Mineral and Bone Consequences of High Dose Denosumab Therapy to Treat an Aneurysmal Bone Cyst, a Child Case Report.

Aneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.

Transforaminal percutaneous endoscopic discectomy for symptomatic gas-filled discal cysts-report of three cases and literature review.

OBJECTIVE: The aim of this retrospective study is to review our experience in the diagnosis and role of transforaminal percutaneous endoscopic discectomy (TPED) for symptomatic gas-filled discal cysts. METHODS: Between May 2014 and June 2017, 3 patients from Lishui Center Hospital (Lishui China), who underwent TPED for symptomatic gas-filled discal cysts, were analyzed. The clinical features, imaging findings, operative findings, and treatment outcomes are presented. In addition, relevant literature regarding gas-filled discal cysts was searched using PubMed, and their characteristics, clinical features, therapeutic strategies, and survival outcomes were reviewed. RESULTS: The median age of the patients was 56.7 years (range, 55-60 years). In all patients, a discal cyst was located in the lumbar region, and the patients presented with backache and numbness in the lower extremities. The diagnosis was made by lumbar 3-dimensional computed tomography (3D-CT) or magnetic resonance imaging (MRI). All patients underwent TPED. All patients recovered successfully and were eventually discharged. Eighteen articles were identified from the searches of the database, and a total of 42 patients were included. There were 28 males and 14 females. The mean age was 56.8 years, ranging from 27 to 85 years. Lower back pain was the major symptom. Twenty-two patients underwent surgery, 4 patients underwent percutaneous needle aspiration, 2 patients underwent drug therapy, 13 patients received nonoperative treatment, and 1 patient was unknown. CONCLUSION: TPED for gas-filled discal cysts is feasible, effective, and successful, although it should be performed by an experienced surgeon with awareness of the potential risk of severe nerve root injury.

Standardized uptake values of 99mTc-MDP in normal vertebrae assessed using quantitative SPECT/CT for differentiation diagnosis of benign and malignant bone lesions.

BACKGROUND: Quantitative bone SPECT/CT is useful for disease follow up and inter-patient comparison. For bone metastatic malignant lesions, spine is the most commonly invaded site. However, Quantitative studies with large sample size investigating all the segments of normal cervical, thoracic and lumbar vertebrae are seldom reported. This study was to evaluate the quantitative tomography of normal vertebrae using 99mTc-MDP with SPECT/CT to investigate the feasibility of standardized uptake value (SUV) for differential diagnosis of benign and malignant bone lesions. METHODS: A retrospective study was carried out involving 221 patients (116 males and 105 females) who underwent SPECT/CT scan using 99mTc-MDP. The maximum SUV (SUVmax), mean SUV (SUVmean) and CT values (Hounsfield Unit, HU) of 2416 normal vertebrae bodies, 157 benign bone lesions and 118 malignant bone metastasis foci were obtained. The correlations between SUVmax of normal vertebrae and CT values of normal vertebrae, age, height, weight, BMI of patients were analyzed. Statistical analysis was performed with data of normal, benign and malignant groups corresponding to same sites and gender. RESULTS: The SUVmax and SUVmean of normal vertebrae in males were markedly higher than those in females (P < 0.0009). The SUVmax of each normal vertebral segment showed a strong negative correlation with CT values in both males and females (r = - 0.89 and - 0.92, respectively; P < 0.0009). The SUVmax of normal vertebrae also showed significant correlation with weight, height, and BMI in males (r = 0.4, P < 0.0009; r = 0.28, P = 0.005; r = 0.22, P = 0.026), and significant correlation with weight and BMI in females (r = 0.32, P = 0.009; r = 0.23, P = 0.031). The SUVmax of normal group, benign bone lesion group and malignant bone metastasis foci group showed statistical differences in both males and females. CONCLUSION: Our study evaluated SUVmax and SUVmean of normal vertebrae, benign bone lesion and malignant bone metastasis foci with a large sample population. Preliminary results proved the potential value of SUVmax in differentiation benign and malignant bone lesions. The results may provide a quantitative reference for clinical diagnosis and the evaluation of therapeutic response in vertebral lesions.

