Drug eluting graft constructs and methods

Abstract

The present invention provides, in certain aspects, medical graft products that incorporate multiple drug depots in and/or on the products. One such product is a sheet graft construct, for example for tissue support that includes a sheet graft material with a plurality of drug depots. The drug depots can be hardened deposits formed directly onto the sheet graft material and/or can be capable of eluting a drug for a minimum of 72 hours.

What is claimed is: 
     
         1 . An implantable device, comprising:
 a sheet graft material having a top side and a bottom side;   a plurality of drug depots attached to the sheet graft material.   
     
     
         2 . The implantable device of  claim 1 , wherein the sheet graft material comprises an extracellular matrix sheet material. 
     
     
         3 . The implantable device of  claim 1  or  2 , wherein:
 the sheet graft material has a porous matrix formed by a network of fibers, the porous matrix having pores formed between the fibers of the network; and 
 the drug depots each comprise solid deposits including a polymeric carrier and a drug, the solid deposits each including a first portion infiltrating pores of the porous matrix and a second portion external of the porous matrix. 
 
     
     
         4 . The implantable device of any preceding claim, wherein the drug is an antibiotic agent. 
     
     
         5 . The implantable device of any preceding claim, wherein the drug is gentamycin. 
     
     
         6 . The implantable device of any preceding claim, wherein the depots are capable of eluting the drug over a period of time greater than about 72 hours when the device is immersed in 66.7 mM phosphate buffered saline at 37° C. 
     
     
         7 . The implantable device of any preceding claim, wherein the depots are attached to the top side of the sheet graft material, and wherein the depots in combination cover less than about 50% of the surface area of the top side of the sheet material. 
     
     
         8 . The implantable device of any preceding claim, having from 2 to about 120 of said drug depots attached to the sheet graft. 
     
     
         9 . The implantable device of any preceding claim, wherein:
 the sheet graft material has a porous matrix formed by a network of fibers, the porous matrix having pores formed between the fibers of the network;   the drug depots each comprise solid deposits including a polymeric carrier and the at least one drug, the solid deposits each including a first portion infiltrating pores of the porous matrix and a second portion external of the porous matrix;   the sheet graft material has a thickness extending between the top surface and the bottom surface; and   the first portions of the drug depots extend only partially through the thickness of the sheet graft material.   
     
     
         10 . The implantable device of any preceding claim, wherein:
 each said drug depot covers a corresponding depot-bearing portion of the sheet graft material, and preferably wherein each depot-bearing portion has a surface area constituting about 0.5% to about 15% of the surface area of the top surface of the sheet graft material, and more preferably wherein each depot-bearing portion has a surface area constituting about 2% to about 10% of the surface area of the top surface of the sheet graft material.   
     
     
         11 . The implantable device of  claim 10 , wherein:
 each said drug depot has a maximum thickness that is greater than a maximum thickness of the corresponding depot-bearing portion of the sheet graft material covered by the depot.   
     
     
         12 . The implantable device of  claim 10  or  11 , wherein:
 each said depot-bearing portion of the sheet graft material is thinner than depot-free portions of the sheet graft material occurring between the depot-bearing portions. 
 
     
     
         13 . The implantable device of any one of  claims 10  to  13 , wherein:
 each said depot-bearing portion of the sheet graft material is denser than depot-free portions of the sheet graft material occurring between the depot-bearing portions. 
 
     
     
         14 . The implantable device of any one of  claims 10  to  14 , wherein:
 each said depot-bearing portion of the sheet graft material is less porous than depot-free portions of the sheet graft material occurring between the depot-bearing portions. 
 
     
     
         15 . The implantable device of any preceding claim, wherein:
 the drug depots are formed by a process including:
 depositing a flowable material including a carrier polymer and the at least one drug onto the top side of the sheet graft material so as to form a plurality of deposited material portions; and 
 hardening the deposited material portions. 
   
     
     
         16 . The implantable device of any preceding claim, wherein:
 the sheet graft material comprises one or more membranous tissue layers harvested from a source tissue of a warm-blooded vertebrate animal and decellularized, the one or more membranous tissue layers each having a porous matrix comprised of a network of collagen fibers, wherein the network of collagen fibers retains an inherent network structure from the source tissue.   
     
