Takashi Kaito

Capillary Vessel Network Integration by Inserting a Vascular Pedicle Enhances Bone Formation in Tissue-Engineered Bone Using Interconnected Porous Hydroxyapatite Ceramics

The aim of the present study was to investigate the possibility of integrating porous hydroxyapatite (HA) ceramics with a capillary vessel network via insertion of a vascular pedicle, and to determine whether this procedure enhances new bone formation in tissue engineering of bone. First, synthetic interconnected porous HA (IP-CHA) was implanted subcutaneously into rat groin with or without insertion of superficial inferior epigastric vessels. At 6 weeks, IP-CHA with vascular insertion contained thick fibrous connective tissue with a number of large blood vessels that seemed to derive from the inserted vascular bundle. Next, IP-CHA loaded with recombinant human bone morphogenetic protein 2 (BMP, 2 or 10 microg/block) was implanted with or without vascular insertion. At 3 weeks, IP-CHA/BMP (10 microg) composite with vascular insertion exhibited abundant new bone formation in the pores of the deep portion close to the inserted vessels. In contrast, IP-CHA/BMP (10 microg) without vascular insertion showed poor bone formation. Histomorphometric analysis demonstrated that vascular insertion significantly increased new bone formation. In IP-CHAs with a lower dose of BMP (2 microg), no bone formation was found, with or without vascular insertion. These results suggest that the present system of integrating a vascular network with IP-CHA is a useful technique for bone tissue engineering.

Induction of early degeneration of the adjacent segment after posterior lumbar interbody fusion by excessive distraction of lumbar disc space

OBJECT Spinal fusion at the L4-5 disc space alters the normal biomechanics of the spine, and the loss of motion at the fused level is compensated by increased motion and load at the other unfused segments. This may lead to deterioration of the adjacent segments of the lumbar spine, called adjacent-segment disease (ASD). In this study, the authors investigate the distracted disc height of the fused segment, caused by cage or bone insertion during surgery, as a novel risk factor for ASD after posterior lumbar interbody fusion (PLIF). METHODS Radiographic L3-4 ASD is defined by development of spondylolisthesis greater than 3 mm, a decrease in disc height of more than 3 mm, or intervertebral angle at flexion smaller than -5 degrees . Symptomatic ASD is defined by a decrease of 4 points or more on the Japanese Orthopaedic Association scale. Eighty-five patients with L-4 spondylolisthesis treated by L4-5 PLIF underwent follow-up for more than 2 years (mean 38.8 +/- 17.1 months). The patients were divided into 3 groups according to the final outcome. Group A comprised those patients without ASD (58), Group B patients had radiographic ASD (14), and Group C patients had symptomatic ASD (13). RESULTS The L4-5 disc space distraction by cage insertion was 3.1 mm in the group without ASD, 4.4 mm in the group with radiographic ASD, and 6.2 mm in the group with symptomatic ASD, as measured using lateral spinal radiographs just after surgery. Multivariate analysis showed that distraction was the most significant risk factor. CONCLUSIONS The excessive distraction of the L4-5 disc space during PLIF surgery is a significant and potentially avoidable risk factor for the development of radiographic, symptomatic ASD.

Long-term results of cervical myelopathy due to ossification of the posterior longitudinal ligament with an occupying ratio of 60% or more.

Study Design. Retrospective study. Objective. We sought to determine the long-term outcomes of laminoplasty versus anterior decompression and fusion in the treatment of cervical myelopathy caused by ossification of the posterior longitudinal ligament (OPLL) and to ascertain what factors should be considered in selecting appropriate surgical procedure. Summary of Background Data. There are little data about long-term results of cervical myelopathy due to OPLL with an occupying ratio 60% or more. Methods. We retrospectively studied 27 patients having OPLL with an occupying ratio 60% or more and a follow-up period of at least 2 years. Clinical outcome was evaluated using Japanese Orthopaedic Association scores and recovery rates (≥75%, excellent; 50%–74%, good; 25%–50%, fair; and <25%, poor). Results. The mean age and the mean duration of follow-up were 57 years and 10.2 years. The mean Japanese Orthopaedic Association score was 9.3 before surgery and 12.4 at the final follow-up examination. There were 15 patients in the laminoplasty group (LAM group) and 12 patients in the anterior decompression and fusion group (ADF group). The ADF group had a significantly better recovery rate at final evaluation (53% vs. 30%; P = 0.04), a longer duration of surgery (314 vs. 128 min; P < 0.01), and greater blood loss (600 vs. 240 mL; P < 0.01) than did the LAM group. In the LAM group, 4 patients with excellent or good results had a significantly larger degree of cervical lordosis (30°vs. 10°; P = 0.002) than others. Conclusion. The ADF group had a significantly better recovery rate than the LAM group, although the degree of surgical invasiveness was high. ADF is generally recommended for OPLL with an occupying ratio 60% or more. Level of Evidence: 3