Deep Gray Matter Iron Deposition and Its Relationship to Clinical Features in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients: A 7.0-T Magnetic Resonance Imaging Study.

Background and Purpose- Distribution patterns of iron deposition in deep gray matter and their association with clinical characteristics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) remain unclear. We aimed to evaluate iron deposition in deep gray matter in patients with CADASIL using 7.0-T susceptibility-weighted imaging and mapping and to explore its correlations with clinical characteristics. Methods- Thirty-nine patients with CADASIL, confirmed via genetic analysis or skin biopsy, were enrolled. We examined patients using the Mini-Mental State Examination, modified Rankin Scale, and brain 7.0-T magnetic resonance imaging and obtained magnetic resonance imaging lesion loads, small vessel disease scores, and susceptibility mapping. The following regions of interest were selected: caudate nucleus, putamen, globus pallidus, thalamus, substantia nigra, and red nucleus. The quantitative differences in the susceptibility of deep gray matter between the CADASIL and control groups and the correlations between deep gray matter susceptibility and clinical characteristics were identified. Results- Compared with the control group, the CADASIL group showed significantly increased susceptibility of caudate nucleus, putamen, thalamus, substantia nigra, and red nucleus. The susceptibility of deep gray matter in basal ganglia region, including caudate nucleus, putamen, and thalamus, significantly increased with age or disease duration and positively correlated with small vessel disease scores in patients with CADASIL. Moreover, the susceptibility of thalamus positively correlated with modified Rankin Scale scores after adjusting for age and disease duration and that of putamen negatively correlated with Mini-Mental State Examination scores in patients with CADASIL after adjusting for age. Conclusions- Our findings indicate an association between abnormal iron deposition in deep gray matter of patients with CADASIL and their clinical characteristics. Therefore, excess iron deposition in deep gray matter, as indicated by 7.0-T susceptibility-weighted imaging and mapping, might not only be a novel magnetic resonance imaging feature but also a potential biomarker for CADASIL severity.

HTRA1 expression profile and activity on TGF-ß signaling in HTRA1 mutation carriers.

High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor-ß (TGF-ß) signaling. A deleterious role in late-onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined. Our aim is to evaluate the expression profile and activity of HTRA1 on TGF-ß signaling in fibroblasts from four subjects carrying the HTRA1 heterozygous mutations-p.E42Dfs*173, p.A321T, p.G295R, and p.Q151K. We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in TGF-ß signaling pathway downstream intermediate, Phospho Smad2/3. However, we found overexpression of genes involved in the extracellular matrix formation in two heterozygous HTRA1 carriers. Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression.

Do Prophylactic Antibiotics Reach the Operative Site Adequately?: A Quantitative Analysis of Serum and Wound Concentrations of Systemic and Local Prophylactic Antibiotics in Spine Surgery.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To analyze the serum and drain concentrations of antibiotics administered by two different routes and compare the results. SUMMARY OF BACKGROUND DATA: Systemic antibiotics are expected to reach the surgical site and maintain adequate concentrations of the drug to prevent infection. However, it is unknown whether systemically administered antibiotics reach and maintain such adequate concentrations at the surgical wound or not. METHODS: Forty patients undergoing elective spine surgery received intra-wound Vancomycin (1 GM) before the wound closure and single dose of intravenous Gentamycin (80MG) immediately after surgery. Blood and drain samples were collected postoperatively to estimate serum and drain concentrations of Gentamycin and Vancomycin. Drug Estimation Protocol: Drug concentrations were estimated by ADVIA Centaur CP immunoassay (direct chemiluminescence). Gentamycin and vancomycin in the test samples competes with their respective acridinium ester-labeled gentamicin and vancomycin derivatives for monoclonal mouse anti-gentamycin and anti-vancomycin antibodies which are covalently coupled to paramagnetic particles in the solid phase. RESULTS: Gentamycin attained peak serum levels at 6 hours following administration with an average value of 9.90 ±â€Š3.1 µg/mL which was decreased to 6.76 ±â€Š2.6 µg/mL at 12 hours and steadily declining thereafter. Even though, the drug concentrations in the drain collection from the wound also attained peak levels at 6 hours, the drug concentrations were lower (3.75 ±â€Š1.4 µg/mL) than that of serum concentrations and inadequately attained the recommended target peak of Gentamycin (4-12 µg/mL).Wound levels of local vancomycin were significantly higher at 6 hours (413.4 ±â€Š217.3 µg/mL) and well maintained even at 72 hours. Serum vancomycin levels were observed to be highest at 6 hours in negligible concentrations of 6.06 ±â€Š2.2 µg/mL. CONCLUSION: After prophylactic systemic administration of the antibiotics, the antibiotic drug concentrations in the wound are much lower than the serum concentrations at any given time. After local intra-wound application of antibiotics, the drug concentrations in the wound are well maintained even after 72 hours. LEVEL OF EVIDENCE: 3.

