Maxillofacial bone augmentation using rhpdgf-bb and a biocompatible matrix

Abstract

The present invention provides effective new methods and materials for maxillofacial bone augmentation, particularly alveolar ridge augmentation, that are free of problems associated with prior art methods. In one embodiment, these materials include human recombinant platelet derived growth factor (rhPDGF-BB) and a biocompatible matrix. In another embodiment, these materials include rhPDGF-BB, a deproteinized bone block or calcium phosphate, and a bioresorbable membrane. The use of these materials in the present method is effective in regenerating maxillofacial bones and facilitating achievement of stable osseointegrated implants. The mandible and maxilla are preferred bones for augmentation, and enhancement of the alveolar ridge is a preferred embodiment of the present invention.

1 - 31 . (canceled) 
     
     
         32 . A method of enhancing bone augmentation in a subject comprising applying a composition consisting of a biocompatible matrix having incorporated therein a solution consisting of platelet derived growth factor (PDGF) in a buffer to a site for desired bone augmentation in the subject;
 wherein the biocompatible matrix: (i) consists of a porous calcium phosphate, (ii) consists of an allograft, (iii) consists of collagen and an allograft, or (iv) consists of a porous calcium phosphate and collagen;   wherein the calcium phosphate or allograft consists of particles in a range of about 75 micron to about 5000 microns in size; and   wherein the calcium phosphate comprises interconnected pores.   
     
     
         33 . The method of  claim 32 , wherein the biocompatible matrix consists of a porous calcium phosphate. 
     
     
         34 . The method of  claim 32 , wherein the biocompatible matrix consists of collagen and a porous calcium phosphate. 
     
     
         35 . The method of  claim 32 , wherein the biocompatible matrix consists of an allograft. 
     
     
         36 . The method of  claim 32 , wherein the biocompatible matrix consists of collagen and an allograft. 
     
     
         37 . The method of  claim 32 , wherein the calcium phosphate or allograft consists of particles in a range of about 100 microns to about 5000 microns in size. 
     
     
         38 . The method of  claim 32 , wherein the calcium phosphate or allograft consists of particles in a range of about 100 microns to about 300 microns in size. 
     
     
         39 . The method of  claim 32 , wherein the calcium phosphate or allograft consists of particles in a range of about 250 microns to about 1000 microns in size. 
     
     
         40 . The method of  claim 32 , wherein the calcium phosphate or allograft consists of particles in a range of about 1000 microns to about 2000 microns in size. 
     
     
         41 . The method of  claim 32 , wherein the biocompatible matrix is bioresorbable. 
     
     
         42 . The method of  claim 32 , wherein the calcium phosphate or allograft has a porosity that facilitates osteoinduction, osteoconduction, or osteoinduction and osteoconduction. 
     
     
         43 . The method of  claim 32 , wherein the calcium phosphate or allograft has macroporosity. 
     
     
         44 . The method of  claim 32 , wherein the calcium phosphate or allograft has a porosity greater than 25%. 
     
     
         45 . The method of  claim 32 , wherein the calcium phosphate or allograft has a porosity greater than 50%. 
     
     
         46 . The method of  claim 32 , wherein the calcium phosphate is β-tricalcium phosphate. 
     
     
         47 . The method of  claim 32 , wherein the PDGF is recombinant PDGF. 
     
     
         48 . The method of  claim 47 , wherein the recombinant PDGF comprises recombinant human PDGF-BB. 
     
     
         49 . The method of  claim 32 , wherein the solution consists of PDGF at a concentration in a range of about 0.01 mg/ml to about 10 mg/ml in a buffer. 
     
     
         50 . The method of  claim 32 , wherein the solution consists of PDGF at a concentration in a range of about 0.05 mg/mL to about 5 mg/mL in a buffer. 
     
     
         51 . The method of  claim 32 , wherein the solution consists of PDGF at a concentration in a range of about 0.1 mg/mL to about 1.0 mg/mL in a buffer. 
     
     
         52 . The method of  claim 32 , wherein the solution consists of PDGF at a concentration of about 0.3 mg/mL in a buffer. 
     
     
         53 . The method of  claim 32 , wherein the PDGF comprises PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, PDGF-DD, or a derivative thereof. 
     
     
         54 . The method of  claim 32 , wherein the PDGF comprises one or more fragments of the B chain, wherein the fragments are selected from the group consisting of: the amino acid sequences 1-31 (SEQ ID NO: 1), 1-32 (SEQ ID NO: 2), 33-108 (SEQ ID NO: 3), 33-109 (SEQ ID NO: 4), and 1-108 (SEQ ID NO: 5) of the B chain. 
     
     
         55 . The method of  claim 32 , wherein the biocompatible matrix consists of a porous calcium phosphate, wherein the calcium phosphate consists of particles in a range of about 100 microns to about 5000 microns in size, wherein the calcium phosphate has a porosity greater than 25%, wherein the calcium phosphate is β-tricalcium phosphate, wherein the PDGF comprises recombinant human PDGF-BB, and wherein the solution consists of PDGF at a concentration in a range of about 0.01 mg/ml to about 10 mg/ml in a buffer. 
     
     
         56 . The method of  claim 32 , wherein the biocompatible matrix consists of collagen and a porous calcium phosphate, wherein the calcium phosphate consists of particles in a range of about 100 microns to about 5000 microns in size, wherein the calcium phosphate has a porosity greater than 25%, wherein the calcium phosphate is β-tricalcium phosphate, wherein the PDGF comprises recombinant human PDGF-BB, and wherein the solution consists of PDGF at a concentration in a range of about 0.01 mg/ml to about 10 mg/ml in a buffer. 
     
