Preclinical testing platforms for mechanical thrombectomy in stroke: a review on phantoms, in-vivo animal, and cadaveric models

Preclinical testing platforms have been instrumental in the research and development of thrombectomy devices. However, there is no single model which fully captures the complexity of cerebrovascular anatomy, physiology, and the dynamic artery-clot-device interaction. This article provides a critical review of phantoms, in-vivo animal, and human cadaveric models used for thrombectomy testing and provides insights into the strengths and limitations of each platform. Articles published in the past 10 years that reported thrombectomy testing platforms were identified. Characteristics of each test platform, such as intracranial anatomy, artery tortuosity, vessel friction, flow conditions, device-vessel interaction, and visualization, were captured and benchmarked against human cerebral vessels involved in large-vessel occlusion stroke. Thrombectomy phantoms have been constructed from silicone, direct 3D-printed polymers, and glass. These phantoms represent oversimplified patient-specific cerebrovascular geometry but enable adequate visualization of devices and clots under appropriate flow conditions. They do not realistically mimic the artery-clot interaction. For the animal models, arteries from swine, canines, and rabbits have been reported. These models can reasonably replicate the artery-clot-device interaction and have the unique value of evaluating the safety of thrombectomy devices. However, the vasculature geometries are substantially less complex and flow conditions are different from human cerebral arteries. Cadaveric models are the most accurate vascular representations but with limited access and challenges in reproducibility of testing conditions. Multiple test platforms should be likely used for comprehensive evaluation of thrombectomy devices. Interpretation of the testing results should take into consideration platform-specific limitations.

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Design, Fabrication, and Accuracy of a Novel Noncovering Lock-Mechanism Bilateral Patient-Specific Drill Guide Template for Nondeformed and Deformed Thoracic Spines

HSS Journal ® ◽

10.1177/1556331621996331 ◽

2021 ◽

pp. 155633162199633

Author(s):

Mehran Ashouri-Sanjani ◽

Shima Mohammadi-Moghadam ◽

Parisa Azimi ◽

Navid Arjmand

Keyword(s):

Thoracic Spine ◽

Sagittal Plane ◽

Ct Scanning ◽

Entry Point ◽

In Vivo Studies ◽

Patient Specific ◽

Plane Angle ◽

Severe Scoliosis ◽

3D Printed

Background: Pedicle screw (PS) placement has been widely used in fusion surgeries on the thoracic spine. Achieving cost-effective yet accurate placements through nonradiation techniques remains challenging. Questions/Purposes: Novel noncovering lock-mechanism bilateral vertebra-specific drill guides for PS placement were designed/fabricated, and their accuracy for both nondeformed and deformed thoracic spines was tested. Methods: One nondeformed and 1 severe scoliosis human thoracic spine underwent computed tomographic (CT) scanning, and 2 identical proportions of each were 3-dimensional (3D) printed. Pedicle-specific optimal (no perforation) drilling trajectories were determined on the CT images based on the entry point/orientation/diameter/length of each PS. Vertebra-specific templates were designed and 3D printed, assuring minimal yet firm contacts with the vertebrae through a noncovering lock mechanism. One model of each patient was drilled using the freehand and one using the template guides (96 pedicle drillings). Postoperative CT scans from the models with the inserted PSs were obtained and superimposed on the preoperative planned models to evaluate deviations of the PSs. Results: All templates fitted their corresponding vertebra during the simulated operations. As compared with the freehand approach, PS placement deviations from their preplanned positions were significantly reduced: for the nonscoliosis model, from 2.4 to 0.9 mm for the entry point, 5.0° to 3.3° for the transverse plane angle, 7.1° to 2.2° for the sagittal plane angle, and 8.5° to 4.1° for the 3D angle, improving the success rate from 71.7% to 93.5%. Conclusions: These guides are valuable, as the accurate PS trajectory could be customized preoperatively to match the patients’ unique anatomy. In vivo studies will be required to validate this approach.

