Ventricular catheter tissue obstruction and shunt malfunction in 9 hydrocephalus etiologies.

OBJECTIVE: Hydrocephalus is a neurological disorder with an incidence of 80-125 per 100,000 births in the United States. The most common treatment, ventricular shunting, has a failure rate of up to 85% within 10 years of placement. The authors aimed to analyze the association between ventricular catheter (VC) tissue obstructions and shunt malfunction for each hydrocephalus etiology. METHODS: Patient information was collected from 5 hospitals and entered into a REDCap (Research Electronic Data Capture) database by hydrocephalus etiology. The hardware samples were fixed, and each VC tip drainage hole was classified by tissue obstruction after macroscopic analysis. Shunt malfunction data, including shunt revision rate, time to failure, and age at surgery, were correlated with the degree of tissue obstruction in VCs for each etiology. RESULTS: Posthemorrhagic hydrocephalus was the most common etiology (48.9% of total cases). Proximal catheter obstruction was the most frequent cause of hardware removal (90.4%). Myelomeningocele (44% ± 29%), other congenital etiologies (48% ± 40%), hydrocephalus with brain tumors (45% ± 35%), and posthemorrhagic hydrocephalus (41% ± 35%) showed tissue aggregates in more than 40% of the VC holes. A total of 76.8% of samples removed because of symptoms of obstruction showed cellular or tissue aggregates. No conclusive etiological associations were detected when correlating the percentage of holes with tissue for each VC and age at surgery, shunt revision rates, or time between shunt implantation and removal. CONCLUSIONS: The proximal VC obstruction was accompanied by tissue aggregates in 76.8% of cases. However, the presence of tissue in the VC did not seem to be associated with hydrocephalus etiology.

Reduction of cell surface attachment in experimental hydrocephalus using a novel ventricular catheter with modified tethered liquid perfluorocarbon.

OBJECTIVE: Ventriculoperitoneal shunting, the most common treatment for the neurological disorder hydrocephalus, has a failure rate of up to 98% within 10 years of placement, mainly because of proximal obstruction of the ventricular catheter (VC). The authors developed a new VC design modified with tethered liquid perfluorocarbon (TLP) and tested it in a porcine model of hydrocephalus. In this study, they aimed to determine if their TLP VC design reduced cell surface attachment and consequent shunt obstruction in the pig model. METHODS: TLP VCs were designed to reduce drainage hole obstruction using modified TLP and slightly enlarged draining holes, but their number and placement remained very similar to standard VCs. First, the authors tested the device in nonhydrocephalic rats to assess biocompatibility. After confirming safety, they implanted the VCs in hydrocephalic pigs. Hydrocephalus was induced by intracisternal kaolin injections in 30-day-old domestic juvenile pigs. Surgical implantation of the ventriculoperitoneal shunt (clinical control or TLP) was performed 10-14 days postinduction and maintained up to 30 days posttreatment. MRI was performed to measure ventricular volume before treatment and 10 and 30 days after treatment. Histological and immunohistochemical analyses of brain tissue and explanted VCs, intracranial pressure measurement, and clinical scoring were performed when the animals were euthanized. RESULTS: TLP VCs showed a similar surgical feel, kink resistance, and stiffness to control VCs. In rats (biocompatibility assessment), TLP VCs did not show brain inflammatory reactions after 30 or 60 days of implantation. In pigs, TLP VCs demonstrated increased survival time, improved clinical outcome scores, and significantly reduced total attached cells on the VCs compared with standard clinical control VCs. TLP VCs exhibited similar, but not worse, results related to ventriculomegaly, intracranial pressure, and the local tissue response around the cortical shunt track in pigs. CONCLUSIONS: TLP VCs may be a strong candidate to reduce proximal VC obstruction and improve hydrocephalus treatment.

A novel, benchtop model for quantitative analysis of resistance in ventricular catheters.

