Extracellular Vesicles Generated by Mesenchymal Stem Cells in Stirred Suspension Bioreactors Promote Angiogenesis in Human-Brain-Derived Endothelial Cells.

Interrupted blood flow in the brain due to ischemic injuries such as ischemic stroke or traumatic brain injury results in irreversible brain damage, leading to cognitive impairment associated with inflammation, disruption of the blood-brain barrier (BBB), and cell death. Since the BBB only allows entry to a small class of drugs, many drugs used to treat ischemia in other tissues have failed in brain-related disorders. The administration of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has shown promise in improving the functional recovery of the brain following cerebral ischemia by inducing blood vessel formation. To facilitate such a treatment approach, it is necessary to develop bioprocesses that can produce therapeutically relevant MSC-EVs in a reproducible and scalable manner. This study evaluated the feasibility of using stirred suspension bioreactors (SSBs) to scale-up the serum-free production of pro-angiogenic MSC-EVs under clinically relevant physioxic conditions. It was found that MSCs grown in SSBs generated EVs that stimulated angiogenesis in cerebral microvascular endothelial cells, supporting the use of SSBs to produce MSC-EVs for application in cerebral ischemia. These properties were impaired at higher cell confluency, outlining the importance of considering the time of harvest when developing bioprocesses to manufacture EV populations.

In vitro flow diversion effect of the ReSolv stent with the shelf technique in a bifurcation aneurysm model.

BACKGROUND: Flow-diverting stents are not currently indicated for the treatment of bifurcation aneurysms, and some case series have demonstrated low occlusion rates, possibly due to a lack in neck coverage. The ReSolv stent is a unique hybrid metal/polymer stent that can be deployed with the shelf technique in order to improve neck coverage. METHODS: A Pipeline, unshelfed ReSolv, and shelfed ReSolv stent were deployed in the left-sided branch of an idealized bifurcation aneurysm model. After determining stent porosity, high-speed digital subtraction angiography runs were acquired under pulsatile flow conditions. Time-density curves were created using two region of interest (ROI) paradigms (total aneurysm and left/right), and four parameters were extracted to characterize flow diversion performance. RESULTS: The shelfed ReSolv stent demonstrated better aneurysm outflow alterations compared to the Pipeline and unshelfed ReSolv stent when using the total aneurysm as the ROI. On the left side of the aneurysm, there was no significant difference between the shelfed ReSolv stent and the Pipeline. On the right side of the aneurysm, however, the shelfed ReSolv stent had a significantly better contrast washout profile than the unshelfed ReSolv stent and the Pipeline stent. CONCLUSIONS: The ReSolv stent with the shelf technique demonstrates the potential to improve flow diversion outcomes for bifurcation aneurysms. Further in vivo testing will help to determine whether the additional neck coverage leads to better neointimal scaffolding and long-term aneurysm occlusion.

Physiological oxygen conditions enhance the angiogenic properties of extracellular vesicles from human mesenchymal stem cells.