     
         17 . The implantable device of  claim 16 , wherein the one or more membranous tissue layers is effective when implanted in a subject to become infiltrated with cells of the subject. 
     
     
         18 . The implantable device of  claim 16  or  17 , wherein the one or more membranous tissue layers is effective when implanted in a subject to become replaced by tissue of the subject. 
     
     
         19 . The implantable device of any one of  claims 16  to  18 , wherein the one or more membranous tissue layers retains native collagen and native elastin from the source tissue. 
     
     
         20 . The implantable device of any one of  claims 16  to  19 , wherein the one or more membranous tissue layers retains from the source tissue least one of native glycosaminoglycans, native proteoglycans, and native growth factors. 
     
     
         21 . The implantable device of  claim 20 , wherein the one or more membranous tissue layers retains from the source tissue native glycosaminoglycans, native proteoglycans, and native growth factors. 
     
     
         22 . The implantable device of any one of  claims 16  to  21 , wherein the sheet graft material comprises a laminate structure including a plurality of said membranous tissue layers. 
     
     
         23 . The implantable device of  claim 22 , wherein said membranous tissue layers are bonded to one another. 
     
     
         24 . The implantable device of  claim 23 , wherein said membranous tissue layers are dehydrothermally bonded to one another. 
     
     
         25 . The implantable device of any one of  claims 16  to  24 , wherein said membranous tissue layers have not been subjected to crosslinking by contact with a chemical crosslinking agent. 
     
     
         26 . The implantable device of any one of  claims 16  to  25 , wherein said membranous tissue layers retain substantially their native level of crosslinking. 
     
     
         27 . The implantable device of any preceding claim, wherein the bottom side of the sheet graft material is free from any drug depots. 
     
     
         28 . The implantable device of any preceding claim, wherein the bottom side of the sheet graft material has a surface provided by one or more membranous tissue layers harvested from a source tissue of a warm-blooded vertebrate animal and decellularized, the one or more membranous tissue layers each having a porous matrix comprised of a network of collagen fibers, wherein the network of collagen fibers retains an inherent network structure from the source tissue. 
     
     
         29 . A method of manufacturing a medical graft, comprising:
 depositing at least one volume of a flowable material comprising a drug onto at least one region of a graft material; and   causing the flowable material to harden.   
     
     
         30 . The method of  claim 29 , wherein the graft material includes a porous matrix, said method also comprising causing at least a portion of the flowable material to infiltrate pores of the porous matrix in the at least one region. 
     
     
         31 . The method of  claim 29  or  30 , wherein the graft material comprises one or more membranous tissue layers harvested from a source tissue of a warm-blooded vertebrate animal and decellularized, the one or more membranous tissue layers each having a porous matrix comprised of a network of collagen fibers. 
     
     
         32 . The method of any one of  claims 29  to  31 , wherein said depositing comprises depositing a plurality of discrete volumes of the flowable material onto a plurality of discrete regions of the graft material. 
     
     
         33 . The method of any one of  claims 29  to  32 , wherein the drug is an antimicrobial agent. 
     
     
         34 . The method of any one of  claims 29  to  33 , wherein said causing comprises removing a solvent from the flowable material. 
     
     
         35 . The method of any one of  claims 29  to  34 , wherein the graft material comprises an extracellular matrix sheet material. 
     
     
         36 . The method of any one of  claims 29  to  35 , wherein said at least one region comprises a reservoir formed in the graft material. 
     
     
         37 . The method of any one of  claims 29  to  36 , wherein said causing forms a hardened material, and wherein the method also comprises reshaping the hardened material. 
     
     
         38 . The method of  claim 37 , wherein said reshaping includes reducing the thickness of the hardened material. 
     
     
         39 . The method of  claim 37  or  38 , wherein said reshaping includes smoothing an upper surface of the hardened material. 
     
     
         40 . The method of claim any one of  claims 37  to  39 , wherein the hardened material includes pores, and wherein said reshaping includes collapsing the pores. 
     
