Tsuyoshi Yamada

Hybrid grafting using bone marrow aspirate combined with porous β-tricalcium phosphate and trephine bone for lumbar posterolateral spinal fusion: a prospective, comparative study versus local bone grafting.

Study Design. A prospective, comparative study. Objective. We developed a hybrid graft (HBG) of porous &bgr;-tricalcium phosphate ceramics/percutaneously harvested bone sticks/autologous bone marrow aspirate for lumbar posterolateral fusion (PLF). The aim of this study was to investigate the efficacy of the HBG as a substitute for conventional corticocancellous iliac autografts. Summary of Background Data. Iliac crest bone graft (ICBG) has been traditionally used as the golden standard for lumbar spinal fusion. The significant complication rate associated with harvesting corticocancellous ICBG, however, has encouraged development of alternative graft substitutes. Methods. From September 2005, 61 consecutive patients underwent decompressive laminotomy and 1-level instrumented PLF. Each patient in this study had the constructs of the HBG placed on 1 side of the intertransverse process gutter. An autologous local bone graft (LBG) harvested during decompressive laminotomy was placed on the other side as a control. Radiographic evaluation was performed at 6 months, 1 year after surgery, and subsequently on an annual basis. The fusion statuses on either side of vertebra were compared. Results. The flexion-extension motion in the dynamic x-rays at the target level decreased over time. Only 1 case exhibited over 5° of angular motion 2 years after surgery. In the evaluation of fusion status, the fusion rate for the HBG side (68.9% at 6 months, 83.6% at 1 year, 93.5% at 2 years) was higher than that for the LBG side (49.2% at 6 months, 75.4% at 1 year, 89.1% at 2 years) with a significant difference at 6 months after surgery. No significant complications at the donor site were found postoperatively. Conclusion. The HBG promoted posterolateral spinal fusion without significant donor site morbidity. Because of its efficacy and safety, this hybrid construct seems promising as an alternative to conventional iliac bone grafts for lumbar spinal fusion.

Dexamethasone Enhances Osteogenic Differentiation of Bone Marrow- and Muscle-Derived Stromal Cells and Augments Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2

We evaluated whether dexamethasone augments the osteogenic capability of bone marrow-derived stromal cells (BMSCs) and muscle tissue-derived stromal cells (MuSCs), both of which are thought to contribute to ectopic bone formation induced by bone morphogenetic protein-2 (BMP-2), and determined the underlying mechanisms. Rat BMSCs and MuSCs were cultured in growth media with or without 10-7 M dexamethasone and then differentiated under osteogenic conditions with dexamethasone and BMP-2. The effects of dexamethasone on cell proliferation and osteogenic differentiation, and also on ectopic bone formation induced by BMP-2, were analyzed. Dexamethasone affected not only the proliferation rate but also the subpopulation composition of BMSCs and MuSCs, and subsequently augmented their osteogenic capacity during osteogenic differentiation. During osteogenic induction by BMP-2, dexamethasone also markedly affected cell proliferation in both BMSCs and MuSCs. In an in vivo ectopic bone formation model, bone formation in muscle-implanted scaffolds containing dexamethasone and BMP-2 was more than two fold higher than that in scaffolds containing BMP-2 alone. Our results suggest that dexamethasone potently enhances the osteogenic capability of BMP-2 and may thus decrease the quantity of BMP-2 required for clinical application, thereby reducing the complications caused by excessive doses of BMP-2. Highlights: 1. Dexamethasone induced selective proliferation of bone marrow- and muscle-derived cells with higher differentiation potential. 2. Dexamethasone enhanced the osteogenic capability of bone marrow- and muscle-derived cells by altering the subpopulation composition. 3. Dexamethasone augmented ectopic bone formation induced by bone morphogenetic protein-2.

Repair of Osteochondral Defects in a Rabbit Model Using a Porous Hydroxyapatite Collagen Composite Impregnated With Bone Morphogenetic Protein-2