BACKGROUND: Following an ischemic injury to the brain, the induction of angiogenesis is critical to neurological recovery. The angiogenic benefits of mesenchymal stem cells (MSCs) have been attributed at least in part to the actions of extracellular vesicles (EVs) that they secrete. EVs are membrane-bound vesicles that contain various angiogenic biomolecules capable of eliciting therapeutic responses and are of relevance in cerebral applications due to their ability to cross the blood-brain barrier (BBB). Though MSCs are commonly cultured under oxygen levels present in injected air, when MSCs are cultured under physiologically relevant oxygen conditions (2-9% O2), they have been found to secrete higher amounts of survival and angiogenic factors. There is a need to determine the effects of MSC-EVs in models of cerebral angiogenesis and whether those from MSCs cultured under physiological oxygen provide greater functional effects. METHODS: Human adipose-derived MSCs were grown in clinically relevant serum-free medium and exposed to either headspace oxygen concentrations of 18.4% O2 (normoxic) or 3% O2 (physioxic). EVs were isolated from MSC cultures by differential ultracentrifugation and characterized by their size, concentration of EV specific markers, and their angiogenic protein content. Their functional angiogenic effects were evaluated in vitro by their induction of cerebral microvascular endothelial cell (CMEC) proliferation, tube formation, and angiogenic and tight junction gene expressions. RESULTS: Compared to normoxic conditions, culturing MSCs under physioxic conditions increased their expression of angiogenic genes SDF1 and VEGF, and subsequently elevated VEGF-A content in the EV fraction. MSC-EVs demonstrated an ability to induce CMEC angiogenesis by promoting tube formation, with the EV fraction from physioxic cultures having the greatest effect. The physioxic EV fraction further upregulated the expression of CMEC angiogenic genes FGF2, HIF1, VEGF and TGFB1, as well as genes (OCLN and TJP1) involved in BBB maintenance. CONCLUSIONS: EVs from physioxic MSC cultures hold promise in the generation of a cell-free therapy to induce angiogenesis. Their positive angiogenic effect on cerebral microvascular endothelial cells demonstrates that they may have utility in treating ischemic cerebral conditions, where the induction of angiogenesis is critical to improving recovery and neurological function.

Natural history of antiplatelet nonresponders undergoing carotid artery stenting.

OBJECTIVE: Routine antiplatelet responsiveness testing for patients undergoing carotid artery stenting procedures is not performed at most endovascular centers and remains a topic of controversy within the neurointerventional community. The objective of this study was to determine if nonresponsiveness to acetylsalicylic acid or clopidogrel was associated with the development of symptomatic thromboembolic events in patients undergoing carotid stenting procedures. METHODS: A prospective study was conducted at the Foothills Medical Centre in Calgary, Alberta, Canada, from August 2019 to July 2021. Patients undergoing carotid artery stenting procedures and who were receiving dual antiplatelet therapy were enrolled in the study. Responsiveness to the antiplatelet medications was determined through whole blood impedance aggregometry. The primary outcome was development of a symptomatic thromboembolic event within 90 days after the procedure. The treating physicians were blinded to the aggregometry results for the duration of the study. RESULTS: One hundred two procedures were performed in 100 patients. Eight thromboembolic events (8%) occurred during the study. Age (p = 0.03) and nonresponsiveness to clopidogrel (p = 0.003) were associated with the development of thromboembolic events. The multivariable model showed that clopidogrel nonresponsiveness was independently associated with the development of a thromboembolic event (adjusted OR 6.14, 95% CI 1.25-30.11, p = 0.03). CONCLUSIONS: This study demonstrated that patients who were identified as clopidogrel nonresponders, using whole blood impedance aggregometry, were at an increased risk of developing thromboembolic events. Larger studies are needed to assess the utility of routine platelet function testing prior to carotid artery stenting procedures.

Distal transradial access for targeted spinal angiography and embolization.

BACKGROUND: Spinal catheter angiography is commonly performed in the evaluation and treatment of spinal vascular lesions. The typical approach to spinal angiography consists of access through the femoral artery with the use of suitably shaped catheters for selective catheterization of the spinal segmental vasculature. The purpose of our study was to evaluate the safety and feasibility of distal transradial access through the "anatomical snuffbox" for targeted spinal angiography, for the investigation and treatment of selected spinal lesions. METHODS: A retrospective review of patients who underwent transradial spinal angiography and embolization was performed from August 2019 to January 2022. A total of eight patients were identified, who underwent targeted spinal angiography through distal transradial access. Outcome measures were documented in a tabular manner. RESULTS: Radial access was successful in all patients. Seven patients had vascular tumors of the spinal column and underwent tumor embolization followed by segmental artery occlusion prior to surgery. One patient had a spinal dural AV fistula that could not be embolized due to feeding vessel tortuosity and eventually went on to have a laminectomy. Mean fluoroscopy time was 31.4 min. There were no access site hemorrhagic complications. One patient experienced transient mild hand numbness during the period of hemostasis with the vascular compression device that resolved completely within 24 h. CONCLUSIONS: Distal transradial access is a feasible and safe option for targeted spinal angiography and treatment in selected patients.

