Impact of the COVID-19 pandemic on the productivity and career prospects of musculoskeletal researchers.

Academic researchers faced a multitude of challenges posed by the COVID-19 pandemic, including widespread shelter-in-place orders, workplace closures, and cessation of in-person meetings and laboratory activities. The extent to which these challenges impacted musculoskeletal researchers, specifically, is unknown. We developed an anonymous web-based survey to determine the pandemic's impact on research productivity and career prospects among musculoskeletal research trainees and faculty. There were 116 musculoskeletal (MSK) researchers with varying demographic backgrounds who completed the survey. Of respondents, 48.3% (n = 56) believed that musculoskeletal funding opportunities decreased because of COVID-19, with faculty members more likely to hold this belief compared to nonfaculty researchers (p = 0.008). Amongst MSK researchers, 88.8% (n = 103) reported research activity was limited by COVID-19, and 92.2% (n = 107) of researchers reported their research was not able to be refocused on COVID-19-related topics, with basic science researchers less likely to be able to refocus their research compared to clinical researchers (p = 0.030). Additionally, 47.4% (n = 55) reported a decrease in manuscript submissions since the onset of the pandemic. Amongst 51 trainee researchers, 62.8% (n = 32) reported a decrease in job satisfaction directly attributable to the COVID-19 pandemic. In summary, study findings indicated that MSK researchers struggled to overcome challenges imposed by the pandemic, reporting declines in funding opportunities, research productivity, and manuscript submission. Trainee researchers experienced significant disruptions to critical research activities and worsening job satisfaction. Our findings motivate future efforts to support trainees in developing their careers and target the recovery of MSK research from the pandemic stall.

Accelerating cryoprotectant delivery using vacuum infiltration.

The ability to cryopreserve bone marrow within the vertebral body (VB) would offer significant clinical and research benefits. However, cryopreservation of large structures, such as VBs, is challenging due to mass transport limitations that prevent the effective delivery of cryoprotectants into the tissue. To overcome this challenge, we examined the potential of vacuum infiltration, along with carbonation, to increase the penetration of cryoprotectants. In particular, we hypothesized that initial exposure to high-pressure carbon dioxide gas would introduce bubbles into the tissue and that subsequent vacuum cycling would cause expansion and contraction of the bubbles, thus enhancing the transport of cryoprotectant into the tissue. Experiments were carried out using colored dye and agarose gel as a model revealing that carbonation and vacuum cycling result in a 14% increase in dye penetration compared to the atmospheric controls. Experiments were also carried out by exposing VBs isolated from human vertebrae to 40% (v/v) DMSO solution. CT imaging showed the presence of gas bubbles within the tissue pores for carbonated VBs as well as control VBs. Vacuum cycling reduced the bubble volume by more than 50%, most likely resulting in replacement of this volume with DMSO solution. However, we were unable to detect a statistically significant increase in DMSO concentration within the VBs using CT imaging. This research suggests that there may be a modest benefit to carbonation and vacuum cycling for introduction of cryoprotectants into larger structures, like VBs.

Bullying, harassment, and discrimination of musculoskeletal researchers and the impact of the COVID-19 pandemic: an international study.

PURPOSE: Bullying, harassment, and discrimination (BHD) are prevalent in academic, scientific, and clinical departments, particularly orthopedic surgery, and can have lasting effects on victims. As it is unclear how BHD affects musculoskeletal (MSK) researchers, the following study assessed BHD in the MSK research community and whether the COVID-19 pandemic, which caused hardships in other industries, had an impact. METHODS: A web-based anonymous survey was developed in English by ORS Spine Section members to assess the impact of COVID-19 on MSK researchers in North America, Europe, and Asia, which included questions to evaluate the personal experience of researchers regarding BHD. RESULTS: 116 MSK researchers completed the survey. Of respondents, 34.5% (n = 40) focused on spine, 30.2% (n = 35) had multiple areas of interest, and 35.3% (n = 41) represented other areas of MSK research. BHD was observed by 26.7% (n = 31) of respondents and personally experienced by 11.2% (n = 13), with mid-career faculty both observing and experiencing the most BHD. Most who experienced BHD (53.8%, n = 7) experienced multiple forms. 32.8% (n = 38) of respondents were not able to speak out about BHD without fear of repercussions, with 13.8% (n = 16) being unsure about this. Of those who observed BHD, 54.8% (n = 17) noted that the COVID-19 pandemic had no impact on their observations. CONCLUSIONS: To our knowledge, this is the first study to address the prevalence and determinants of BHD among MSK researchers. MSK researchers experienced and observed BHD, while many were not comfortable reporting and discussing violations to their institution. The COVID-19 pandemic had mixed-effects on BHD. Awareness and proactive policy changes may be warranted to reduce/eliminate the occurrence of BHD in this community.