     
         57 . The method of  claim 32 , wherein the biocompatible matrix consists of an allograft, wherein the allograft consists of particles in a range of about 100 microns to about 5000 microns in size, wherein the allograft has a porosity greater than 25%, wherein the PDGF comprises recombinant human PDGF-BB, and wherein the solution consists of PDGF at a concentration in a range of about 0.01 mg/ml to about 10 mg/ml in a buffer. 
     
     
         59 . The method of  claim 32 , further comprising administering a bisphosphonate to the subject. 
     
     
         60 . The method of  claim 32 , wherein the site is a maxillofacial site and a maxillofacial bone is augmented. 
     
     
         61 . The method of  claim 60 , wherein the maxillofacial site is an alveolar ridge, a bone defect, a wall of the maxillary sinus, or an extraction socket. 
     
     
         62 . The method of  claim 60 , wherein the maxillofacial site is located in a maxilla or a mandible. 
     
     
         63 . The method of  claim 32 , wherein the subject is diabetic. 
     
     
         64 . The method of  claim 32 , wherein the subject is an osteoporotic subject. 
     
     
         65 . The method of  claim 32 , wherein the subject is a smoker. 
     
     
         66 . The method of  claim 32 , wherein the subject is a steroid user. 
     
     
         67 . The method of  claim 32 , wherein the method facilitates achievement of a stable osseointegrated implant. 
     
     
         68 . The method of  claim 32 , wherein the method comprises repair of an extraction socket. 
     
     
         69 . The method of  claim 32 , further comprising covering the composition with a bioresorbable membrane. 
     
     
         70 . The method of  claim 36 , wherein the bioresorbable membrane comprises collagen. 
     
     
         71 . The method of  claim 32 , wherein the bioresorbable membrane comprises PDGF. 
     
     
         72 . A method of enhancing soft tissue healing or soft tissue augmentation in a subject comprising applying a composition of a biocompatible matrix having incorporated therein a solution of platelet derived growth factor (PDGF) in a buffer to a site for desired soft tissue healing or soft tissue augmentation in the subject;
 wherein the biocompatible matrix: (i) consists of a porous calcium phosphate, (ii) consists of an allograft, (iii) consists of collagen and an allograft, or (iv) consists of a porous calcium phosphate and collagen;   wherein the calcium phosphate or allograft consists of particles in a range of about 75 micron to about 5000 microns in size; and   wherein the calcium phosphate comprises interconnected pores.   
     
     
         73 . A kit comprising:
 a first container consisting essentially of a biocompatible matrix, and   a second container consisting essentially of a solution of platelet derived growth factor (PDGF) in a buffer, wherein the PDGF is present in the solution at a concentration in a range of about 0.1 mg/mL to about 1.0 mg/mL;   wherein the biocompatible matrix: (i) consists of a porous calcium phosphate, (ii) consists of an allograft, (iii) consists of collagen and an allograft, or (iv) consists of a porous calcium phosphate and collagen;   wherein the calcium phosphate or allograft consists of particles in a range of about 75 micron to about 5000 microns in size; and   wherein the calcium phosphate comprises interconnected pores.   
     
     
         74 . The kit of  claim 73 , wherein the PDGF is rhPDGF-BB and the buffer is an acetate buffer. 
     
     
         75 . The kit of  claim 73 , wherein the calcium phosphate or allograft has a porosity that facilitates osteoinduction, osteoconduction, or osteoinduction and osteoconduction. 
     
     
         76 . The kit of  claim 72 , further comprising a third container comprising a bioresorbable membrane. 
     
     
         77 . The kit of  claim 73 , further comprising a bisphosphonate. 
     
     
         78 . The method of  claim 56 , wherein the PDGF is present in the solution at a concentration of about 0.1 to about 1.0 mg/ml. 
     
     
         79 . The method of  claim 56 , wherein the PDGF is present in the solution at a concentration of about 0.3 mg/ml. 
     
     
         80 . The method of  claim 56 , wherein the calcium phosphate consists of particles in a range of about 100 microns to about 300 microns in size. 
     
     
         81 . The method of  claim 56 , wherein the calcium phosphate consists of particles in a range of about 250 microns to about 1000 microns in size. 
     
     
         82 . The method of  claim 56 , wherein the calcium phosphate consists of particles in a range of about 1000 microns to about 2000 microns in size. 
     
     
         83 . The method of  claim 56 , wherein the calcium phosphate has a porosity that facilitates osteoinduction, osteoconduction, or osteoinduction and osteoconduction. 
     
     
         84 . The method of  claim 48 , wherein the recombinant human PDGF-BB (rhPDGF-BB) comprises at least 65% intact rhPDGF-B. 
     
     
         85 . The method of  claim 56 , wherein the calcium phosphate consists of particles in a range of about 100 microns to about 300 microns in size. 
     
     
         86 . The method of  claim 55 , wherein the calcium phosphate consists of particles in a range of about 250 microns to about 1000 microns in size. 
     
     
         87 . The method of  claim 55 , wherein the calcium phosphate consists of particles in a range of about 1000 microns to about 2000 microns in size. 
     
     
         88 . The method of  claim 55 , wherein the calcium phosphate has a porosity that facilitates osteoinduction, osteoconduction, or osteoinduction and osteoconduction. 
     
     
         89 . The method of any one of  claims 55 ,  56 ,  57 , and  72 , wherein the biocompatible matrix is bioresorbable. 
     
     
         90 . The method of any one of  claims 32 ,  55 ,  56 ,  57 , and  72 , wherein the biocompatible matrix is resorbable such that the biocompatible matrix is resorbed within one year of being implanted. 
     
     
         91 . The method of any one of  claims 32 ,  55 ,  56 ,  57 , and  72 , wherein the biocompatible matrix is flowable, moldable, and/or extrudable.