Rapid calcification propensity testing in blood using a temperature controlled microfluidic polymer chip.

Phosphate toxicity is a major threat to cardiovascular health in chronic kidney disease. It is associated with oxidative stress, inflammation and the accumulation of calcium phosphate commonly known as calcification in soft tissues leading to functional disorders of blood vessels. An improved calcification propensity test for the assessment of phosphate toxicity was developed, which measures the velocity of calcium phosphate mineralization from colloidal precursors in vitro. This so called T50 test measures the transformation from a primary into a secondary form of nanosized colloidal plasma protein-calcium phosphate particles known as calciprotein particles. The T50 test in its previous form required a temperature controlled nephelometer and several hours of continuous measurement, which precluded rapid bed side testing. We miniaturized the test using microfluidic polymer chips produced by ultrasonic hot embossing. A cartridge holder contained a laser diode for illumination, light dependent resistor for detection and a Peltier element for thermo control. Increasing the assay temperature from 37°C to 75°C reduced the T50 test time 36-fold from 381 ± 10 min at 37°C to 10.5 ± 0.3 min at 75°C. Incorporating sputtered micro mirrors into the chip design increased the effective light path length, and improved signal-to-noise ratio 9-fold. The speed and reproducibility of the T50 chip-based assay run at 75°C suggest that it may be suitable for rapid measurements, preferably in-line in a dialyser or in a portable microfluidic analytic device with the chip inserted as a disposable cartridge.

Novel imaging of the intervertebral disk and pain.

T-1-rho (T1ρ) magnetic resonance imaging (MRI) and disc height ratio (DHR) are potential biomarkers of degenerative disk disease (DDD) related to biochemical composition and morphology of the intervertebral disk (IVD), respectively. To objectively detect DDD at an early stage, the hypothesis was tested that the average T1ρ relaxation time of the nucleus pulposus (NP) correlates with the disk height of degenerate IVDs, measured by MRI. Studies were performed on a 3-T Siemens Tim Trio clinical MRI scanner (Siemens Healthcare, Malvern, Pennsylvania, United States) on patients being treated for low back pain whose disks were categorized into (1) painful and (2) nonpainful subgroups based on provocative diskography and (3) age-matched healthy controls. Painful disks presented both low DHR and T1ρ values, nonpainful disks measured the highest DHR and extended to a higher range of T1ρ, and control disks presented a midrange DHR with the highest T1ρ values. T1ρ MRI evaluated in the NP of IVDs may be useful to establish a threshold (120 milliseconds here) above which indicates a healthy disk, and disks measuring low NP T1ρ (50 to 120 milliseconds here) would require disk height analysis to further categorize the disk. Combining T1ρ MRI and disk height analysis may hold promise in predicting painful disks without provocative diskography, and predictive models should be developed.

New treatments and imaging strategies in degenerative disease of the intervertebral disks.

Magnetic resonance (MR) imaging in patients with persistent low back pain and sciatica effectively demonstrates spine anatomy and the relationship of nerve roots and intervertebral disks. Except in cases with nerve root compression, disk extrusion, or central stenosis, conventional anatomic MR images do not help distinguish effectively between painful and nonpainful degenerating disks. Hypoxia, inflammation, innervation, accelerated catabolism, and reduced water and glycosaminoglycan content characterize degenerated disks, the extent of which may distinguish nonpainful from painful ones. Applied to the spine, "functional" imaging techniques such as MR spectroscopy, T1ρ calculation, T2 relaxation time measurement, diffusion quantitative imaging, and radio nucleotide imaging provide measurements of some of these degenerative features. Novel minimally invasive therapies, with injected growth factors or genetic materials, target these processes in the disk and effectively reverse degeneration in controlled laboratory conditions. Functional imaging has applications in clinical trials to evaluate the efficacy of these therapies and eventually to select patients for treatment. This report summarizes the biochemical processes in disk degeneration, the application of advanced disk imaging techniques, and the novel biologic therapies that presently have the most clinical promise.

A prospective randomized FDA-IDE trial comparing Cortoss with PMMA for vertebroplasty: a comparative effectiveness research study with 24-month follow-up.