Molecular and Genetic Mechanisms of Spinal Stenosis Formation: Systematic Review.

Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among people over 50 years old. We perform a systematic review of molecular and genetic mechanisms that cause SS. The five main mechanisms of SS were found to be ossification of the posterior longitudinal ligament (OPLL), hypertrophy and ossification of the ligamentum flavum (HLF/OLF), facet joint (FJ) osteoarthritis, herniation of the intervertebral disc (IVD), and achondroplasia. FJ osteoarthritis, OPLL, and HLF/OLFLF/OLF have all been associated with an over-abundance of transforming growth factor beta and genes related to this phenomenon. OPLL has also been associated with increased bone morphogenetic protein 2. FJ osteoarthritis is additionally associated with Wnt/ß-catenin signaling and genes. IVD herniation is associated with collagen type I alpha 1 and 2 gene mutations and subsequent protein dysregulation. Finally, achondroplasia is associated with fibroblast growth factor receptor 3 gene mutations and fibroblast growth factor signaling. Although most publications lack data on a direct relationship between the mutation and SS formation, it is clear that genetics has a direct impact on the formation of any pathology, including SS. Further studies are necessary to understand the genetic and molecular changes associated with SS.

Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology.

Dynamic loading is a shared feature of tendon tissue homeostasis and pathology. Tendon cells have the inherent ability to sense mechanical loads that initiate molecular-level mechanotransduction pathways. While mature tendons require physiological mechanical loading in order to maintain and fine tune their extracellular matrix architecture, pathological loading initiates an inflammatory-mediated tissue repair pathway that may ultimately result in extracellular matrix dysregulation and tendon degeneration. The exact loading and inflammatory mechanisms involved in tendon healing and pathology is unclear although a precise understanding is imperative to improving therapeutic outcomes of tendon pathologies. Thus, various model systems have been designed to help elucidate the underlying mechanisms of tendon mechanobiology via mimicry of the in vivo tendon architecture and biomechanics. Recent development of model systems has focused on identifying mechanoresponses to various mechanical loading platforms. Less effort has been placed on identifying inflammatory pathways involved in tendon pathology etiology, though inflammation has been implicated in the onset of such chronic injuries. The focus of this work is to highlight the latest discoveries in tendon mechanobiology platforms and specifically identify the gaps for future work. An interdisciplinary approach is necessary to reveal the complex molecular interplay that leads to tendon pathologies and will ultimately identify potential regenerative therapeutic targets.

3D-printed cranial models simulating operative field depth for microvascular training in neurosurgery.

BACKGROUND: The skills required for neurosurgical operations using microsurgical techniques in a deep operating field are difficult to master in the operating room without risk to patients. Although there are many microsurgical training models, most do not use a skull model to simulate a deep field. To solve this problem, 3D models were created to provide increased training in the laboratory before the operating room, improving patient safety. METHODS: A patient's head was scanned using computed tomography. The data were reconstructed and converted into a standard 3D printing file. The skull was printed with several openings to simulate common surgical approaches. These models were then used to create a deep operating field while practicing on a chicken thigh (femoral artery anastomosis) and on a rat (abdominal aortic anastomosis). RESULTS: The advantages of practicing with the 3D printed models were clearly demonstrated by our trainees, including appropriate hand position on the skull, becoming comfortable with the depth of the anastomosis, and simulating proper skull angle and rigid fixation. One limitation is the absence of intracranial structures, which is being explored in future work. CONCLUSION: This neurosurgical model can improve microsurgery training by recapitulating the depth of a real operating field. Improved training can lead to increased accuracy and efficiency of surgical procedures, thereby minimizing the risk to patients.

Comparison of MRI Visualization Following Minimally Invasive and Open TLIF: A Retrospective Single-Center Study.

