AO Spine Guideline for the Use of Osteobiologics (AOGO) in Anterior Cervical Discectomy and Fusion for Spinal Degenerative Cases.

STUDY DESIGN: Guideline. OBJECTIVES: To develop an international guideline (AOGO) about the use of osteobiologics in anterior cervical discectomy and fusion (ACDF) for treating degenerative spine conditions. METHODS: The guideline development process was guided by AO Spine Knowledge Forum Degenerative (KF Degen) and followed the Guideline International Network McMaster Guideline Development Checklist. The process involved 73 participants with expertise in degenerative spine diseases and surgery from 22 countries. Fifteen systematic reviews were conducted addressing respective key topics and evidence was collected. The methodologist compiled the evidence into GRADE Evidence-to-Decision frameworks. Guideline panel members judged the outcomes and other criteria and made the final recommendations through consensus. RESULTS: Five conditional recommendations were created. A conditional recommendation is about the use of allograft, autograft or a cage with an osteobiologic in primary ACDF surgery. Other conditional recommendations are about the use of osteobiologic for single- or multi-level ACDF, and for hybrid construct surgery. It is suggested that surgeons use other osteobiologics rather than human bone morphogenetic protein-2 (BMP-2) in common clinical situations. Surgeons are recommended to choose 1 graft over another or 1 osteobiologic over another primarily based on clinical situation, and the costs and availability of the materials. CONCLUSION: This AOGO guideline is the first to provide recommendations for the use of osteobiologics in ACDF. Despite the comprehensive searches for evidence, there were few studies completed with small sample sizes and primarily as case series with inherent risks of bias. Therefore, high-quality clinical evidence is demanded to improve the guideline.

The Use of Osteobiologics in Single versus Multi-Level Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic literature review. OBJECTIVES: In this study we assessed evidence for the use of osteobiologics in single vs multi-level anterior cervical discectomy and fusion (ACDF) in patients with cervical spine degeneration. The primary objective was to compare fusion rates after single and multi-level surgery with different osteobiologics. Secondary objectives were to compare differences in patient reported outcome measures (PROMs) and complications. METHODS: After a global team of reviewers was selected, a systematic review using different repositories was performed, confirming to PRISMA and GRADE guidelines. In total 1206 articles were identified and after applying inclusion and exclusion criteria, 11 articles were eligible for analysis. Extracted data included fusion rates, definition of fusion, patient reported outcome measures, types of osteobiologics used, complications, adverse events and revisions. RESULTS: Fusion rates ranged from 87.7% to 100% for bone morphogenetic protein 2 (BMP-2) and 88.6% to 94.7% for demineralized bone matrix, while fusion rates reported for other osteobiologics were lower. All included studies showed PROMs improved significantly for each osteobiologic. However, no differences were reported when comparing osteobiologics, or when comparing single vs multi-level surgery specifically. CONCLUSION: The highest fusion rates after 2-level ACDF for cervical spine degeneration were reported when BMP-2 was used. However, PROMs did not differ between the different osteobiologics. Further blinded randomized trials should be performed to compare the use of BMP-2 in single vs multi-level ACDF specifically.

[Staphylococcus aureus osteomyelitis in children]. / Atypisch beloop van osteomyelitis doorStaphylococcus aureus bij kinderen.

Osteomyelitis is an infectious disease of the bone that primarily affects children. Here we discuss three patients, aged 11-13 years that were diagnosed with osteomyelitis. Despite the fact that in all three patients the infection was caused by the Staphylococcus Aureus bacteria, the clinical presentation and diagnostic results in all three was different. This case report presents various courses of the same disease, each with a slightly different treatment and outcome. Although the incidence of osteomyelitis is decreasing, it is of great importance to consider osteomyelitis as a diagnosis in pediatric bone complaints so that it can be recognized and treated in time to decrease the risk of bone destruction and growth disorders.

Development of a national medical leadership competency framework: the Dutch approach.