Residual and Recurrent Spinal Cord Cavernous Malformations: Outcomes and Techniques to Optimize Resection and a Systematic Review of the Literature.

BACKGROUND: Intramedullary spinal cord cavernous malformations (SCCMs) account for only 5% of overall cavernous malformations (CMs). The occurrence of recurrent or residual SCCMs has not been well discussed, nor have the technical nuances of resection. OBJECTIVE: To assess the characteristics of residual SCCMs and surgical outcomes and describe the techniques to avoid leaving lesion remnants during primary resection. METHODS: Demographic, radiologic, intraoperative findings and surgical outcomes data for a cohort of surgically managed intramedullary SCCMs were obtained from an institutional database and retrospectively analyzed. A systematic literature review was performed using PRISMA guidelines. RESULTS: Of 146 SCCM resections identified, 17 were for residual lesions (12%). Patients with residuals included 13 men and 4 women, with a mean age of 43 years (range 16-70). All patients with residual SCCMs had symptomatic presentations: sensory deficits, paraparesis, spasticity, and pain. Residuals occurred between 3 and 264 months after initial resection. Approaches for 136 cases included posterior midline myelotomy (28.7%, n = 39), pial surface entry (37.5%, n = 51), dorsal root entry zone (27.9%, n = 38), and lateral entry (5.9%, n = 8). Follow-up outcomes were similar for patients with primary and residual lesions, with the majority having no change in modified Rankin Scale score (63% [59/93] vs 75% [9/12], respectively, P = .98). CONCLUSION: SCCMs may cause significant symptoms. During primary resection, care should be taken to avoid leaving residual lesion remnants, which can lead to future hemorrhagic events and neurological morbidity. However, satisfactory results are achievable even with secondary or tertiary resections.

North American multicenter experience with the Flow Redirection Endoluminal Device in the treatment of intracranial aneurysms.

OBJECTIVE: Flow diverters have revolutionized the endovascular treatment of intracranial aneurysms. Here, the authors present the first large-scale North American multicenter experience using the Flow Redirection Endoluminal Device (FRED) in the treatment of cerebral aneurysms. METHODS: Consecutive cerebral aneurysms treated with FRED at 7 North American centers between June 2020 and November 2021 were included. Data collected included patient demographic characteristics, aneurysm characteristics, periprocedural and long-term complications, modified Rankin Scale (mRS) scores, and radiological follow-up. RESULTS: In total, 133 aneurysms in 116 patients were treated with 123 FRED deployment procedures and included in this study. One hundred twenty-six aneurysms (94.7%) were unruptured, 117 (88.0%) saccular, and 123 (92.5%) located in anterior circulation. The mean (range) aneurysm maximal width and neck width sizes were 7.2 (1.5-42.5) mm and 4.1 (1.0-15.1) mm, respectively. Successful FRED deployment was achieved in 122 procedures (99.2%). Adjunctive coiling was used in 4 procedures (3.3%). Radiological follow-up was available for 101 aneurysms at a median duration of 7.0 months. At last follow-up, complete occlusion was observed in 55.4% of patients, residual neck in 8.9%, and filling aneurysm in 35.6%; among cases with radiological follow-up duration > 10 months, these values were 21/43 (48.8%), 3/43 (7.0%), and 19/43 (44.2%), respectively. On multivariate regression analysis, age (OR 0.93, p = 0.001) and aneurysm neck size (OR 0.83, p = 0.048) were negatively correlated with odds of complete occlusion at latest follow-up. The retreatment rate was 6/124 (4.8%). The overall complication rate was 31/116 (26.7%). Parent vessel occlusion, covered branch occlusion, and in-stent stenosis were detected in 9/99 (9.1%), 6/63 (9.5%), and 15/99 (15.2%) cases, respectively. The FRED-related, symptomatic, thromboembolic, and hemorrhagic complication rates were 22.4%, 12.9%, 6.9%, and 0.9% respectively. The morbidity rate was 10/116 patients (8.6%). There was 1 death due to massive periprocedural internal carotid artery stroke, and 3.6% of the patients had an mRS score > 2 at the last follow-up (vs 0.9% at baseline). CONCLUSIONS: As the first large-scale North American multicenter FRED experience, this study confirmed the ease of successful FRED deployment but suggested lower efficacy and a higher rate of complications than reported by previous European and South American studies on FRED and other flow-diverting devices. The authors recommend judicious use of this device until future studies can better elucidate the long-term outcomes of FRED treatment.

