Motohiro Okada

A prospective randomized study of clinical outcomes in patients with cervical compressive myelopathy treated with open-door or French-door laminoplasty.

Study Design. A prospective randomized clinical study. Objective. To compare the clinical outcomes of open-door and French-door laminoplasties. Summary of Background Data. Expansive laminoplasty for cervical compressive myelopathy is well established and a variety of modifications procedures have been developed. The procedures are mainly classified into open-door and French-door. It has never been prospectively investigated as to which surgical procedure, open-door or French-door laminoplasty, results in a more favorable outcome. Methods. After informed consent was obtained from 40 patients, they were randomized into 2 surgical groups A and B. Patients in group A had open-door laminoplasty, and patients in group B underwent French-door laminoplasty with reattachment of the spinous process and extensor musculatures. The following criteria were evaluated: operation time, blood loss, perioperative complications, Japanese Orthopedic Association (JOA) scores, recovery rates, axial pain, and short-form 36 (SF-36). For radiographic evaluation, cervical lordosis was reviewed as lordotic angles, which were measured at C2–C7. Results. Although the operation time was significantly less in group A as compared with group B, the mean blood loss in group A was significantly more than group B. Perioperative complications occurred more frequently in group A than in group B. Although there were no significant differences in postoperative JOA scores and recovery rates between the 2 groups, axial pain was significantly decreased in group B at final follow-up. The scores of every subscale of the SF-36 were higher in group B than group A. Conclusion. Perioperative complications occurred more frequently in open-door laminoplasty than in French-door laminoplasty. JOA scores and recovery rates suggested that both open-door and French-door laminoplasties could be similarly effective in decompressing the spinal cord. Axial pain was improved in French-door laminoplasty but became worse in open-door laminoplasty. SF-36 suggested that French-door laminoplasty could be more beneficial than open-door laminoplasty for patients with cervical compressive myelopathy.

The effects of bone morphogenetic protein and basic fibroblast growth factor on cultured mesenchymal stem cells for spine fusion.

Study Design. Posterolateral lumbar transverse process fusion was carried out using cultured mesenchymal stem cells with or without bone morphogenetic protein (BMP) and basic fibroblast growth factor (FGF). Objectives. To determine the ability of BMP and basic FGF to enhance the efficacy of bone marrow-derived mesenchymal stem cells in lumbar arthrodesis. Summary of Background Data. Our previous study hypothesized that it would be important to differentiate into osteogenic cells and to implant a large number of cells for achieving solid spinal fusions. Methods. Thirty-six adult rabbits underwent single-level bilateral posterolateral intertransverse process fusions at L4–L5. Animals were divided into 5 groups, each according to the material implanted: (1) autologous bone (autograft; n = 8); (2) mesenchymal stem cells (n = 7); (3) mesenchymal stem cells with recombinant human bone morphogenetic protein (rhBMP)-2 (mesenchymal stem cell-BMP; n = 7); (4) mesenchymal stem cells with basic FGF (mesenchymal stem cell-FGF; n = 7); and (5) mesenchymal stem cells with rhBMP-2 and basic FGF (mesenchymal stem cell-BMP-FGF; n = 7). Fresh bone marrow cells from the iliac crest of each animal were cultured in a standard medium for 2 weeks. For an additional week, the mesenchymal stem cells (1 × 106cells/mL) were cultured in 10−8M dexamethasone, type I collagen gel and porous hydroxyapatite particles with or without rhBMP-2 (2 &mgr;g/mL) and basic FGF (5 &mgr;g/mL). Animals were killed 6 weeks after surgery. Radiograph, manual palpation, and histology were used to evaluate spinal fusions. Results. Fusion rates were 5/7 in the autograft group, 0/7 in the mesenchymal stem cell group, 2/7 in the mesenchymal stem cell-BMP group, 3/7 in the mesenchymal stem cell-FGF group, and 6/7 in the mesenchymal stem cell-BMP-FGF group. The histology in some of both mesenchymal stem cell-BMP and mesenchymal stem cell-FGF groups demonstrated that fibrous tissues and cartilages remained in grafted areas. In the mesenchymal stem cell-BMP-FGF group, each grafted fragment was connected with new bone ingrowths. Conclusions. This study showed that bone marrow-derived mesenchymal stem cells cultured with rhBMP-2 and basic FGF act as a substitute for autograft in lumbar arthrodesis. This technique may yield a more consistent quality of fusion bone as compared to that with autograft.

