Joel Delecrin

Induction of Osteogenesis in Mesenchymal Stem Cells by Activated Monocytes/Macrophages Depends on Oncostatin M Signaling†‡§

Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein, and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high‐throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL‐6 family, as a major coupling factor produced by activated circulating CD14+ or bone marrow CD11b+ monocytes/macrophages that induce osteoblast differentiation and matrix mineralization from human mesenchymal stem cells while inhibiting adipogenesis. Upon activation of toll‐like receptors (TLRs) by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase‐2 and prostaglandin‐E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR, or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of CCAAT‐enhancer‐binding protein δ, Cbfa1, and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines have also a potent role in bone formation induced by monocytes/macrophages and activation of TLRs: IL‐6 and leukemia inhibitory factor. We propose that during bone inflammation, infection, or injury, the IL‐6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies. STEM CELLS 2012; 30:762–772

Macroporous biphasic calcium phosphate ceramics: influence of five synthesis parameters on compressive strength.

Compressive strength measurements were conducted on 32 macroporous biphasic calcium phosphate (MBCP) samples to evaluate the influences and interactions of five synthesis factors: chemical composition, percentage of macropores, mean size of macropores, isostatic compaction pressure, and sintering temperature. These parameters were varied simultaneously between two limit levels. Experiments used a factorial design method (FDM) allowing optimization of the number of samples as well as statistical analysis of results. FDM showed that compressive strength, in a defined experimental area, can be described by a first-order polynomial equation in which the percentage of macroporosity and sintering temperature are the major influences. This study leads up to an isoresponse line diagram that will allow the manufacture of some classes of MBCP with fitted compressive strength.

A synthetic porous ceramic as a bone graft substitute in the surgical management of scoliosis: A prospective, randomized study

STUDY DESIGN A prospective randomized study. OBJECTIVES To assess the clinical and radiologic performances of a synthetic ceramic as a bone graft substitute in scoliosis surgery. SUMMARY OF BACKGROUND DATA Surgery on the skeleton frequently requires harvesting of autogenous bone grafts from the pelvis, but this procedure often is complicated by problems. METHODS Fifty-eight patients with idiopathic scoliosis, ages 13 to 25 years, were treated by posterior correction and arthrodesis using Cotrel-Dubousset instrumentation. Posterior spinal fusion was performed using local bone grafts combined with autogenous iliac bone grafts in 30 patients, and combined with porous biphasic calcium phosphate ceramic blocks comprising hydroxyapatite and tricalcium phosphate in another 28 patients. The patients were observed for a minimum of 24 months after surgery, with a mean postoperative observation time of 48 months. The results were assessed clinically and radiographically. RESULTS Patients in the ceramic group had a lower average blood loss than those in the iliac graft group. They also were free from postoperative local complications in the iliac region, which were experienced by a significantly high proportion of patients belonging to the iliac graft group. Radiography demonstrated successful incorporation of the ceramic blocks within 12 months. The correction of the deformity was maintained similarly and satisfactorily in both groups. CONCLUSIONS These results justify and favor the use of calcium phosphate ceramics as bone graft substitutes for instrumented posterior spinal fusion in teenagers and young adults. Potentially hazardous harvesting of pelvic bone is no longer necessary for such operations.

Surgical Treatment of Idiopathic Scoliosis in Adults : An Age-Related Analysis of Outcome

Study Design. A retrospective outcome study was conducted. Objective. To analyze the clinical and radiographic outcome of surgical treatment for idiopathic scoliosis in patients treated at the age of 20 years or older. Summary of Background Data. Idiopathic scoliosis continues to pose problems in many patients after adolescence. Surgical treatment of idiopathic scoliosis in adults still is a challenging subject, but no outcome analysis in terms of different age groups had been performed. Methods. In this study, 58 adult patients with idiopathic scoliosis who underwent surgery using Cotrel–Dubousset instrumentation were followed up for 2 to 7 years, and the results were studied clinically and radiographically. Results. The prevalence of pain that requires specific treatment decreased from 16% to 5%, and the pain improvement was reliably obtained in the older patients. Radiographically, the mean rate of Cobb angle correction was 53% for both the thoracic and lumbar curves, whereas it decreased age dependently, especially in relation to the thoracic curve. The sagittal plane correction generally was satisfactory in patients younger than 50 years, but appropriate lumbar lordosis was difficult to maintain after the age of 50 years. Frontal and sagittal balance often was difficult to achieve in patients older than 50 years. Conclusions. This study clarified specific characteristics and problems in the surgical treatment of adult idiopathic scoliosis according to different age groups. Although pain was the most important indication for surgery in patients older than 40 years, it was improved reliably by surgery in most of these patients. On the other hand, the radiographic results tended to be less satisfactory in the older patients in an age-dependent manner. These results provide useful information concerning the indications and strategies of adult scoliosis surgery.