Prx1+ MPCs Accumulate in the Dura Mater of Wild-Type and p21-/- Mice Followed by a Specific Reduction in p21-/- Dural MPCs.

Epidural fat contains a population of mesenchymal progenitor cells (MPCs), and this study explores the behavior of these cells on the adjacent dura mater during growth and in response to injury in a p21 knockout mouse model. p21-/- mice are known to have increased cell proliferation and enhanced tissue regeneration post-injury. Therefore, it is hypothesized that the process by which epidural fat MPCs maintain the dura mater can be accelerated in p21-/- mice. Using a Prx1 lineage tracing mouse model, the epidural fat MPCs are found to increase in the dura mater over time in both C57BL/6 (p21+/+ ) and p21-/- mice; however, by 3 weeks post-tamoxifen induction, few MPCs are observed in p21-/- mice. These endogenous MPCs also localize to dural injuries in both mouse strains, with MPCs in p21-/- mice demonstrating increased proliferation. When epidural fat MPCs derived from p21-/- mice are transplanted into dural injuries in C57BL/6 mice, these MPCs are found in the injury site. It is demonstrated that epidural fat MPCs play a role in dural tissue maintenance and are able to directly contribute to dural injury repair. This suggests that these MPCs have the potential to treat injuries and/or pathologies in tissues surrounding the spinal cord.

Proteoglycan 4 is present within the dura mater and produced by mesenchymal progenitor cells.

Mesenchymal progenitor cells (MPCs) have been recently identified in human and murine epidural fat and have been hypothesized to contribute to the maintenance/repair/regeneration of the dura mater. MPCs can secrete proteoglycan 4 (PRG4/lubricin), and this protein can regulate tissue homeostasis through bio-lubrication and immunomodulatory functions. MPC lineage tracing reporter mice (Hic1) and human epidural fat MPCs were used to determine if PRG4 is expressed by these cells in vivo. PRG4 expression co-localized with Hic1+ MPCs in the dura throughout skeletal maturity and was localized adjacent to sites of dural injury. When Hic1+ MPCs were ablated, PRG4 expression was retained in the dura, yet when Prx1+ MPCs were ablated, PRG4 expression was completely lost. A number of cellular processes were impacted in human epidural fat MPCs treated with rhPRG4, and human MPCs contributed to the formation of epidural fat, and dura tissues were xenotransplanted into mouse dural injuries. We have shown that human and mouse MPCs in the epidural/dura microenvironment produce PRG4 and can contribute to dura homeostasis/repair/regeneration. Overall, these results suggest that these MPCs have biological significance within the dural microenvironment and that the role of PRG4 needs to be further elucidated.

Immediate flow-diversion characteristics of a novel primarily bioresorbable flow-diverting stent.