Biomechanical assessment of minimally invasive decompression for lumbar spinal canal stenosis: a cadaver study.

Study Design A biomechanical study on the cadaveric human lumbar spine. Objective We focused on a biomechanical comparison of the changes wrought on motion segments after a minimally invasive decompression and after a conventional medial facetectomy. Summary of Background Data Minimally invasive posterior decompression using a microscope or an endoscope is becoming popular for elderly patients with lumbar spinal canal stenosis. An advantage of the technique is that the cauda equina and nerve roots are in clear view and the facet joints, paravertebral muscles, and spinous process are well preserved. Methods Eight human lumbar motion segments were used in this study. Each specimen was tested according to the following loading protocol: axial compression, flexion, extension, lateral bending to the right and to the left, and axial rotation to the right and to the left. This loading protocol was applied to each motion segment after the following surgical interventions: (1) left fenestration, (2) bilateral decompression via unilateral approach, (3) medial facetectomy, and (4) total facetectomy. The relative stiffness of the motion segments was determined and compared with a normalized stiffness for the specimen when intact. Results Bilateral decompression via unilateral approach produces less biomechanical effect in terms of stiffness changes as compared with medial facetectomy. Bilateral decompression leaves the spine more than 80% as stiff as the intact spine. Conclusions These results go toward supporting a minimally invasive bilateral decompression. Minimally invasive bilateral decompression, as opposed to a conventional medial facetectomy, preserves the facet joints as much as possible. Preserving the facet joints during the decompression should produce less postoperative instability.

Development and optimization of a cell-based assay for the selection of synthetic compounds that potentiate bone morphogenetic protein-2 activity

The requirement of large amounts of the recombinant human bone morphogenetic protein‐2 (BMP‐2) produces a huge translational barrier for its routine clinical use due to high cost. This leads to an urgent need to develop alternative methods to lower costs and/or increase efficacies for using BMP‐2. In this study, we describe the development and optimization of a cell‐based assay that is sensitive, reproducible, and reliable in identifying reagents that potentiate the effects of BMP‐2 in inducing transdifferentiation of C2C12 myoblasts into the osteoblastic phenotype. The assay is based on a BMP‐responsive Smad1‐driven luciferase reporter gene. LIM mineralization protein‐1 (LMP‐1) is a novel intracellular LIM domain protein that has been shown by our group to enhance cellular responsiveness to BMP‐2. Our previous report elucidated that the binding of LMP‐1 with the WW2 domain in Smad ubiquitin regulatory factor‐1 (Smurf1) rescues the osteogenic Smads from degradation. Here, using the optimized cell‐based assay, we first evaluated the activity of the recombinantly prepared proteins, LMP‐1, and its mutant (LMP‐1ΔSmurf1) that lacks the Smurf1‐WW2 domain‐binding motif. Both the wild type and the mutant proteins were engineered to contain an 11‐amino acid HIV‐TAT protein derived membrane transduction domain to aid the cellular delivery of recombinant proteins. The cell‐based reporter assay confirmed that LMP‐1 potentiates the BMP‐induced stimulation of C2C12 cells towards the osteoblastic phenotype. The potentiating effect of LMP‐1 was significantly reduced when a specific‐motif known to interact with Smurf1 was mutated. We validated the results obtained in the reporter assay by also monitoring the expression of mRNA for osteocalcin and alkaline phosphatase (ALP) which is widely accepted osteoblast differentiation marker genes. Finally, we provide further confirmation of our results by measuring the activity of alkaline phosphatase in support of the accuracy and reliability of our cell‐based assay. Direct delivery of synthesized protein can be limited by high cost, instability or inadequate post‐translational modifications. Thus, there would be a clear benefit for a low cost, cell penetrable chemical compound. We successfully used our gene expression‐based assay to choose an active compound from a select group of compounds that were identified by computational screenings as the most likely candidates for mimicking the function of LMP‐1. Among them, we selected SVAK‐3, a compound that showed a dose‐dependent potentiation of BMP‐2 activity in inducing osteoblastic differentiation of C2C12 cells. We show that either the full length LMP‐1 protein or its potential mimetic compound consistently exhibit similar potentiation of BMP‐2 activity even when multiple markers of the osteoblastic phenotype were parallely monitored. Published in 2009 by John Wiley & Sons, Ltd.

