title: Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing.
abstract: Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.
authors.affiliation: Department of Orthopaedics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, NJ 07103, USA. dnp6@njit.edu
authors.forename: David N
authors.initials: DN
authors.lastname: Paglia
authors.forename: Aaron
authors.initials: A
authors.lastname: Wey
authors.forename: Eric A
authors.initials: EA
authors.lastname: Breitbart
authors.forename: Jonathan
authors.initials: J
authors.lastname: Faiwiszewski
authors.forename: Siddhant K
authors.initials: SK
authors.lastname: Mehta
authors.forename: Loay
authors.initials: L
authors.lastname: Al-Zube
authors.forename: Swaroopa
authors.initials: S
authors.lastname: Vaidya
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Cottrell
authors.forename: Dana
authors.initials: D
authors.lastname: Graves
authors.forename: Joseph
authors.initials: J
authors.lastname: Benevenia
authors.forename: J Patrick
authors.initials: JP
authors.lastname: O'Connor
authors.forename: Sheldon S
authors.initials: SS
authors.lastname: Lin
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018483:Diaphyses / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015552:Injections, Intralesional; D061406:Insulin, Ultralente / Q000494:pharmacology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011859:Radiography; D011897:Random Allocation; D051381:Rats; D011913:Rats, Inbred BB; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D061406:Insulin, Ultralente; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat