Long-Term Clinical Experience with Selectively Constrained SECURE-C Cervical Artificial Disc for 1-Level Cervical Disc Disease: Results from Seven-Year Follow-Up of a Prospective, Randomized, Controlled Investigational Device Exemption Clinical Trial.

BACKGROUND: This research was initiated to compare the long-term clinical safety and effectiveness of the selectively constrained SECURE-C (Globus Medical, Audubon, Pennsylvania) Cervical Artificial Disc to anterior cervical discectomy and fusion (ACDF). To preserve segmental motion, cervical total disc replacement (CTDR) was developed as an alternative to ACDF. Current CTDR designs incorporate constrained and unconstrained metal-on-metal or metal-on-polymer articulation with various means of fixation. METHODS: Eighteen investigational sites participated in this prospective clinical trial; 380 patients were enrolled and treated in the investigational device exemption study. The first 5 patients treated at each site were nonrandomized and received the investigational SECURE-C device. Patients were randomized, treated surgically, and evaluated postoperatively at 6 weeks, 3 months, 6 months, 12 months, 24 months, and annually thereafter through 84 months postoperative. RESULTS: Overall results for the randomized cohorts demonstrated statistical superiority of the investigational SECURE-C group over the control ACDF group at 84 months postoperative. SECURE-C showed clinically significant improvement in pain and function in terms of neck disability index and visual analog scale scores, and superiority in patient satisfaction was also achieved for patients treated with SECURE-C. CONCLUSION: Clinical study results indicated that the selectively constrained SECURE-C Cervical Artificial Disc is as safe and effective as ACDF. Long-term results from the Post Approval Study demonstrated that SECURE-C is statistically superior to ACDF in terms of overall success and patient satisfaction. Lower rates of subsequent index-level surgeries and device-related adverse events were observed in the SECURE-C group than in the ACDF group. The long-term, level 1 clinical evidence presented here is consistent with other reports supporting the safety and efficacy of cervical arthroplasty, and furthers advocacy for motion preservation as a viable alternative to fusion.

Extracorporeal shockwave lithotripsy in infants.

INTRODUCTION: Pediatric urolithiasis is relatively uncommon and limited information is available on the application of minimally invasive management modalities in young children. We present a single centre experience with extracorporeal shockwave lithotripsy (ESWL) for infants with upper urinary tract calculi. MATERIAL AND METHODS: A total of 74 infants aged 3 months to 24 months with upper urinary tract calculi were treated with ESWL under general anesthesia using the Wolf 2500 and the 2501 Piezolith lithotriptors over a 14 and a half-year period. Patient and stone characteristics, risk factors for urolithiasis, treatment parameters, clinical outcomes and long-term follow-up were assessed and recorded. RESULTS: The mean patient age was 14.5 (range 3 to 24) months. The mean renal stone size was 18.2 (range 7 to 32) mm while the mean ureteral stone size was 9.4 (range 5 to 14) mm. Metabolic abnormalities, structural anomalies and urinary tract infections were identified as contributory factors for stone formation in 34% of the infants. At the 3-month follow-up there was an overall successful outcome in 72 infants (97%) that included 65 (88%) who were rendered stone-free and 7 (9%) who had clinically insignificant stone fragments. Retreatment was required in 27 (35%) patients, auxiliary procedures after ESWL were needed in 5 (7%) and secondary operative procedures were required in 2 (3%). Major complications were encountered in 5 (7%) patients that included complete ureteral obstruction with sepsis in 2, partial ureteral obstruction in 1 and febrile urinary tract infection in 2 other children. Long-term follow-up was recorded in 39 infants: 8 developed recurrent stones, 2 had stone regrowth and 1 developed mild hypertension but none had significant deterioration of renal function. CONCLUSIONS: ESWL is an effective treatment for upper urinary tract calculi in infants. In the short-term, complications are minimal but long-term follow-up is important.

Effect of lower two-level anterior cervical fusion on the superior adjacent level.

