Cyclic implant perfusion, cleaning and passivation process and implant produced thereby

Abstract

This invention is a novel method for perfusion of a porous implant which achieves efficient interpenetration of desired factors into and removal of undesirable factors from the pores of the implant, cleaning of the implant, efficient passivation of the implant (inactivation of pathogens, microorganisms, cells, viruses and the like and reduction in antigenicity thereof), and the novel implant produced by such treatment. The process presents a system wherein the rate of pressure cycling, the fact of pressure cycling, and the amplitude of pressure cycling, results in highly cleaned tissues and other implants for implantation. Target decontamination goals for this process include between about a one (1) to twelve (12) log reduction in bacterial contamination, between about a one (1) to fifteen (15) log reduction in enveloped virus contamination, up to about a five (5) log reduction in non-enveloped virus contamination, between about a two (2) to ten (10) fold reduction in endotoxin, maintenance of implant or graft biologic and biomechanical properties, absence of tissue toxicity due to cleaning solutions used, and reduced implant antigenicity.

What is claimed is:  
     
         1 . An implant cleaning, perfusion and passivation process which comprises cyclic exposure of said implant to increased and decreased positive or negative pressures, or both.  
     
     
         2 . The process according to  claim 1  wherein said cyclic exposure of said implant to increased and decreased pressures occurs in the presence of a cleaning solution.  
     
     
         3 . The process according to  claim 2  wherein said process occurs, at least in part, with concurrent exposure of said implant to sonication.  
     
     
         4 . The process according to  claim 3  wherein said cycling between increased and decreased pressures occurs rapidly according to a defined program.  
     
     
         5 . The process according to  claim 4  wherein said implant is selected from the group consisting of porous metallic, ceramic or synthetic materials, or allograft, autograft or xenograft tissue selected from: cortical bone, cancellous bone, fascia, whole joints, tendons, ligaments, dura, pericardia, heart valves, veins, neural tissue, submucoal tissue, and cartilage.  
     
     
         6 . The process according to  claim 5  wherein said cycling of increased and decreased pressures is achieved through an oscillation of pressure in a chamber containing said implant in the presence of a cleaning solution.  
     
     
         7 . The process according to  claim 6  comprising: 
 a. rapidly evacuating said chamber containing said implant;  
 b. rapidly backfilling said chamber with a cleaning solution or a mixture of cleaning solutions;  
 c. pressurizing said chamber; and  
 d. rapidly cycling between steps (a) and (c), for between about 1-150 cycles, maintaining a temperature of between about 35-40 degrees centigrade, with optional application of ultrasonic energy.  
 
     
     
         8 . The process according to  claim 7 , further comprising the step of: 
 e. machining said implant to final dimensions if not previously so machined.    
     
     
         9 . The process according to  claim 8 , further comprising the step of: 
 f. conducting steps (a)-(d) using the same or a different cleaning solutions.    
     
     
         10 . The process according to  claim 9 , wherein step (f) is conducted under elevated or reduced temperatures.  
     
     
         11 . The process according to  claim 10  further comprising placing said implant into a sterile, sealable package, and performing a surface decontamination step prior to or after sealing said package.  
     
     
         12 . The process according to  claim 7  wherein said implant is a tissue derived from a single donor.  
     
     
         13 . The process according to  claim 7  wherein said implant is a tissue derived from a pool of donor tissues.  
     
     
         14 . The process according to  claim 7  wherein said cleaning solution is selected from the group consisting of: sterile water, Triton X-100, TNBP, 3% hydrogen peroxide, a water-miscible alcohol, saline solution povidone iodine, ascorbic acid solution, aromatic or aliphatic hydrocarbons, ethers, ketones, amines, urea, guanidine hydrochloride, esters, glycoproteins, proteins, saccharides, enzymes, gasseous acids or peroxides, and mixtures thereof.  
     
     
         15 . The process according to  claim 12  wherein said tissue is pooled with similarly treated tissue from at least one other donor, and is further cleaned by conducting steps (a)-(d) using the same or different cleaning solutions.  
     
     
         16 . The process according to  claim 15  wherein said cleaning solution is selected from the group consisting of 6% hydrogen peroxide, 1% sodium hypochlorite, 6M urea, 4M guanidine hydrochloride, 1 N sodium hydroxide, isopropanol, water, saline and mixtures thereof.  
     
     
         17 . The process according to  claim 16  wherein said process is conducted at a temperature between about thirty-seven (37) degrees centigrade and about eighty (80) degrees centigrade.  
     
     
         18 . The process according to  claim 17  wherein said process is conducted at about 50-60 degrees centigrade.  
     
