Bone Morphogenetic Protein-2 Rapidly Heals Two Distinct Critical Sized Segmental Diaphyseal Bone Defects in a Porcine Model.

INTRODUCTION: Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. MATERIALS AND METHODS: Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. RESULTS: BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P < .0001). mRUST scores increased from 8.2 (±1.1) in ORIF40 Cont to 14.3 (±1.0) in ORIF40 BMP specimens (P < .01). CT scans confirmed all BMP-2 specimens had healed and none of the control specimens had healed in both IMN and ORIF groups. BMP-2 restored 114% and 93% of intact torsional stiffness in IMN25 BMP and ORIF40 BMP specimens. CONCLUSIONS: We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.

Internal Fixation Construct and Defect Size Affect Healing of a Translational Porcine Diaphyseal Tibial Segmental Bone Defect.

BACKGROUND AND OBJECTIVE: Porcine translational models have become the gold-standard translational tool to study the effects of major injury and hemorrhagic shock because of their similarity to the human immunologic response to trauma. Segmental bone defects (SBDs) typically occur in warfighters with associated severe limb trauma. The purpose of this study was to develop a translational porcine diaphyseal SBD model in Yucatan minipigs (YMPs), which could be used in bone healing investigations that simulate injury-relevant conditions. We were specifically working toward developing a critical sized defect (CSD). METHODS: We used an adaptive experimental design in which both 25.0 mm and 40.0 mm SBDs were created in the tibial mid-diaphysis in skeletally mature YMPs. Initially, eight YMPs were subjected to a 25.0 mm SBD and treated with intramedullary nailing (intramedullary nail [IMN] 25mm). Due to unanticipated wound problems, we subsequently treated four specimens with identical 25.0 mm defect with dual plating (open reduction with internal fixation [ORIF] 25mm). Finally, a third group of four YMPs with 40.0 mm defects were treated with dual plating (ORIF 40mm). Monthly radiographs were made until sacrifice. Modified Radiographic Union Score for Tibia fractures (mRUST) measurements were made by three trauma-trained orthopedic surgeons. CT scans of the tibias were used to verify the union results. RESULTS: At 4 months post-surgery, mean mRUST scores were 11.7 (SD ± 1.8) in the ORIF 25mm YMPs vs. 8.5 (SD ± 1.4) in the IMN 25mm YMPs (P < .0001). All four ORIF 25mm YMPs were clinically healed. In contrast, none of the IMN 25mm YMPs were clinically healed and seven of eight IMN 25mm YMPs developed delayed wound breakdown. All four of the ORIF 40mm YMPs had flail nonunions with complete hardware failure by 3 months after surgery and were sacrificed early. CT scanning confirmed that none of the IMN 25mm YMPs, none of the ORIF 40mm YMPs, and two of four ORIF 25mm YMPs were healed. A third ORIF 25mm specimen was nearly healed on CT scanning. Inter-rater and intra-rater reliability interclass coefficients using the mRUST scale were 0.81 and 0.80, respectively. CONCLUSIONS: YMPs that had a 40 mm segment of bone removed from their tibia and were treated with dual plating did not heal and could be used to investigate interventions that accelerate bone healing. In contrast, a 25 mm SBD treated with dual plating demonstrated delayed but successful healing, indicating it can potentially be used to investigate bone healing adjuncts or conversely how concomitant injuries may impair bone healing. Pigs treated with IMN failed to heal and developed consistent delayed wound breakdown presumably secondary to chronic limb instability. The porcine YMP SBD model has the potential to be an effective translational tool to investigate bone healing under physiologically relevant injury conditions.

Transvertebral Transsacral strut grafting for high-grade isthmic spondylolisthesis L5-S1 with fibular allograft.

STUDY DESIGN: A clinical retrospective study was conducted. OBJECTIVE: To evaluate the clinical and radiographic outcomes of 25 consecutive patients with symptomatic high-grade isthmic spondylolisthesis at L5-S1 treated by decompression and transvertebral, transsacral strut grafting with fibular allograft. SUMMARY OF BACKGROUND DATA: Symptomatic high-grade isthmic spondylolisthesis serves as a challenging clinical problem. Traditional treatment by in situ posterolateral arthrodesis has been associated with pseudarthrosis rates up to 50%. Even with successful posterolateral fusion, the graft is in an unfavorable biomechanical environment, owing to it being under tension, which can allow for progression of lumbosacral kyphosis (slip angle) and sagittal translation (slip). Open reduction of spondylolisthesis improves the biomechanical situation by allowing a trapezoidal interbody graft at L5-S1, but is associated with neurologic deficits in up to 30% of patients. The technique used in this particular study achieves the biomechanical goal of a structural interbody construct without the necessity of anatomically reducing the translational slip. The fibular strut grafts were placed through an anterior approach as part of an anterior/posterior procedure, or via a posterior approach as part of a posterior-only procedure. METHODS: A consecutive series of 25 symptomatic patients with high-grade isthmic spondylolisthesis at L5-S1 had an average age of 29.8 years. Six patients were 16 years or younger. Eight patients underwent a posterior-only approach with posterior transosseous fibular strut grafting across S1 into the L5 vertebral body combined with posterolateral arthrodesis L4-S1 using a pedicle screw-rod construct. Seventeen patients underwent a combined anterior/posterior approach with transosseous fibular allograft strut grafting at L5-S1 and L4-L5 interbody arthrodesis using a femoral ring allograft supplemented with L4-S1 posterior pedicle screw-rod instrumentation. No reduction attempts were performed, other than those occurring spontaneously by patient positioning and decompression. Patients were evaluated for clinical improvement and radiographically. Clinical outcomes were measured with the scoliosis research society outcome instrument. Radiographs were followed for arthrodesis, translation, and slip angle. Mean follow-up was 39 months (range, 30 to 71 mo). All patients preoperatively had a grade III to V slip using the Meyerding classification (mean 3.7). The slip angle averaged 37 degrees. RESULTS: The postoperative mean slip grade was 3.5 compared with 3.7 preoperatively (no significant difference). The mean slip angle improved to 27 degrees (8 to 40 degrees) postoperatively from 37 degrees (13 to 51 degrees) preoperatively (P<0.05). All patients went on to a stable arthrodesis, with no progression in slip or slip angle. There were no permanent neurologic deficits among any of the subjects, and all patients demonstrated improvement in their preoperative gait disturbance. Scoliosis research society functional outcome score showed 24/25 extremely satisfied or somewhat satisfied at latest follow-up. CONCLUSIONS: Treatment by this method showed improvement in lumbosacral kyphosis while avoiding the neurologic injury risk associated with open slip-reduction maneuvers. Despite no reduction in translational deformity, this technique offers excellent fusion results, good clinical outcomes, and prevents further sagittal translation and lumbosacral kyphosis progression.