Do the Adjacent Level Intervertebral Discs Degenerate After a Lumbar Spinal Fusion? An Experimental Study Using a Rabbit Model

Study Design. A rabbit model of disc degeneration adjacent to a lumbar spinal fusion. Objective. To use a rabbit model to determine the long-term changes in the intervertebral discs at the levels above (cephalad) and below (caudad) 2 fused lumbar levels. Summary of Background Data. Lumbar spinal fusion is generally carried out to eliminate motion at a specific lumbar level. However, it is commonly thought that by eliminating motion at a level, one increases the motion at the adjacent levels cephalad and caudad the fused levels. There have been studies that have reported on degeneration occurring at the cephalad and caudad levels adjacent to the fused levels. Methods. A total of 9 New Zealand white, female rabbits: 4 rabbits in the control group and 5 rabbits in the experimental group. The 5 rabbits in the experimental group underwent a posterolateral 2-level lumbar spinal fusion from L3 to L5. The changes in the lumbar discs were assessed using radiographs, magnetic resonance (MR) images, and histology at 6 months and 12 months. Results. The results at 6 months are less clear than those at 12 months. The results at 12 months for the experimental group are (1) the intervertebral disc height decreased at the caudad adjacent level and to a lesser extent at the cephalad adjacent level; (2) the MRI scores for the discs at the caudad and cephalad adjacent levels showed severe loss of signal intensity as compared to the discs at the same levels in the control group. This loss was more pronounced at the caudad level where the loss of signal intensity was similar to that seen at the fused levels; (3) the histologic analysis showed severe degenerative changes with a lack of live cells in the nucleus pulposus and in the endplate at the caudad adjacent level. At the cephalad level, live cells were apparent (albeit few) in the nucleus pulposus, and there was a more normal looking endplate with live cells. Conclusion. The intervertebral discs at both the cephalad and the caudad levels adjacent to the 2 fused lumbar levels in this rabbit-model experiment carried out over 12 months after surgery showed degenerative changes asassessed using disc-height measurements, MR images, and histology, and the effect was more severe at the caudad adjacent level.

Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, attenuates neurogenic pain induced by nucleus pulposus in rats.

Study Design. An in vivo study using a rat lumbar disc herniation model. Objectives. To evaluate the effects of sarpogrelate hydrochloride on neurogenic pain induced by nucleus pulposus translocation and to elucidate its mechanism. Summary of Background Data. Sarpogrelate, an antiplatelet agent with selective 5-hydroxytryptamine (5-HT) receptor 2A antagonist activity, has been reported to improve low back pain, sciatica, and numbness of lower extremities in patients with lumbar disc herniation. However, the efficacy of sarpogrelate for pain relief in this situation has not been established by clinical studies and its mechanism remains unknown. Methods. The autologous nucleus pulposus was placed onto the left L4 and L5 nerve roots of 30 Sprague-Dawley rats allotted to sarpogrelate (100 mg/kg, n = 15) and control (vehicle, n = 15) treatment groups. Sarpogrelate or vehicle was administered orally once daily between days 7 and 14 after surgery. Mechanical allodynia was measured before and after treatment. The right and left nerve roots and dorsal root ganglions were isolated from 5 animals in each group to assay 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine on day 5 of administration (= day 11 after surgery). Results. Sarpogrelate treatment significantly reduced mechanical allodynia on days 5 and 8 of administration. The placement of the nucleus pulposus onto nerve roots increased norepinephrine but not 5-HT and 5-HIAA contents in inflamed nerve roots or dorsal root ganglions. Sarpogrelate did not affect these levels. Conclusions. Sarpogrelate attenuated pain-related behavior induced by the nucleus pulposus in the animal model. Although further investigation is needed concerning the mechanism of action, this study supported the hypothesis that sarpogrelate is efficacious for treating the pain of lumbar disc herniation.

