Bone healing induced by local delivery of an engineered parathyroid hormone prodrug

Abstract Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a ma...

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Bibliographic Details
Published in:Biomaterials 2009-03, Vol.30 (9), p.1763-1771
Main Authors: Arrighi, Isabelle, Mark, Silke, Alvisi, Monica, von Rechenberg, Brigitte, Hubbell, Jeffrey A, Schense, Jason C
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Biological Assay
Bone and Bones - drug effects
Bone and Bones - pathology
Bone graft
Bone healing
Dentistry
Drug Delivery Systems
Electrophoresis, Polyacrylamide Gel
Fibrin
Fibrin - metabolism
Fibrinolysin - metabolism
Humans
Osteoblast
Parathyroid Hormone - administration & dosage
Parathyroid Hormone - pharmacology
Peptide
Prodrugs - administration & dosage
Prodrugs - pharmacology
Receptors, Parathyroid Hormone - metabolism
Sheep
Transglutaminases - metabolism
Wound Healing - drug effects
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Summary:Abstract Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH1–34 ), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH1–34 ). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH–fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2008.12.023