OBJECTIVE: Flow-diverting stents with a resorbable component have significant theoretical benefits over full metal stents, although currently there are none in clinical use. In this study, the authors sought to determine the immediate flow-diversion characteristics of a novel primarily bioresorbable flow-diverting stent. METHODS: Bioresorbable stents were deployed into glass tube models to determine porosity and pore density. In vitro flow diversion behavior was evaluated using high frame rate angiography under pulsatile flow conditions in a patient-specific silicone aneurysm model treated with the resorbable stent as well as the Surpass Evolve stent. In vivo flow diversion was characterized by deployment into 20 rabbit saccular aneurysm models, and grading was based on the O'Kelly-Marotta scale and the 4F-flow diversion predictive score. RESULTS: Porosities and pore densities of the bioresorbable stent were in the flow-diverting range for all target vessel diameters. Quantified results of immediate angiography after placement of the bioresorbable stent into a silicone aneurysm model demonstrated greater flow diversion compared to the Evolve stent. Bioresorbable stent placement in saccular aneurysm models resulted in an immediate O'Kelly-Marotta grade of A3 or better and a 4F-flow diversion predictive score of 4 or better in all cases. CONCLUSIONS: The bioresorbable stent has immediate flow-diversion characteristics that are comparable to commercially available metal stents. Longer-term studies are underway to determine the ability of the resorbable fibers to act as a neointimal scaffold and result in long-term aneurysm occlusion.

Prx1 + and Hic1+ Mesenchymal Progenitors Are Present Within the Epidural Fat and Dura Mater and Participate in Dural Injury Repair.

Epidural fat is commonly discarded during spine surgery to increase the operational field. However, mesenchymal progenitor cells (MPCs) have now been identified in human epidural fat and within the murine dura mater. This led us to believe that epidural fat may regulate homeostasis and regeneration in the vertebral microenvironment. Using two MPC lineage tracing reporter mice (Prx1 and Hic1), not only have we found that epidural fat MPCs become incorporated in the dura mater over the course of normal skeletal maturation, but have also identified these cells as an endogenous source of repair and regeneration post-dural injury. Moreover, our results reveal a partial overlap between Prx1+ and Hic1+ populations, indicating a potential hierarchical relationship between the two MPC populations. This study effectively challenges the notion of epidural fat as an expendable tissue and mandates further research into its biological function and relevance.

Optimal Glucose Target After Aneurysmal Subarachnoid Hemorrhage: A Matched Cohort Study.

BACKGROUND: Hyperglycemia has been associated with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, there remains debate as to what optimal glucose targets should be in this patient population. OBJECTIVE: To assess whether we could identify an optimal glucose target for patients with aSAH. METHODS: We performed a post hoc analysis of the "clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage" trial data set. Patients had laboratory results drawn daily for the entirety of their intensive care unit stay. Maximum blood glucose levels were assessed for a relationship with unfavorable outcomes using multiple logistic regression analysis. Maximum blood glucose levels were dichotomized based on the Youden index, which identified a maximum level of <9.2 mmol/L as the optimal cut point for prediction of unfavorable outcomes. Nearest neighbor matching was used to assess the relationship between maintaining glucose levels below the cut point and unfavorable functional outcomes (defined as a modified Rankin score of >2 at 3 mo post-aSAH). The matching was performed after calculation of a propensity score based on identified predictors of outcome and glucose levels. RESULTS: Three hundred eighty-nine patients were included in the matched analysis. Propensity scores were balanced on both the covariates and outcomes of interest. There was a significant average treatment effect (-0.143: 95% confidence interval -0.267 to -0.019) for patients who maintained glucose levels <9.2 mmol/L. CONCLUSION: Maintaining glucose levels below the identified cut point was associated with a decreased risk for unfavorable outcomes in this retrospective matched study.

Intra-arterial injection of mesenchymal stem cells to accelerate neointima formation after endovascular stenting in a rabbit model.