Articular cartilage has a limited capacity for spontaneous repair, and an effective method to repair damaged articular cartilage has not yet been established. The purpose of this study was to evaluate the effect of transplantation of porous hydroxyapatite collagen (HAp/Col) impregnated with bone morphogenetic protein-2 (BMP-2). To evaluate the characteristics of porous HAp/Col as a drug delivery carrier of recombinant human BMP-2 (rhBMP-2), the rhBMP-2 adsorption capacity and release kinetics of porous HAp/Col were analyzed. Porous HAp/Col impregnated with different amounts of rhBMP-2 (0, 5, and 25 μg) was implanted into osteochondral defects generated in the patellar groove of Japanese white rabbits to evaluate the effect on osteochondral defect regeneration. At 3, 6, 12, and 24 weeks after operation, samples were harvested and subjected to micro-computed tomography analysis and histological evaluation of articular cartilage and subchondral bone repair. The adsorption capacity was 329.4 μg of rhBMP-2 per cm(3) of porous HAp/Col. Although 36% of rhBMP-2 was released within 24 h, more than 50% of the rhBMP-2 was retained in the porous HAp/Col through the course of the experiment. Defects treated with 5 μg of rhBMP-2 showed the most extensive subchondral bone repair and the highest histological regeneration score, and differences against the untreated defect group were significant. The histological regeneration score of defects treated with 25 μg of rhBMP-2 increased up to 6 weeks after implantation, but then decreased. Porous HAp/Col, therefore, is an appropriate carrier for rhBMP-2. Implantation of porous HAp/Col impregnated with rhBMP-2 is effective for rigid subchondral bone repair, which is important for the repair of the smooth articular surface.

Modified K-line in magnetic resonance imaging predicts insufficient decompression of cervical laminoplasty.

Study Design. A retrospective single-center study. Objective. To clarify preoperative factors predicting unsatisfactory indirect decompression after laminoplasty in patients with cervical spondylotic myelopathy. Summary of Background Data. Many authors have shown that inadequate indirect decompression after laminoplasty can inhibit neural recovery and should be considered a complication. We previously demonstrated that residual anterior compression of the spinal cord (ACS) impaired recovery of upper extremity motor function. Although the K-line has been established as a predictive index indicating that laminoplasty is required in patients with ossification of the posterior longitudinal ligament, it remains unclear what preoperative factors can predict insufficient posterior cord decompression in patients with cervical spondylotic myelopathy. Methods. Forty-six consecutive patients who underwent laminoplasty for the treatment of cervical spondylotic myelopathy at our hospital were reviewed. A modified K-line was defined as the line connecting the midpoints of the spinal cord at C2 and C7 on a T1-weighted sagittal magnetic resonance image. We also determined the minimum interval between the tip of local kyphosis and a line connecting the midpoint of the cord at the level of the inferior endplates of C2 and C7 (INTmin) on the midsagittal image. Data analysis involved logistic regression and receiver operating characteristic curve analysis to select the most valuable index for predicting postoperative ACS. Results. Ten patients had ACS immediately after laminoplasty. Logistic regression analysis showed that INTmin was a significant predictive factor for the occurrence of postoperative ACS (odds ratio = 0.485; 95% confidence interval = 0.29–0.81; P = 0.02). Receiver operating characteristic curve analysis showed an area under the curve of 0.871. A cutoff of 4.0 mm had a sensitivity of 80% and a specificity of 80.6% for prediction of postoperative ACS. Conclusion. The parameter INTmin correlated with the occurrence of postoperative ACS. A cutoff point of 4.0 mm is most appropriate for alerting spine surgeons to a high likelihood of postoperative ACS.

Modified K-line in magnetic resonance imaging predicts clinical outcome in patients with nonlordotic alignment after laminoplasty for cervical spondylotic myelopathy.

Study Design. Retrospective single-center study. Objective. To investigate whether a preoperative index predicts clinical outcome after laminoplasty for cervical spondylotic myelopathy. Summary of Background Data. This is the first study using the modified K-line, which connects the midpoints of the spinal cord at the C2 and C7 levels on midsagittal magnetic resonance imaging, to assess the relationship between postoperative clinical outcome and anticipated degree of spinal cord shifting. Methods. Sixty-one consecutive patients who underwent laminoplasty for the treatment of cervical spondylotic myelopathy between 2000 and 2011 at our hospital were retrospectively reviewed. The interval between the preoperative mK-line and the anterior structure of the spinal canal at each segment of the C3 to C6 levels (INTn, n = 3–6) were measured on sagittal T1-weighted magnetic resonance imaging, and the sum of the INTn (INTsum) was then calculated. The degree of posterior cord shift was defined as follows: %Csum = &Sgr;Cn; Cn = (Bn−An) × 100/An (n = 3–6; An and Bn represent the preoperative and postoperative intervals between the midpoint of the spinal cord and the anterior impingement at each segment on sagittal T1-weighted magnetic resonance imaging, respectively). In addition, we defined INTmin as the minimum interval of the INTn in each patient. All patients were divided into lordotic and nonlordotic groups on the basis of lateral neutral radiography. The Japanese Orthopaedic Association (JOA) scoring system and recovery rate of the JOA score for cervical myelopathy was evaluated as clinical outcomes. Results. The recovery rate of the JOA score was 48.1%. The lordotic and nonlordotic groups contained 38 and 23 patients, respectively. Linear regression analysis revealed that INTmin was significantly correlated with the recovery rate of the patients in the nonlordotic group, whereas INTsum was not associated with recovery of the JOA score. Conclusion. We identified INTmin as a predictive factor for clinical outcomes in patients with nonlordotic alignment after laminoplasty. Level of Evidence: 4