Analysis of magnetic resonance image (MRI) quality after open (Op)-transforaminal interbody fusion (TLIF) and minimally invasive (MI)-TLIF with the implantation of structurally different systems has not previously been performed. The objective of this study was to conduct a comparative analysis of the postoperative MRI following MI and Op one-segment TLIF. MATERIAL AND METHODS: The nonrandomized retrospective single-center study included 80 patients (46 men and 24 women) aged 48 + 14.2 years. In group I (n = 20) Op-TLIF with open transpedicular screw fixation (TSF) was performed, in II group (n = 60), the MI-TLIF technique was used: IIa (n = 20)-rigid interspinous stabilizer; IIb (n = 20)-unilateral TSF and contralateral facet fixation; IIc (n = 20)-bilateral TSF. RESULTS: Comparison of the quality of postoperative imaging in IIa and IIb subgroups showed fewer MRI artifacts and a significantly greater MR deterioration after Op and MI TSF. Comparison of the multifidus muscle area showed less atrophy after MI-TLIF and significantly greater atrophy after Op-TLIF. CONCLUSION: MI-TLIF and Op-TLIF with TSF have comparable postoperative MR artifacts at the operative level, with a greater degree of muscle atrophy using the Op-TLIF. Rigid interspinous implant and unilateral TSF with contralateral facet fixation have less artifacts and changes in the multifidus muscle area.

Patient-specific apparent diffusion maps used to model nutrient availability in degenerated intervertebral discs.

INTRODUCTION: In this study, magnetic resonance imaging data was used to (1) model IVD-specific gradients of glucose, oxygen, lactate, and pH; and (2) investigate possible effects of covariate factors (i.e., disc geometry, and mean apparent diffusion coefficient values) on the IVD's microenvironment. Mathematical modeling of the patient's specific IVD microenvironment could be important when selecting patients for stem cell therapy due to the increased nutrient demand created by that treatment. MATERIALS AND METHODS: Disc geometry and water diffusion coefficients were extracted from MRIs of 37 patients using sagittal T1-weighted images, T2-weighted images, and ADC Maps. A 2-D steady state finite element mathematical model was developed in COMSOL Multiphysics® 5.4 to compute concentration maps of glucose, oxygen, lactate and pH. RESULTS: Concentration of nutrients (i.e., glucose, and oxygen) dropped with increasing distance from the cartilaginous endplates (CEP), whereas acidity levels increased. Most discs experienced poor nutrient levels along with high acidity values in the inner annulus fibrosus (AF). The disc's physiological microenvironment became more deficient as degeneration progressed. For example, minimum glucose concentration in grade 4 dropped by 31.1% compared to grade 3 (p < 0.0001). The model further suggested a strong effect of the following parameters: disc size, AF and CEP diffusivities, metabolic reactions, and cell density on solute concentrations in the disc (p < 0.05). CONCLUSION: The significance of this work implies that the individual morphology and physiological conditions of each disc, even among discs of the same Pfirrmann grade, should be evaluated when modeling IVD solute concentrations.

Genetic Predisposition to Symptomatic Lumbar Disk Herniation in Pediatric and Young Adult Patients.

STUDY DESIGN: Case-control whole-genome sequencing analysis of a highly select, young cohort with symptomatic lumbar disk herniation (LDH) compared with the standard variation in a large reference population. OBJECTIVE: To assess genetic influences predisposing pediatric and young adult patients to symptomatic LDH. SUMMARY OF BACKGROUND DATA: LDH has traditionally been attributed to natural weakening or mechanical insult, but recent literature supports a potential genetic influence. METHODS: Young patients with symptomatic, clinically confirmed LDH who underwent surgical treatment were included. Patients were younger than the average age of presentation, limiting the influence of environmental risks. DNA collected from these patients was compared with a reference genome (1000 Genomes Project). A genome-wide association study using whole-genome sequencing was used to characterize genetic mutations potentially associated with LDH. RESULTS: Among the 61 candidate genes flagged, 20 had missense mutations in 2 or more LDH cases. Missense mutations in collagen-encoding genes were observed in 12 of 15 patients (80%). A potential association with clinical presentation was indicated by odds ratios of key single-nucleotide polymorphism (SNP) variants in genes that encode collagen. Relative to the reference population, the LDH cohort demonstrated two statistically significant SNP variants in the gene encoding for aggrecan, a protein that facilitates load-bearing properties in the cartilaginous end plate. Aggrecan genes SNPs rs3817428 and rs11638262 were significantly associated with decreased odds of symptomatic LDH: odds ratio 0.05 (0.02-0.11) and 0.04 (0-0.26), respectively (P < 1 × 10 for both). CONCLUSION: These results suggest that collagen-encoding variants may be a genetic risk factor for LDH. They also shed new light on the role of variants that impact aggrecan, which sustains the cartilaginous end plate. Genetic predisposition to LDH may therefore be related to a multimodal combination of mutations that affect the nucleus pulposus, annulus fibrosus, and the cartilaginous end plates. LEVEL OF EVIDENCE: 4.

Apoptosis, nutrition, and metabolism of transplanted intervertebral disc cells / Apoptose, nutrição e metabolismo de células de discos intervertebrais transplantadas / Apoptosis, nutrición y metabolismo de las células de discos intervertebrales trasplantadas

ABSTRACT Introduction: Apoptosis is a contributing factor to degenerating intervertebral disc (IVD). Disc regeneration has been attempted by transplanting cells into the disc, with some gains in disc height achieved in animal models. Here, we study whether the apoptotic microenvironment affects the transplanted disc cells. Methods: Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were grown in media then starved for 5 days in vitro by not changing the media. Three aspects of apoptotic cell influence on the transplanted cells were tested in a total of 32 samples: 1) the effect of apoptotic cytokines in the media, 2) reduced glucose in the media, and 3) apoptotic cell bodies in the flask. The Trypan Blue, AlamarBlue®, and 1,9-Dimethyl-Methylene Blue assays for sulfated glycosaminoglycan (sGAG) content were performed (n=4). Results: There were significant decreases in cell viability between the control, 25% conditioned media (CM) and starved control group. There were no significant differences in cell number, metabolic activity or sGAG production in cells grown in different conditioned media compared to cells grown in complete media. The cells of the control decreased in viability and number over the 5 days without feeding, then improved dramatically when feeding was resumed. Flasks that received transplanted cells in addition to renewed feeding did not recover as much as the cells in the re-fed group. Conclusions: Cytokines from starved cells negatively impact on the viability of healthy cells. Starving cells that receive new sources of nutrition have even higher viability than transplanted cells. This indicates that altering and improving the nutrient supply problem in the IVD could be a valuable option. Level of Evidence III; Case control studyg.

RESUMO Introdução: A apoptose é um fator que contribui para a degeneração do disco intervertebral (DIV). A tentativa de regenerar o disco foi por meio de transplante de células no disco, com alguns ganhos de altura do disco alcançados em modelos animais. Aqui estudamos se o microambiente apoptótico afeta as células do disco transplantadas. Métodos: Células humanas do ânulo fibroso (AF) e do núcleo pulposo (NP) foram cultivadas in vitro em meio de cultura e privadas de nutrição por cinco dias, sem alteração dos meios. Três aspectos da influência de células apoptóticas em células transplantadas foram testados em um total de 32 amostras: 1) o efeito de citocinas apoptóticas no meio de cultura, 2) redução de glicose no meio e 3) corpos celulares apoptóticos no frasco. Realizaram-se ensaios com azul de tripano, AlamarBlue® e 1,9-dimetil azul de metileno para o teor de glicosaminoglicano sulfatado (sGAG) (n = 4). Resultados: Constataram-se decréscimos significativos na viabilidade celular entre o grupo controle, meio condicionado (MC) a 25% e grupo controle privado de nutrição. Não houve diferenças significativas no número de células, atividade metabólica ou produção de sGAG em células cultivadas em diferentes meios condicionados em comparação com o meio completo. As células de controle tiveram redução de viabilidade e de número ao longo dos 5 dias sem alimentação; a seguir, houve melhorara substancial ao se retomar a alimentação. Os frascos que receberam células transplantadas, além da alimentação renovada, não se recuperaram tanto quanto as células do grupo realimentado. Conclusões: As citocinas de células famintas tiveram impacto negativo sobre a viabilidade das células saudáveis. As células famintas que recebem novas fontes de nutrição têm viabilidade ainda maior do que as células transplantadas. Isso indica que alterar e melhorar o fornecimento de nutrientes no DIV pode ser uma opção valiosa. Nível de Evidência III; Estudo de caso controleg.