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Thrombus Imaging Using 3D Printed Middle Cerebral Artery Model and Preclinical Imaging Techniques: Application to Thrombus Targeting and Thrombolytic Studies

Pharmaceutics ◽

10.3390/pharmaceutics12121207 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1207

Author(s):

Andrea Vítečková Wünschová ◽

Adam Novobilský ◽

Jana Hložková ◽

Peter Scheer ◽

Hana Petroková ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Imaging Techniques ◽

Barium Sulphate ◽

Flow Conditions ◽

Preclinical Imaging ◽

Blood Clots ◽

3D Printed

Diseases with the highest burden for society such as stroke, myocardial infarction, pulmonary embolism, and others are due to blood clots. Preclinical and clinical techniques to study blood clots are important tools for translational research of new diagnostic and therapeutic modalities that target blood clots. In this study, we employed a three-dimensional (3D) printed middle cerebral artery model to image clots under flow conditions using preclinical imaging techniques including fluorescent whole-body imaging, magnetic resonance imaging (MRI), and computed X-ray microtomography (microCT). Both liposome-based, fibrin-targeted, and non-targeted contrast agents were proven to provide a sufficient signal for clot imaging within the model under flow conditions. The application of the model for clot targeting studies and thrombolytic studies using preclinical imaging techniques is shown here. For the first time, a novel method of thrombus labeling utilizing barium sulphate (Micropaque®) is presented here as an example of successfully employed contrast agents for in vitro experiments evaluating the time-course of thrombolysis and thus the efficacy of a thrombolytic drug, recombinant tissue plasminogen activator (rtPA). Finally, the proof-of-concept of in vivo clot imaging in a middle cerebral artery occlusion (MCAO) rat model using barium sulphate-labelled clots is presented, confirming the great potential of such an approach to make experiments comparable between in vitro and in vivo models, finally leading to a reduction in animals needed.

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Construction of a comprehensive endovascular test bed for research and device development in mechanical thrombectomy in stroke

Journal of Neurosurgery ◽

10.3171/2020.1.jns192732 ◽

2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Adithya S. Reddy ◽

Yang Liu ◽

Joshua Cockrum ◽

Daniel Gebrezgiabhier ◽

Evan Davis ◽

...

Keyword(s):

Flow Rate ◽

Hydraulic System ◽

Mechanical Thrombectomy ◽

Low Cost ◽

Quality Analysis ◽

Test Bed ◽

Vessel Occlusion ◽

Physiological Flow ◽

3D Printed ◽

Device Interaction

OBJECTIVEThe development of new endovascular technologies and techniques for mechanical thrombectomy in stroke has greatly relied on benchtop simulators. This paper presents an affordable, versatile, and realistic benchtop simulation model for stroke.METHODSA test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with 3D-printed and commercially available cerebrovascular phantoms, a customized hydraulic system to generate physiological flow rate and pressure, and 2 types of embolus analogs (elastic and fragment-prone) capable of causing embolic occlusions under physiological flow.RESULTSThe test bed was highly versatile and allowed realistic, radiation-free mechanical thrombectomy for stroke due to large-vessel occlusion with rapid exchange of geometries and phantom types. Of the transparent cerebrovascular phantoms tested, the 3D-printed phantom was the easiest to manufacture, the glass model offered the best visibility of the interaction between embolus and thrombectomy device, and the flexible model most accurately mimicked the endovascular system during device navigation. None of the phantoms modeled branches smaller than 1 mm or perforating arteries, and none underwent realistic deformation or luminal collapse from device manipulation or vacuum. The hydraulic system created physiological flow rate and pressure leading to iatrogenic embolization during thrombectomy in all phantoms. Embolus analogs with known fabrication technique, structure, and tensile strength were introduced and consistently occluded the middle cerebral artery bifurcation under physiological flow, and their interaction with the device was accurately visualized.CONCLUSIONSThe test bed presented in this study is a low-cost, comprehensive, realistic, and versatile platform that enabled high-quality analysis of embolus–device interaction in multiple cerebrovascular phantoms and embolus analogs.

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Patient-specific 3D-printed coronary models based on coronary computed tomography angiography volumes to investigate flow conditions in coronary artery disease

Biomedical Physics & Engineering Express ◽

10.1088/2057-1976/ab8f6e ◽

2020 ◽

Vol 6 (4) ◽

pp. 045007 ◽

Cited By ~ 2

Author(s):

Kelsey N Sommer ◽

Lauren M Shepard ◽

Dimitrios Mitsouras ◽

Vijay Iyer ◽

Erin Angel ◽

...