Changes in the unfused lumbar spine in patients with idiopathic scoliosis. A 5- to 9-year assessment after cotrel-dubousset instrumentation.

Study Design. Postoperative changes in the lumbar spine were studied retrospectively in patients with adolescent idiopathic scoliosis who had been treated with Cotrel‐Dubousset instrumentation. Objective. To examine middle‐term changes in the unfused lumbar segments below an instrumented scoliosis fusion. Summary of Background Data. Scoliosis fusion by the Harrington method is known to be associated with a flat back in the fused area and subsequent degenerative changes in the segments below the fusion. No data have yet been published concerning a segmental instrumentation system. Patients and Methods. Thirty patients with idiopathic scoliosis, between the ages of 14 and 22 years at the time of surgery, were observed for 5–9 years after surgery. Activity, pain, complications, and 21 radiographic parameters were assessed. Results. The prevalence of low back pain increased from 3% before surgery to 20% at the final follow‐up visit, although in none of the patients was the pain so severe that specific treatment was required. Radiographically, uninstrumented lumbar segments generally were realigned successfully in the frontal plane. Analyses in the sagittal plane revealed tendencies to a gradual increase in lumbar lordosis, anterior‐upward tilting of the lowest instrumented vertebra, and posterior shift of the sagittal spinal balance. During the follow‐up period, seven patients (23%) developed degenerative changes, including mild junctional kyphosis, retrolisthesis, narrowing of disc spaces, or osteophytes. Conclusion. Whereas the overall clinical and radiographic results of surgery were satisfactory, the unfused lumbar segments required careful surveillance, especially in the sagittal plane.

Combined spinal cord monitoring using neurogenic mixed evoked potentials and collision techniques

Study Design. Neurogenic mixed evoked potentials are used routinely to monitor the spinal cord during spine surgery. This study investigates the differential sensory–motor contribution by using collision techniques. Objective. To demonstrate that neurogenic mixed evoked potentials do contain a motor component. Summary of Background Data. Spinal cord monitoring is now routinely used during spine deformity surgery. Neurogenic mixed evoked potentials (i.e., potentials recorded from lower limb nerves after spinal cord stimulation) represent a reliable and sensitive technique. However, their specificity (sensory and motor spinal pathways) remains debated. Methods. Neurogenic mixed evoked potentials and collisions were performed in 24 consecutive patients during scoliosis surgery. Neurogenic mixed evoked potentials were elicited by a high thoracic spinal test stimulation and recorded from the tibial nerve at the ankle. A peripheral conditioning stimulation was delivered at the popliteal fossa 15 ms before spinal stimulation, inducing an ascending volley. The antidromic ascending motor component stops at the anterior horn cell level, whereas the orthodromic sensory component reaches the dorsal columns. The 15-ms interstimulus interval between peripheral conditioning and spinal test stimulation makes the collision with descending volleys occur in the spinal cord. The descending sensory volley is blocked, whereas the descending motor volley is unaffected. Results. Reproducible evoked potentials were recorded from the tibial nerve in all the patients studied when the conditioning stimulation was performed. These conditioned neurogenic mixed evoked potentials consist of a small and polyphasic wave whose amplitude represents approximately 26% that of the wave of unconditioned neurogenic mixed evoked potentials. It is likely that they correspond to motor spinal pathway activation. Conclusion. Both standard and conditioned neurogenic mixed evoked potentials are proposed to provide combined sensory and motor spinal pathway monitoring.

Usefulness of neurogenic motor evoked potentials for spinal cord monitoring : findings in 112 consecutive patients undergoing surgery for spinal deformity