INTRODUCTION: The mechanisms of catheter obstruction are still poorly understood, but the literature suggests that resistance to fluid flow plays a significant role. We developed and assessed a gravity-driven device that measures flow through ventricular catheters. We used this device to quantitatively analyze the resistances of unused ventricular catheters used in the treatment of hydrocephalus; failed hydrocephalus catheters from our catheter biorepository were also evaluated quantitatively. METHODS: Catheters of three manufacturing companies were inserted into the benchtop model, which records time, flow rate, and pressure data using sensors. The relative resistances of catheters across six design models were evaluated. Experiments were performed to evaluate changes in the relative resistance of a catheter when the catheter's holes were progressively closed. The relative resistance of explanted catheters from our catheter biorepository was also measured. RESULTS: Experimental results showed significant differences (P<0.05) between the relative resistances of different catheter models just after being removed from their packaging. A non-linear trend of increasing resistance was observed in experiments on catheters with artificially obstructed holes. Data from five individual benchtop models were compared, and the differences in measured data between the models were found to be negligible. A significant increase (P < 0.05) in relative resistance was observed in explanted catheters. CONCLUSION: The current study sought to propose a novel in-vitro model and use it to examine data on differences in relative resistance among catheter models. From these experiments, we can rapidly correlate clinical patient cohorts to identify mechanisms of luminal shunt obstruction.

Exploration of clinical predictors of the degree of ventricular catheter obstruction: a multicenter retrospective study.

OBJECTIVE: The aim of this study was to explore how clinical factors, including the number of lifetime revision surgeries and the duration of implantation, affect the degree of obstruction and failure rates of ventricular catheters (VCs) used to manage hydrocephalus. METHODS: A total of 343 VCs and their associated clinical data, including patient demographics, medical history, and surgical details, were collected from 5 centers and used for this analysis. Each VC was classified by the degree of obstruction after macroscopic analysis. Univariate, multivariate, and binned analyses were conducted to test for associations between clinical data and degree of VC obstruction. RESULTS: VCs from patients with 0 to 2 lifetime revisions had a larger proportion of VC holes obstructed than VCs from patients with 10 or more revisions (p = 0.0484). VCs implanted for less than 3 months had fewer obstructed holes with protruding tissue aggregates than VCs implanted for 13 months or longer (p = 0.0225). Neither duration of implantation nor the number of lifetime revisions was a significant predictor of the degree of VC obstruction in the regression models. In the multinomial regression model, contact of the VCs with the ventricular wall robustly predicted the overall obstruction status of a VC (p = 0.005). In the mixed-effects model, the age of the patient at their first surgery emerged as a significant predictor of obstruction by protruding tissue aggregates (p = 0.002). VCs implanted through the parietal entry site were associated with more holes with nonobstructive growth and fewer empty holes than VCs implanted via other approaches (p = 0.001). CONCLUSIONS: The number of lifetime revisions and duration of implantation are correlated with the degree of VC obstruction but do not predict it. Contact of the VC with the ventricular wall and the age of the patient at their first surgery are predictors of the degree of VC obstruction, while the entry site of the VC correlates with it.

Direct Comparison of Peak Bulk Flow Rate of Programmable Intermittent Epidural Bolus and Manual Epidural Bolus Using a Closed-End Multiorifice Catheter: An Experimental Study.

BACKGROUND: The programmable intermittent epidural bolus (PIEB) has been popularized as the optimal delivery technique for labor analgesia. Suggested advantages of this method are less local anesthetic consumption, improved maternal satisfaction, potentially shorter duration of labor, and decreased workload requirements for the anesthesia providers. However, a manual bolus is still routinely used for breakthrough pain when the PIEB is underperforming. METHODS: We conducted a laboratory-based study to quantify the flow through a multiorifice epidural catheter using the PIEB setting on an epidural pump compared to the manual epidural bolus. Four syringe volumes, 3, 5, 10, and 20 mL, were selected for this experiment. The flow in a manual bolus was also studied with and without the presence of an epidural catheter filter. A generalized estimating equation analysis was done to compare data between the groups. RESULTS: Regardless of the syringe size, there was a several-fold increase in flow when a manual bolus was used compared to a pump-administered dose, with the highest difference in the peak flow rate observed in 3-mL boluses with up to a 12-fold difference, while the difference was, at most, 7-fold in 5-mL and 10-mL boluses. Manual boluses without a filter achieve a mean peak flow rate higher than manual boluses with a filter. CONCLUSIONS: Our study found that manual boluses produced a higher flow rate compared to the CADD-Solis epidural pump (Smiths Medical). This study also found that the placement of a particulate filter reduces the flow rates generated while bolusing. Bulk flow rate is directly correlated with induced pressure and solution spread. Because higher bolus pressure has been shown to provide a more efficient distribution of local anesthetic and more efficient pain relief, these results may have impactful clinical significance and will pave the way for future studies.