     
         19 . The process according to  claim 13  wherein said tissue is pooled with similarly treated tissue from at least one other donor, and is cleaned by conducting steps (a)-(d) using the same or different cleaning solutions.  
     
     
         20 . The process according to  claim 19  wherein said cleaning solution is selected from the group consisting of 6% hydrogen peroxide, 1% sodium hypochlorite, 6M urea, 4 M guanidine hydrochloride, 1 N sodium hydroxide, isopropanol, water, saline and mixtures thereof.  
     
     
         21 . The process according to  claim 20  wherein said process is conducted at a temperature between about thirty-seven (37) degrees centigrade and about eighty (80) degrees centigrade.  
     
     
         22 . The process according to  claim 21  wherein said process is conducted at about 50-60 degrees centigrade.  
     
     
         23 . The process according to  claim 1  wherein the thus treated implant is packaged in a sterile environment upon performing a surface or terminal decontamination step, preferably with the implant in its final packaging.  
     
     
         24 . The process according to  claim 23  wherein said surface or terminal decontamination step comprises contacting the implant with vapor-phase H202, peracetic acid, exposure to gamma irradiation, electron beam irradiation, exposure to ethylene oxide, or a mixture of these.  
     
     
         25 . The process according to  claim 1  wherein the cycling of pressures is conducted at pressures above one atmosphere, below one atmosphere, or both.  
     
     
         26 . The process according to  claim 25  wherein vacuum pressures of between about 60 to 100 torr and the vapor pressure of the solutions in contact with the implant and backfill pressures of between about 6-10 atmospheres are employed, and wherein concurrent sonication occurs throughout or at specific stages in said cycling of pressures.  
     
     
         27 . The process according to  claim 1  wherein the implant is perfused or coated with a bioactive substance.  
     
     
         28 . The process according to  claim 27  wherein said bioactive substance is a drug or a growth factor.  
     
     
         29 . The process according to  claim 28  wherein said growth factor is selected from the group consisting of a bone morphogenetic protein, tissue growth factor beta or member of the tissue growth factor beta family of growth factors, cartilage derived morphogenetic proteins I or II or both, and any related cartilage derived growth factors, angiogenic factors, and platelet derived growth factor.  
     
     
         30 . The process according to  claim 1  which results in any one or all of: 
 (a) between about a one (1) to twelve (12) log reduction in bacterial contamination;  
 (b) between about a one (1) to fifteen (15) log reduction in enveloped virus contamination;  
 (c) up to about a five (5) log reduction in non-enveloped virus contamination;  
 (d) between about a two (2) to ten (10) fold reduction in endotoxin;  
 (e) maintenance of implant or graft biologic and biomechanical properties;  
 (f) absence of tissue toxicity due to cleaning solutions used; and  
 (g) reduced implant antigenicity.  
 
     
     
         31 . An implant treated according to the process of  claim 1 .  
     
     
         32 . The implant of  claim 31  wherein said implant is composed of a porous metal, ceramic, synthetic polymer, allograft, autograft or xenograft.  
     
     
         33 . The implant according to  claim 31  which is composed of bone and which, as a result of being treated by said process of  claim 1 , has reduced antigenicity.  
     
     
         34 . An apparatus for conducting the process according to  claim 1  comprising: a programmable logic controller to activate or deactivate valves or solenoids  301   a - h  at pre-determined times in the cleaning cycle; a sealable reaction chamber  310  into which a tissue to be cleaned is placed; a chemical mixing tank  330  from which cleaning fluids are introduced into said sealable reaction chamber  310 ; a vacuum receiver tank  360 , linkable to said reaction chamber  310  so that essentially instantaneous vacuum of known dimensions may be applied to the reaction chamber  310 , without the need for a vacuum pump to gradually develop negative pressure in said reaction chamber  310 ; a source of sterile water, physiological saline, or like aqueous solution; a pressure tank  380  which is pressurized by a compressor of filtered gas, to retain sterility in the reaction tank  310 .  
     
     
         35 . A process facility for conducting the process according to  claim 1 , comprising at least one tissue debridement chamber  510 , wherein tissue to be cleaned is debrided of gross, adventitious and unwanted tissues; at least one sealable port  515  into a reaction chamber  310  for cyclic pressurization and depressurization of said tissue in the presence of at least one cleaning solvent; at least one graft-production room  530 , wherein final implant dimensioning and machining is conducted; at least one reaction chamber  310 ′ into which dimensioned implant is inserted via at least one sealable port  535  for cyclic pressurization and depressurization of said dimensioned implant in the presence of at least one cleaning solution; at least one sealable port  536  for removal of cleaned implant; and at least one terminal sterilization and packaging station  540  for sterile packaging of cleaned implant.