfur-oxygen compound comprises a thiosulfate compound.  
     
     
         25 . The prosthetic tissue of  claim 18  further comprising an adduct of organic sulfates and aldehyde groups.  
     
     
         26 . The prosthetic tissue of  claim 18  further comprising a growth factor.  
     
     
         27 . The prosthetic tissue of  claim 26  wherein the growth factor is vascular endothelial growth factor.  
     
     
         28 . The prosthetic tissue of  claim 18  further comprising compounds that attract cell precursors.  
     
     
         29 . The prosthetic tissue of  claim 18  further comprising adducts of aldehyde groups and an amino acid, adducts of aldehyde groups and ammonia/ammonium, and a surfactant.  
     
     
         30 . A heart valve prosthesis comprising prosthetic tissue of  claim 18 .  
     
     
         31 . A vascular graft comprising prosthetic tissue of  claim 18 .  
     
     
         32 . A prosthetic tissue comprising adducts of aldehyde groups and ammonia/ammonium groups and adducts of aldehyde groups and sulfur-oxygen groups.  
     
     
         33 . The prosthetic tissue of  claim 32  wherein the sulfur-oxygen groups comprises organic sulfate groups.  
     
     
         34 . A method for reducing residual reactive aldehyde groups associated with an aldehyde crosslinked tissue, the method comprising contacting an aldehyde crosslinked tissue with an inorganic sulfur-oxygen compound.  
     
     
         35 . The method of  claim 34  wherein the sulfur-oxygen compound comprises a bisulfate compound.  
     
     
         36 . The method of  claim 34  wherein the sulfur-oxygen compound comprises a thiosulfate compound.  
     
     
         37 . The method of  claim 34  further comprising contacting the tissue with an amine.  
     
     
         38 . The method of  claim 37  wherein the amine compound comprises an amino acid.  
     
     
         39 . The method of  claim 34  further comprising contacting the tissue with an ammonium ion or ammonia.  
     
     
         40 . The method of  claim 39  further comprising contacting the tissue with an amino acid.  
     
     
         41 . The method of  claim 40  further comprising contacting the tissue with a surfactant.  
     
     
         42 . The method of  claim 34  further comprising contacting the tissue with a surfactant.  
     
     
         43 . A composition comprising an inorganic sulfur-oxygen group and an amine.