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Critical bone defects pose a formidable orthopaedic problem in patients with bone loss. We developed a preclinical model based on the induced membrane technique using a synthetic graft to replace autograft for healing critical bone defects. Additionally, we used a novel osteoconductive scaffold coupled with a synthetic membrane to evaluate the potential for single‐stage bone regeneration. Three experimental conditions were investigated in critical femoral defects in rats. Group A underwent a two‐stage procedure with insertion of a polymethylmethacrylate (PMMA) spacer followed by replacement with a 3D printed polycaprolactone(PCL)/β‐tricalcium phosphate (β‐TCP) osteoconductive scaffold after 4 weeks. Group B received a single‐stage PCL/β‐TCP scaffold wrapped in a PCL‐based microporous polymer film creating a synthetic membrane. Group C received a single‐stage bare PCL/β‐TCP scaffold. All groups were examined by serial radiographs for callus formation. After 12 weeks, the femurs were explanted and analyzed with micro‐CT and histology. Mean callus scores tended to be higher in Group A. Group A showed statistically significant greater bone formation on micro‐CT compared with other groups, although bone volume fraction was similar between groups. Histology results suggested extensive bone ingrowth and new bone formation within the macroporous scaffolds in all groups and cell infiltration into the microporous synthetic membrane. This study supports the use of a critical size femoral defect in rats as a suitable model for investigating modifications to the induced membrane technique without autograft harvest. Future investigations should focus on bioactive synthetic membranes coupled with growth factors for single‐stage bone healing. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [ABSTRACT FROM AUTHOR]

Fracture healing is a complex process of many coordinated biological pathways. This system can go awry resulting in nonunion, which leads to significant patient morbidity. The Hedgehog (Hh) signaling pathway is upregulated in fracture healing. We hypothesized that the Hh signaling pathway can be pharmacologically modulated to positively affect fracture healing. Diaphyseal femur fractures were created in elderly mice (18 months, C57BL/6 females), which have a blunted and delayed healing response compared to younger mice, and were stabilized with intramedullary pins. To activate the Hh pathway we targeted the receptor Smoothened using an agonist (Hh‐Ag1.5 [Hh‐Ag]) and compared this to a vehicle control. Expression of Hh target genes were significantly increased in the fracture callus of the agonist group compared to controls, indicating pathway activation. Expression of osteogenic and chondrogenic‐related genes was greatly upregulated in fracture callus versus intact femora, although Hh agonist treatment did not consistently enhance this response. Blindly graded, radiographic callus healing scores were significantly higher in the Hh‐Ag groups at post operative day (POD) 14, indicating earlier callus bridging. On microCT, Hh‐Ag treatment led to greater callus volume (+40%) and bone volume (+25%) at POD21. By day 14, callus vascularity, as assessed by 3D microCT angiography vessel volume, was 85% greater in the Hh‐Ag group. Finally, mechanical strength of the calluses in the Hh‐Ag groups was significantly greater than in the control groups at POD21. In conclusion, systemic administration of a Hh agonist appears to improve the osseous and vascular healing responses in a mouse fracture healing‐impaired model. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [ABSTRACT FROM AUTHOR]