Toyomi Yoshiiwa

Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model

Bone repair involves a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone matrix at the fracture site. It has been reported that the optimal time point for single-dose zoledronic acid (ZA) administration systemically increased the strength of bone morphogenetic protein (BMP)-7-mediated callus. However, its repair mechanism during bone fracture healing remains unknown. We aimed to investigate the synergic effect of recombinant human (rh) BMP-2 and ZA in a rat femoral fracture model. Fifty-eight rats were divided into 4 groups. Group I (n=14) animals were implanted with a carrier alone. Group II (n=15) animals were implanted with a carrier containing 1-μg rhBMP-2. Group III (n=14) animals were implanted with a carrier and a subcutaneous systemic ZA injection 2 weeks after surgery. Group IV (n=15) animals were implanted with a carrier containing 1-μg rhBMP-2 and ZA subcutaneous injection 2 weeks after surgery. The rats were euthanized after 6 weeks and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high-resolution micro-computerized tomography (micro-CT) and were subjected to biomechanical and histological analysis. The fusion rates in Group IV (93.3%) were considerably higher than those in Groups I (28.6%), II (53.3%), and III (57.1%). Additionally, the radiographic scores of Group IV were higher than those in Groups I, II, and III. In micro-CT analysis, the tissue volume (TV) of the callus was higher in Group IV than in Groups I and II (p<0.05). New bone volume (BV) and trabecular spacing (Tb.Sp) also showed essentially the same trend as that of TV. The ratio of BV to TV (BV/TV), the trabecular number (Tb.N), and the trabecular thickness (Tb.Th) was higher in Groups III and IV than in Groups I and II (p<0.05). In biomechanical analysis, the ultimate loads at failure and stiffness in Groups III and IV were on average higher than those in Groups I and II (p<0.05), while the energy absorption of Group IV was higher than those of Groups I and II (p<0.05). The synergic effect of rhBMP-2 and ZA given systemically as a single dose at the optimal time was efficacious for fracture repair and significantly enhanced bone fusion. Our results suggest that this combination facilitates bone healing and has potential clinical application.

Manipulation of anabolic and catabolic responses with bone morphogenetic protein and zoledronic acid in a rat spinal fusion model.

Bone fusion involves a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone matrix at the surgical site. It has been reported that systemically administering a single dose of zoledronic acid (ZA) at the optimal time increases the strength of the bone morphogenetic protein (BMP)-mediated callus. In the present study, we aimed to investigate the effect of BMP-2 and ZA in a rat spinal model. Sixty-seven rats were divided into 6 groups: group I (n=11) animals were implanted with a carrier alone, group II (n=12) animals were implanted with a carrier and a subcutaneous injection of ZA was administered 2weeks after surgery, group III (n=12) animals were implanted with a carrier containing 1μg of rhBMP-2, group IV (n=12) animals were implanted with a carrier containing 1μg of rhBMP-2 and a subcutaneous injection of ZA was administered 2weeks after surgery, group V (n=10) animals were implanted with a carrier containing 3μg of rhBMP-2, and group VI (n=10) animals were implanted with a carrier containing 3μg of rhBMP-2 and a subcutaneous injection of ZA was administered 2weeks after surgery. The rats were euthanized after 6weeks, and their spines were explanted and assessed by manual palpation, radiography, high-resolution micro-computerized tomography (micro-CT), and histologic analysis. The fusion rates in group VI (60%) were considerably higher than those in the groups I (0%), II (0%), III (12.5%), IV (20.8%), and V (35%), (P<0.05). Additionally, the radiographic scores of group VI were higher than those in the other groups, (P<0.05). In micro-CT analysis, the tissue and bone volumes of the callus were significantly higher in group VI than those in the other groups, (P<0.05). The trabecular number was significantly higher and the trabecular spacing was significantly lower in group VI than those in the other groups, (P<0.05). The combination of rhBMP-2 and ZA administered systemically as a single dose at the optimal time was efficacious in our rat spinal fusion model. Our results suggest that this combination facilitates spinal fusion and has potential clinical application.