OBJECTIVE: Delayed neointima formation over a neurovascular stent is associated with thrombotic complications that can lead to stroke. The purpose of this study was to evaluate whether an intra-arterial injection of mesenchymal stem cells (MSCs) after stent placement leads to improved neointima and reduced thrombus formation over the device. METHODS: Solitaire stents were placed into the aortas of rabbits that were divided into MSC and control groups. The MSC group received an intra-arterial injection of MSCs through the same microcatheter used for stent deployment. Optical coherence tomography (OCT) was used to evaluate and compare neointima and thrombus formation in a blinded fashion. Explanted specimens were also imaged with scanning electron microscopy (SEM) and evaluated by observers blinded to group allocation using an endothelialization scoring system. RESULTS: The 3-day MSC group was similar to the 7-day controls in terms of stent strut coverage ratio and maximum neointimal thickness, but these values were significantly higher than the 3-day control group based on a hierarchical mixed-effects linear regression analysis. SEM revealed a significantly higher endothelialization score for the MSC group compared with controls at the same time point. There was no difference in thrombus formation between any of the groups. CONCLUSIONS: The intra-arterial injection of MSCs after endovascular stenting accelerated early neointima formation but had no effect on thrombus formation in this study. Larger studies are required to verify these findings and determine the durability and mechanism of this effect.

Fluoroscopy, CT, and MR imaging characteristics of a novel primarily bioresorbable flow-diverting stent for aneurysms.

BACKGROUND: Five to ten percent of the global population have unruptured intracranial aneurysms, and ruptured brain aneurysms cause approximately 500,000 deaths a year. Flow-diverting stent treatment is a less invasive intracranial aneurysm treatment that induces aneurysm thrombosis. The imaging characteristics of a novel primarily bioresorbable flow-diverting stent (BFDS) are assessed in comparison to the leading metal stent using fluoroscopy, CT, and MRI. METHODS: X-ray/fluoroscopic images of stents were taken using a human cadaveric skull model. CT and MRI were acquired using silicone flow models of residual aneurysms. Images were analyzed with Likert scales in anonymous surveys by neurointerventionalists. Quantitative measurements of radiographic density (CT) and artifact boundary size (CT & MRI) were also obtained. RESULTS: Visibility of the BFDS on X-ray was less than the metal stent but deemed adequate for deployment and intraprocedural assessment. The metal stent was more radiopaque than the BFDS on CT, but qualitative assessment was not significantly different for the two stents. MRI imaging was significantly better using the BFDS in terms of overall artifact and intraluminal assessment. CONCLUSIONS: The BFDS has adequate visualization on X-ray/fluoroscopy and should be clinically acceptable for fluoroscopic deployment. On MRI, there is less quantitative artifact as well as overall improved qualitative assessment that will allow for more detailed non-invasive imaging follow-up of treated aneurysms, potentially reducing the need for digital subtraction catheter angiography.

Engineering a 3D human intracranial aneurysm model using liquid-assisted injection molding and tuned hydrogels.

Physiologically relevant intracranial aneurysm (IA) models are crucially required to facilitate testing treatment options for IA. Herein, we report the development of a new in vitro tissue-engineered platform, which recapitulates the microenvironment, structure, and cellular complexity of native human IA. A new modified liquid-assisted injection molding technique was developed to fabricate a three-dimensional hollow IA model with clinically relevant IA dimensions within a mechanically tuned Gelatin Methacryloyl (GelMA) hydrogel. An endothelium lining was created inside the IA model by culturing human umbilical vein endothelial cells over pre-cultured human brain vascular smooth muscle cells. These cellularized IA models were subjected to medium perfusion at flow rates between 6.3 and 15.75 mL/min for inducing biomimetic vessel wall shear stress (10-25 dyn/cm2) to the cells for ten days. Both cell types maintained their secretome profiles and showed more than 96% viability, demonstrating the biocompatibility of the hydrogel during perfusion cell culture at such flow rates. Based on the characterized viscoelastic properties of the GelMA hydrogel and with the aid of a fluid-structure interaction model, the capability of the IA model in predicting the response of the IA to different fluid flow profiles was mathematically shown. With physiologically relevant behavior, our developed in vitro human IA model could allow researchers to better understand the pathophysiology and treatment of IA. STATEMENT OF SIGNIFICANCE: A three-dimensional intracranial aneurysm (IA) tissue model recapitulating the microenvironment, structure, and cellular complexity of native human IA was developed. • An endothelium lining was created inside the IA model over pre-cultured human brain vascular smooth muscle cells over at least 10-day successful culture. • The cells maintained their secretome profiles, demonstrating the biocompatibility of hydrogel during a long-term perfusion cell culture. • The IA model showed its capability in predicting the response of IA to different fluid flow profiles. • The cells in the vessel region behaved differently from cells in the aneurysm region due to alteration in hemodynamic shear stress. • The IA model could allow researchers to better understand the pathophysiology and treatment options of IA.