The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure.

BACKGROUND: The composition of tissue obstructing neuroprosthetic devices is largely composed of inflammatory cells with a significant astrocyte component. In a first-of-its-kind study, we profile the astrocyte phenotypes present on hydrocephalus shunts. METHODS: qPCR and RNA in-situ hybridization were used to quantify pro-inflammatory (A1) and anti-inflammatory (A2) reactive astrocyte phenotypes by analyzing C3 and EMP1 genes, respectively. Additionally, CSF cytokine levels were quantified using ELISA. In an in vitro model of astrocyte growth on shunts, different cytokines were used to prevent the activation of resting astrocytes into the A1 and A2 phenotypes. Obstructed and non-obstructed shunts were characterized based on the degree of actual tissue blockage on the shunt surface instead of clinical diagnosis. RESULTS: The results showed a heterogeneous population of A1 and A2 reactive astrocytes on the shunts with obstructed shunts having a significantly higher proportion of A2 astrocytes compared to non-obstructed shunts. In addition, the pro-A2 cytokine IL-6 inducing proliferation of astrocytes was found at higher concentrations among CSF from obstructed samples. Consequently, in the in vitro model of astrocyte growth on shunts, cytokine neutralizing antibodies were used to prevent activation of resting astrocytes into the A1 and A2 phenotypes which resulted in a significant reduction in both A1 and A2 growth. CONCLUSIONS: Therefore, targeting cytokines involved with astrocyte A1 and A2 activation is a promising intervention aimed to prevent shunt obstruction.

Testing and validation of reciprocating positive displacement pump for benchtop pulsating flow model of cerebrospinal fluid production and other physiologic systems.

BACKGROUND: The flow of physiologic fluids through organs and organs systems is an integral component of their function. The complex fluid dynamics in many organ systems are still not completely understood, and in-vivo measurements of flow rates and pressure provide a testament to the complexity of each flow system. Variability in in-vivo measurements and the lack of control over flow characteristics leave a lot to be desired for testing and evaluation of current modes of treatments as well as future innovations. In-vitro models are particularly ideal for studying neurological conditions such as hydrocephalus due to their complex pathophysiology and interactions with therapeutic measures. The following aims to present the reciprocating positive displacement pump, capable of inducing pulsating flow of a defined volume at a controlled beat rate and amplitude. While the other fluidic applications of the pump are currently under investigation, this study was focused on simulating the pulsating cerebrospinal fluid production across profiles with varying parameters. METHODS: Pumps were manufactured using 3D printed and injection molded parts. The pumps were powered by an Arduino-based board and proprietary software that controls the linear motion of the pumps to achieve the specified output rate at the desired pulsation rate and amplitude. A range of 0.01 [Formula: see text] to 0.7 [Formula: see text] was tested to evaluate the versatility of the pumps. The accuracy and precision of the pumps' output were evaluated by obtaining a total of 150 one-minute weight measurements of degassed deionized water per output rate across 15 pump channels. In addition, nine experiments were performed to evaluate the pumps' control over pulsation rate and amplitude. RESULTS: Volumetric analysis of a total of 1200 readings determined that the pumps achieved the target output volume rate with a mean absolute error of -0.001034283 [Formula: see text] across the specified domain. It was also determined that the pumps can maintain pulsatile flow at a user-specified beat rate and amplitude. CONCLUSION: The validation of this reciprocating positive displacement pump system allows for the future validation of novel designs to components used to treat hydrocephalus and other physiologic models involving pulsatile flow. Based on the promising results of these experiments at simulating pulsatile CSF flow, a benchtop model of human CSF production and distribution could be achieved through the incorporation of a chamber system and a compliance component.

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments.

BACKGROUND: Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. METHODS: Acquired hydrocephalus was induced in 33-41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11-42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14-38-days post-kaolin. Behavioral and neurological status were assessed. RESULTS: Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11-43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45-55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20-30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction. CONCLUSIONS: Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus.

