Process for improving the biostability of tissue implant devices and bioprosthetic implants so produced

Claim 2

A process for improving the biophysical stability and calcification resistance of bioprosthetic tissue, said process comprising the steps of: loading harvested tissue with calcification inhibitor; treating said loaded tissue with tissue cross-linking reagent; loading said treated tissue with bridging reagent; binding said bridging reagent to said bridging reagent treated tissue; loading said bridging reagent bound treated tissue with calcification inhibitor; and treating said calcification inhibitor loaded bridging reagent bound treated tissue with tissue cross-linking reagent.

Claim 3

The process of claim 1 wherein said treated tissue is loaded with said bridging reagent by immersing said treated tissue in a hypertonic salt solution incorporating said bridging reagent.

Claim 4

The process of claim 1 wherein said bridging reagent is bound to said bridging reagent loaded treated tissue by immersing said tissue in a hypertonic salt solution incorporating a carbodiimide.

Claim 5

The process of claim 1 wherein said harvested tissue is collagenous tissue.

Claim 6

The process of claim 1 wherein said calcification inhibitor is selected from the group consisting of anionic polysaccharides, diphosponates, and phosphoproteins.

Claim 7

The process of claim 1 wherein said calcification inhibitor is 3-aminopropane-1-hydroxy-1,1-diphosphonate.

Claim 8

The process of claim 1 wherein said crosslinking reagent is glutaraldehyde.

Claim 9

The process of claim 1 wherein said bridging reagent is a dialkylamine.

Claim 10

A process for improving the biophysical stability and calcification resistance of bioprosthetic tissue, said process comprising the steps of: loading harvested tissue with 3-aminopropane -1-hydroxy-1,1-diphosphonate; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded tissue with glutaraldehyde; loading said glutaraldehyde treated tissue with hexanediamine, said loading step performed in an aqueous hypertonic solution of hexanediamine; binding said hexanediamine to said hexanediamine loaded tissue in an aqueous hypertonic solution of 1-ethyl-3-(-dimethylaminopropyl)-carbodiimide.HCl; loading said hexanediamine bound tissue with aminopropanehydroxydiphosphonate; and treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded hexane diamine bound tissue with glutaraldehyde.

Claim 11

A process for improving the biophysical stability and calcification resistance of bioprosthetic tissue, said process comprising the steps of: loading harvested tissue with 3-aminopropane -1-hydroxy-1,1-diphosphonate; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded tissue with glutaraldehyde; loading said glutaraldehyde treated tissue with hexanediamine, said loading step performed in an aqueous hypertonic solution of hexanediamine; binding said hexanediamine to said hexanediamine loaded tissue in an aqueous hypertonic solution of 1-ethyl-3-(-dimethylaminopropyl)-carbodiimide.HCl; loading said hexanediamine bound tissue with aminopropanehydroxydiphosphonate; and treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded hexane diamine bound tissue with glutaraldehyde.

Claim 12

The process of claim 9 wherein said aqueous hypertonic solution has a concentration of approximately 0.5 molar NaCl.

Claim 13

The process of claim 9 wherein said loading of said harvested tissue is carried out in an aqueous solution having a concentration of approximately 1% wt/vol 3-aminopropane-1-hydroxy-1,1-diphosphonate.

Claim 14

The process of claim 9 wherein said treating of said 3-aminopropane-1-hydroxy-1,1-diphosphonate loaded tissue is accomplished through the additional steps of: immersing said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded tissue in an aqueous solution incorporating approximately 2% vol/vol glutaraldehyde; rinsing said glutaraldehyde treated tissue a plurality of times in an aqueous solution of approximately 0.35% vol/vol glutaraldehyde; and soaking said rinsed tissue in an aqueous solution of approximately 0.35% vol/vol glutaraldehyde.

Claim 15

The process of claim 9 wherein said aqueous hypertonic solution of hexanediamine has a concentration of approximately 2% wt/vol hexanediamine.

Claim 16

The process of claim 9 wherein said aqueous hypertonic solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl has a concentration of approximately 2% wt/vol 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.HCl.

Claim 17

The process of claim 9 wherein said loading of said hexanediamine bound tissue is accomplished in an aqueous solution of approximately 2% by volume 3-aminopropane -1-hydroxy-1,1-diphosphonate for a period of several hours.

Claim 18

The process of claim 9 wherein said treating of said 3-aminopropane-1-hydroxy-1,1-diphosphonate loaded hexanediamine bound tissue is accomplished through the additional steps of: immersing said 3-aminopropane-1-hydroxy-1,1-diphosphonate loaded hexanediamine bound tissue in an aqueous saline solution of approximately 2% vol/vol glutaraldehyde; rinsing said 2% vol/vol glutaraldehyde treated tissue a plurality of times with an aqueous hypertonic solution of approximately 0.35% vol/vol glutaraldehyde; and soaking said treated tissue in an aqueous solution of approximately 0.35% vol/vol glutaraldehyde for a prolonged period of time.