RESUMEN Introducción: La apoptosis es un factor que contribuye a la degeneración del disco intervertebral (DIV). El intento de regenerar el disco fue por medio de trasplante de células en el disco, con el que se ganó el aumento de altura del disco logrado en modelos animales. Aquí estudiamos si el microambiente apoptótico afecta a las células del disco trasplantadas. Métodos: Células humanas del anillo fibroso (AF) humano y del núcleo pulposo (NP) fueron cultivadas in vitro en medio de cultivo y privadas de nutrición por 5 días, sin alteración de los medios. Tres aspectos de la influencia de las células apoptóticas trasplantadas se probaron en un total de 32 muestras: 1) el efecto de las citoquinas apoptóticas en el medio de cultivo, 2) reducción de la glucosa en el medio y 3) los cuerpos celulares apoptóticos en el matraz. Se realizaron ensayos con azul de tripano, AlamarBlue® y 1,9-dimetil-azul de metileno para el contenido de glicosaminoglicano sulfatado (sGAG) (n = 4). Resultados: Se constataron disminuciones significativas de la viabilidad celular entre el grupo control, medio condicionado (MC) al 25% y el grupo control privado de nutrición. No hubo diferencias significativas en el número de células, la actividad metabólica o producción de sGAG en células cultivadas en diferentes medios condicionados en comparación con el medio completo. Las células de control tuvieron reducción de viabilidad y de número a lo largo de los 5 días sin alimentación; luego, hubo una mejora sustancial al reanudar la alimentación. Los matraces que recibieron células trasplantadas, además de la alimentación renovada, no se recuperaron tanto como las células del grupo alimentado nuevamente. Conclusiones: Las citoquinas de las células privadas de alimento tuvieron un impacto negativo en la viabilidad de las células sanas. Las células hambrientas que reciben nuevas fuentes de nutrición tienen mayor viabilidad que las células trasplantadas. Esto indica que cambiar y mejorar suministro de nutrientes en el DIV puede ser una opción valiosa. Nivel de Evidencia III; Estudio de caso controlg.

Apparent diffusion coefficient maps in the assessment of surgical patients with lumbar spine degeneration.

PURPOSE: To assess the utility of apparent diffusion coefficient (ADC) maps for the assessment of patients with advanced degenerative lumbar spine disease and describe characteristic features of ADC maps in various degenerative lumbar spinal conditions. METHODS: T1-weighted, T2-weighted and diffusion weighted (DWI) MR images of 100 consecutive patients admitted to the spinal surgery service were assessed. ADC maps were generated from DWI images using Osyrix software. The ADC values and characteristic ADC maps were assessed in the regions of interest over the different pathological entities of the lumbar spine. RESULTS: The study included 452 lumbar vertebral segments available for analysis of ADCs. Characteristic ADC map features were identified for protrusion, extrusion and sequester types of lumbar disk herniations, spondylolisthesis, reactive Modic endplate changes, Pfirrmann grades of IVD degeneration, and compromised spinal nerves. Compromised nerve roots had significantly higher mean ADC values than adjacent (p < 0.001), contralateral (p < 0.001) or adjacent contralateral (p < 0.001) nerve roots. Compared to the normal bone marrow, Modic I changes showed higher ADC values (p = 0.01) and Modic 2 changes showed lower ADC values (p = 0.02) respectively. ADC values correlated with the Pfirrmann grading, however differed from herniated and non-herniated disks of the matched Pfirrmann 3 and 4 grades. CONCLUSION: Quantitative and qualitative evaluation of ADC mapping may provide additional useful information regarding the fluid dynamics of the degenerated spine and may complement standard MRI imaging protocol for the comprehensive assessment of surgical patients with lumbar spine pathology. ADC maps were advantageous in differentiating reactive bone marrow changes, and more precise assessment of the disk degeneration state. ADC mapping of compressed nerve roots showed promise but requires further investigation on a larger cohort of patients.

Preoperative estimation of disc herniation recurrence after microdiscectomy: predictive value of a multivariate model based on radiographic parameters.