A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus.

BACKGROUND: Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. METHODS: 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. RESULTS: 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p < 0.02). Mean length of time of implantation of occluded VCs, 33.22 months was greater than for non-occluded VCs, 23.8 months (p = 0.02). Patients with myelomeningocele had a greater probability of having an occluded VC (p = 0.0426). VCs with occlusions had greater numbers of macrophages and astrocytes in comparison to non-occluded VCs (p < 0.01). Microglia comprised only 2-6% of the VC-obstructing tissue aggregates. Histologic analysis showed choroid plexus occlusion in 24%, vascularized glial tissue occlusion in 24%, prevalent lymphocytic inflammation in 29%, and foreign body giant cell reactions in 5% and no ependyma. CONCLUSION: Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence.

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure.

It has been hypothesized that physiological shear forces acting on medical devices implanted in the brain significantly accelerate the rate to device failure in patients with chronically indwelling neuroprosthetics. In hydrocephalus shunt devices, shear forces arise from cerebrospinal fluid flow. The shunt's unacceptably high failure rate is mostly due to obstruction with adherent inflammatory cells. Astrocytes are the dominant cell type bound directly to obstructing shunts, rapidly manipulating their activation via shear stress-dependent cytokine secretion. Here we developed a total internal reflection fluorescence microscopy combined with a microfluidic shear device chip (MSDC) for quantitative analysis and direct spatial-temporal mapping of secreted cytokines at the single-cell level under physiological shear stress to identify the root cause for shunt failure. Real-time secretion imaging at 1-min time intervals enabled successful detection of a significant increase of astrocyte IL-6 cytokine secretion under shear stress greater than 0.5 dyne/cm2, validating our hypothesis and highlighting the importance of reducing shear stress activation of cells.

Factors Impacting Hydrocephalus Incidence in Intracerebral Hemorrhage: A Retrospective Analysis.

OBJECTIVE: To test which intracerebral hemorrhage (ICH) characteristics impact incidence of hydrocephalus and characterize subsequent impact on outcomes. METHODS: A search of the electronic medical record of Sinai Grace Hospital between January 2009 and April 2018 using International Classification of Diseases, Ninth Revision and Tenth Revision codes for ICH identified 847 patients. After excluding patients with hemorrhagic conversion of stroke, subarachnoid hemorrhage, and traumatic hemorrhage, 560 patients remained for analysis. Generalized linear modeling was used to assess variance in modified Rankin Scale (mRS) score and length of stay. RESULTS: Incidence of hydrocephalus on arrival varied with ICH volume (P < 0.001), intraventricular hemorrhage (IVH) status (P < 0.001), bleed location (P < 0.001), and external ventricular drain (EVD) status (P < 0.001). An EVD was inserted in 47% of patients presenting with IVH (n = 102/217), while 4% of patients without IVH received an EVD (n = 14/343) (P < 0.001). Hemorrhage locations had different rates of EVD placement: thalamic 43%, basal ganglia 22%, cerebellar 28%, brainstem 21%, lobar 7% (P < 0.001). Shunt dependency did not vary between bleed locations (P = 0.072). Variance in mRS score was explained by IVH, bleed location, hydrocephalus on arrival, and ICH volumes. In particular, cerebellar hemorrhage location was associated with better outcomes (mean discharge mRS score of 3.3 vs. 3.9, P < 0.001). CONCLUSIONS: Bleed characteristics affect incidence of hydrocephalus on admission, rates of long-term shunt dependency, and outcomes. Hemorrhage location did not predict shunt dependency; however, it did predict outcomes. Specifically, cerebellar ICH was associated with a better discharge mRS score.

Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction.

BACKGROUND: Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. METHODS: Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. RESULTS: Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. CONCLUSION: Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

Response of Astrocytes to Blood Exposure due to Shunt Insertion in vitro.