A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common spinal disorder among the elderly that causes myelopathy and radiculopathy. To identify genetic factors for OPLL, we performed a genome-wide association study (GWAS) in ∼8,000 individuals followed by a replication study using an additional ∼7,000 individuals. We identified six susceptibility loci for OPLL: 20p12.3 (rs2423294: P = 1.10 × 10−13), 8q23.1 (rs374810: P = 1.88 × 10−13), 12p11.22 (rs1979679: P = 4.34 × 10−12), 12p12.2 (rs11045000: P = 2.95 × 10−11), 8q23.3 (rs13279799: P = 1.28 × 10−10) and 6p21.1 (rs927485: P = 9.40 × 10−9). Analyses of gene expression in and around the loci suggested that several genes are involved in OPLL etiology through membranous and/or endochondral ossification processes. Our results bring new insight to the etiology of OPLL.

Neurological complications of cervical laminoplasty for patients with ossification of the posterior longitudinal ligament - A multi-institutional retrospective study

Study Design. Retrospective multi-institutional study. Objective. To investigate the incidence of neurological deficits after cervical laminoplasty for ossification of the posterior longitudinal ligament (OPLL). Summary of Background Data. According to analysis of long-term results, laminoplasty for cervical OPLL has been reported as a safe and effective alternative procedure with few complications. However, perioperative neurological complication rates of laminoplasty for cervical OPLL have not been well described. Methods. Subjects comprised 581 patients (458 men and 123 women; mean age: 62 ± 10 years; range: 30–86 years) who had undergone laminoplasty for cervical OPLL at 27 institutions between 2005 and 2008. Continuous-type OPLL was seen in 114, segmental-type in 146, mixed-type in 265, local-type in 24, and not judged in 32 patients. Postoperative neurological complications within 2 weeks after laminoplasty were analyzed in detail. Cobb angle between C2 and C7 (C2/C7 angle), maximal thickness, and occupying rate of OPLL were investigated. Pre- and postoperative magnetic resonance imaging was performed on patients with postoperative neurological complications. Results. Open-door laminoplasty was conducted in 237, double-door laminoplasty in 311, and other types of laminoplasty in 33 patients. Deterioration of lower-extremity function occurred after laminoplasty in 18 patients (3.1%). Causes of deterioration were epidural hematoma in 3, spinal cord herniation through injured dura mater in 1, incomplete laminoplasty due to vertebral artery injury while making a trough in 1, and unidentified in 13 patients. Prevalence of unsatisfactory recovery not reaching preoperative level by 6-month follow-up was 7/581 (1.2%). Mean occupying rate of OPLL for patients with deteriorated lower-extremity function was 51.2 ± 13.6% (range, 21.0%–73.3%), significantly higher than the 42.3 ± 13.0% for patients without deterioration. OPLL thickness was also higher in patients with deterioration (mean, 6.6 ± 2.2 mm) than in those without deterioration (mean, 5.7 ± 2.0 mm). No significant difference in C2/C7 lordotic angle was seen between groups. Conclusion. Although most neurological deterioration can be expected to recover to some extent, the frequency of short-term neurological complications was higher than the authors expected.

Perioperative complications of primary posterior lumbar interbody fusion for nonisthmic spondylolisthesis: analysis of risk factors