BACKGROUND CONTEXT: Recurrence of lumbar disc herniation (rLDH) is one of the unfavorable outcomes after microdiscectomy. Prediction of the patient population with increased risk of rLDH is important because patients may benefit from preventive measures or other surgical options. PURPOSE: The study assessed preoperative factors associated with rLDH after microdiscectomy and created a mathematical model for estimation of chances for rLDH. STUDY DESIGN/SETTING: This is a retrospective case-control study. PATIENT SAMPLE: The study includes patients who underwent microdiscectomy for LDH. OUTCOME MEASURES: Lumbar disc herniation recurrence was determined using magnetic resonance imaging. METHODS: The study included 350 patients with LDH and a minimum of 3 years of follow-up. Patients underwent microdiscectomy for LDH at the L4-L5 and L5-S1 levels from 2008 to 2012. Patients were divided into two groups to identify predictors of recurrence: those who developed rLDH (n=50) within 3 years and those who did not develop rLDH (n=300) within the same follow-up period. Multivariate analysis was performed using patient baseline clinical and radiography data. Non-linear, multivariate, logistic regression analysis was used to build a predictive model. RESULTS: Recurrence of LDH occurred within 1 to 48 months after microdiscectomy. Preoperatively, patients who developed rLDH were smokers (70% vs. 27%, p<.01; odds ratio [OR]=6.31, 95% confidence interval [CI]: 3.27-12.16) and had higher body mass index (29.0±6.1 vs. 27.0±4.3, p=.03; OR=1.09 per 0.01 unit change). Radiological parameters that were associated with rLDH were higher disc height index (0.35±0.007 vs. 0.26±0.002, p<.001), higher segmental range of motion (9.8±0.28° vs. 7.6±0.11°, p<.001; OR=0.53 per 0.01 unit change), and lower central angle of lumbar lordosis (33.4±0.81° vs. 47.1±0.47°, p<.001; OR=0.53 per 0.01 unit change). Additionally, Pfirrmann grade 3 (OR=16.62, 95% CI: 8.10-34.11), protrusion type of LDH (OR=5.90, 95% CI: 3.06-11.36), and Grogan sclerosis grades 3 and 4 (OR=4.81, 95% CI: 2.50-9.22) were also associated with rLDH. Multivariate non-linear modeling allowed for more accurate prediction of rLDH (90% correct prediction of rLDH; 99% correct prediction of no rLDH) than other univariate logit models. CONCLUSIONS: Preoperative radiographic parameters in patients with LDH can be used to assess the risk of recurrence after microdiscectomy. The multifactorial non-linear model provided more accurate rLDH probability estimation than the univariate analyses. The software developed from this model may be implemented during patient counseling or decision making when choosing the type of primary surgery for LDH.

Biomechanical and Endplate Effects on Nutrient Transport in the Intervertebral Disc.

BACKGROUND: Physical data are lacking on nutrient transport in human intervertebral discs (IVDs), which support regeneration. Our objective was to study nutrient transport in porcine IVDs to determine the effects of biomechanical and physiological factors. METHODS: In vitro testing of whole porcine IVDs was performed under different loading conditions. Fifty cervical, thoracic, and lumbar discs with attached end plates were removed from 4 Yorkshire pigs (90-150 lbs). Discs were placed in Safranin O or Fast Green FCF histological stains in diffusion or diurnal compression-tested groups. The end plate was studied by the use of polyurethane to block it. Traction was studied with a mechanical testing frame. Discs were cut transversely and photographed. Images were analyzed for depth of annulus fibrosus (AF) stained. The nucleus pulposus (NP) was assigned a staining score. RESULTS: Results showed no difference in AF staining between the 2 stains (P = 0.60). The depth of AF staining did not increase (P = 0.60) due to convection or disc height change via diurnal loading. The NP in all open end plate samples was stained completely by day 3. NP staining was decreased in blocked end plate samples (P = 0.07) and AF staining was significantly less in traction samples than in diffusion-only samples (P = 0.04). CONCLUSIONS: This method showed that most small molecule nutrient transport occurs via the end plate. Compressive load was a negligible benefit or hindrance to transport. Traction hindered transport in the short term. This method can be used to study strategies for increasing nutrient transport in IVDs.

Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury.