BACKGROUND: The concept of medical leadership (ML) can enhance physicians' inclusion in efforts for higher quality healthcare. Despite ML's spiking popularity, only a few countries have built a national taxonomy to facilitate ML competency education and training. In this paper we discuss the development of the Dutch ML competency framework with two objectives: to account for the framework's making and to complement to known approaches of developing such frameworks. METHODS: We designed a research approach and analyzed data from multiple sources based on Grounded Theory. Facilitated by the Royal Dutch Medical Association, a group of 14 volunteer researchers met over a period of 2.5 years to perform: 1) literature review; 2) individual interviews; 3) focus groups; 4) online surveys; 5) international framework comparison; and 6) comprehensive data synthesis. RESULTS: The developmental processes that led to the framework provided a taxonomic depiction of ML in Dutch perspective. It can be seen as a canonical 'knowledge artefact' created by a community of practice and comprises of a contemporary definition of ML and 12 domains, each entailing four distinct ML competencies. CONCLUSIONS: This paper demonstrates how a new language for ML can be created in a healthcare system. The success of our approach to capture insights, expectations and demands relating leadership by Dutch physicians depended on close involvement of the Dutch national medical associations and a nationally active community of practice; voluntary work of diverse researchers and medical practitioners and an appropriate research design that used multiple methods and strategies to circumvent reverberation of established opinions and conventionalisms. IMPLICATIONS: The experiences reported here may provide inspiration and guidance for those anticipating similar work in other countries to develop a tailored approach to create a ML framework.

Tandem Disc Herniation of the Lumbar and Cervical Spine: Case Series and Review of the Epidemiological, Pathophysiological and Genetic Literature.

Introduction Lumbar disc herniation (LDH) and cervical disc herniation (CDH) represent a relevant public health problem. Patients with symptomatic tandem herniations of the cervical and lumbar spine are rare and not described in the literature. In these patients, certain variables may predispose the development of disc herniation which could increase the understanding of the development of disc herniations. Our aim is to present the first case series of tandem disc herniation, and to elucidate whether tandem herniation is attributable to a certain propensity for disc herniation or not. Methods  From a prospective registry, patients with symptomatic tandem disc herniations were included, and the literature was reviewed on the comparative pathophysiology, genetics, and epidemiology of disc herniation and disc degeneration. Results Out of 3,156 patients with disc herniations in our registry, 16 presented with symptomatic tandem LDH and CDH that required discectomy. Therefore, we estimate the incidence of tandem disc herniation at 0.51% (95% confidence interval (CI): 0.26% - 0.75%) in the surgical population. The mean number of degenerated lumbar discs was 2.1 ± 1.1. Compared to the 1,241 patients with isolated LDH, no investigated factors were significantly associated with tandem herniations. Conclusion From a genetic, pathophysiological, and epidemiological position, disc herniation is not commonly a consequence of disc degeneration. Rather, degeneration and herniation seem to exist as two separate and distinctly different processes. Based on the literature, it is tenable that tandem disc herniation does not deviate from the normal pathophysiology, but rather occurs in the rare case that two individual herniated discs coincide.

Changes in Intervertebral Disk Mechanical Behavior During Early Degeneration.

Intervertebral disk (IVD) degeneration is commonly described by loss of height and hydration. However, in the first stage of IVD degeneration, this loss has not yet occurred. In the current study, we use an ex vivo degeneration model to analyze the changes in IVDs mechanical behavior in the first phase of degeneration. We characterize these changes by stretched-exponential fitting, and suggest the fitted parameters as markers for early degeneration. Enzymatic degeneration of healthy lumbar caprine IVDs was induced by injecting 100 µL of Chondroïtinase ABC (Cabc) into the nucleus. A no-intervention and phosphate buffered saline (PBS) injected group were used as controls. IVDs were cultured in a bioreactor for 20 days under diurnal, simulated-physiological loading (SPL) conditions. Disk deformation was continuously monitored. Changes in disk height recovery behavior were quantified using stretched-exponential fitting. Disk height, histological sections, and water- and glycosaminoglycan (GAG)-content measurements were used as gold standards for the degenerative state. Cabc injection caused significant GAG loss from the nucleus and had detrimental effects on poro-elastic mechanical properties of the IVDs. These were progressive over time, with a propensity toward more linear recovery behavior. On histological sections, both PBS and Cabc injected IVDs showed moderate degeneration. A small GAG loss yields changes in IVD recovery behavior, which can be quantified with stretched-exponential fitting. Parameters changed significantly compared to control. Studies on disk degeneration and biomaterial engineering for degenerative disk disease (DDD) could benefit from focusing on IVD biomechanical behavior rather than height and water-content, as a marker for early disk degeneration.