OBJECT Although posterior lumbar interbody fusion (PLIF) is an excellent procedure to attain circumferential decompression, it is technically demanding and can lead to various surgical complications. The authors retrospectively reviewed consecutive patients with nonisthmic spondylolisthesis who underwent PLIF to reveal the incidence and risk factors for perioperative complications of PLIF. METHODS A total of 240 patients underwent PLIF. The fusion level was at L4-5 in 220, L3-4 in 18, and L5-S1 in 2. The medial walls of the fusion segments facet joints were resected, and the VSP Spine System was used for the pedicle screw instrumentation. The operations were performed by 7 surgeons, who were divided into 4 groups according to their level of experience with spinal surgery. RESULTS The average operation time was 175 +/- 49 minutes, and the estimated blood loss was 746 +/- 489 ml. A total of 90 patients (37.5%) experienced complications; 41 (17%) experienced transient neurological complications, and 18 (7.5%) experienced permanent neurological complications. The mean neurological score according to the Japanese Orthopaedic Association improved from 14.3 +/- 3.8 to 24.7 +/- 4.0 in the patients without complications and from 14.8 +/- 3.6 to 24.0 +/- 3.9 in the patients with complications. Multivariate analysis concerning the relationship between complications and risk factors (operation time, estimated intraoperative blood loss, and surgeon experience) revealed that operation time was the only significant risk factor for complications. CONCLUSIONS Perioperative complications of PLIF were more frequent in this homogeneous study group than in other studies of various implants. Total excision of the facet joints might preclude neurological complications.

Effect of Biological Agents on Cervical Spine Lesions in Rheumatoid Arthritis

Study Design. A retrospective cohort analysis. Objective. To determine the effect of biological agents (BAs) on the development and progression of cervical spine lesions and identify predictors of lesion progression. Summary of Background Data. The introduction of BAs has facilitated advances in the treatment of rheumatoid arthritis (RA). BAs reduce disease activity and limit structural joint damage. However, the effect of BAs on cervical spine lesions remains unclear. Methods. Thirty-eight subjects who received more than 2 years of continuous BA treatment were enrolled. The mean x-ray interval was 4.4 years. RA activity was evaluated by disease activity score (DAS)-C reactive protein (CRP) and matrix metalloproteinase (MMP)-3. Radiographical definitions of cervical lesions were atlanto-dental interval (ADI) more than 3 mm for atlanto-axial subluxation (AAS), Ranawat value less than 13 mm for vertical subluxation (VS), and anterior or posterior listhesis more than 2 mm for subaxial subluxation (SS). Definitions of radiographical progression were an increase of ADI more than 2 mm for AAS, a decrease of both Ranawat and Redlund-Johnell values more than 2 mm for VS, and an increase of listhesis more than 2 mm for SS. Results. RA activity responded dramatically to BA therapy (DAS-CRP from 4.3 to 2.3, P < 0.01; MMP-3 from 207.9 ng/mL to 105.6 ng/mL, P < 0.01). Baseline radiographical evaluation showed no pre-existing cervical spine lesions in 12 cases, AAS in 15 cases, and VS in 11 cases. Radiological progression was found in 1 (8%) patient in the no lesion group, 12 patients (80%) in the AAS group, and 9 patients (80%) in the VS group. The incidence of progression was significantly lower in the no lesion group compared with the other groups. Multivariate regression analysis showed that the presence of pre-existing cervical lesions was the single greatest predictor of progression. Conclusion. BAs prevented the development of de novo cervical spine lesions in patients with RA, but failed to inhibit progression of pre-existing RA lesions.

Postoperative displacement of hydroxyapatite spacers implanted during double-door laminoplasty

OBJECT Double-door laminoplasty using hydroxyapatite (HA) spacers has been widely performed for compressive cervical myelopathy and has provided good neurological outcome. Although HA spacers are used for preventing reclosure of the opened laminae, they are often displaced or dislocated from their original position. The authors investigated the incidence and patterns of postoperative HA spacer displacement to determine the reasons for this unfavorable event. METHODS Eighty-six patients with compressive myelopathy underwent double-door laminoplasty in which a total of 278 HA spacers were used. The displacement of HA spacers and opened laminae were assessed using postoperative lateral radiographs and CT scans. RESULTS Postoperative dorsal migration > 2 mm was found in 116 (42%) of 278 implanted HA spacers. In addition, 33 (38%) of 86 HA spacers rotated > 10 degrees and 29 (34%) of the 86 opened laminae tilted > 10 degrees. Moreover, deformation of the newly formed spinal canal was observed in 51 (59%) of 86 cases, and bone fusion between the HA spacer and spinous process was achieved in only 15 (8.7%) of 172 cases. Neurological worsening and neck pain, however, were not associated with displacement of HA spacers or deformation of the spinal canal. CONCLUSIONS In double-door laminoplasty, postoperative displacement of the HA spacer with deformation of the enlarged spinal canal occurred frequently. Hydroxyapatite spacers tend to become displaced after surgery. Placing the HA spacer at the base of the spinous process close to the dura mater may prevent postoperative displacement.