Keyword(s):

Computed Tomography ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Computed Tomography Angiography ◽

Coronary Computed Tomography Angiography ◽

Patient Specific ◽

Flow Conditions ◽

Coronary Computed Tomography ◽

3D Printed ◽

Artery Disease

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Numerical Simulations of Flow in Cerebral Aneurysms: Comparison of CFD Results and In Vivo MRI Measurements

Journal of Biomechanical Engineering ◽

10.1115/1.2970056 ◽

2008 ◽

Vol 130 (5) ◽

Cited By ~ 56

Author(s):

Vitaliy L. Rayz ◽

Loic Boussel ◽

Gabriel Acevedo-Bolton ◽

Alastair J. Martin ◽

William L. Young ◽

...

Keyword(s):

Flow Fields ◽

Patient Specific ◽

Flow Ratio ◽

Flow Conditions ◽

Velocity Measurements ◽

Cfd Simulations ◽

Specific Flow ◽

Inlet Flow ◽

Good Agreement

Computational fluid dynamics (CFD) methods can be used to compute the velocity field in patient-specific vascular geometries for pulsatile physiological flow. Those simulations require geometric and hemodynamic boundary values. The purpose of this study is to demonstrate that CFD models constructed from patient-specific magnetic resonance (MR) angiography and velocimetry data predict flow fields that are in good agreement with in vivo measurements and therefore can provide valuable information for clinicians. The effect of the inlet flow rate conditions on calculated velocity fields was investigated. We assessed the internal consistency of our approach by comparing CFD predictions of the in-plane velocity field to the corresponding in vivo MR velocimetry measurements. Patient-specific surface models of four basilar artery aneurysms were constructed from contrast-enhanced MR angiography data. CFD simulations were carried out in those models using patient-specific flow conditions extracted from MR velocity measurements of flow in the inlet vessels. The simulation results computed for slices through the vasculature of interest were compared with in-plane velocity measurements acquired with phase-contrast MR imaging in vivo. The sensitivity of the flow fields to inlet flow ratio variations was assessed by simulating five different inlet flow scenarios for each of the basilar aneurysm models. In the majority of cases, altering the inlet flow ratio caused major changes in the flow fields predicted in the aneurysm. A good agreement was found between the flow fields measured in vivo using the in-plane MR velocimetry technique and those predicted with CFD simulations. The study serves to demonstrate the consistency and reliability of both MR imaging and numerical modeling methods. The results demonstrate the clinical relevance of computational models and suggest that realistic patient-specific flow conditions are required for numerical simulations of the flow in aneurysmal blood vessels.

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Use of Patient Specific 3D Printed Neurovascular Phantoms To Simulate Mechanical Thrombectomy

10.21203/rs.3.rs-697127/v1 ◽

2021 ◽

Author(s):

Kelsey Sommer ◽

Mohammad Mahdi Shiraz Bhurwani ◽

Vincent Tutino ◽

Adnan Siddiqui ◽

Jason Davies ◽

...

Keyword(s):

Mechanical Thrombectomy ◽

Blood Clot ◽

Patient Specific ◽

P Value ◽

Fluid Temperature ◽

Flow Loop ◽

Vessel Occlusion ◽

Before And After ◽

Device Placement ◽

3D Printed

Abstract Background: The ability of the patient specific 3D printed neurovascular phantoms to accurately replicate the anatomy and hemodynamics of the chronic neurovascular diseases has been demonstrated by many studies. Acute occurrences, however, may still require further development and investigation and therefore we studied acute ischemic stroke (AIS). The efficacy of endovascular procedures such as mechanical thrombectomy (MT) for the treatment of large vessel occlusion (LVO), can be improved by testing the performance of thrombectomy devices and techniques using patient specific 3D printed neurovascular models.Methods: 3D printed phantoms were connected to a flow loop with physiologically relevant flow conditions, including input flow rate and fluid temperature. A simulated blood clot was introduced into the model and placed in the proximal Middle Cerebral Artery (MCA) region. Clot location, composition, length, and arterial angulation were varied and MTs were simulated using stent retrievers. Device placement relative to the clot and the outcome of the thrombectomy were recorded for each situation. Digital subtraction angiograms (DSA) were captured before and after LVO simulation. Recanalization outcome was evaluated using DSA as either ‘no recanalization’ or ‘recanalization’. Forty-two 3DP neurovascular phantom benchtop experiments were performed. Results: Clot angulation within the MCA region had the most significant impact on the MT outcome, with a p-value of 0.016. Other factors such as clot location, clot composition, and clot length correlated weakly with the MT outcome.Conclusions: This project allowed us to gain knowledge of how such characteristics influence thrombectomy success and can be used in making clinical decisions when planning the procedure and selecting specific thrombectomy tools and approaches.