Osteoarthritis and intervertebral disc degeneration: Quite different, quite similar.

Intervertebral disc degeneration describes the vicious cycle of the deterioration of intervertebral discs and can eventually result in degenerative disc disease (DDD), which is accompanied by low-back pain, the musculoskeletal disorder with the largest socioeconomic impact world-wide. In more severe stages, intervertebral disc degeneration is accompanied by loss of joint space, subchondral sclerosis, and osteophytes, similar to osteoarthritis (OA) in the articular joint. Inspired by this resemblance, we investigated the analogy between human intervertebral discs and articular joints. Although embryonic origin and anatomy suggest substantial differences between the two types of joint, some features of cell physiology and extracellular matrix in the nucleus pulposus and articular cartilage share numerous parallels. Moreover, there are great similarities in the response to mechanical loading and the matrix-degrading factors involved in the cascade of degeneration in both tissues. This suggests that the local environment of the cell is more important to its behavior than embryonic origin. Nevertheless, OA is widely regarded as a true disease, while intervertebral disc degeneration is often regarded as a radiological finding and DDD is undervalued as a cause of chronic low-back pain by clinicians, patients and society. Emphasizing the similarities rather than the differences between the two diseases may create more awareness in the clinic, improve diagnostics in DDD, and provide cross-fertilization of clinicians and scientists involved in both intervertebral disc degeneration and OA.

Identifying subsets of patients with single-level degenerative disc disease for lumbar fusion: the value of prognostic tests in surgical decision making.

BACKGROUND CONTEXT: Fusion surgery for degenerative disc disease (DDD) has become a standard of care, albeit not without controversy. Outcomes are inconsistent and a superiority over conservative treatment is debatable. Proper patient selection is key to clinical success, and a comprehensive understanding of prognostic tests does not currently exist. PURPOSE: This study aimed to investigate the value of prognostic tests and sociodemographic factors in predicting outcomes following lumbar fusion surgery for DDD. STUDY DESIGN: This is a retrospective analysis of prospectively collected data. PATIENT SAMPLE: We included patients who underwent fusion surgery for DDD between 2010 and 2016. OUTCOME MEASURES: The outcome measures included pre- and postoperative visual analog scale and Oswestry Disability Index scores. MATERIALS AND METHODS: Prospectively collected patient data were reviewed for preoperative tests, perioperative data, and clinical outcomes. Prognostic tests used were discography, pantaloon cast test (PCT), Modic changes, and a summary of physical symptoms, coined "loading factor." By means of multivariate stepwise regression, prognostic factors that were useful in predicting outcomes were identified. RESULTS: A total of 91 patients fit the inclusion criteria, with a mean follow-up of 33±16 months. Discography, Modic changes, and loading factor were of no value for predicting outcome scores (p>.05). A positive PCT predicted improved outcomes in back pain severity, but only in patients without prior surgery (p=.02). Demographic factors that showed a consistent reduction in back pain were female sex (p=.021) and no prior surgery at index level (p=.009). No other sociodemographic factors were of predictive value (p>.05). CONCLUSIONS: In patients without prior surgery, the PCT appears to be the most promising prognostic tool. Other prognostic selection tools such as discography and Modic changes yield disappointing results. In this study, female patients and those without prior spine surgery appear to be most likely to benefit from fusion surgery for DDD.

Are axial intervertebral disc biomechanics determined by osmosis?