The breakdown of the ventricular zone (VZ) with the presence of blood in cerebrospinal fluid (CSF) has been shown to increase shunt catheter obstruction in the treatment of hydrocephalus, but the mechanisms by which this occurs are generally unknown. Using a custom-built incubation chamber, we immunofluorescently assayed cell attachment and morphology on shunt catheters with and without blood after 14 days. Samples exposed to blood showed significantly increased cell attachment (average total cell count 392.0±317.1 versus control of 94.7±44.5, P<0.0001). Analysis of the glial fibrillary acidic protein (GFAP) expression showed similar trends (854.4±450.7 versus control of 174.3±116.5, P<0.0001). An in vitro model was developed to represent the exposure of astrocytes to blood following an increase in BBB permeability. Exposure of astrocytes to blood increases the number of cells and their spread on the shunt.

Analysis of N-acetyl cysteine modified polydimethylsiloxane shunt for improved treatment of hydrocephalus.

A major cause of hydrocephalus shunt failure is cell adhesion and obstruction of shunt catheter holes. An estimated 50% of pediatric shunts fail in the first 2 years of insertion, decreasing cell attachment and catheter obstruction can prolong the lifetime and effectiveness of the device. From previous studies, it was shown that treatment of the polydimethylsiloxane (PDMS) surface of a standard catheter with an N-acetyl-cysteine (NAC/1-ethyl-3-(3-dimethylanimopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide) layer increases the wettability of the surface and has been shown to decrease cell adhesion. Other studies indicate that NAC's antioxidant behavior induces glutathione and in turn modulates cell inflammatory pathways. The current study explores the longevity of the NAC coating from the surface of the catheter over time and shows its effect on valve function. Using SEM imaging, contact angle testing, and nanodrop spectrophotometry, this release was quantified for shunt samples incubated for 0, 10, 30, 60, and 90 days. Contact angle showed a significant increase in wettability of the surface when shunts were treated with NAC, confirming successful surface modification. Pressure assays determined that if the coating is release it had no detrimental downstream effects, such as on the shunt valve mechanism. SEM imaging revealed slight deformations in surface coating indicative of salt deposition on the modified shunt samples, while nanodrop spectrophotometry and contact angle data trends suggested some discharge of the NAC coating from the catheter surfaces. The effects of NAC on cell activity may transform the way hydrocephalus is treated in the future by increasing the longevity of the shunt to protect from obstruction.

A preliminary exploration of acute intracranial pressure-cerebrospinal fluid production relationships in experimental hydrocephalus.

CONTEXT: By occluding the fourth ventricle simultaneously obtaining telemetric data on intracranial pressure (ICP) and cerebrospinal fluid (CSF) production, the authors of this study investigate a variety of physiologic parameters in cases of experimental hydrocephalus. AIMS: The aim of this study is to provide a new context on the disrupted homeostasis in hydrocephalus and guide toward improved treatment based on multiple physiological parameters. MATERIALS AND METHODS: Hydrocephalus was induced in ten 21-day-old Sprague-Dawley rats by blocking the flow of CSF to the fourth ventricle with kaolin. Ten days post induction, when physical signs of ventriculomegaly reached Evan's ratio (ER) of ≥0.46, CSF flow and ICP were measured while manipulating body position (0°, 45°, 90°) and heart rate. RESULTS: In hydrocephalic animals (ER ≥0.46), we found a near-steady average acute ICP (13.638 ± 2.331) compared to age-matched controls (ER <0.30) (13.068 ± 8.781), whose ICP fluctuated with the position. Hydrocephalic and controls exhibited an insignificant degree of parabolic shifts in CSF production when body position was changed from prone to 90° and again when moved back to the prone position, a trend more noteworthy in controls (P = 0.1322 and 0.2772). A Pearson's Correlation found CSF production and ICP to be correlated at baseline 0° posture (P = 0.05) in the control group, but not the hydrocephalic group. Weight appeared to play a role when animals were held at 90°. No significant changes in ICP or CSF flow patterns were observed when the heart rate was increased within either group. CONCLUSIONS: These preliminary findings suggest that our standard assumptions of posture-dependent changes in ICP created using data from physiologic data may be inaccurate in the hydrocephalic patient, and thus describe a need to further explore these relationships.

Investigation of ventriculoperitoneal shunt disconnection for hydrocephalus treatment.