Increased Fibrogenic Gene Expression in Multifidus Muscles of Patients With Chronic Versus Acute Lumbar Spine Pathology.

STUDY DESIGN: Prospective observational study-basic science (Level 1). OBJECTIVE: The aim of this study was to compare expression of functional groups of genes within the atrophic, myogenic, fibrogenic, adipogenic, and inflammatory pathways between paraspinal muscle biopsies from individuals with acute and chronic lumbar spine pathology. SUMMARY OF BACKGROUND DATA: Low back pain is a complex and multifactorial condition that affects a majority of the general population annually. Changes in muscle tissue composition (i.e., fatty and fibrotic infiltration) are a common feature in individuals with lumbar spine pathology associated with low back pain, which often results in functional loss. Understanding the molecular underpinnings of these degenerative changes in different phases of disease progression may improve disease prevention and treatment specificity. METHODS: Intraoperative biopsies of the multifidus muscle were obtained from individuals undergoing surgery for acute (<6-month duration) or chronic (>6-month duration) lumbar spine pathology. Expression of 42 genes related to myogenesis, atrophy, adipogenesis, metabolism, inflammation, and fibrosis were measured in 33 samples (eight acute, 25 chronic) using qPCR, and tissue composition of fat, muscle, and fibrosis was quantified using histology. RESULTS: We found that tissue composition of the biopsies was heterogeneous, resulting in a trend toward lower RNA yields in biopsies with higher proportions of fat (r <-0.39, P < 0.1). There were no significant differences in gene expression patterns for atrophy (P > 0.635), adipogenesis (P > 0.317), myogenesis (P > 0.320), or inflammatory (P > 0.413) genes after adjusting for the proportion of muscle, fat, and connective tissue. However, in the fibrogenesis pathway, we found significant upregulation of CTGF (P = 0.046), and trends for upregulation of COL1A1 (P = 0.061), and downregulation of MMP1 and MMP9 (P = 0.061) in the chronic group. CONCLUSION: There is increased fibrogenic gene expression in individuals with chronic disease when compared to acute disease, without significant differences in atrophic, myogenic, adipogenic, or inflammatory pathways, suggesting increased efforts should be made to prevent or reverse fibrogenesis to improve patient function in this population. LEVEL OF EVIDENCE: N/A.

Bone mineral density and bone remodeling markers in chronic low back pain patients with active discopathy: A case-control exploratory study.

OBJECTIVE: We aimed to compare bone mineral density (BMD) and bone remodeling markers in chronic low back pain (cLBP) patients with and without active discopathy (Modic 1 changes). DESIGN: We conducted a single center case-control exploratory study. For 18 months, all patients referred to a tertiary care physical medicine and rehabilitation department in France were consecutively screened. Patients fulfilling the inclusion criteria were prospectively enrolled. Cases were defined as cLBP patients with lumbar active discopathy detected on MRI and controls as cLBP patients without active discopathy. Bone mineral density (BMD) at the spine, femoral neck and total femur was assessed by dual-energy X-ray absorptiometry, and bone remodeling markers were assessed in fasting serum samples. Overall, 37 cLBP patients (13 cases and 24 controls) fulfilled inclusion criteria and were included. RESULTS: The median age was 42.0 years (Q1-Q3: 36.0-51.0) and mean (SD) LBP duration 72.3 (57.4) months. We found that BMD and levels of bone remodeling markers in cLBP patients did not differ with and without active discopathy. CONCLUSION: Our results do not support the association between active discopathy and systemic bone fragility.