The intervertebral disc faces high compressive forces during daily activities. Axial compression induces creeping fluid loss and reduction in disc height. With degeneration, disc fluids and height are progressively lost, altering biomechanics. It is assumed that this reduction of fluids is caused by a decline of osmolality within the disc due to proteoglycan depletion. Here we investigate the isolated effect of a reduction in osmosis on the biomechanical properties of the intervertebral disc. Continuous diurnal loading was applied to healthy caprine intervertebral discs in a loaded disc culture system for a total of 6days. We increased testing bath osmolality with two doses of polyethylene-glycol (PEG), thereby reducing the osmotic gradient between the disc and the surrounding fluid. This way we could study the isolated effect of reduced osmosis on axial creep, without damaging the disc. We evaluated: daily creep and recovery, recovery time-constants and compressive stiffness. Additionally, we investigated water content. There was a strong dose-dependent effect of PEG concentration on water content and axial creep behaviour: disc height, amplitude and rate of creep and recovery were all significantly reduced. Axial compressive stiffness of the disc was not affected. Reduction of water content and amplitude of creep and recovery showed similarity to degenerative disc biomechanics. However, the time-constants increased, indicating that the hydraulic permeability was reduced, in contrast to what happens with degeneration. This suggests that besides the osmotic gradient, the permeability of the tissues determines healthy intervertebral disc biomechanics.

Intradiscal pressure measurements: A challenge or a routine?

Intradiscal pressure (IDP) is an essential biomechanical parameter and has been the subject of numerous in vivo and in vitro investigations. Although currently available sensors differ in size and measurement principles, no data exist regarding inter-sensor reliability in measuring IDP. Moreover, although discs of various species vary significantly in size and mechanics, the possible effects of sensor insertion on the IDP have never been investigated. The present in vitro study aimed to address these issues. The synchronized signals of two differently sized pressure transducers (Ø1.33 and Ø0.36 mm) obtained during the measurements in two species (bovine and caprine) and their influence on the measured pressure were compared. First, the discs were subjected to three loading periods, and the pressure was measured simultaneously to assess the inter-sensor reliability. In the second test, the effect of the sensor size was evaluated by alternatingly inserting one transducer into the disc while recording the resulting pressure change with the second transducer. Although both sensors yielded similar pressure values (ICC: consistency: 0.964-0.999; absolute agreement: 0.845-0.996) when used simultaneously, the sensor size was determined to influence the measured pressure during the insertion tests. The magnitude of the effect differed between species; it was insignificant in the bovine specimens but significant in the caprine specimens, with a pressure increase of 0.31-0.64 MPa (median: 0.43 MPa) obtained when the larger sensor was inserted. The results suggest that sensor selection for IDP measurements requires special attention and can be crucial for species with smaller disc sizes.

Can Exercise Positively Influence the Intervertebral Disc?

To better understand what kinds of sports and exercise could be beneficial for the intervertebral disc (IVD), we performed a review to synthesise the literature on IVD adaptation with loading and exercise. The state of the literature did not permit a systematic review; therefore, we performed a narrative review. The majority of the available data come from cell or whole-disc loading models and animal exercise models. However, some studies have examined the impact of specific sports on IVD degeneration in humans and acute exercise on disc size. Based on the data available in the literature, loading types that are likely beneficial to the IVD are dynamic, axial, at slow to moderate movement speeds, and of a magnitude experienced in walking and jogging. Static loading, torsional loading, flexion with compression, rapid loading, high-impact loading and explosive tasks are likely detrimental for the IVD. Reduced physical activity and disuse appear to be detrimental for the IVD. We also consider the impact of genetics and the likelihood of a 'critical period' for the effect of exercise in IVD development. The current review summarises the literature to increase awareness amongst exercise, rehabilitation and ergonomic professionals regarding IVD health and provides recommendations on future directions in research.

The poro-elastic behaviour of the intervertebral disc: A new perspective on diurnal fluid flow.