OBJECTIVE Spinal cord injury occurs in 2 phases. The initial trauma is followed by inflammation that leads to fibrous scar tissue, glial scarring, and cavity formation. Scarring causes further axon death around and above the injury. A reduction in secondary injury could lead to functional improvement. In this study, hyaluronic acid (HA) hydrogels were implanted into the gap formed in the hemisected spinal cord of Sprague-Dawley rats in an attempt to attenuate damage and regenerate tissue. METHODS A T-10 hemisection spinal cord injury was created in adult male Sprague-Dawley rats; the rats were assigned to a sham, control (phosphate-buffered saline), or HA hydrogel-treated group. One cohort of 23 animals was followed for 12 weeks and underwent weekly behavioral assessments. At 12 weeks, retrograde tracing was performed by injecting Fluoro-Gold in the left L-2 gray matter. At 14 weeks, the animals were killed. The volume of the lesion and the number of cells labeled from retrograde tracing were calculated. Animals in a separate cohort were killed at 8 or 16 weeks and perfused for immunohistochemical analysis and transmission electron microscopy. Samples were stained using H & E, neurofilament stain (neurons and axons), silver stain (disrupted axons), glial fibrillary acidic protein stain (astrocytes), and Iba1 stain (mononuclear cells). RESULTS The lesions were significantly smaller in size and there were more retrograde-labeled cells in the red nuclei of the HA hydrogel-treated rats than in those of the controls; however, the behavioral assessments revealed no differences between the groups. The immunohistochemical analyses revealed decreased fibrous scarring and increased retention of organized intact axonal tissue in the HA hydrogel-treated group. There was a decreased presence of inflammatory cells in the HA hydrogel-treated group. No axonal or neuronal regeneration was observed. CONCLUSIONS The results of these experiments show that HA hydrogel had a neuroprotective effect on the spinal cord by decreasing the magnitude of secondary injury after a lacerating spinal cord injury. Although regeneration and behavioral improvement were not observed, the reduction in disorganized scar tissue and the retention of neurons near and above the lesion are important for future regenerative efforts. In addition, this gel would be useful as the base substrate in the development of a more complex scaffold.

Prospective Comparison of Microsurgical, Tubular-Based Endoscopic, and Endoscopically Assisted Diskectomies: Clinical Effectiveness and Complications in Railway Workers.

OBJECTIVE: Although endoscopic diskectomy is superior to microsurgical diskectomy in terms of incision size, postoperative pain, and cosmetic appeal, the effectiveness and indications for endoscopic versus microsurgical diskectomy remain active discussion topics. Because of the increasing incidence of diskectomies being performed in Russia, further assessment of these techniques is needed. We performed a comparative analysis of 1-year clinical results and complications of microsurgical, tubular-based interlaminar endoscopic, and endoscopically assisted microsurgical diskectomies for patients with herniated lumbar disks. METHODS: The patient cohort included 131 patients who were enrolled in a prospective, randomized controlled study and 617 patients for whom data were gathered retrospectively. The quality of life was assessed using the Oswestry Disability Index (version 2.1a) and pain severity was analyzed using the visual analog scale for pain preoperatively, at discharge, and at 3, 6, and 12 months postoperatively. RESULTS: Microsurgical, tubular-based endoscopic, and endoscopically assisted microsurgical diskectomies were all effective in relieving acute radicular symptoms. Recurrent disk herniation occurred more frequently after tubular-based endoscopic diskectomy than after the other approaches. CONCLUSIONS: Our findings indicate that these 3 surgical techniques are highly effective and have similar clinical results at 1-year follow-up. Although this study points to differences in complications resulting from the 3 techniques, larger prospective studies are needed to more definitively assess possible surgical differences, complications, and outcomes. The endoscopically assisted diskectomy technique allows for minimally invasive surgery and offers enhanced visualization of the anatomy that is hidden from view in microscopic procedures.

Antimicrobial distribution from local delivery depends on dose : a pilot study with MRI.

BACKGROUND: Tissue distribution after local delivery has been quantified over a period of 5 hours on 7-T MRI in a rabbit model using gadolinium-labeled diethylenetriamine pentaacetic acid (Gd-DTPA) as an antimicrobial surrogate; however, it is unknown how the Gd-DTPA load in a local depot will affect the duration of high-concentration Gd-DTPA in local tissues after surgical débridement. QUESTIONS/PURPOSES: We determined whether the Gd-DTPA load in bone cement affected its local tissue distribution over a period of 1 month after local delivery. METHODS: A 1-cm3 soft tissue dead space was created in the quadriceps of seven rabbits and filled with gadolinium-loaded bone cement. At 7, 14, and 33 days, the volume of tissue with a Gd-DTPA concentration of more than 14 µg/mL was calculated from T1-weighted images using 7-T MRI. Differences in volumes of distribution were analyzed with ANOVA. RESULTS: The volume of tissue with more than 14 µg/mL Gd-DTPA was much larger from higher gadolinium loads on Day 7 (p=0.02) (2121 mm3 for 10 g and 665 mm3 for 1 g) and smaller with time for the 10-g formulation (2121 mm3 on Day 7 and 1241 mm3 on Day 14). CONCLUSIONS: Volume of distribution and duration of Gd-DTPA after local delivery increased with increasing load in the cement and decreased with time. CLINICAL RELEVANCE: For local delivery, high antimicrobial concentrations would be expected in greater volumes of tissue, for longer durations, when higher antimicrobial loads are used.