OBJECTIVE: This investigation is aimed at gaining a better understanding of the factors that lead to mechanical failure of shunts used for the treatment of hydrocephalus, including shunt catheter-valve disconnection and shunt catheter fracture. METHODS: To determine the root cause of mechanical failure, the authors created a benchtop mechanical model to mimic mechanical stressors on a shunt system. To test shunt fracture, cyclical loading on the catheter-valve connection site was tested with the shunt catheter held perpendicular to the valve. Standard methods were used to secure the catheter and valves with Nurolon. These commercial systems were compared to integrated catheters and valves (manufactured as one unit). To test complete separation/disconnection of the shunt catheter and valve, a parallel displacement test was conducted using both Nurolon and silk sutures. Finally, the stiffness of the catheters was assessed. All mechanical investigations were conducted on shunts from two major shunt companies, assigned as either company A or company B. RESULTS: Cyclical loading experiments found that shunts from company B fractured after a mean of 4936 ± 1725 cycles (95% CI 2990-6890 cycles), while those of company A had not failed after 8000 cycles. The study of parallel displacement indicated complete disconnection of company B's shunt catheter-valve combination using Nurolon sutures after being stretched an average 32 ± 5.68 mm (95% CI 25.6-38.4 mm), whereas company A's did not separate using either silk or Nurolon sutures. During the stiffness experiments, the catheters of company B had statistically significantly higher stiffness of 13.23 ± 0.15 N compared to those of company A, with 6.16 ± 0.29 N (p < 0.001). CONCLUSIONS: Mechanical shunt failure from shunt catheter-valve disconnection or fracture is a significant cause of shunt failure. This study demonstrates, for the first time, a correlation between shunt catheters that are less mechanically stiff and those that are less likely to disconnect from the valve when outstretched and are also less likely to tear when held at an angle from the valve outlet. The authors propose an intervention to the standard of care wherein less stiff catheters are trialed to reduce disconnection.

Characterization of a multicenter pediatric-hydrocephalus shunt biobank.

BACKGROUND: Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. METHODS: To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. RESULTS: 293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p value < 0.001). The leading etiology at all centers was post-hemorrhagic hydrocephalus, a fisher's exact test showed there to be statistically significant differences in etiology between center (p = 0.01). Regression showed age (p < 0.01), race (p = 0.038) and hospital-center (p < 0.001) to explain significant variance in the number of revisions. Our model accounted for 31.9% of the variance in revisions. Generalized linear modeling showed hydrocephalus etiology (p < 0.001), age (p < 0.001), weight and physician (p < 0.001) to impact the number of ventricular obstructions. CONCLUSION: The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

The Flow Limiting Operator: A New Approach to Environmental Control in Flow Bioreactors.

Bioreactors have become a critical step for the testing of new biomaterials and pharmaceuticals. They need to be controllable, ideally high-throughput, and produce a biologically relevant environment. For example, in the brain, it is essential to recreate multiple flow-pressure profiles and mimic brain fluid movement for a bioreactor to be more physiologic. In this study, we demonstrate a scalable system that regulates flow rate, pressure, and pulsation amplitude. We also show that with new microcontroller technology, up to 15 chambers running in parallel is theoretically possible. Our system, the Flow Limiting Operator (FLO), achieves these goals by multiplexing a series of valves and pumps to control pressure and volumetric flow rate instead of relying on head gas pressure. With the ability to control multiple parameters and its ease of use, both scientists and clinicians can use FLO to study the effects of pulsation amplitude of the fluid flow, flow rate, and pressure on intercellular interactions for both biomaterials and pharmaceuticals.

Cerebrospinal fluid circulation: What do we know and how do we know it?

The central nervous system's (CNS) complicated design is a double-edged sword. On the one hand, the complexity is what gives rise to higher order thinking; but on the other hand, damage to the CNS evokes its unforgiving nature. The cerebrospinal fluid (CSF) circulation system is an intricate system embedded in and around the CNS that has been the topic of debate since it was first described in the 18th century. It is underscored by the choroid plexus's distinct vascular network which has conventionally been seen as the most prominent structure in CSF production through a variety of active transporters and channels. Despite the ubiquity of this circulation system in vertebrates, some aspects remain understudied. Recent advances in scientific methodology and experimentation have proven to be effective tools for elucidating the mechanisms of the CSF circulation system and the pathological conditions associated with its malfunction. In this review, we capitulate the classical understanding of CSF physiology as well as a new, emerging theory on CSF production.