Diurnal disc height changes, due to fluid in- and outflow, are in equilibrium while daytime spinal loading is twice as long as night time rest. A direction-dependent permeability of the endplates, favouring inflow over outflow, reportedly explains this; however, fluid flow through the annulus fibrosus should be considered. This study investigates the fluid flow of entire intervertebral discs. Caprine discs were preloaded in saline for 24h under four levels of static load. Under sustained load, we modulated the disc׳s swelling pressure by exchanging saline for demineralised water (inflow) and back to saline (outflow), both for 24h. We measured disc height creep and used stretched exponential models to determine time-constants. During inflow disc height increased in relation to applied load, and during outflow disc height decreased to preload levels. When comparing in- and outflow phases, there was no difference in creep, and time-constants were similar indicating no direction-dependent resistance to fluid flow in the entire intervertebral disc. Results provoked a new hypothesis for diurnal fluid flow: in vitro time-constants for loading are shorter than for unloading and in vivo daytime loading is twice as long as night time unloading, i.e. in diurnal loading the intervertebral disc is closer to loading equilibrium than to unloading equilibrium. Per definition, fluid flow is slower close to equilibrium than far from equilibrium; therefore, as diurnal loading occurs closer to loading equilibrium, fluid inflow during night time unloading can balance fluid outflow during daytime loading, despite a longer time-constant.

Bioluminescence-mediated longitudinal monitoring of adipose-derived stem cells in a large mammal ex vivo organ culture.

Recently, ex vivo three-dimensional organ culture systems have emerged to study the physiology and pathophysiology of human organs. These systems also have potential as a translational tool in tissue engineering; however, this potential is limited by our ability to longitudinally monitor the fate and action of cells used in regenerative therapies. Therefore, we investigated luciferase-mediated bioluminescence imaging (BLI) as a non-invasive technique to continuously monitor cellular behavior in ex vivo whole organ culture. Goat adipose-derived stem cells (gADSCs) were transduced with either Firefly luciferase (Fluc) or Gaussia luciferase (Gluc) reporter genes and injected in isolated goat intervertebral discs (IVD). Luciferase activity was monitored by BLI for at least seven days of culture. Additionally, possible confounders specific to avascular organ culture were investigated. Gluc imaging proved to be more suitable compared to Fluc in monitoring gADSCs in goat IVDs. We conclude that BLI is a promising tool to monitor spatial and temporal cellular behavior in ex vivo organ culture. Hence, ex vivo organ culture systems allow pre-screening and pre-validation of novel therapeutic concepts prior to in vivo large animal experimentation. Thereby, organ culture systems can reduce animal use, and improve the speed of innovation by overcoming technological, ethical and financial challenges.

The effects of single-level instrumented lumbar laminectomy on adjacent spinal biomechanics.

Study Design Biomechanical study. Objective Posterior instrumentation is used to stabilize the spine after a lumbar laminectomy. However, the effects on the adjacent segmental stability are unknown. Therefore, we studied the range of motion (ROM) and stiffness of treated lumbar spinal segments and cranial segments after a laminectomy and after posterior instrumentation in flexion and extension (FE), lateral bending (LB), and axial rotation (AR). These outcomes might help to better understand adjacent segment disease (ASD), which is reported cranial to the level on which posterior instrumentation is applied. Methods We obtained 12 cadaveric human lumbar spines. Spines were axially loaded with 250 N for 1 hour. Thereafter, 10 consecutive load cycles (4 Nm) were applied in FE, LB, and AR. Subsequently, a laminectomy was performed either at L2 or at L4. Thereafter, load-deformation tests were repeated, after similar preloading. Finally, posterior instrumentation was added to the level treated with a laminectomy before testing was repeated. The ROM and stiffness of the treated, the cranial adjacent, and the control segments were calculated from the load-displacement data. Repeated-measures analyses of variance used the spinal level as the between-subject factor and a laminectomy or instrumentation as the within-subject factors. Results After the laminectomy, the ROM increased (+19.4%) and the stiffness decreased (-18.0%) in AR. The ROM in AR of the adjacent segments also increased (+11.0%). The ROM of treated segments after instrumentation decreased in FE (-74.3%), LB (-71.6%), and AR (-59.8%). In the adjacent segments after instrumentation, only the ROM in LB was changed (-12.9%). Conclusions The present findings do not substantiate a biomechanical pathway toward or explanation for ASD.

A biodegradable glue for annulus closure: evaluation of strength and endurance.