OBJECT: Symptomatic multisegment disease is most common at the C5-6 and C6-7 levels, and two-level anterior cervical discectomy and fusion (ACDF) is performed most often at these levels. Therefore, it may be clinically important to know whether a C5-7 fusion affects the superior C4-5 segment. A biomechanical study was carried out using cadaveric cervical spine specimens to determine the effect of lower two-level anterior cervical fusion on intradiscal pressure and segmental motion at the superior adjacent vertebral level. METHODS: Five cadaveric cervical spine specimens were used in this study. The specimens were stabilized at T-1 and loaded at C-3 to 15 degrees flexion, 10 degrees extension, and 10 degrees lateral bending before and after simulated two-level ACDF with plate placement at C5-7. Intradiscal pressure was recorded at the C4-5 level, and segmental motion was recorded from C-4 through C-7. Differences in mean intradiscal pressures were calculated and analyzed using a paired Student t-test. When the maximum calibrated intradiscal pressures were exceeded ("overshot") during measurements, data from the specimens involved were analyzed using the motion data with a Student t-test. Values for pressure and motion obtained before and after simulated ACDF were compared. RESULTS: During flexion, the mean intradiscal pressure changes (+/- standard deviations) in the pre- and post-ACDF measurements were 1275 (+/- 225) mm Hg and 2475 (+/- 75) mm Hg, respectively (p < 0.05). When the results of pre-ACDF testing were compared with post-ACDF results, no significant difference was found in the mean changes in the intradiscal pressure during extension and lateral bending. The maximum calibrated intradiscal pressures were exceeded during the post-ACDF testing in four specimens in extension, three in flexion, and two in lateral bending. Comparison of pre- and post-ACDF data for all five specimens revealed significant differences in motion and intradiscal pressure (p < 0.05) during flexion, significant differences in motion (p < 0.05) but not in intradiscal pressure during extension, and significant differences in intradiscal pressure changes (p < 0.05) but not in motion during lateral bending. CONCLUSIONS: Simulated C5-7 ACDF caused a significant increase in intradiscal pressure and segmental motion in the superior adjacent C4-5 level during physiological motion. The increased pressure and hypermobility might accelerate normal degenerative changes in the vertebral levels adjacent to the anterior cervical fusion.

Modified anatrophic nephrolithotomy: A useful treatment option for complete complex staghorn calculi.

INTRODUCTION: Management of complete staghorn calculi represents a challenging problem for urologists. We describe our technique and clinical experience with modified anatrophic nephrolithotomy in patients harboring large, extensively branched staghorn calculi. MATERIALS AND METHODS: From October 1996 to February 2005 twenty-six patients with complete staghorn calculi defined as filling the entire collecting system or at least 80% of it, were treated employing a modification of the classical anatrophic nephrolithotomy technique. The mean patient age was 46 (range 16-70) years and the mean stone size was 3150 (range 1375-4800) mm2. Intra-operative data, complications and stone-free rates were recorded. Long-term follow-up was completed in 22 patients with a mean duration of 38 (range 12-96) months. Renal function was evaluated by 99mTc dimercapto succinic acid renal scintigraphy before and 6 months after treatment. RESULTS: The mean ischemia time was 36 (range 20-45) minutes, mean operative time was 195 (range 170-235) minutes and the mean blood loss was 475 (range 300-750) ml. Length of hospital stay averaged 8.8 days. One patient developed significant hematuria requiring renal angiography and embolization of a pseudoaneurysm. Overall, 22 patients (85%) were rendered stone-free at discharge while 23 patients (88%) were observed to be stone-free after 3 months. Long-term follow-up demonstrated recurrent stone fragments less than 4 mm in three patients. Isotope studies revealed that renal function remained unchanged in 55%, improved in 32% and became worse in the small number of remaining patients. CONCLUSIONS: Modified anatrophic nephrolithotomy is a valuable treatment option for patients with complete staghorn calculi. Because of its efficacy, safety and simplicity we believe that the use of this surgical procedure is warranted in patients with a large, extensively branched, complex renal stone burden.