STUDY DESIGN: Randomized, controlled, prospective (AAOS therapeutic level I) trial conducted under Food and Drug Administration Investigational Device Exemption hypothesized noninferiority of a novel bioactive composite material to polymethylmethacrylate (PMMA). OBJECTIVE: To determine the safety and efficacy of a new, nonresorbable bioactive composite (Cortoss) compared with PMMA, the standard treatment of vertebral compression fractures (VCFs). SUMMARY OF BACKGROUND DATA: Vertebroplasty with PMMA, the widely adopted treatment for VCFs nonresponsive to conservative care, provides effective, immediate pain relief, but the material has received criticism for its properties. A new bioactive composite material designed specifically for vertebroplasty showed promising results in animals and nonrandomized clinical studies and was subsequently compared with PMMA in a randomized study. This study represents the first prospective study evaluating vertebroplasty comparing PMMA with another material with 24-month follow-up. METHODS: Using 2:1 randomization, vertebroplasty was performed with Cortoss on 162 patients and PMMA on 94 patients. Inclusion criteria were painful osteoporotic VCFs with a visual analogue scale pain score of at least 50 mm on a 100-mm scale and at least 30% disability as measured by the Oswestry Disability Index. Evaluations at pretreatment, treatment day, and 7 posttreatment intervals out to 24 months included pain, disability, neurological status, adverse events, quality of life, patient satisfaction, analgesic use, and independently reviewed radiographs. RESULTS: Noninferiority of Cortoss relative to PMMA was observed, with Cortoss-treated patients experiencing significant pain relief at 3 months (P = 0.0395) and better maintenance or improvement in function at 24 months (P = 0.0299). Incidence of serious device-related adverse events was 4.3% in both groups; none were life threatening. CONCLUSION: Vertebroplasty using either Cortoss or PMMA provides effective, immediate, and lasting pain relief and prevents further loss of function. Both materials performed comparably at most time points; Cortoss demonstrated better results for pain reduction at 3 months and for function at 24 months.

T1ρ magnetic resonance imaging and discography pressure as novel biomarkers for disc degeneration and low back pain.

STUDY DESIGN: Prospective magnetic resonance imaging (MRI) study of patients low back pain (LBP) requiring discography as part of their routine clinical diagnoses and asymptomatic age-matched volunteers. OBJECTIVE: To determine whether T1ρ MRI and discography opening pressure (OP) are quantitative biomarkers of disc degeneration in LBP patients and in asymptomatic volunteers. SUMMARY OF BACKGROUND DATA: Disc degenerative disease, a common cause of LBP, is related to the patient's prognosis and serves as a target for therapeutic interventions. However, there are few quantitative measures in the clinical setting. Discography OP and T1ρ MRI are potential biomarkers of disc degenerative disease related to biochemical composition of the intervertebral disc. METHODS: The institutional review board approved all experiments, and informed consent was provided by each subject. Patients being treated for LBP (n = 17; 68 levels; mean age, 44 ± 6 years; and range, 30-53) and control subjects (n = 11; 44 levels; mean age, 43 ± 17 years; and range, 22-76) underwent T1ρ and T2 MRI on a Siemens 3T Tim Trio clinical scanner (Siemens Medical Solutions, Malvern, PA). The LBP patients also received multilevel provocative discography before their MRI. OP was recorded as the pressure when fluid first enters the nucleus of the intervertebral disc. RESULTS: T1ρ was significantly lower in the painful discs (55.3 ± 3.0 ms, mean ± SE) from control (92.0 ± 4.9 ms, P < 0.001) and nonpainful discs (83.6 ± 3.2 ms, P < 0.001). Mean OP for the painful discs (11.8 ± 1.0 psi, mean ± SE) was significantly lower than that for nonpainful discs (19.1 ± 0.7 psi, P < 0.001). Both T1ρ and OP correlated moderately with Pfirrmann degenerative grade. Receiver-operating-characteristic area under the curve was 0.91 for T1ρ MRI and 0.84 for OP for predicting painful discs. CONCLUSION: T1ρ and OP are quantitative measures of degeneration that are consistent across both control subjects and LBP patients. A significant and strong correlation exists between T1ρ values and in vivo OP measurements obtained by discography in LBP patients.

Clinical experience using Cortoss for treating vertebral compression fractures with vertebroplasty and kyphoplasty: twenty four-month follow-up.