Chondrocyte-Specific Knockout of TSC-1 Leads to Congenital Spinal Deformity in Mice.

Congenital spinal deformity is the most severe clinical orthopedic issue worldwide. Among all the pathological processes of congenital spinal deformity, the imbalance of endochondral ossification is considered to be the most important developmental cause of spinal dysplasia. We established chondrocyte-specific TSC-1 knockout (KO) mice to overactivate the energy metabolic component, mammalian target of rapamycin complex 1 (mTORC1), and measured the spinal development by general, imaging, histological, and Western-blot assessments. In addition to skeletal dysplasia, the KO mice displayed severe congenital spinal deformity and significant intervertebral disc changes. This study suggests that, in the process of endochondral ossification, excessive activation of mTORC1 signaling in chondrocytes induces obvious spinal deformity, and the chondrocytes may be the cell type responsible for congenital spinal deformity.

New insights into mechanisms of small vessel disease stroke from genetics.

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.

[Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL)].

Cerebral small vessel disease (CSVD) is frequently observed among the elderly and is known to cause dementia and gait disturbance associated with white matter lesions, lacunar infarcts, and cerebral hemorrhage. Molecular mechanistic studies promise to provide new insights into the pathogenesis of hereditary CSVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is one of the hereditary CSVDs caused by a mutation in the high-temperature requirement serine peptidase A1 (HTRA1) gene. The loss of HTRA1 protease activity increases signaling via transforming growth factor (TGF)ß, thereby resulting in CARASIL. Although the CARASIL has been characterized by juvenile onset alopecia and spondylosis deformans, these features are not always observed in individuals with an HTRA1 mutation. Moreover, some HTRA1 mutations cause CSVD in heterozygous states. Therefore, the clinical features of CSVD resulting from an HTRA1 mutation extend to patients with CSVD alone or to those with dominantly inherited CSVD.

Notch signaling pathways in human thoracic ossification of the ligamentum flavum.

This study investigated the pathological process of Notch signaling in the osteogenesis of ligamentum flavum tissues and cells, and the associated regulatory mechanisms. Notch receptors, ligands, and target genes were identified by quantitative polymerase chain reaction (qPCR) in ligamentum flavum cells and immunohistochemistry in ligamentum flavum sections from ossification of the ligamentum flavum (OLF) patients and controls. The temporospatial expression patterns of JAG1/Notch2/HES1 in human ligamentum flavum cells during osteogenic differentiation were determined by qPCR. Lentiviral vectors for Notch2 overexpression and knockdown were constructed and transfected into ligamentum flavum cells before osteogenic differentiation to examine the function of Notch signaling pathways in the osteogenic differentiation of ligamentum flavum cells. Alkaline phosphatase, Runx2, Osterix, osteocalcin, and osteopontin mRNA levels, alkaline phosphatase activity, and Alizarin Red staining were used as indicators of osteogenic differentiation. JAG1/Notch2/HES1 mRNA levels were up-regulated in ligamentum flavum cells from OLF patients, which increased during osteogenic differentiation. Immunohistochemical analysis suggested positive Notch2 expression at the ossification front. Down-regulation of Notch2 expression decelerated osteogenic differentiation of ligamentum flavum cells, and Notch2 overexpression promoted osteogenic differentiation of ligamentum flavum cells. Expression of Runx2 and Osterix increased in a manner similar to that of Notch2 during osteogenic differentiation of ligamentum flavum cells, and Notch2 knockdown and overexpression influenced their expression levels. Notch signaling plays an important role in OLF, and Notch may affect the osteogenic differentiation of ligamentum flavum cells via interactions with Runx2 and Osterix.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1481-1491, 2016.