Injurious Loading of Articular Cartilage Compromises Chondrocyte Respiratory Function.

OBJECTIVE: To determine whether repeatedly overloading healthy cartilage disrupts mitochondrial function in a manner similar to that associated with osteoarthritis (OA) pathogenesis. METHODS: We exposed normal articular cartilage on bovine osteochondral explants to 1 day or 7 consecutive days of cyclic axial compression (0.25 MPa or 1.0 MPa at 0.5 Hz for 3 hours) and evaluated the effects on chondrocyte viability, ATP concentration, reactive oxygen species (ROS) production, indicators of oxidative stress, respiration, and mitochondrial membrane potential. RESULTS: Neither 0.25 MPa nor 1.0 MPa of cyclic compression caused extensive chondrocyte death, macroscopic tissue damage, or overt changes in stress-strain behavior. After 1 day of loading, differences in respiratory activities between the 0.25 MPa and 1.0 MPa groups were minimal; however, after 7 days of loading, respiratory activity and ATP levels were suppressed in the 1.0 MPa group relative to the 0.25 MPa group, an effect prevented by pretreatment with 10 mM N-acetylcysteine. These changes were accompanied by increased proton leakage and decreased mitochondrial membrane potential, as well as by increased ROS formation, as indicated by dihydroethidium staining and glutathione oxidation. CONCLUSION: Repeated overloading leads to chondrocyte oxidant-dependent mitochondrial dysfunction. This mitochondrial dysfunction may contribute to destabilization of cartilage during various stages of OA in distinct ways by disrupting chondrocyte anabolic responses to mechanical stimuli.

Holmium laser cystolithotripsy in children: initial experience.

INTRODUCTION: Management of vesical calculi in children poses an interesting challenge to the urologist. The treatment options currently available include open surgery, transurethral pneumatic cystolithotripsy, percutaneous suprapubic cystolithotomy and shockwave lithotripsy (SWL). Holmium: YAG (Ho: YAG) laser cystolithotripsy represents a novel modality of treatment that is minimally invasive. MATERIALS AND METHODS: From July 1999 to January 2003 we treated 23 children with vesical calculi using transurethral Ho: YAG laser lithotripsy. The indications for cystolithotripsy were stone size < or = 4 cm (N=19), or multiple stones with combined stone burden < or = 4 cm (N=4). The mean patient age was 7.8 (range 2-12) years and the mean stone size was 2.7 (range 0.9-4) cm. Access was obtained with an 8F ureteroscope and holmium laser energy (0.6-1.8 J/pulse at 5-12 Hz) was applied through a 550-mum. end-firing fibre under video guidance. The calculi were pulverized to tiny fragments about 2-3 mm in size. An 8F urinary catheter was placed for one night in all patients. Post-operatively the children were evaluated at 3 and 18 months with radiological imaging and uroflowmetry to confirm stone-free status and exclude urethral stricture formation. RESULTS: The mean duration of the endoscopic procedure was 38 (range 19-62) minutes while the mean length of hospital stay was 2.2 (range 2-3) days. All the children were rendered stone-free following a single operative session. Laser-induced major complications were not observed in any of the children. At the mean follow-up of 42 (range 26-69) months none of the children developed stone recurrence, urinary tract infections or urethral strictures. CONCLUSIONS: Transurethral Ho: YAG laser lithotripsy was found to be an efficient and safe modality for the treatment of vesical calculi in children.

Modeling and simulation of the effects of cyclic loading on articular cartilage lesion formation.

We present a model of articular cartilage lesion formation to simulate the effects of cyclic loading. This model extends and modifies the reaction-diffusion-delay model by Graham et al., 2012 for the spread of a lesion formed though a single traumatic event. Our model represents 'implicitly' the effects of loading, meaning through a cyclic sink term in the equations for live cells. Our model forms the basis for in silico studies of cartilage damage relevant to questions in osteoarthritis, for example, that may not be easily answered through in vivo or in vitro studies. Computational results are presented that indicate the impact of differing levels of erythropoietin on articular cartilage lesion abatement.

