Feasibility of robot-assisted neuroendovascular procedures

OBJECTIVE Geographic factors prevent equitable access to urgent advanced neuroendovascular treatments. Robotic technologies may enable remote endovascular procedures in the future. The authors performed a translational, benchtop-to-clinical study to evaluate the in vitro and clinical feasibility of the CorPath GRX Robotic System for robot-assisted endovascular neurointerventional procedures. METHODS A series of bench studies was conducted using patient-specific 3D-printed models to test the system’s compatibility with standard neurointerventional devices, including microcatheters, microwires, coils, intrasaccular devices, and stents. Optimal baseline setups for various procedures were determined. The models were further used to rehearse clinical cases. Subsequent to these investigations, a prospective series of 6 patients was treated using robotic assistance for complex, wide-necked intracranial saccular aneurysms between November 2019 and February 2020. The technical success, incidence of periprocedural complications, and need for conversion to manual procedures were evaluated. RESULTS The ideal robotic setup for treatment of both anterior and posterior circulation aneurysms was determined to consist of an 80-cm guide catheter with a 115-cm-long intermediate catheter, a microcatheter between 150 and 170 cm in length, and a microwire with a minimum length of 300 cm. All coils, intrasaccular devices, and stents tested were compatible with the system and could be advanced or retracted safely and placed accurately. All 6 clinical procedures were technically successful, with all intracranial steps being performed robotically with no conversions to manual intervention or failures of the robotic system. There were no procedure-related complications or adverse clinical outcomes. CONCLUSIONS This study demonstrates the feasibility of robot-assisted neurointerventional procedures. The authors’ results represent an important step toward enabling remote neuroendovascular care and geographic equalization of advanced endovascular treatments through so-called telestroke intervention.

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Abstract TP57: Tenzing™ 7 Delivery Catheter: A Novel Delivery Assist Catheter Significantly Facilitates Catheter Delivery in an Anatomically Challenging Stroke Model

Stroke ◽

10.1161/str.51.suppl_1.tp57 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Andreas M Frölich ◽

Joey English ◽

Olav Jansen ◽

Markus Möhlenbruch ◽

István Szikora ◽

...

Keyword(s):

Carotid Artery ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Ophthalmic Artery ◽

Carotid Bifurcation ◽

Patient Specific ◽

Target Vessel ◽

Vessel Occlusion ◽

Guide Catheter

Background: In large vessel occlusion stroke, intracranial navigation of large-bore aspiration catheters can be impeded by vessel curvature and ophthalmic artery origin. Novel conically-shaped delivery assist devices are designed to facilitate delivery. We assessed aspiration catheter deliverability in several patient-specific in vitro models. Methods: In a flow model replicating vascular access from the femoral to the middle cerebral artery, two different commercially available aspiration catheters were repeatedly advanced through a commercial 0.088” sheath from the carotid bifurcation to the middle cerebral artery by five neurointerventionalists under fluoroscopy. Three craniocervical access scenarios were manufactured based on challenging patient anatomy. Catheter deliverability was assessed with standard microwire/microcatheter combinations (MC) and the Tenzing™ 7 catheter (T7). Procedural characteristics were recorded, and operators rated carotid artery deflection, guide catheter pushback and difficulty passing the ophthalmic artery origin on a 5-point scale (1=none, 5=most severe). Results: Among 117 delivery attempts, the target vessel was reached significantly more often with T7 (96%) than with MC (66%, p<0.001). Successful delivery was faster with T7 (33s, 95%CI:30-35s) than with MC (69s, 95%CI:55-83s, p<0.001) and there was less need to cross the occlusion site with T7 (12%) than with MC (53%, p<0.001). Operators assigned superior ratings to T7 than to MC regarding carotid artery deflection (2, IQR1-3 vs. 3, IQR2-4, p=0.014), guide catheter pushback (2, IQR1-3,5 vs. 3, IQR3-4, p=0.005) and ophthalmic artery origin passage (2, IQR1-2 vs. 4, IQR3-5, p<0.001). Conclusion: Compared to microcatheter & microwire combinations, the T7 delivery assist catheter significantly facilitates aspiration catheter delivery to the target vessel in vitro.

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Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids

Molecular Autism ◽

10.1186/s13229-021-00413-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Dwaipayan Adhya ◽

George Chennell ◽

James A. Crowe ◽

Eva P. Valencia-Alarcón ◽

James Seyforth ◽

...