STUDY DESIGN: Forty patients were enrolled in 2 FDA-approved pilot Investigational Device Exemption (IDE) studies using Cortoss for the treatment of vertebral compression fractures (VCF). Twenty patients were treated at 3 centers, using vertebroplasty (VP) and 20 patients were treated at 5 centers, using kyphoplasty (KP). OBJECTIVE: To assess the feasibility and clinical outcomes using Cortoss to treat osteoporotic VCF. SUMMARY OF BACKGROUND DATA: Cortoss is an injectable bioactive, self-setting, radiopaque composite shown to stabilize and provide immediate weight bearing support to fractured vertebrae. Cortoss is approved for use in Europe for both screw and vertebral augmentation. METHODS.: Patient assessments were conducted before surgery and after surgery through 24 months using Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and quality-of-life assessment (SF-12) questionnaires. Extravasations were evaluated using radiographs and CT scans. RESULTS: Immediate pain improvement was seen in VP patients with VAS scores decreasing from 75.7 before surgery to 35.9 at 72 hours. Continued improvement from baseline was seen out to 2 years (average VAS of 48.9). Disability improved with average ODI scores decreasing from 52.2% preoperative to 38.3% at 2 years for VP patients. Immediate pain improvement was also seen in KP patients with VAS scores decreasing from 78.1 before surgery to 42.7 at 72 hours. Continued improvement from baseline was seen out to 2 years (average VAS of 25.4). ODI scores improved from 60.5% preoperative to 34.5% at 2 years for KP patients. Average material volumes injected were 1.85 mL for VP and 4.13 mL for KP. Extravasations from both techniques were minor, anatomically close to the treated vertebrae and asymptomatic. No cardiac irregularities or pulmonary emboli were observed. CONCLUSION: These studies indicate Cortoss is safe and effective in treating osteoporotic VCF using vertebroplasty or kyphoplasty. Pain relief and restoration of function with Cortoss is comparable to results found in the literature for polymethylmethacrylate.

Algorithmic approach to the management of the patient with lumbar spinal stenosis.

A 71-year-old generally healthy woman presents for her first visit in 3 years. She ambulates slowly from the waiting room, with a more stooped posture than previously. She reports a 2-year history of slowly worsening buttock and leg pain when she walks any distance. She has noticed that her symptoms are much less when she leans on a shopping cart in the grocery store. Her buttock/leg pain resolves within a few minutes when she sits down. The patient exhibits signs and symptoms suggestive of lumbar spinal stenosis.

Augmentation improves human cadaveric vertebral body compression mechanics for lumbar total disc replacement.

STUDY DESIGN: Cadaveric biomechanical study. OBJECTIVE: To quantify the effects of vertebral body augmentation on biomechanics under axial compression by a total disc replacement (TDR) implant. SUMMARY OF BACKGROUND DATA: TDR is a surgical alternative to lumbar spinal fusion to treat degenerative disc disease. Osteoporosis in the adjacent vertebrae to the interposed TDR may lead to implant subsidence or vertebral body fracture. Vertebral augmentation is used to treat osteoporotic compression fracture. This study sought to evaluate whether vertebral augmentation improves biomechanics under TDR axial loading. METHODS: Forty-five L1-L5 lumbar vertebral body segments with intact posterior elements were used. Peripheral quantitative computed tomography scans were performed to determine bone density, and specimens were block-randomized by bone density into augmentation and control groups. A semiconstrained keeled lumbar disc replacement device was implanted, providing 50% endplate coverage. Vertebral augmentation of 17.6% +/- 0.9% vertebral volume fill with Cortoss was performed on the augmentation group. All segments underwent axial compression at a rate of 0.2 mm/s to 6 mm. RESULTS: The load-displacement response for all specimens was nonlinear. Subfailure mechanical properties with augmentation were significantly different from control; in all cases, the augmented group was 2 times higher than control. At failure, the maximum load and stiffness with augmentation was not significantly different from control. The maximum apparent stress and modulus with augmentation were 2 times and 1.3 times greater than control, respectively. The subfailure stress and apparent modulus with augmentation were moderately correlated with bone density whereas the control subfailure properties were not. The augmented maximum stress was not correlated with bone density, whereas the control was weakly correlated. The maximum apparent modulus was moderately correlated with bone density for both the augmented and the control groups. CONCLUSION: Augmentation improved the mechanical properties of the lumbar vertebral body for compression by a TDR implant.