Organ culture stability of the intervertebral disc: rat versus rabbit.

There is a need to develop mechanically active culture systems to better understand the role of mechanical stresses in intervertebral disc (IVD) degeneration. Motion segment cultures that preserve the native IVD structure and adjacent vertebral bodies are preferred as model systems, but rapid ex vivo tissue degeneration limits their usefulness. The stability of rat and rabbit IVDs is of particular interest, as their small size makes them otherwise suitable for motion segment culture. The goal of this study was to determine if there are substantial differences in the susceptibility of rat and rabbit IVDs to culture-induced degeneration. Lumbar IVD motion segments were harvested from young adult male Sprague-Dawley rats and New Zealand White rabbits and cultured under standard conditions for 14 days. Biochemical assays and safranin-O histology showed that while glycosaminoglycan (GAG) loss was minimal in rabbit IVDs, it was progressive and severe in rat IVDs. In the rat IVD, GAG loss was concomitant with the loss of notochordal cells and the migration of endplate (EP) cells into the nucleus pulposus (NP). None of these changes were evident in the rabbit IVDs. Compared to rabbit IVDs, rat IVDs also showed increased matrix metalloproteinase-3 (MMP-3) and sharply decreased collagen type I and II collagen expression. Together these data indicated that the rabbit IVD was dramatically more stable than the rat IVD, which showed culture-related degenerative changes. Based on these findings we conclude that the rabbit motion segments are a superior model for mechanobiologic studies.

Mechanical stress and ATP synthesis are coupled by mitochondrial oxidants in articular cartilage.

Metabolic adaptation of articular cartilage under joint loading is evident and matrix synthesis seems to be critically tied to ATP. Chondrocytes utilize the glycolytic pathway for energy requirements but seem to require mitochondrial reactive oxygen species (ROS) to sustain ATP synthesis. The role of ROS in regulating ATP reserves under a mechanically active environment is not clear. It is believed that physiological strains cause deformation of the mitochondria, potentially releasing ROS for energy production. We hypothesized that mechanical loading stimulates ATP synthesis via mitochondrial release of ROS. Bovine osteochondral explants were dynamically loaded at 0.5 Hz with amplitude of 0.25 MPa for 1 h. Cartilage response to mechanical loading was assessed by imaging with dihydroethidium (ROS indicator) and a Luciferase-based ATP assay. Electron transport inhibitor rotenone and mitochondrial ROS scavenger MitoQ significantly suppressed mechanically induced ROS production and ATP synthesis. Our findings indicate that mitochondrial ROS are produced as a result of physiological mechanical strains. Taken together with our previous findings of ROS involvement in blunt impact injuries, mitochondrial ROS are important contributors to cartilage metabolic adaptation and their precise role in the pathogenesis of osteoarthritis warrants further investigation.

Biocompatibility and preclinical feasibility tests of a temperature-sensitive hydrogel for the purpose of surgical wound pain control and cartilage repair.

We recently introduced a novel pluronic F127 and hyaluronic acid-based hydrogel (HG) designed to deliver a broad range of therapeutics. The reverse-thermal responsive HG exhibits physical properties that seem to be ideal for the local delivery of drug- and cell-based therapies to specific anatomic sites through percutaneous injection. However, questions related to the HG's safety and efficacy must first be addressed. To address these issues, we performed standard in vitro cytotoxicity and drug release tests and in vivo biocompatibility tests in a rat model. In addition, we determined whether the HG was an effective stem cell carrier in a rat cartilage defect model. We found that the HG showed viability and biocompatibility levels similar to those reported for F127 or hyaluronic acid alone. In vitro drug release studies with bupivacaine, a drug used clinically for local pain relief, revealed that after an initial burst bupivacaine was released continuously for 10 days. Stem cells loaded in the HG were retained in situ and stimulated cartilage regeneration in experimental defects. Taken as a whole, these findings support further efforts to develop the HG as a versatile system for the delivery of a wide range of therapeutic agents in humans. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.