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Use of patient specific 3D printed neurovascular phantoms to simulate mechanical thrombectomy

3D Printing in Medicine ◽

10.1186/s41205-021-00122-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Kelsey N. Sommer ◽

Mohammad Mahdi Shiraz Bhurwani ◽

Vincent Tutino ◽

Adnan Siddiqui ◽

Jason Davies ◽

...

Keyword(s):

Mechanical Thrombectomy ◽

Blood Clot ◽

Patient Specific ◽

Fluid Temperature ◽

Flow Loop ◽

Vessel Occlusion ◽

Before And After ◽

Device Placement ◽

3D Printed ◽

Stent Retrievers

Abstract Background The ability of the patient specific 3D printed neurovascular phantoms to accurately replicate the anatomy and hemodynamics of the chronic neurovascular diseases has been demonstrated by many studies. Acute occurrences, however, may still require further development and investigation and therefore we studied acute ischemic stroke (AIS). The efficacy of endovascular procedures such as mechanical thrombectomy (MT) for the treatment of large vessel occlusion (LVO), can be improved by testing the performance of thrombectomy devices and techniques using patient specific 3D printed neurovascular models. Methods 3D printed phantoms were connected to a flow loop with physiologically relevant flow conditions, including input flow rate and fluid temperature. A simulated blood clot was introduced into the model and placed in the proximal Middle Cerebral Artery (MCA) region. Clot location, composition, length, and arterial angulation were varied and MTs were simulated using stent retrievers. Device placement relative to the clot and the outcome of the thrombectomy were recorded for each situation. Digital subtraction angiograms (DSA) were captured before and after LVO simulation. Recanalization outcome was evaluated using DSA as either ‘no recanalization’ or ‘recanalization’. Forty-two 3DP neurovascular phantom benchtop experiments were performed. Results Clot angulation within the MCA region had the most significant impact on the MT outcome, with a p-value of 0.016. Other factors such as clot location, clot composition, and clot length correlated weakly with the MT outcome. Conclusions This project allowed us to gain knowledge of how such characteristics influence thrombectomy success and can be used in making clinical decisions when planning the procedure and selecting specific thrombectomy tools and approaches.

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Adapting the Pore Size of Individual, 3D-Printed CPC Scaffolds in Maxillofacial Surgery

Journal of Clinical Medicine ◽

10.3390/jcm10122654 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2654

Author(s):

David Muallah ◽

Philipp Sembdner ◽

Stefan Holtzhausen ◽

Heike Meissner ◽

André Hutsky ◽

...

Keyword(s):

Mechanical Properties ◽

Cell Migration ◽

Pore Size ◽

High Pressures ◽

Maxillofacial Surgery ◽

Patient Specific ◽

Porous Scaffolds ◽

Bone Augmentation ◽

3D Printed

Three dimensional (3D) printing allows additive manufacturing of patient specific scaffolds with varying pore size and geometry. Such porous scaffolds, made of 3D-printable bone-like calcium phosphate cement (CPC), are suitable for bone augmentation due to their benefit for osteogenesis. Their pores allow blood-, bone- and stem cells to migrate, colonize and finally integrate into the adjacent tissue. Furthermore, the pore size affects the scaffold’s stability. Since scaffolds in maxillofacial surgery have to withstand high forces within the jaw, adequate mechanical properties are of high clinical importance. Although many studies have investigated CPC for bone augmentation, the ideal porosity for specific indications has not been defined yet. We investigated 3D printed CPC cubes with increasing pore sizes and different printing orientations regarding cell migration and mechanical properties in comparison to commercially available bone substitutes. Furthermore, by investigating clinical cases, the scaffolds’ designs were adapted to resemble the in vivo conditions as accurately as possible. Our findings suggest that the pore size of CPC scaffolds for bone augmentation in maxillofacial surgery necessarily needs to be adapted to the surgical site. Scaffolds for sites that are not exposed to high forces, such as the sinus floor, should be printed with a pore size of 750 µm to benefit from enhanced cell infiltration. In contrast, for areas exposed to high pressures, such as the lateral mandible, scaffolds should be manufactured with a pore size of 490 µm to guarantee adequate cell migration and in order to withstand the high forces during the chewing process.

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