Bone Defect Regeneration by a Combination of a β-Tricalcium Phosphate Scaffold and Bone Marrow Stromal Cells in a Non-Human Primate Model

Background: Reconstruction of large bone defects is a great challenge in orthopedic research. In the present study, we prepared composites of bone marrow-derived stromal cells (BMSCs) and β-tricalcium phosphate (β-TCP) with three novel aspects: proliferation of BMSCs with continuous dexamethasone treatment, cell loading under low pressure, and use of autologous plasma as the cell loading medium. The effectiveness of the resulting composite for large bone-defect reconstruction was tested in a non-human primate model, and the bone union capability of the regenerated bones was examined. Materials and Methods: Primary surgery: Bone defects (5 cm long) were created in the left femurs of nine cynomolgus monkeys with resection of the periosteum (five cases) or without resection (four cases), and porous β-TCP blocks were transplanted into the defects. Secondary surgery: Bone marrow aspirates harvested from seven of the nine monkeys were cultured with dexamethasone, and BMSCs were obtained. BMSCs were suspended in autologous plasma and introduced into a porous β-TCP block under low-pressure conditions. The BMSC/β-TCP composites were transplanted into bone defects created at the same sites as the primary surgery. Bone union evaluation: Five regenerated femurs were shortened by osteotomy surgery 8 to 15 months after transplantation of the β-TCP/BMSC composites, and bone union was evaluated radiographically. Results: After the primary surgery and treatment with β-TCP alone, one of the five periosteum-resected monkeys and two of the four periosteum-preserved monkeys exhibited successful bone reconstruction. In contrast, five of the seven cases treated with the β-TCP/MSC composite showed successful bone regeneration. In four of the five osteotomy cases, bone union was confirmed. Conclusion: We validated the effectiveness of a novel β-TCP/BMSC composite for large bone defect regeneration and confirmed the bone union capability of the regenerated bone.

Porous/dense Composite Hydroxyapatite for Anterior Cervical Discectomy and Fusion

Study Design. A prospective analysis Objective. Our aim was to investigate the efficacy of new synthetic porous/dense composite hydroxyapatite (HA) for use in anterior cervical discectomy and fusion (ACDF). Summary of Background Data. Iliac crest bone graft (ICBG) has been traditionally used as the “gold standard” for ACDF. The significant complication rate associated with harvesting tricortical ICBG, however, has encouraged development of alternative graft substitutes. Methods. The morphology of the porous/dense HA was observed by scanning electron microscopy (SEM), and the in vitro compressive strength of the composite HA was measured. From April 2005, 51 consecutive patients underwent 81 levels of ACDF using the composite HA with percutaneously harvested trephine bone chips. Clinical and radiological evaluation was performed during the postoperative hospital stay and at follow-up. Furthermore, the outcomes in ACDF using the composite HA were compared with those using tricortical ICBG. Results. The SEM images demonstrated 100- to 300-&mgr;m pores (approximately 40% of porosity) in the porous layers of the HA. The compressive strength of the composite HA was 203.1 ± 4.1 MPa. In the clinical study, the demographic data of the patients were similar in HA and ICBG groups. The fusion rates in HA group were comparable with those in ICBG group. The cervical lordosis was enhanced postoperatively in both groups and well preserved at 2-year follow-up without significant differences between the groups. The intraoperative blood loss in HA group was significantly lesser than that in ICBG group. Donor site complications were found in 29.2% of the patients in ICBG group, whereas no donor site morbidity was found in HA group. No major collapse or fragmentation of the composite HA was found. Conclusion. The hybrid graft of composite HA and percutaneously harvested trephine chips seemed promising as a graft substitute for ACDF. Level of Evidence: 4

Prevalence and Distribution of Ossified Lesions in the Whole Spine of Patients with Cervical Ossification of the Posterior Longitudinal Ligament A Multicenter Study (JOSL CT study).

