Glycation Cross-link Breakers to Increase Resistance to Enzymatic Degradation

Abstract

The present invention relates to a method to treat a grafts, implant, scaffold, and constructs, including allografts, xenografts, autografts, and prosthetics comprising collagen, with an inhibitor of collagen cross-links and/or advanced glycation endproducts (AGE), in order to alleviate the mechanical weakness induced by the cross-links. The invention also provides for kits for use in the operating theater during autograft, allograft or xenograft procedures, or for preparing allograft, xenografts or prosthetics that have not been already treated prior to packaging. The kit comprises a first agent or agents that inhibit collagen cross-links and/or advanced glycation endproducts, instructions for use, optionally a wash or rinse agent, and a device for containing the graft and first agent.

1 . A method of modifying, reducing, inhibiting or eliminating cross-links in collagen in a graft, implant, scaffold, or construct suitable for implantation into a subject for the treatment, repair or replacement of defects or injury in a biological tissue or organ, by contacting or incubating the graft, implant, scaffold or construct with an agent that modifies, reduces, inhibits and/or eliminates cross-links in collagen for a time and at a temperature in which the cross-links in collagen are modified, reduced, inhibited and/or eliminated, prior to implantation of the graft, implant, scaffold or construct into the subject, wherein at least a portion of the graft, implant, scaffold, or construct contains collagen. 
     
     
         2 . The method of  claim 1 , wherein the cross-links in collagen are advanced glycation endproducts. 
     
     
         3 . The method of  claim 1 , wherein the graft, implant, scaffold, or construct is an allograft, an isograft, an allograft, a xenograft, or a prosthetic. 
     
     
         4 . The method of  claim 1 , wherein the biological tissue is musculoskeletal, vascular, epidermal, dermal, connective, neurological, or dental. 
     
     
         5 . The method of  claim 1 , wherein the organ is skin, heart, lung esophagus, kidney, liver, or lymph glands. 
     
     
         6 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         7 . The method of  claim 6 , wherein the mammal is a human, a non-human primate, an ovine, a porcine, an equine, a canine, a feline, or a bovine. 
     
     
         8 . The method of  claim 1 , wherein the agent is Alagabrium, ALT-462, ALT-486, ALT-946, N-phenacylthiazolium bromide (PTB), 4,5-dimethyl-3-phenylacylthiazolium chloride (DPTC), TRC4186, TRC4149, C36 or C16. 
     
     
         9 . The method of  claim 1 , further comprising an additional step of rinsing or washing the agent from the graft, implant, scaffold or construct, prior to implantation of the graft, implant, scaffold or construct, into the subject. 
     
     
         10 . A method of modifying, reducing, inhibiting or eliminating cross-links in collagen in a graft, implant, scaffold, or construct suitable for implantation into a subject for the monitoring and/or facilitating the function of a biological tissue or organ, by contacting or incubating the graft, implant, scaffold or construct with an agent that modifies, reduces, inhibits and/or eliminates cross-links in collagen for a time and at a temperature in which the cross-links in collagen are modified, reduced, inhibited and/or eliminated, prior to implantation of the graft, implant, scaffold or construct into the subject, wherein at least a portion of the graft, implant, scaffold, or construct contains collagen. 
     
     
         11 . The method of  claim 10 , wherein the cross-links in collagen are advanced glycation endproducts. 
     
     
         12 . The method of  claim 10 , wherein the graft, implant, scaffold, or construct is an allograft, an isograft, an allograft, a xenograft, or a prosthetic. 
     
     
         13 . The method of  claim 10 , wherein the biological tissue is musculoskeletal, vascular, epidermal, dermal, connective, neurological, or dental. 
     
     
         14 . The method of  claim 10 , wherein the organ is skin, heart, lung esophagus, kidney, liver, or lymph glands. 
     
     
         15 . The method of  claim 10 , wherein the subject is a mammal. 
     
     
         16 . The method of  claim 15 , wherein the mammal is a human, a non-human primate, an ovine, a porcine, an equine, a canine, a feline, or a bovine. 
     
     
         17 . The method of  claim 10 , wherein the agent is Alagabrium, ALT-462, ALT-486, ALT-946, N-phenacylthiazolium bromide (PTB), 4,5-dimethyl-3-phenylacylthiazolium chloride (DPTC), TRC4186, TRC4149, C36 or C16. 
     
     
         18 . The method of  claim 10 , further comprising an additional step of rinsing or washing the agent from the graft, implant, scaffold or construct, prior to implantation of the graft, implant, scaffold or construct, into the subject. 
     
     
         19 . A kit comprising a one or more first agents that modifies, reduces, inhibits and/or eliminates cross links in collagen in dosage amounts sufficient to modify, reduce, inhibit, and/or eliminate cross-links in collagen, and instructions of use of the agents. 
     
     
         20 . The kit of  claim 19 , further comprising one or more second agents for washing and/or rinsing the first agents from the graft, implant, scaffold or construct. 
     
     
         21 . The kit of  claim 19 , further comprising one or more devices that contain the graft, implant, scaffold or construct and the first agents. 
     
     
         22 . The kit of  claim 19 , wherein the first agent or agents modifies, reduces, inhibits and/or eliminates advance glycation endproducts.