Pedicle screw augmentation with polyethylene tape: a biomechanical study in the osteoporotic thoracolumbar spine.

Study Design Biomechanical study using human thoracolumbar spines. Objective To assess the strength of fixation of pedicle screws augmented with Nesplon tape applied sublaminar or applied subpars. Summary of Background Data There are no reports on the biomechanical assessment of Nesplon tape used for pedicle screw augmentation. Methods Experiment 1: pedicle screws were inserted into bilateral pedicles as follows: (1) pedicle screw alone connected to a rod (PS alone), (2) pedicle screw augmented with Nesplon tape applied sublaminar, connected to a rod [pedicle screw applied sublaminar (PSSL)], and (3) pedicle screw augmented with tape applied subpars, connected to a rod [pedicle screw applied subpars (PSSP)]. The rods were pulled and pushed until the pedicle screw was loose. Experiment 2: 6 thoracolumbar spines were biomechanically tested as follows: axial compression, flexion, extension, left and right lateral bending, and left and right axial rotation. This sequence was applied to: (1) the intact spine; (2) the spine made unstable; (3) the spine fixed by pedicle screws and rods (PS alone); (4) the same as 3, but with the pedicle screws augmented using Nesplon tape applied sublaminar (PSSL); and (5) the same as 3, but with pedicle screws augmented using tape applied subpars (PSSP). From the load-deformation curves, stiffness values were calculated. Results Experiment 1: the pedicle screws augmented by sublaminar or subpars tape (PSSL or PSSP) showed significantly greater fixation strength compared with those pedicles that were not augmented by tape (PS alone). Experiment 2: a pedicle screw/rod construct augmented by tape provided a stiffer construct than the same construct without augmentation. Conclusions Pedicle screws that are inserted into the osteoporotic thoracolumbar spine and augmented by Nesplon tape applied sublaminar or subpars provide firmer fixation of the screws and a stiffer pedicle screw/rod construct than the same construct without augmentation by tape.

Safety of epidural administration of Osteogenic Protein-1 (OP-1/BMP-7): behavioral and macroscopic observation.

Study Design. To assess the safety of epidural administration of Osteogenic Protein-1 (OP-1). Objectives. To examine if epidural administration of OP-1 or administration into the nucleus pulposus (NP) resulted in ectopic bone formation and/or pain-related behavior. Summary of Background Data. OP-1 has the potential for treatment of degenerative disc disease. However, OP-1s safety, when it is applied into the epidural space or herniated nucleus pulposus, is not well established. Methods. Forty rats were divided into 5 groups. Sham group: Left L4 and L5 nerve roots were exposed. NP group: The NP obtained from the tail was relocated onto the exposed nerve roots. NP+OP group: The NP obtained from the tail and injected with 0.2 &mgr;g of OP-1 in 1 &mgr;L of 5% lactose-buffered solution was placed on the nerve roots. GS group: A gelatin sponge was applied on the nerve roots. GS+OP group: A gelatin sponge soaked with 0.2 &mgr;g of OP-1 in 1 &mgr;L of 5% lactose-buffered solution was placed onto the nerve roots. Motor function and reflex responses to mechanical noxious stimuli were measured in all rats up to 3 weeks after surgery. Three weeks after surgery, all rats were killed for analysis of ectopic bone formation and magnitude of neural compression. Results. Motor paresis was not observed in any groups. Only rats in the NP group showed evidence of irreversible mechanical hyperalgesia after surgery. There were no differences in the mechanical stimuli response among all groups except the NP group. Macroscopic examination revealed no ectopic bone formation or differences in neural compression among the groups. Conclusion. OP-1 application in the epidural space is safe based on behavioral measures and macroscopic observation on ectopic bone formation at 21 days after surgery.