Actin Out: Regulation of the Synaptic Cytoskeleton.

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease.

Characteristic features and progression of abnormalities on MRI for CARASIL.

OBJECTIVES: The objective of this study was to clarify the characteristic brain MRI findings for genetically diagnosed CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). METHODS: Seven patients with CARASIL carrying HTRA1 mutations (representing 6 Japanese families) were included in this study. Eighteen brain MRIs were reviewed and evaluated with a new rating scale based on scoring for abnormal hyperintense lesions and atrophy. RESULTS: At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami. Patients with longer time from the onset of cognitive impairment had higher MRI severity score. The atrophy advanced, followed by white matter lesion progression. During the early stage, hyperintense lesions were observed in the frontal white matter, external capsule, and pons. During the late stage, the arc-shaped hyperintense lesion from the pons to the middle cerebellar peduncles, which we designated the "arc sign," became evident. The arc sign was a characteristic finding for CARASIL in the advanced stage. CONCLUSIONS: These characteristic MRI findings for CARASIL are useful for selecting patients for genetic testing. The rating scale correlates well with disease duration and might be useful for assessing disease progression.

Cerebral small vessel disease-related protease HtrA1 processes latent TGF-ß binding protein 1 and facilitates TGF-ß signaling.

High temperature requirement protein A1 (HtrA1) is a primarily secreted serine protease involved in a variety of cellular processes including transforming growth factor ß (TGF-ß) signaling. Loss of its activity causes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an inherited form of cerebral small vessel disease leading to early-onset stroke and premature dementia. Dysregulated TGF-ß signaling is considered to promote CARASIL pathogenesis, but the underlying molecular mechanisms are incompletely understood. Here we present evidence from mouse brain tissue and embryonic fibroblasts as well as patient skin fibroblasts for a facilitating role of HtrA1 in TGF-ß pathway activation. We identify latent TGF-ß binding protein 1 (LTBP-1), an extracellular matrix protein and key regulator of TGF-ß bioavailability, as a novel HtrA1 target. Cleavage occurs at physiological protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into the extracellular matrix. Hence, our data suggest an attenuation of TGF-ß signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathogenesis.

Effect of acupotomy on nitric oxide synthase and beta-endorphin in third lumbar vertebrae transverse process syndrome model rats.

OBJECTIVE: To explore the long-term effects and pain relief mechanism of acupotomy by observing changes in nitric oxide synthase (NOS) and beta-endorphin (beta-EP) in the hypothalamus, spinal cord, and peripheral blood of rats with third lumbar vertebrae (L3) transverse process syndrome. METHODS: Twenty-eight SD rats were randomly assigned to normal, model, electroacupuncture (EA), and acupotomy group. The last three groups were put through an operation to emulate L3 transverse process syndrome. Fourteen days after the simulation operation, EA and acupotomy treatments were applied to the respective groups. Fifty-six days after the simulation operation, biochemistry tests and enzyme-linked immunosorbent assay were used to measure NOS and beta-EP in the hypothalamus, spinal cord, and peripheral blood. RESULTS: Rats with the simulation operation showed significantly higher levels of NOS and beta-EP in the hypothalamus, spinal cord, and peripheral blood than those in the normal group. The EA and acupotomy groups had significantly lower levels of NOS and beta-EP than those in the model group. There was no statistical difference between the EA and acupotomy groups. CONCLUSION: EA and acupotomy treatments significantly lowered NOS and beta-EP levels in the hypothalamus, spinal cord, and peripheral blood and alleviated L3 transverse process syndrome.

Intervertebral discs from spinal nondeformity and deformity patients have different mechanical and matrix properties.