Distribution of molecules locally delivered from bone cement.

Revision of infected orthopedic implants is successful in most cases when antimicrobials are delivered locally (mixed with bone cement or bone graft which is placed in the site from which the infected tissue was removed); however, there is still a substantial rate of recurrence most likely due to the antimicrobials not achieving a therapeutic dose at all locations in the tissue. To study transport within this environment, gadolinium chelated in diethylene triamine pentaacetic acid (Gd-DTPA), a MRI contrast agent with size and solubility similar to two common antimicrobials (gentamicin and vancomycin), was mixed with bone cement, implanted in vivo into two models of orthopedic surgical wounds, and imaged using MRI 5.5 h after implantation. Image thresholding was used to create two-dimensional and three-dimensional representations of areas/volumes containing detectable concentrations of Gd-DTPA. Distribution is found to be anisotropic with Gd-DTPA transporting preferentially anterior of the implant toward the skin. When fascia is not closed over the implant site, Gd-DTPA transports to the skin and along the subcutaneous plane. The distance transported indicates that transport is likely driven by convection. Finally, the tissue concentration of Gd-DTPA is much less than the concentration loaded into the bone cement.

Spatiotemporal quantification of local drug delivery using MRI.

Controlled release formulations for local, in vivo drug delivery are of growing interest to device manufacturers, research scientists, and clinicians; however, most research characterizing controlled release formulations occurs in vitro because the spatial and temporal distribution of drug delivery is difficult to measure in vivo. In this work, in vivo magnetic resonance imaging (MRI) of local drug delivery was performed to visualize and quantify the time resolved distribution of MRI contrast agents. Three-dimensional T1 maps (generated from T1-weighted images with varied TR) were processed using noise-reducing filtering. A segmented region of contrast, from a thresholded image, was converted to concentration maps using the equation 1/T1=1/T1,0+R1C, where T1,0 and T1 are the precontrast and postcontrast T1 map values, respectively. In this technique, a uniform estimated value for T 1,0 was used. Error estimations were performed for each step. The practical usefulness of this method was assessed using comparisons between devices located in different locations both with and without contrast. The method using a uniform T1,0, requiring no registration of pre- and postcontrast image volumes, was compared to a method using either affine or deformation registrations.

Jeannette Wilkins Award: Can locally delivered gadolinium be visualized on MRI? A pilot study.

BACKGROUND: Management of orthopaedic infections relies on débridement and local delivery of antimicrobials; however, the distribution and concentration of locally delivered antimicrobials in postdébridement surgical sites is unknown. Gadolinium-DTPA (Gd-DTPA) has been proposed as an imaging surrogate for antimicrobials because it is similar in size and diffusion coefficient to gentamicin. QUESTIONS/PURPOSES: Is in vivo distribution of locally delivered Gd-DTPA (1) visible on MRI; (2) reliably visualized by different observers; (3) affected by the anatomic delivery site; and (4) affected by the in vitro release rate from the delivery vehicle? METHODS: Twenty-four local delivery depots were imaged in nine rabbits using two anatomic sites (intramedullary canal, quadriceps) with Gd-DTPA in intermediate-porosity polymethylmethacrylate (PMMA) or high-porosity PMMA; six of the nine rabbits also had Gd-DTPA delivered in collagen at a third site (hamstring). A total of 45,000 fat-suppressed T1-weighted RARE scans were acquired using a 7-T Bruker Biospec MRI: nine rabbits, 2-mm slices over 10 cm, four TR values, 25 time periods (pre, every 15 minutes for 6 hours). T1 maps were constructed at every time period. Gd-DTPA distribution was observed qualitatively on the T1 maps. Interobserver reliability was determined. RESULTS: Locally delivered Gd-DTPA was visible. Interobserver agreement was excellent. Intramuscular delivery followed intermuscular planes; intramedullary delivery was contained within the canal by bone. Distribution from collagen decreased after 1 hour but from PMMA increased over 6 hours. CONCLUSIONS: Locally delivered Gd-DTPA can be visualized on MRI; distribution is affected by anatomical location and delivery vehicle. CLINICAL RELEVANCE: Contrast-based imaging using locally delivered Gd-DTPA may be useful as an antibiotic surrogate to determine antibiotic distribution in surgical sites.