Effect of Intermittent Administration of Teriparatide (Parathyroid Hormone 1-34) on Bone Morphogenetic Protein-Induced Bone Formation in a Rat Model of Spinal Fusion.

BACKGROUND Although clinical bone morphogenetic protein (BMP) therapy is effective at enhancing bone formation in patients managed with spinal arthrodesis, the required doses are very high. Teriparatide (parathyroid hormone 1-34) is approved by the U.S. Food and Drug Administration to treat osteoporosis and is a potent anabolic agent. In this study, intermittent administration of parathyroid hormone 1-34 combined with transplantation of BMP was performed to elucidate the effect of parathyroid hormone 1-34 on the fusion rate and quality of newly formed bone in a rat model. METHODS A total of forty-eight male Sprague-Dawley rats underwent posterolateral lumbar spinal arthrodesis with one of three different treatments with recombinant human (rh) BMP-2: (1) 0 μg (control), (2) 2 μg (low dose), or (3) 50 μg (high dose). Each of the rhBMP-2 treatments was studied in combination with intermittent injections of either parathyroid hormone 1-34 (180 μg/kg/wk) or saline solution starting two weeks before the operation and continuing until six weeks after the operation. Osseous fusion was assessed with use of radiographs and a manual palpation test. Microstructural indices of the newly formed bone were evaluated with use of micro-computed tomography. The serum markers of bone metabolism were also quantified. RESULTS The fusion rate in the group treated with 2 μg of rhBMP-2 significantly increased (from 57% to 100%) with the administration of parathyroid hormone 1-34 (p < 0.05). The fusion rates in the other groups did not change significantly with the administration of parathyroid hormone 1-34. The bone volume density of the newly formed bone significantly increased in both the 2-μg and 50-μg rhBMP-2 treatment groups with the administration of parathyroid hormone 1-34 (p < 0.01). Micro-computed tomography scans of the newly formed bone clearly demonstrated an abundance of trabecular bone formation in the group treated with parathyroid hormone 1-34. In addition, serum levels of osteocalcin were significantly increased in the parathyroid hormone 1-34 treatment group. CONCLUSIONS Intermittent administration of parathyroid hormone 1-34 significantly increased fusion rates in the group treated with low-dose rhBMP-2, and it improved the quality of the newly formed bone in both the high and low-dose groups in a rat model of rhBMP-2-induced spinal fusion. CLINICAL RELEVANCE Our results suggest that the combined administration of rhBMP-2 and parathyroid hormone 1-34 may lead to efficient bone regeneration.

Synergistic effect of bone morphogenetic proteins 2 and 7 by ex vivo gene therapy in a rat spinal fusion model.

BACKGROUND Previous studies have suggested that the co-expression of two different bone morphogenetic protein (BMP) genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP-2 and BMP-7 gene transfer was performed ex vivo to compare the resulting new bone formation with that of single-BMP gene transfer in a rat spinal fusion model. METHODS Forty-four athymic rats underwent posterolateral fusion at L4-L5 and were implanted with a collagen sponge containing human adipose-derived stem cells. Group A received untreated cells, and the remaining groups received cells transfected with various genes in a lentivirus vector. The transferred genes were GFP (green fluorescent protein) in Group B, BMP-2 in Group C, BMP-7 in Group D, and both BMP-2 and BMP-7 in Group E. In vitro production of BMP-2 and BMP-7 was quantified by means of an enzyme-linked immunosorbent assay (ELISA) specific to BMP-2 or BMP-7. Osseous fusion was quantified with use of radiography and microcomputed tomography. RESULTS ELISA demonstrated that Group E, which was treated with both BMP-2 and BMP-7, produced less than one-fourth as much BMP as the groups treated with a single transfected BMP (Groups C and D). Radiographs showed that all of the spines in Groups C, D, and E appeared to be fused by eight weeks; the spines in Groups A and B showed minimal evidence of new bone formation. Measurements confirmed that the mean bone formation area was significantly greater in Groups C, D, and E compared with Groups A and B (p < 0.001). In addition, the bone formation area was significantly greater in Group E compared with Groups C and D (p < 0.001). CONCLUSIONS Combined BMP-2 and BMP-7 ex vivo gene transfer was found to be significantly more effective for inducing new bone formation compared with ex vivo gene transfer of an individual BMP in a rat spinal fusion model. CLINICAL RELEVANCE Combined BMP-2 and BMP-7 therapy may lead to efficient bone regeneration.