Analysis of the Relationship between Ligamentum Flavum Thickening and Lumbar Segmental Instability, Disc Degeneration, and Facet Joint Osteoarthritis in Lumbar Spinal Stenosis

Study Design Cross-sectional study. Purpose To investigate the relationship between ligamentum flavum (LF) thickening and lumbar segmental instability and disc degeneration and facet joint osteoarthritis. Overview of Literature Posterior spinal structures, including LF thickness, play a major role in lumbar spinal canal stenosis pathogenesis. The cause of LF thickening is multifactorial and includes activity level, age, and mechanical stress. LF thickening pathogenesis is unknown. Methods We examined 419 patients who underwent computed tomography (CT) myelography and magnetic resonance imaging after complaints of clinical symptoms. To investigate LF hypertrophy, 57 patients whose lumbar vertebra had normal disc heights at L4–5 were selected to exclude LF buckling as a hypertrophy component. LF thickness, disc space widening angulation in flexion, segmental angulation, presence of a vacuum phenomenon, and lumbar lordosis at T12–S1 were investigated. Disc and facet degeneration were also evaluated. Facet joint orientation was measured via an axial CT scan. Results The mean LF thickness in all patients was 4.4±1.0 mm at L4–5. There was a significant correlation between LF thickness and disc degeneration; LF thickness significantly increased with severe disc degeneration and facet joint osteoarthritis. There was a tendency toward increased LF thickness in more sagittalized facet joints than in coronalized facet joints. Logistic regression analysis showed that LF thickening was influenced by segmental angulation and facet joint osteoarthritis. Patient age was associated with LF thickening. Conclusions LF hypertrophy development was associated with segmental instability and severe disc degeneration, severe facet joint osteoarthritis, and a sagittalized facet joint orientation.

Analysis of measured D-dimer levels for detection of deep venous thrombosis and pulmonary embolism after spinal surgery.

Study Design A retrospective clinical study. Objectives To show the prevalence of deep venous thrombosis (DVT) and pulmonary embolism (PE) after spinal surgery using a D-dimer assay followed by screening with computed tomographic (CT) pulmonary angiography and CT venography. Summary of Background Data A few studies on DVT development after spinal surgery have been reported. Methods A complete surveillance examination for DVT and PE was conducted in 88 patients who underwent spinal surgery [male patients, 48; female patients, 40; average age at operation, 62.4 y (range, 17 to 85 y)] through a D-dimer assay combined with CT pulmonary angiography and CT venography. The operation levels were the cervical spine (21 cases), the thoracic spine (16 cases), and the lumbar spine (51 cases). We adopted a D-dimer cut-off point of 10 &mgr;g/mL, and classified the patients into high D-dimer (HD; D-dimer level ≥10 &mgr;g/mL) and low D-dimer (LD; D-dimer level <10 &mgr;g/mL) groups. Results Nine (10.2%) patients showed D-dimer levels of ≥10 &mgr;g/mL (HD group); of these, 5 patients (5.7%) had DVT. Two (2.2%) of the 5 DVT patients had PE. DVT was evident in 1 (6.2%) of the 16 patients who underwent thoracic procedures and 4 (7.8%) of the 51 patients who underwent lumbar procedures. Statistical comparison between the HD (excluding 5 patients with DVT or PE) and LD groups showed a significant difference in intraoperative blood loss between the groups (P=0.02). Conclusions The D-dimer assay was useful in predicting DVT development. A D-dimer level of ≥10 &mgr;g/mL is considered to be a risk factor for thromboembolic disease after spinal surgery. False-positive cases of thromboembolic disease preclude the use of this assay as a stand-alone test for DVT diagnosis. CT venography and CT pulmonary angiography are recommended to confirm thromboembolic disease.

Morphological analysis of the cervical pedicles, lateral masses, and laminae in developmental canal stenosis.