Keyword(s):

High Resolution ◽

Human Brain ◽

Light Sheet ◽

Autism Spectrum ◽

Model Systems ◽

Large Field ◽

Autism Spectrum Conditions ◽

Patient Specific ◽

Airy Beam

Abstract Background The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points. Results Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified, in vitro tissues, in both speed and resolution when compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes. Conclusion We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and cleared in vitro human brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. This process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes in vitro.

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Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T

International Journal of Molecular Sciences ◽

10.3390/ijms22084009 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4009

Author(s):

Maik Liedtke ◽

Christin Völkner ◽

Alexandra V. Jürs ◽

Franziska Peter ◽

Michael Rabenstein ◽

...

Keyword(s):

Oxidative Stress ◽

Transmembrane Protein ◽

Hereditary Disease ◽

Cholesterol Homeostasis ◽

Patient Specific ◽

Differentiated Cells ◽

Npc1 Gene ◽

Niemann Pick

Niemann-Pick type C2 (NP-C2) disease is a rare hereditary disease caused by mutations in the NPC2 gene. NPC2 is a small, soluble protein consisting of 151 amino acids, primarily expressed in late endosomes and lysosomes (LE/LY). Together with NPC1, a transmembrane protein found in these organelles, NPC2 accomplishes the exclusion of cholesterol; thus, both proteins are essential to maintain cellular cholesterol homeostasis. Consequently, mutations in the NPC2 or NPC1 gene result in pathophysiological accumulation of cholesterol and sphingolipids in LE/LY. The vast majority of Niemann-Pick type C disease patients, 95%, suffer from a mutation of NPC1, and only 5% display a mutation of NPC2. The biochemical phenotype of NP-C1 and NP-C2 appears to be indistinguishable, and both diseases share several commonalities in the clinical manifestation. Studies of the pathological mechanisms underlying NP-C2 are mostly based on NP-C2 animal models and NP-C2 patient-derived fibroblasts. Recently, we established induced pluripotent stem cells (iPSCs), derived from a donor carrying the NPC2 mutations c.58G>T/c.140G>T. Here, we present a profile of pathophysiological in vitro features, shared by NP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs. Profiling comprised a determination of the NPC2 protein level, detection of cholesterol accumulation by filipin staining, analysis of oxidative stress, and determination of autophagy. As expected, the NPC2-deficient cells displayed a significantly reduced amount of NPC2 protein, and, accordingly, we observed a significantly increased amount of cholesterol. Most notably, NPC2-deficient cells displayed only a slight increase of reactive oxygen species (ROS), suggesting that they do not suffer from oxidative stress and express catalase at a high level. As a site note, comparable NPC1-deficient cells suffer from a lack of catalase and display an increased level of ROS. In summary, this cell line provides a valuable tool to gain deeper understanding, not only of the pathogenic mechanism of NP-C2, but also of NP-C1.

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Depression patient-derived cortical neurons reveal potential biomarkers for antidepressant response

Translational Psychiatry ◽

10.1038/s41398-021-01319-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yishai Avior ◽

Shiri Ron ◽

Dana Kroitorou ◽

Claudia Albeldas ◽

Vitaly Lerner ◽

...

Keyword(s):

Cortical Neurons ◽

Antidepressant Treatment ◽

Patient Specific ◽

Specific Gene ◽

Specific Information ◽

Patient Response ◽

Patient Will ◽

Gene Expression Alterations ◽

Treatment Alternatives

AbstractMajor depressive disorder is highly prevalent worldwide and has been affecting an increasing number of people each year. Current first line antidepressants show merely 37% remission, and physicians are forced to use a trial-and-error approach when choosing a single antidepressant out of dozens of available medications. We sought to identify a method of testing that would provide patient-specific information on whether a patient will respond to a medication using in vitro modeling. Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression study were used to rapidly generate cortical neurons and screen them for bupropion effects, for which the donor patients showed remission or non-remission. We provide evidence for biomarkers specific for bupropion response, including synaptic connectivity and morphology changes as well as specific gene expression alterations. These biomarkers support the concept of personalized antidepressant treatment based on in vitro platforms and could be utilized as predictors to patient response in the clinic.

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Generation of vascular chimerism within donor organs

Scientific Reports ◽

10.1038/s41598-021-92823-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shahar Cohen ◽

Shirly Partouche ◽

Michael Gurevich ◽

Vladimir Tennak ◽

Vadym Mezhybovsky ◽

...