BACKGROUND CONTEXT: It is well-established that disc mechanical properties degrade with degeneration. However, prior studies utilized cadaveric tissues from donors with undefined back pain history. Disc degeneration may present with pain at the affected motion segment, or it may be present in the absence of back pain. The mechanical properties and matrix quantity of discs removed and diagnosed for degeneration with patient chronic pain may be distinct from those with other diagnoses, such as spinal deformity. PURPOSE: To test the hypothesis that discs from nondeformity segments have inferior mechanical properties than deformity discs owing to differences in matrix quality. STUDY DESIGN/SETTING: In vitro study comparing the mechanical and matrix properties of discs from surgery patients with spinal nondeformity and deformity. METHODS: We analyzed nucleus and annulus samples (8-11 specimens per group) from surgical discectomy patients as part of a fusion or disc replacement procedure. Tissues were divided into two cohorts: nondeformity and deformity. Dynamic indentation tests were used to determine energy dissipation, indentation modulus, and viscoelasticity. Tissue hydration at a physiologic pressure was assessed by equilibrium dialysis. Proteoglycan, collagen, and collagen cross-link content were quantified. Matrix structure was assessed by histology. RESULTS: We observed that energy dissipation was significantly higher in the nondeformity nucleus than in the deformity nucleus. Equilibrium dialysis experiments showed that annulus swelling was significantly lower in the nondeformity group. Consistent with this, we observed that the nondeformity annulus had lower proteoglycan and higher collagen contents. CONCLUSIONS: Our data suggest that discs from nondeformity discs have subtle differences in mechanical properties compared with deformity discs. These differences were partially explained by matrix biochemical composition for the annulus, but not for the nucleus. The results of this study suggest that compromised matrix quality and diminished mechanical properties are features that potentially accompany discs of patients undergoing segmental fusion or disc replacement for disc degeneration and chronic back pain. These features have previously been implicated in pain via instability or reduced motion segment stiffness.

Tissue-engineered bone formation in vivo for artificial laminae of the vertebral arch using ß-tricalcium phosphate bioceramics seeded with mesenchymal stem cells.

STUDY DESIGN: A rabbit laminectomy model was used to evaluate the efficacy of artificial laminae of vertebral arch using bone marrow-derived mesenchymal stem cells (MSCs) transplanted in porous beta-calcium phosphates (ß-TCP) bioceramics. OBJECTIVE: The aim of this study was to establish artificial lamina of the vertebral arch for bone tissue engineering using ß-TCP bioceramics seeded with MSCs in a rabbit model of decompressive laminectomy. SUMMARY OF BACKGROUND DATA: Decompressive laminectomy may induce various degrees of scar tissue and adhesion formation in the epidural space, and thus is the most common cause of failed back surgery syndrome. However, there is no effective method of bone defect treatment to control and reduce the scar tissue formation. METHODS: MSCs were harvested from New Zealand rabbits (2-week old) by femoral bone marrow extraction. These cells were seeded into porous ß-TCP bioceramics and cultivated for up to 3 weeks in the presence of osteogenic supplements. Segmental defects (20 × 8 mm) were created in 48 adult New Zealand rabbits that underwent laminectomy at the L5 to L6 levels. The animals were transplanted with cell media (control), ß-TCP bioceramics (group I), or MSC-loaded ß-TCP bioceramics (group II). Bone formation was evaluated after operation using scanning electron microscopy, computed tomography, magnetic resonance imaging, histomorphometry, and immunohistochemistry. RESULTS: Scanning electron microscopy showed that MSCs filled the pores and surfaces of bioceramics in MSC-loaded ß-TCP. In addition, significant increases in bone formation were observed in group II compared with other groups. Computed tomography and magnetic resonance imaging at 16 weeks showed that the artificial lamina of the vertebral arch was successfully formed. Hematoxylin-eosin and Masson trichrome staining were used to show the artificial laminae of the vertebral arch and the degraded bioceramics. In addition, immunohistochemistry results showed that the expression of bone morphogenetic protein-2 increased significantly in group II compared with group I at 2,4, and 8 weeks after implantation (P < 0.05). CONCLUSION: ß-TCP bioceramics seeded with MSCs are a promising source of tissue-engineered bone for the artificial lamina of the vertebral arch.