Neurogenic motor evoked potential (NMEP) monitoring, which basically represents a monitoring of both motor and somatosensory tracts, has been proposed as a warning system in preventing neural damage during spinal surgery. The aim of this study was to report our clinical experience in 112 consecutive patients undergoing surgery for spinal deformity, and to emphasize the interest of NMEP monitoring. NMEPs were elicited in each patient by electrical stimulation of the spinal cord via needle electrodes placed by the surgeon in the rostral part of the surgical field, and recorded from the right and left sciatic nerves. Concomitantly, somatosensory evoked potentials (SSEPs) were obtained using a standard method. No false-negative cases of intra-operative spinal cord damage were reported. In 3 patients, both NMEPs and SSEPs suddenly disappeared during specific surgical manipulations of the vertebral implants. In these patients, the level of the lesion was easily recognized by moving the stimulating electrodes of NMEPs along the spinal cord, allowing the surgeon to perform laminectomy at the appropriate vertebral level. Spinal cord decompression was a success in two patients, the last unfortunately being paraplegic. Two additional patients exhibited transient reduction in NMEP amplitude at the insertion of a rod while SSEPs did not change significantly. In these two cases, the surgeon modified his procedure according to the NMEP changes, possibly avoiding a neurological complication. Each time evoked potentials were significantly altered, significant information was more rapidly acquired with NMEPs than with SSEPs. These results suggest that NMEPs can be used as primary choice for detecting impeding lesion of the spinal cord during critical steps of spinal surgery.

Intraspinal Metallosis Causing Delayed Neurologic Symptoms After Spinal Instrumentation Surgery

Study Design. Two cases of intraspinal metallosis causing delayed neurologic symptoms secondary to spinal instrumentation surgery are reported. Objective. To present an unusual delayed neurologic complication after spinal instrumentation surgery. Summary of Background Data. Metal-related complications caused by orthopedic implants have long been a concern in the field of arthroplasty or internal fixation of fractures, but no such complications have been reported for spinal instrumentation. Methods. Retrospective case report of two patients with degenerative scoliosis who presented with delayed neurologic symptoms months to years after uneventful, but without secondary degenerative changes or dislodgement of the implants. Results. In both reported cases, a granulation–tissue mass characterized by marked metallosis had been formed in the spinal canal adjacent to a loosened laminar hook. Conclusions. Intraspinal metallosis should be kept in mind as a rare cause of delayed neurologic symptoms after spinal instrumentation surgery. With the metal implants in place, myelography was the sole informative examination for diagnosis.

Interpretation and utility of traction radiography in scoliosis surgery. Analysis of patients treated with Cotrel-Dubousset instrumentation.

Study Design. An analysis of a standardized method of traction radiography for the evaluation of reducibility of scoliosis. Objectives. To determine whether and how preoperative traction radiography can provide objective information and to compare traction radiography with supine side‐bending radiography. Summary of Background Data. Flexibility of scoliosis deformity remains an arbitrary concept. No objective method of preoperative evaluation of reducibility has been established. Methods. The utility of a standardized method of traction radiography was evaluated in 74 patients with idiopathic scoliosis who were aged 14‐22 years and treated with Cotrel‐Dubousset instrumentation. Results. In thoracic curves, the postoperative Cobb angle was highly correlated with the preoperative Cobb angle in traction (r = 0.82). However, such correlation was much lower with lumbar curves (r = 0.54). The reducibility of the thoracic curve by traction as expressed by the ratio to the original curve was dependent on the magnitude of the original curve (P = 0.005), and this parameter proved less informative than the absolute angle values. Time‐related analysis of 30 patients who were observed for more than 5 years revealed that the high correlation between the preoperative angle of thoracic curves in traction and their postoperative angle decreased with the follow‐up time (r = 0.80 − 0.65). A comparison of traction radiography and supine side‐bending radiography showed that these two tests were practically equivalent in terms of evaluating the reducibility of curves. Conclusion. The results provide an objective interpretation of traction radiographs for scoliosis.

The vertebral interbody grafting site's low concentration in osteogenic progenitors can greatly benefit from addition of iliac crest bone marrow.

The ability of bone substitutes to promote bone fusion is contigent upon the presence of osteoinductive factors in the bone environment at the fusion site. Osteoblast progenitor cells are among these environmental osteoinductive factors, and one of the most abundant and available sources of osteoblastic cells is the bone marrow. As far as biological conditions are concerned, the vertebral interbody space appears as a favorable site for fusion, as it is surrounded by spongy bone, theoretically rich in osteogenic cells. This site may, however, not be as rich in osteogenic precursor cells especially at the time of grafting, because decortication of the vertebral end plates during the grafting process may modifiy cell content of the surrounding spongy bone. We tested this hypothesis by comparing the abundance of human osteogenic precursor cells in bone marrow derived from the iliac crest, the vertebral body, and the decorticated intervertebral body space. The number of potential osteoblast progenitors in each site was estimated by counting the alkaline phosphatase–expressing colony-forming units (CFU-AP). The results, however, demonstrate that the vertebral interbody space is actually poorer in osteoprogenitor cells than the iliac crest (P<0.001) and vertebral body (P<0.01), especially at the time of graft implantation. In light of our results, we advocate addition of iliac crest bone marrow aspirate to increase the success rate of vertebral interbody fusion.