A novel microendoscopically assisted approach for the treatment of recurrent lumbar disc herniation: transosseous discectomy surgery.

BACKGROUND AND OBJECT Microendoscopic discectomy (MED) is still regarded as contraindicated for the treatment of recurrent lumbar disc herniation by many surgeons. Moreover, the presence of epidural scar tissue makes surgical manipulation difficult. To successfully remove the herniated disc in such cases, an open technique with a wide exposure may be required. We devised a new minimally invasive endoscopic approach, which is using a transosseous route. This is a retrospective review of a consecutive case series to examine the operative and clinical results of this new approach. MATERIAL AND METHODS Fifty-seven patients who underwent surgery for recurrent lumbar disc herniation were divided into two groups based on the operative procedure. Thirty patients underwent microendoscopic transosseous discectomy (TD) and 27 underwent MED. We graded operative results and clinical outcomes using the Japanese Orthopaedic Association (JOA) score for low-back pain before surgery and 1 year after surgery and compared the scores of the two groups. RESULTS No conversion to open procedure was necessary in either group. The mean TD operative time was 89.2 minutes with a mean intraoperative blood loss of 16.5 mL. Mean MED operative time was 92.0 minutes with a mean blood loss of 19.3 mL. There were two dural tears in the MED group, and one tear was combined with a fracture of the inferior articular process. No dural tears occurred in the TD group. No patients in either group had experienced re-recurrence of lumbar disc herniation at the time of the last follow-up. The JOA score improved significantly after surgery in both groups (p < 0.001). CONCLUSION TD is a safe and effective surgical approach for the treatment of recurrent lumbar disc herniation. Operative time, intraoperative blood loss, and clinical results compare favorably with MED.

The effect of spinal shortening after total en bloc spondylectomy: a biomechanical study in the thoracic spine.

Study Design: A biomechanical study using human cadaveric thoracic spine specimens. Objective: To evaluate and compare the biomechanical effects of spinal shortening and cross‐links in reconstruction after total en bloc spondylectomy (TES). Summary of Background Data: There have been no studies that have examined the biomechanical effects of spinal reconstruction after multilevel TES or the biomechanical effects of spinal shortening in reconstruction after TES. Methods: Eight human cadaveric spines (T2‐T9) were used. After the intact specimen had been biomechanically tested to determine the stiffness in compression, flexion, extension, left and right lateral bending, and left and right axial rotation, a TES at T5‐6 was carried out. Three reconstruction methods were tested biomechanically (same as for the intact specimen) for their ability to restore stiffness to the specimen: (1) anterior short cage and multilevel posterior instrumentation at T3‐8 with 2 cross‐links (S2C), (2) anterior short cage and multilevel posterior instrumentation at T3‐8 with 1 cross‐link (S1C), and (3) anterior long cage and multilevel posterior instrumentation at T3‐8 with 2 cross‐links (L2C). A cage that was 6–10 mm shorter in height than the space created by the TES at T5‐6 was selected as the “short cage” and a cage 10 mm taller in height than the short cage was selected as the “long cage” in each specimen. Results: All 3 reconstruction methods using an anterior cage and multilevel posterior instrumentation provides a stiffer construct than that shown by the intact specimen. The reconstruction method using the 10‐mm shorter cage (S2C vs. L2C) provided more stiffness than the one using the longer cage. The reconstruction using 2 cross‐links (S2C vs. S1C) did not provide a stiffer construct than the one using 1 cross‐link. Conclusions: The reconstructions using an anterior cage and multilevel posterior instrumentation provided a stiffer construct than that shown by the intact specimen. The reconstruction using a 10‐mm shorter cage provided a stiffer construct than the reconstruction using the longer cage.