Intradiscal electrothermal therapy (IDET) provides effective symptom relief in patients with discogenic low back pain.

STUDY DESIGN: Single-arm, prospective clinical trial. OBJECTIVE: To evaluate back pain severity, physical function, and quality of life outcomes in highly selected patients with lumbar discogenic pain treated with intradiscal electrothermal therapy (IDET). SUMMARY OF BACKGROUND DATA: Degeneration and disruption of the intervertebral disc can be the source of severe low back pain and the associated physical dysfunction. IDET is a minimally invasive treatment option in the continuum of care between conservative nonoperative management and spinal surgery. METHODS: Using magnetic resonance imaging, pressure-controlled discography, and postdiscogram computed tomography findings, 56 patients with lumbar discogenic pain were identified, underwent IDET treatment and followed for 20.5+/-4.4 months, on average. Outcomes included assessments of back pain severity by visual analog scale, sitting, standing, and walking tolerances, and health-related quality of life using the SF-36. RESULTS: Mean pain severity scores (visual analog scale) improved from 6.1+/-1.8 pretreatment to 2.4+/-2.6 at final follow-up (P=0.0001). Mean tolerance times (minutes) improved from 40.9+/-40.6 to 84.5+/-54.4, 46.8+/-42.9 to 84.4+/-54.2, and 39.2+/-39.6 to 77.9+/-50.8 between baseline and final follow-up for sitting, standing, and walking, respectively (P=0.0001 for all comparisons). Seven of 8 quality of life domains showed significant (P=0.0001 for all comparisons) improvement over baseline. Forty-two patients (75%) were classified as a treatment success by virtue of a >or=2-point improvement in pain severity or a >or=10-point improvement in either the physical functioning or bodily pain domain of the SF-36. CONCLUSIONS: The findings of this study suggest that durable clinical improvements can be realized after IDET in highly selected patients with mild disc degeneration, confirmatory imaging evidence of annular disruption, and concordant pain provocation by low pressure discography.

Trunk muscle recruitment patterns in specific chronic low back pain populations.

BACKGROUND: It is hypothesized that injury or degeneration of osteoligamentous spinal structures would require compensation by trunk musculature and alterations in motor control to maintain spine stability. While, biomechanical modeling has supported this hypothesis, studies of muscle recruitment patterns in chronic low back pain patients both with and without significant osteoligamentous damage have been limited. This study utilized a non-randomized case-control design to investigate trunk muscle recruitment patterns around the neutral spine position between subgroups of patients with chronic mechanical low back pain and asymptomatic controls. METHODS: Twenty subjects with chronic low back pain attributed to clinical lumbar instability were matched to 20 asymptomatic controls. In addition 12 patients with non-specific chronic low back pain were studied. Surface EMG from five trunk muscles was analyzed to determine activation levels and patterns of recruitment during a standing reach under two different loading conditions. FINDINGS: The chronic low back pain group with symptoms attributed to clinical instability demonstrated significantly higher activation levels of the external oblique and rectus abdominus muscles and lower abdominal synergist ratios than the control group. No significant differences were found between patient subgroups. INTERPRETATION: While these data demonstrate altered muscle recruitment patterns in patients with chronic low back pain, the changes are not consistent with Panjabi's theory suggesting that these alterations are driven by passive subsystem damage. However, the higher activation of global abdominal musculature and altered synergist patterns may represent a motor control pattern that has consequences for continued dysfunction and chronic pain.

Preoperative evaluation of adult isthmic spondylolisthesis with diskography.

Fourteen consecutive patients with a diagnosis of isthmic spondylolisthesis (grade I and II) underwent provocative lumbar diskography (L2-S1) to evaluate the disk adjacent to the spondylolisthesis. Seven (50%) of 14 patients had concordant pain at the disk above the slip and 2 patients had no pain at the slip level. Surgical treatment included anteroposterior fusion of the slip level and any adjacent concordant levels. Clinical results included 3 excellent, 7 good, 2 fair, and 1 poor outcome. This data supports the hypothesis that the disk adjacent to an isthmic slip is predisposed to symptomatic degeneration in the adult patient with axial pain. It does not prove that a fusion is indicated or that clinical outcomes would be improved with this approach.