Claim 19

The process of claim 16 wherein said aqueous hypertonic solution is 0.5 molar NaCl.

Claim 20

The process of claim 9 further comprising the additional step of rinsing said glutaraldehyde treated tissue in an aqueous solution of approximately 0.9% NaCl prior to loading said glutaraldehyde treated tissue with hexane-diamine.

Claim 21

The process of claim 9 wherein said aqueous hypertonic solution of 1-ethyl-3-(-dimettylaminopropyl)carbodimide HCl is buffered to a pH of approximately 4.7.

Claim 22

A bioprosthetic device having enhanced biophysical stability and calcification resistance, said bioprosthetic device comprising bioprosthetic tissue treated according to the process of claim 9.

Claim 23

The bioprosthetic device of claim 20 wherein said bioprosthetic tissue is selected from the group consisting of porcine heart vlaves and bovine pericardia.

Claim 24

A process for improving the biophysical stability and calcification resistance of collagenous tissue said process comprising the steps of: loading harvested collagenous tissue with 3-aminopropane-1-hydroxy-1,1-diphosphonate through immersion in an aqueous solution incorporating approximately 1% wt/vol of 3-aminopropane -1-hydroxy-1,1-diphosphonate, for a period of approximately 20 hours; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded collagenous tissue with an aqueous solution incorporating approximately 2% vol/vol glutaraldehyde for a period of approximately 2 hours; rinsing said glutaraldehyde treated collagenous tissue a plurality of times in an aqueous solution of approximately 0.35% vol/vol lutaraldehyde; soaking said rinsed collagenous tissue in an aqueous solution incorporating approximately 0.35% glutaraldehyde; loading said soaked collagenous tissue with hexanediamine through immersion in an aqueous 0.5 molar NaCl solution of hexanediamine; binding said loaded hexanediamine to said collagenous tissue through immersion in an aqueous 0.5 molar NaCl solution of 1-ethyl-3-(-dimethylaminopropyl)carbodiimide.HCl buffered to a pH of approximately 4.7; loading said hexanediamine bound collagenous tissue with 3-aminopropane-1-hydroxy-1,1-diphosphonate through immersion in an aqueous solution of approximately 2% 3-aminopropane-1-hydroxy-1,1-diphosphonate for a period of approximately 20 hours; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded hexanediamine bound collagenous tissue with an aqueous saline solution of approximately 2% vol/vol glutaraldehyde for a period of approximately 20 minutes; rinsing said glutaraldehyde treated collagenous tissue a plurality of times with an aqueous 0.5 molar NaCl solution of approximately 0.35% vol/vol glutaraldehyde; and soaking said rinsed tissue in an aqueous solution of approximately 0.35% vol/vol glutaraldehyde for a prolonged period of time.

Claim 25

A process for improving the biophysical stability and calcification resistance of collagenous tissue said process comprising the steps of: loading harvested collagenous tissue with 3-aminopropane-1-hydroxy-1,1-diphosphonate through immersion in an aqueous solution incorporating approximately 1% wt/vol of 3-aminopropane -1-hydroxy-1,1-diphosphonate, for a period of approximately 20 hours; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded collagenous tissue with an aqueous solution incorporating approximately 2% vol/vol glutaraldehyde for a period of approximately 2 hours; rinsing said glutaraldehyde treated collagenous tissue a plurality of times in an aqueous solution of approximately 0.35% vol/vol lutaraldehyde; soaking said rinsed collagenous tissue in an aqueous solution incorporating approximately 0.35% glutaraldehyde; loading said soaked collagenous tissue with hexanediamine through immersion in an aqueous 0.5 molar NaCl solution of hexanediamine; binding said loaded hexanediamine to said collagenous tissue through immersion in an aqueous 0.5 molar NaCl solution of 1-ethyl-3-(-dimethylaminopropyl)carbodiimide.HCl buffered to a pH of approximately 4.7; loading said hexanediamine bound collagenous tissue with 3-aminopropane-1-hydroxy-1,1-diphosphonate through immersion in an aqueous solution of approximately 2% 3-aminopropane-1-hydroxy-1,1-diphosphonate for a period of approximately 20 hours; treating said 3-aminopropane -1-hydroxy-1,1-diphosphonate loaded hexanediamine bound collagenous tissue with an aqueous saline solution of approximately 2% vol/vol glutaraldehyde for a period of approximately 20 minutes; rinsing said glutaraldehyde treated collagenous tissue a plurality of times with an aqueous 0.5 molar NaCl solution of approximately 0.35% vol/vol glutaraldehyde; and soaking said rinsed tissue in an aqueous solution of approximately 0.35% vol/vol glutaraldehyde for a prolonged period of time.