Innovation in unruptured intracranial aneurysm coiling: At which price or efficacy are new technologies cost-effective?

BACKGROUND: Unruptured intracranial aneurysms (UIA) are increasingly being treated by endovascular coiling as opposed to open surgical clipping. Unfortunately, endovascular coiling imparts an approximate 25% recanalization rate, leading to additional procedures and increased rupture risk. While a new health technology innovation (HTI) that reduces this recanalization rate would benefit patients, few advancements have been made. We aim to determine whether cost-effectiveness has been a barrier to HTI. METHODS: A probabilistic Markov model was constructed from the healthcare payer perspective to compare standard endovascular treatment of UIA to standard treatment plus the addition of a HTI adjunct. Costs were measured in 2018 USD and health outcomes were measured in quality-adjusted life-years (QALY). In the base case, the HTI was a theoretical mesenchymal stem cell therapy which reduced the aneurysm recanalization rate by 50% and cost $10,000 per procedure. All other model inputs were derived from the published scientific literature. RESULTS: Based on the model results, we found that for a given HTI price (y) and relative risk reduction of aneurysm recanalization (x), the HTI was always cost-effective if the following equation was satisfied: y ≤ 20268 ∙ x, using a willingness-to-pay threshold of $50,000 per QALY. The uncertainty surrounding whether an aneurysm would recanalize was a significant driver within the model. When the uncertainty around the risk of aneurysm recanalization was eliminated, the 10-year projected additional benefit to the United States healthcare system was calculated to be $113,336,994. CONCLUSION: Cost-effectiveness does not appear to be a barrier to innovation in reducing the recanalization rate of UIA treated by endovascular coil embolization. Our model can now be utilized by academia and industry to accentuate economically feasible HTI and by healthcare payers to calculate their maximum willingness-to-pay for a new technology. Our results also indicate that predicting a patient's baseline risk of aneurysm recanalization is a critical area of future research.

Creating Clinically Relevant Aneurysm Sizes in the Rabbit Surgical Elastase Model.

BACKGROUND: Creating aneurysm sizes in animal models that resemble human aneurysms is essential to study and test neuroendovascular devices. The commonly used rabbit surgical elastase model, however, produces saccular aneurysms that are smaller than those typically treated in humans. The goal of this study was to determine whether an increased vessel stump length and the addition of calcium chloride to the incubation solution has an effect on the resulting aneurysm size. METHODS: Using a modified aneurysm creation method, 32 female New Zealand White rabbits underwent aneurysm creation procedures. Subjects were equally allocated into 4 different groups based on vessel stump length (2 cm controls vs. 3 cm) and incubation solution (elastase alone controls vs. a 1:1 mixture of elastase and calcium chloride). At 4 weeks, all animals underwent angiography to determine the resulting aneurysm size by a neurointerventionalist who was blinded to treatment group. RESULTS: An increase in stump length from 2 cm to 3 cm resulted in a significant increase in the height of aneurysm (P < 0.05). Compared with control animals, the combination of a 3-cm stump length and the addition of calcium chloride to the incubation solution resulted in a significant increase in aneurysm height, width, and volume (P < 0.05). CONCLUSIONS: Creating larger aneurysms is necessary for the rabbit model to be more clinically relevant. Our study demonstrated that the utilization of a 3-cm vessel stump as well as both calcium chloride and elastase in the incubation solution results in aneurysm sizes that more closely resemble the population of aneurysms treated in humans.