Study Design. Retrospective cross-sectional study. Objective. This study aimed to elucidate the relationship between developmental spinal canal stenosis (DCS) and morphologic features in the cervical spine by comparing the features between DCS and nondevelopmental spinal canal stenosis (NDCS). Summary of Background Data. DCS is an important predisposing factor for cervical myelopathy. Further, various posterior cervical spinal instrumentations have been developed. However, no study has specifically addressed the cervical posterior morphology of DCS. Methods. A total of 52 consecutive patients underwent cervical spine computed tomography myelography. Axial images of the largest pedicle diameter were selected from C3 to C7 vertebrae and 260 images were analyzed. The following parameters were measured: spinal canal longitudinal diameter (SCLD), spinal canal transverse diameter, osseous spinal canal area, dural sac area, spinal cord area, pedicle outer width, pedicle axis length, pedicle transverse angulation, lateral mass longitudinal diameter, lateral mass transverse diameter, lamina outer width, and lamina axis length. The participants were classified into 2 groups: DCS group (SCLD <12 mm at any level) and NDCS group (SCLD ≧12 mm at all levels). Results. The mean osseous spinal canal area and dural sac area at C3–C5 in the DCS group were less than those in the NDCS group. The mean spinal cord area did not differ significantly at C3–C7 between the groups. The mean pedicle outer width at C6 and C7 in the DCS group was less than that in NDCS group. The mean lateral mass transverse diameter at C5 and mean lateral mass longitudinal diameter at C3, C5, and C6 in the DCS group were less than those in the NDCS group. Conclusion. Myelopathy is expected to progress in patients with DSC and these patients with severe neurologic symptoms may need cervical operation. However, posterior screw insertions should be considered more carefully than in NDCS patients.

Analysis of the Relationship between Hypertrophy of the Ligamentum Flavum and Lumbar Segmental Motion with Aging Process

Study Design Retrospective cross-sectional study. Purpose To investigate the relationship between ligamentum flavum (LF) hypertrophy and lumbar segmental motion. Overview of Literature The pathogenesis of LF thickening is unclear and whether the thickening results from tissue hypertrophy or buckling remains controversial. Methods 296 consecutive patients underwent assessment of the lumbar spine by radiographic and magnetic resonance imaging (MRI). Of these patients, 39 with normal L4–L5 disc height were selected to exclude LF buckling as one component of LF hypertrophy. The study group included 27 men and 12 women, with an average age of 61.2 years (range, 23–81 years). Disc degeneration and LF thickness were quantified on MRI. Lumbar segmental spine instability and presence of a vacuum phenomenon were identified on radiographic images. Results The distribution of disc degeneration and LF thickness included grade II degeneration in 4 patients, with a mean LF thickness of 2.43±0.20 mm; grade III in 10 patients, 3.01±0.41 mm; and grade IV in 25 patients, 4.16±1.12 mm. LF thickness significantly increased with grade of disc degeneration and was significantly correlated with age (r=0.55, p<0.01). Logistic regression analysis identified predictive effects of segmental angulation (odds ratio [OR]=1.55, p=0.014) and age (OR=1.16, p=0.008). Conclusions Age-related increases in disc degeneration, combined with continuous lumbar segmental flexion-extension motion, leads to the development of LF hypertrophy.

Analysis of the relationship between facet joint angle orientation and lumbar spine canal diameter with respect to the kinematics of the lumbar spinal unit.

Study Design Retrospective cross-sectional study. Objective This study aimed to elucidate the relationship among facet orientation, kinematics of a spinal unit, and change in lumbar spine canal diameter by using kinetic magnetic resonance imaging. Summary of Background Data Some studies have suggested an association between increased sagittally oriented facet angles and degenerative lumbar spondylolisthesis. However, no study has specifically addressed the association of facet orientation with the kinematics of a spinal unit and change in canal diameter. Methods Kinetic magnetic resonance imagings were performed with patients in flexion, neutral, and extension positions. Study subjects were classified into 6 groups—AA, BB, CC, AB (BA), BC (CB), and AC (CA)—on the basis of bilateral facet angles (A, narrow; B, normal; and C, wide) and disc and facet joint degeneration. A magnetic resonance imaging analyzer was used for anatomic measurements and for calculating changes in canal diameters and disc bulging as well as the lumbar spine kinematics. Results Osseous canal diameters were significantly smaller in the group AA than in the group BB, whereas they were significantly larger in the group CC than in the group BB. Canal diameter at the disc level was significantly smaller in the group AA than in the group BB in all 3 positions, whereas it was significantly larger in the group CC than in the group BB. Translational motion was significantly more in the group AA than in the group BB, whereas it was significantly lesser in the group CC than in the group BB. Conclusions We demonstrated the relationship among facet orientation, osseous canal diameter, kinematics of a spinal unit, and change in lumbar spine canal diameter. Patients with sagittally oriented facets had narrow osseous canals with mobility, whereas those with coronally oriented facets had stable and wider osseous canals. This finding is helpful in understanding the mechanism underlying lumbar spinal canal stenosis and degenerative spondylolisthesis.