Keyword(s):

Ex Vivo ◽

Patient Specific ◽

Machine Perfusion ◽

Organ Perfusion ◽

Perfusion Process ◽

Hind Limbs ◽

Porcine Organs ◽

Immunological Barrier

AbstractWhole organ perfusion decellularization has been proposed as a promising method to generate non-immunogenic organs from allogeneic and xenogeneic donors. However, the ability to recellularize organ scaffolds with multiple patient-specific cells in a spatially controlled manner remains challenging. Here, we propose that replacing donor endothelial cells alone, while keeping the rest of the organ viable and functional, is more technically feasible, and may offer a significant shortcut in the efforts to engineer transplantable organs. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. In addition, vascular decellularization of selected organs was performed in situ, within the donor body, achieving better control over the perfusion process. Human placenta-derived endothelial progenitor cells (EPCs) were used as immunologically-acceptable human cells to repopulate the luminal surface of de-endothelialized aorta (in vitro), kidneys, lungs and hind limbs (ex vivo). This study provides evidence that artificially generating vascular chimerism is feasible and could potentially pave the way for crossing the immunological barrier to xenotransplantation, as well as reducing the immunological burden of allogeneic grafts.

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The applicability of patient-Specific 3D models in the planning of nerve-sparing robot-assisted radical prostatectomy

European Urology ◽

10.1016/s0302-2838(21)01469-x ◽

2021 ◽

Vol 79 ◽

pp. S1556-S1557

Author(s):

H. Veerman ◽

T.N. Boellaard ◽

C. Hoeks ◽

J.A. Van Eick ◽

J. Sluijter ◽

...

Keyword(s):

Radical Prostatectomy ◽

3D Models ◽

Patient Specific ◽

Nerve Sparing ◽

Robot Assisted

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In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Cancers ◽

10.3390/cancers13030368 ◽

2021 ◽

Vol 13 (3) ◽

pp. 368

Author(s):

Joline Roze ◽

Elena Sendino Garví ◽

Ellen Stelloo ◽

Christina Stangl ◽

Ferdinando Sereno ◽

...

Keyword(s):

Granulosa Cell ◽

Cell Lines ◽

Combination Treatment ◽

Drug Testing ◽

Drug Application ◽

Hormonal Treatment ◽

Patient Specific ◽

Granulosa Cell Tumors ◽

Potential Synergy

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.

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In vitro evaluation of cerebrospinal fluid velocity measurement in type I Chiari malformation: repeatability, reproducibility, and agreement using 2D phase contrast and 4D flow MRI

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00246-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Gwendolyn Williams ◽

Suraj Thyagaraj ◽

Audrey Fu ◽

John Oshinski ◽

Daniel Giese ◽

...

Keyword(s):

Chiari Malformation ◽

Phase Contrast ◽

Patient Specific ◽

Type I ◽

4D Flow ◽

Csf Dynamics ◽

Flow Measurements ◽

Repeatability And Reproducibility ◽

Flow Techniques

Abstract Background Phase contrast magnetic resonance imaging, PC MRI, is a valuable tool allowing for non-invasive quantification of CSF dynamics, but has lacked adoption in clinical practice for Chiari malformation diagnostics. To improve these diagnostic practices, a better understanding of PC MRI based measurement agreement, repeatability, and reproducibility of CSF dynamics is needed. Methods An anatomically realistic in vitro subject specific model of a Chiari malformation patient was scanned three times at five different scanning centers using 2D PC MRI and 4D Flow techniques to quantify intra-scanner repeatability, inter-scanner reproducibility, and agreement between imaging modalities. Peak systolic CSF velocities were measured at nine axial planes using 2D PC MRI, which were then compared to 4D Flow peak systolic velocity measurements extracted at those exact axial positions along the model. Results Comparison of measurement results showed good overall agreement of CSF velocity detection between 2D PC MRI and 4D Flow (p = 0.86), fair intra-scanner repeatability (confidence intervals ± 1.5 cm/s), and poor inter-scanner reproducibility. On average, 4D Flow measurements had a larger variability than 2D PC MRI measurements (standard deviations 1.83 and 1.04 cm/s, respectively). Conclusion Agreement, repeatability, and reproducibility of 2D PC MRI and 4D Flow detection of peak CSF velocities was quantified using a patient-specific in vitro model of Chiari malformation. In combination, the greatest factor leading to measurement inconsistency was determined to be a lack of reproducibility between different MRI centers. Overall, these findings may help lead to better understanding for application of 2D PC MRI and 4D Flow techniques as diagnostic tools for CSF dynamics quantification in Chiari malformation and related diseases.

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