     
         41 . The method of any one of  claims 37  to  40 , wherein said reshaping includes compressing the hardened material against a surface. 
     
     
         42 . The method of any one of  claims 29  to  41 , wherein said graft material is a flexible sheet graft material. 
     
     
         43 . The method of any one of  claims 29  to  41 , conducted so as to form a plurality of drug depot wafers from the flowable material, the drug depot wafers attached to the graft material. 
     
     
         44 . The method of  claim 43 , wherein the medical graft has a total dose of the drug, and wherein said plurality of drug depot wafers includes 2 to 100 drug depot wafers incorporating at least 50% of the total dose of the drug. 
     
     
         45 . The method of  claim 44 , wherein said plurality of drug depot wafers includes 10 to about 60 drug depot wafers incorporating at least 80% of the total dose of the drug. 
     
     
         46 . The method of any one of  claims 29  to  45 , wherein the graft material is a sheet graft material, and wherein the method is conducted so as to form a plurality of discrete drug depots from the flowable material, wherein the drug depots have top surfaces that, taken together, define a surface area that is less than 50% of the surface area defined by the top surface of the of the sheet graft material. 
     
     
         47 . An implantable device, comprising:
 a graft material having a porous matrix formed by a network of fibers, the porous matrix having pores formed between the fibers of the network; and   one or more drug depots including a polymeric carrier and a drug, the one or more drug depots including a first portion infiltrating pores of the porous matrix and a second portion external of the porous matrix.   
     
     
         48 . The implantable device of  claim 47 , wherein the graft material comprises an extracellular matrix material. 
     
     
         49 . The implantable device of  claim 47  or  48 , wherein the drug is an antibiotic agent. 
     
     
         50 . The implantable device of any one of  claims 47  to  49 , wherein the drug is gentamycin. 
     
     
         51 . The implantable device of any one of  claims 47  to  50 , wherein the one or more drug depots are capable of eluting the drug over a period of time of at least about 72 hours when the device is immersed in aqueous phosphate buffered saline at 37° C. 
     
     
         52 . The implantable device of any one of  claims 47  to  51 , wherein the one or more drug depots are attached to a top side of the graft material, and wherein the depots in combination cover less than about 50% of the surface area of the top side of the graft material. 
     
     
         53 . The implantable device of any one of  claims 47  to  51 , wherein from 2 to no more than 100 of said drug depots incorporate at least 50% of a total dose of the drug on the device. 
     
     
         53 . The implantable device of any one of  claims 47  to  51 , wherein from 5 to about 80 of said drug depots incorporate at least 80% of a total dose of the drug on the device. 
     
     
         54 . The implantable device of any one of  claims 47  to  51 , wherein from 10 to about 60 of said drug depots incorporate at least 99% of a total dose of the drug on the device. 
     
     
         55 . The implantable device of any one of  claims 47  to  54 , wherein:
 said first portion of the one or more drug depots extends only partially through a thickness of the graft material. 
 
     
     
         56 . The implantable device of any one of  claims 47  to  55 , wherein said sheet graft comprises a laminate of a plurality of extracellular matrix layers. 
     
     
         57 . The implantable device of  claim 56 , wherein said extracellular matrix layers have a native collagen architecture retained from an animal source tissue for the extracellular matrix layers. 
     
     
         58 . The implantable device of  claim 56  or  57 , wherein said extracellular matrix layers retain at least one native growth factor from an animal source tissue for the extracellular matrix layers. 
     
     
         59 . The implantable device of any one of  claims 1  to  28  or  47  to  58 , wherein the graft material includes a synthetic polymeric mesh and at least one extracellular matrix sheet. 
     
     
         60 . The implantable device of  claim 59 , wherein the graft material includes the synthetic polymeric mesh sandwiched between a first extracellular matrix sheet and a second extracellular matrix sheet. 
     
     
         61 . A method for treating a patient, comprising implanting in the patient an implantable device according to any one of  claims 1  to  28  or  47  to  60 . 
     
     
         62 . The method of  claim 61 , wherein said implanting comprises implanting the device so as to support soft tissue of the patient. 
     
     
         63 . The method of  claim 62 , wherein said implanting is to repair a hernia.