Enhancement of the Effects of Exfoliated Carbon Nanofibers by Bone Morphogenetic Protein in a Rat Femoral Fracture Model

Exfoliated carbon nanofibers (ExCNFs) are expected to serve as excellent scaffolds for promoting and guiding bone‐tissue regeneration. We aimed to enhance the effects of ExCNFs with bone morphogenetic proteins (BMPs) and examine their feasibility and safety in clinical applications using a rat femoral fracture model. Group I (n = 16) animals were implanted with control MedGEL. Group II (n = 17) animals were implanted with MedGEL containing ExCNFs. Group III (n = 15) animals were implanted with MedGEL containing 1 μg rhBMP‐2. Group IV (n = 15) animals were implanted with MedGEL containing 1 μg rhBMP‐2 and ExCNFs. The rats were euthanized after 6 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high‐resolution microcomputerized tomography (micro‐CT); the femurs were also subjected to biomechanical and histological analysis. The fusion rates in Group IV (73.3%) were considerably higher than those in Groups I (25.0%), II (52.9%), and III (46.7%). The results demonstrated the enhancement of the bone repair effects of ExCNFs by BMP in a rat femoral fracture model. Our results suggest that the enhancement of the effects of ExCNFs by BMP makes the combination a possible attractive therapy for various orthopedic surgeries.

Symptomatic Spinal Cord Kinking Due to Focal Adhesive Arachnoiditis, With Ossification of the Ligamentum Flavum: A Case Report

Study Design. A case report. Objective. To describe a rare case of symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with ossification of the ligamentum flavum (OLF). Summary of Background Data. Spinal cord kinking without spinal surgery is rare, and symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with OLF is even rarer. Methods. A 66-year-old female presented with numbness of the lower extremities and subsequently experienced gait disturbance due to motor weakness. Magnetic resonance imaging of the thoracic spine showed anterior displacement and kinking of the spinal cord from T11 to T12. Laminectomy and OLF resection were performed. The arachnoid membrane at the affected part was markedly thick and seemed cloudy. Adhesiolysis for arachnoid adhesion and release of spinal kinking were performed. Results. She could walk with a cane 6 months postoperatively. One year postoperatively, thoracic computed tomography–myelography showed that the cord was repositioned in the dural sac, and that release of the spinal cord kink was maintained. Conclusion. Symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with OLF is a rare clinical condition. It was difficult to diagnose the precise pathology of the spinal cord before surgery. Microsurgical arachnoidolysis resolved the spinal cord kinking, and no recurrence was noted within the follow-up period. Level of Evidence: N/A

Predictable Imaging Signs of Cauda Equina Entrapment in Thoracolumbar and Lumbar Burst Fractures with Greenstick Lamina Fractures

Study Design A retrospective study. Purpose The aim of present study was to investigate imaging findings suggestive of cauda equina entrapment in thoracolumbar and lumbar burst fractures. Overview of Literature Burst fractures with cauda equina entrapment can cause neurologic deterioration during surgery. However, dural tears and cauda equina entrapment are very difficult to diagnose clinically or radiographically before surgery. Methods Twenty-three patients who underwent spinal surgery for thoracolumbar or lumbar burst fractures were enrolled in this study. In magnetic resonance imaging T2-weighted images of the transverse plane, we defined cauda equina notch sign (CENS) as a v-shaped image that entrapped cauda equina gathers between lamina fractures. We evaluated the fractured spine by using CENS and lamina fractures and the rate of available space for the spinal canal at the narrowest portion of the burst fracture level. We classified patients into entrapment group or non-entrapment group, based on whether cauda equina entrapment existed. Results Lamina fractures were detected in 18 (78.3%) and CENS were detected in 6 (26.1%) of 23 burst-fracture patients. Cauda equina entrapment existed in all the patients with CENS. In addition, the rate of available space for the spinal canal increased according to logistic regression. The size of the retropulsed fragment in the spinal canal was the most reliable of all the factors, suggesting cauda equina entrapment. Conclusions CENS was the most predictable sign of cauda equina entrapment associated with burst fractures.