Biocompatibility and preclinical feasibility tests of a temperature-sensitive hydrogel for the purpose of surgical wound pain control and cartilage repair.

We recently introduced a novel pluronic F127 and hyaluronic acid-based hydrogel (HG) designed to deliver a broad range of therapeutics. The reverse-thermal responsive HG exhibits physical properties that seem to be ideal for the local delivery of drug- and cell-based therapies to specific anatomic sites through percutaneous injection. However, questions related to the HG's safety and efficacy must first be addressed. To address these issues, we performed standard in vitro cytotoxicity and drug release tests and in vivo biocompatibility tests in a rat model. In addition, we determined whether the HG was an effective stem cell carrier in a rat cartilage defect model. We found that the HG showed viability and biocompatibility levels similar to those reported for F127 or hyaluronic acid alone. In vitro drug release studies with bupivacaine, a drug used clinically for local pain relief, revealed that after an initial burst bupivacaine was released continuously for 10 days. Stem cells loaded in the HG were retained in situ and stimulated cartilage regeneration in experimental defects. Taken as a whole, these findings support further efforts to develop the HG as a versatile system for the delivery of a wide range of therapeutic agents in humans.

Reaction-diffusion-delay model for EPO/TNF-α interaction in articular cartilage lesion abatement.

BACKGROUND: Injuries to articular cartilage result in the development of lesions that form on the surface of the cartilage. Such lesions are associated with articular cartilage degeneration and osteoarthritis. The typical injury response often causes collateral damage, primarily an effect of inflammation, which results in the spread of lesions beyond the region where the initial injury occurs. RESULTS AND DISCUSSION: We present a minimal mathematical model based on known mechanisms to investigate the spread and abatement of such lesions. The first case corresponds to the parameter values listed in Table 1, while the second case has parameter values as in Table 2. In particular we represent the "balancing act" between pro-inflammatory and anti-inflammatory cytokines that is hypothesized to be a principal mechanism in the expansion properties of cartilage damage during the typical injury response. We present preliminary results of in vitro studies that confirm the anti-inflammatory activities of the cytokine erythropoietin (EPO). We assume that the diffusion of cytokines determine the spatial behavior of injury response and lesion expansion so that a reaction diffusion system involving chemical species and chondrocyte cell state population densities is a natural way to represent cartilage injury response. We present computational results using the mathematical model showing that our representation is successful in capturing much of the interesting spatial behavior of injury associated lesion development and abatement in articular cartilage. Further, we discuss the use of this model to study the possibility of using EPO as a therapy for reducing the amount of inflammation induced collateral damage to cartilage during the typical injury response. CONCLUSIONS: The mathematical model presented herein suggests that not only are anti-inflammatory cytokines, such as EPO necessary to prevent chondrocytes signaled by pro-inflammatory cytokines from entering apoptosis, they may also influence how chondrocytes respond to signaling by pro-inflammatory cytokines.

Towards a new spatial representation of bone remodeling.

Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed. There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes. We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur in vitro and in vivo. By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as in vitro and in vivo. This makes it possible to perform in silica experiments more closely resembling experimental observations.

Selection of reference genes for normalization of quantitative real-time PCR in organ culture of the rat and rabbit intervertebral disc.