Ossification of the posterior longitudinal ligament (OPLL) can cause severe and irreversible paralysis in not only the cervical spine but also the thoracolumbar spine. To date, however, the prevalence and distribution of OPLL in the whole spine has not been precisely evaluated in patients with cervical OPLL. Therefore, we conducted a multi-center study to comprehensively evaluate the prevalence and distribution of OPLL using multi-detector computed tomography (CT) images in the whole spine and to analyze what factors predict the presence of ossified lesions in the thoracolumbar spine in patients who were diagnosed with cervical OPLL by plain X-ray. Three hundred and twenty-two patients with a diagnosis of cervical OPLL underwent CT imaging of the whole spine. The sum of the levels in which OPLL was present in the whole spine was defined as the OP-index and used to evaluate the extent of ossification. The distribution of OPLL in the whole spine was compared between male and female subjects. In addition, a multiple regression model was used to ascertain related factors that affected the OP-index. Among patients with cervical OPLL, women tended to have more ossified lesions in the thoracolumbar spine than did men. A multiple regression model revealed that the OP-index was significantly correlated with the cervical OP-index, sex (female), and body mass index. Furthermore, the prevalence of thoracolumbar OPLL in patients with a cervical OP-index ≥ 10 was 7.8 times greater than that in patients with a cervical OP-index ≤ 5. The results of this study reveal that the extent of OPLL in the whole spine is significantly associated with the extent of cervical OPLL, female sex, and obesity.

After repeated division, bone marrow stromal cells express inhibitory factors with osteogenic capabilities, and EphA5 is a primary candidate

The differentiation capability of human bone marrow stromal cells (hBMSCs) is thought to deteriorate over multiple doubling processes. To clarify the deterioration mechanisms, the multilineage differentiation capabilities of short- and long-term passaged BMSCs were compared. Predictably, long-term passaged BMSCs showed reduced differentiation capacities compared to short-term passaged cells. Furthermore, a non-human primate heterotopic bone formation model demonstrated that long-term passaged BMSCs have bone formation capabilities but also exert inhibitory effects on bone formation. This finding indicated that long-term passaged BMSCs express higher levels of inhibitory factors than short-term passaged BMSCs do. Co-culture assays of short- and long-term passaged BMSCs suggested that the inhibitory signals required cell-cell contact and would therefore be expressed on the cell membrane. A microarray analysis of BMSCs identified ephrin type-A receptor 5 (EphA5) as an inhibitory factor candidate. Quantitative PCR revealed that among all members of the ephrin and Eph receptor families, only the expression of EphA5 was increased by BMSC proliferation. A gene knockdown analysis using siRNAs demonstrated that knockdown of EphA5 gene expression in long-term passaged BMSCs led to an increase in ALP mRNA expression. These results indicate that EphA5 may be a negative regulator of bone formation. A better understanding of the roles of the ephrin and Eph receptor families in hBMSCs may lead to alternative approaches for manipulating hBMSC fate. In addition, this avenue of discovery may provide new therapeutic targets and quality-control markers of the osteogenic differentiation capabilities of hBMSCs.

Anterior decompression with fusion versus posterior decompression with fusion for massive cervical ossification of the posterior longitudinal ligament with a ≥50% canal occupying ratio: a multicenter retrospective study.

BACKGROUND CONTEXT Previous studies have shown that compared with laminoplasty, anterior decompression with fusion (ADF) is superior for postoperative neurologic improvement in patients with massive cervical ossification of the posterior longitudinal ligament (OPLL) with a ≥50% canal occupying ratio. However, it is unknown which method, ADF or posterior decompression with fusion (PDF), is more effective for the treatment of massive OPLL. PURPOSE This study aimed to investigate the surgical outcomes of ADF and PDF for the treatment of massive OPLL. STUDY DESIGN A multicenter retrospective case-control study was carried out. PATIENT SAMPLE A total of 61 OPLL patients with a ≥50% canal occupying ratio were included in this study. The mean age of the patients was 60.9 years (49 males and 12 females); 39 patients (31 males and 8 females, average age 61.1 years) underwent ADF, and 22 patients underwent PDF (18 males and 4 females, average age 60.6 years). OUTCOME MEASURES The data collected from both groups included age, gender, neurologic symptoms evaluated based on the Japanese Orthopedic Association score, neck pain assessed using the visual analogue scale, and radiographic parameters, including cervical lordosis and the OPLL canal occupying ratio. METHODS Clinical and radiological outcomes were compared between the ADF and PDF groups with a minimum of 2 years follow-up. RESULTS There were no significant differences in the postoperative neurologic recovery rate between the two groups. However, in patients with kyphotic alignment (C2-C7 angle <0 degrees), the recovery rate was higher in the ADF group. Postoperative cervical pain was greater in the PDF group. The improvement in cervical alignment at C2-C7 was greater in the ADF group. The operating time was longer in the ADF group, whereas the intraoperative blood loss was greater in the PDF group. Approach-related complications were more frequently observed in the ADF group than in the PDF group. CONCLUSIONS The present study demonstrated that the postoperative recovery rate was similar in the ADF and PDF group. In patients with massive OPLL with kyphotic alignment, neurologic recovery rate in the ADF was superior to that in the PDF (in situ fusion). Additionally, postoperative neck pain was less severe in the ADF group. However, the occurrence of perioperative complications was more common in the ADF group.