STUDY DESIGN: A biodegradable glue was biomechanically tested for annulus closure using nondegenerated goat intervertebral discs. Ultimate strength and endurance tests were performed using native and punctured discs as positive and negative controls, respectively. OBJECTIVE: The aim of this study was to investigate the feasibility and biomechanical properties of a biodegradable glue for annulus closure. SUMMARY OF BACKGROUND DATA: There is an unmet clinical need for annulus closure techniques. Isocyanate-terminated tissue glues show potential because they adhere to annulus tissue, have an elastic modulus similar to the annulus, and show limited cytotoxicity to human annulus fibrosus cells. METHODS: Three biomechanical tests were performed divided in 2 parts: part 1: ultimate strength tests comparing native, punctured (2.4-mm needle), and glued caprine intervertebral discs (n = 11 per group); part 2: 10 discs per group were subjected to a 10-day ex vivo endurance test of 864,000 load cycles, followed by ultimate strength tests. Outcome parameters include the restoration of strength after puncture, reduction of herniation in the endurance test, and conservation of glue strength after endurance testing. RESULTS: Part 1: The glue partially restored subsidence to failure and yield strength/ultimate strength ratio of intervertebral discs. Part 2: During endurance testing, 40% of punctured discs failed compared with none of the glued discs. Endurance testing did not affect glue strength, and pooling of ultimate strength tests showed that the glue restored ultimate strength, work to failure, and yield strength/ultimate strength to 79%, 75%, and 119% of native values, respectively. CONCLUSION: A biodegradable isocyanate-terminated glue increases the force at which nucleus protrusion occurs, and it limits herniations during endurance or ultimate strength tests. Biomechanical tests in a bioreactor provide a low-cost assessment for annulus repair strategies; however, the clinical efficacy needs to be further addressed using long-term in vivo studies. LEVEL OF EVIDENCE: N/A.

Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.

PURPOSE: Intervertebral discs exhibit time-dependent deformation (creep), which could influence the relation between applied stress and intradiscal pressure. This study investigates the effect of prolonged dynamic loading on intradiscal pressure, disc height and compressive stiffness, and examines their mutual relationships. METHODS: Fifteen caprine lumbar discs with 5 mm of vertebral bone on either side were compressed by 1 Hz sinusoidal load for 4.5 h. After preload, 'High' (130 ± 20 N) or 'Low' (50 ± 10 N) loads were alternated every half hour. Continuous intradiscal pressure measurement was performed with a pressure transducer needle. RESULTS: Each disc showed a linear relationship between axial compression and intradiscal pressure (R (2) > 0.91). The intercept of linear regression analysis declined over time, but the gradient remained constant. Disc height changes were correlated to intradiscal pressure changes (R (2) > 0.98): both decreased during High loading, and increased during Low loading. In contrast, compressive stiffness increased during High loading, and was inversely related to intradiscal pressure and disc height. CONCLUSIONS: Intradiscal pressure is influenced by recent loading due to fluid flow. The correlations found in this study suggest that intradiscal pressure is important for disc height and axial compliance. These findings are relevant for mechanobiology studies, nucleus replacements, finite element models, and ex vivo organ culture systems.

The use of poly(L-lactide-co-caprolactone) as a scaffold for adipose stem cells in bone tissue engineering: application in a spinal fusion model.

Since the early 1990s, tissue engineering has been heralded as a strategy that may solve problems associated with bone grafting procedures. The original concept of growing bone in the laboratory, however, has proven illusive due to biological, logistic, and regulatory problems. Fat-derived stem cells and synthetic polymers open new, more practicable routes for bone tissue engineering. In this paper, we highlight the potential of poly(L-lactide-co-caprolactone) (PLCL) to serve as a radiolucent scaffold in bone tissue engineering. It appears that PLCL quickly and preferentially binds adipose stem cells (ASCs), which proliferate rapidly and eventually differentiate into the osteogenic phenotype. An in vivo spinal fusion study in a goat model provides a preclinical proof-of-concept for a one-step surgical procedure with ASCs in bone tissue engineering.