Findings Predictive of Poor Outcome in Grade 5 Subarachnoid Hemorrhage: A Cohort Study.

BACKGROUND: Most patients with World Federation of Neurological Surgeons (WFNS) grade 5 subarachnoid hemorrhage (SAH) have poor outcomes. Accurate assessment of prognosis is important for treatment decisions and conversations with families regarding goals of care. Unjustified pessimism may lead to "self-fulfilling prophecy," where withdrawal of life-sustaining measures (WLSM) is invariably followed by death. METHODS: We performed a cohort study involving consecutive patients with WFNS grade 5 SAH to identify variables with >= 90% and >= 95% positive predictive value (PPV) for poor outcome (1-year modified Rankin Score >= 4), as well as findings predictive of WLSM. RESULTS: Of 140 patients, 38 (27%) had favorable outcomes. Predictors with >= 95% PPV for poor outcome included unconfounded 72-hour Glasgow Coma Scale motor score <= 4, absence of >= 1 pupillary light reflex (PLR) at 24 hours, and intraventricular hemorrhage (IVH) score of >= 20 (volume >= 54.6 ml). Intracerebral hemorrhage (ICH) volume >= 53 ml had PPV of 92%. Variables associated with WLSM decisions included a poor motor score (p < 0.0001) and radiographic evidence of infarction (p = 0.02). CONCLUSIONS: We identified several early predictors with high PPV for poor outcome. Of these, lack of improvement in motor score during the initial 72 hours had the greatest potential for confounding from "self-fulfilling prophecy." Absence of PLR at 24 hours, IVH score >= 20, and ICH volume >= 53 ml predicted poor outcome without a statistically significant effect on WLSM decisions. More research is needed to validate prognostic variables in grade 5 SAH, especially among patients who do not undergo WLSM.

Promoting endothelialization of flow-diverting stents: a review.

Intracranial flow-diverting (FD) stents have revolutionized the treatment of intracranial aneurysms in recent years, but complications resulting from failed endothelialization can still occur. Approaches to promote endothelialization are understudied, but hold promise in mitigating both short- and long-term complications associated with FD stent insertion. The aim of this review is to highlight the various features of and modifications that have been made to FD stents in order to expedite endothelialization. More specifically, we focus on how endothelialization can be influenced by the stent design, wall apposition, surface modifications, and the inclusion of biological agents.

A Novel Parameter to Predict Supraclinoid Aneurysm Persistence After Flow Diversion with the Pipeline Embolization Device.

BACKGROUND: Aneurysm recurrence after Pipeline Embolization Device (PED) placement can be caused by oversizing of the stent as well as poor wall apposition, both of which can lead to elongation. The objective of this study was to assess whether a novel parameter for measuring device elongation based on two-dimensional imaging could be predictive for persistent aneurysm filling after treatment with the PED. METHODS: A retrospective cohort analysis was initially completed on 41 aneurysms from institution A, examining demographic, aneurysmal, and device measurements. Device measurements, including the ratio of the measured length to the nominal length (ML/NL) of the PED, were taken by reviewers blinded to the primary end point, which was aneurysm occlusion status on 6 month catheter angiogram. Findings were then externally validated against 30 aneurysms (supraclinoid only) from institution B. RESULTS: Data from institution A showed 61% complete aneurysm occlusion at 6 months, and were lower for aneurysms in the supraclinoid region. For supraclinoid aneurysms alone, combined data from both institutions showed higher rates of nonocclusion with aneurysm neck size >4 mm (P = 0.008) and a trend toward significance in aneurysms with a branch vessel (P = 0.051). The mean ML/NL ratio was significantly larger in the nonoccluded group compared with the occluded group at both institution A (ratio, 1.37 versus 1.10; P < 0.001) and institution B (ratio, 1.36 vs. 1.11; P = 0.002). CONCLUSIONS: Our data suggest that a novel parameter based on two-dimensional angiography may serve as a rapid technique to measure device elongation and predict occlusion of supraclinoid aneurysms after PED placement.