BACKGROUND: The accuracy of quantitative real-time RT-PCR (qRT-PCR) is often influenced by experimental artifacts, resulting in erroneous expression profiles of target genes. The practice of employing normalization using a reference gene significantly improves reliability and its applicability to molecular biology. However, selection of an ideal reference gene(s) is of critical importance to discern meaningful results. The aim of this study was to evaluate the stability of seven potential reference genes (Actb, GAPDH, 18S rRNA, CycA, Hprt1, Ywhaz, and Pgk1) and identify most stable gene(s) for application in tissue culture research using the rat and rabbit intervertebral disc (IVD). FINDINGS: In vitro, four genes (Hprt1, CycA, GAPDH, and 18S rRNA) in rat IVD tissue and five genes (CycA, Hprt1, Actb, Pgk1, and Ywhaz) in rabbit IVD tissue were determined as most stable for up to 14 days in culture. Pair-wise variation analysis indicated that combination of Hprt1 and CycA in rat and the combination of Hprt1, CycA, and Actb in rabbit may most stable reference gene candidates for IVD tissue culture. CONCLUSIONS: Our results indicate that Hprt1 and CycA are the most stable reference gene candidates for rat and rabbit IVD culture studies. In rabbit IVD, Actb could be an additional gene employed in conjunction with Hprt1 and CycA. Selection of optimal reference gene candidate(s) should be a pertinent exercise before employment of PCR outcome measures for biomedical research.

Oxidant conditioning protects cartilage from mechanically induced damage.

Articular cartilage degeneration in osteoarthritis has been linked to abnormal mechanical stresses that are known to cause chondrocyte apoptosis and metabolic derangement in in vitro models. Evidence implicating oxidative damage as the immediate cause of these harmful effects suggests that the antioxidant defenses of chondrocytes might influence their tolerance for mechanical injury. Based on evidence that antioxidant defenses in many cell types are stimulated by moderate oxidant exposure, we hypothesized that oxidant preconditioning would reduce acute chondrocyte death and proteoglycan depletion in cartilage explants after exposure to abnormal mechanical stresses. Porcine cartilage explants were treated every 48 h with tert-butyl hydrogen peroxide (tBHP) at nonlethal concentrations (25, 100, 250, and 500 microM) for a varying number of times (one, two, or four) prior to a bout of unconfined axial compression (5 MPa, 1 Hz, 1800 cycles). When compared with untreated controls, tBHP had significant positive effects on post-compression viability, lactate production, and proteoglycan losses. Overall, the most effective regime was 100 microM tBHP applied four times. RNA analysis revealed significant effects of 100 microM tBHP on gene expression. Catalase, hypoxia-inducible factor-1alpha (HIF-1alpha), and glyceraldehyde 6-phosphate dehydrogenase (GAPDH) were significantly increased relative to untreated controls in explants treated four times with 100 microM tBHP, a regime that also resulted in a significant decrease in matrix metalloproteinase-3 (MMP-3) expression. These findings demonstrate that repeated exposure of cartilage to sublethal concentrations of peroxide can moderate the acute effects of mechanical stress, a conclusion supported by evidence of peroxide-induced changes in gene expression that could render chondrocytes more resistant to oxidative damage.

Rat spinal motion segment in organ culture: a cell viability study.

STUDY DESIGN: This study investigated tissue integrity and viability of cells in an organ culture system of intervertebral disc (IVD) with adjoining vertebral bodies. OBJECTIVE: The goal of this study was to design a methodology to maintain an IVD motion segment in organ culture, thereby preserving viability and tissue architecture. SUMMARY OF BACKGROUND DATA: Study of IVD mechanobiology in vitro necessitates availability of vertebral bodies for controlled application of complex loads. METHODS: IVD motion segments were dissected from rat lumbar segments and maintained in organ culture and cell viability was evaluated histochemically using NitroBlue Tetrazolium. Tissue integrity and morphology were evaluated using conventional histologic techniques. RESULTS: The in vitro organ culture of motion segments maintained the viability and tissue integrity for 14 days. More than 95% viability in all three regions of interest (anulus fibrosus, nucleus pulposus, end plates) was maintained for 14 days in culture. CONCLUSION: Our initial results suggest that long-term motion segment culture is practical, and the inclusion of vertebral bodies will facilitate anchoring during biomechanical stimulation. Thus, we expect the culture system to provide us with an excellent model for studying the pathomechanics of IVD degeneration and the effects of mechanical stimulation on the biology of IVD cells.