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Abstract
Background Preclinical testing of intracranial stents is currently performed in the peripheral circulation, and rarely in the basilar artery of the dog.
Objective To test the feasibility of intracranial stenting in the middle cerebral artery (MCA) of the dog and explore the use of MRI to detect thromboembolic complications.
Methods Six purpose-bred cross-hound dogs were used for proof-of-concept stenting of both MCAs in each animal. Immediately following the procedure, the animals were imaged with MRI. MRI was repeated weekly for 1 month. After the final angiography at 30 days, the animals were euthanized for pathological assessment of the stents and the brain.
Results We successfully deployed 12 stents in the MCAs of all animals. We deployed three techniques for microcatheterization of the MCA—namely, directly through the internal carotid artery (ICA), using anastomotic arteries from the external carotid artery, or via the contralateral ICA through the anterior communicating artery. Two iatrogenic perforations of the ICA with formation of an arteriovenous fistula occurred, without clinical sequelae, which spontaneously resolved on follow-up. All animals tolerated the procedure and completed the follow-up surveillance. MRI revealed procedural thromboembolic induced areas of restricted diffusion, and only one instance of a delayed thromboembolic lesion during surveillance. At follow-up angiography, the devices were all patent.
Conclusion We describe a new preclinical model of intracranial stenting in the MCA. Such a model may prove useful for evaluating new surface modifications.
- aneurysm
- atherosclerosis
- device
- intervention
Data availability statement
Data are available upon reasonable request. Data are available by contacting the corresponding author.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Preclinical vascular healing of neurovascular implants is evaluated in the peripheral circulation of laboratory animals—a required study for use in man. Although testing implants in the intended organ is preferred, that has previously not been feasible in laboratory models.
WHAT THIS STUDY ADDS
We describe the technical feasibility of delivering and implanting next-generation intracranial stents in the middle cerebral artery of the dog model. Neuroimaging, functional outcomes, intravascular imaging, and pathological assessments are proposed for rigorous output metrics.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Sophisticated advances in surface modifications and active drug coatings are under investigation to reduce the potential for thromboembolic events and perhaps dependence on dual antiplatelet therapy. These advances will benefit from a true intracranial stenting model where thromboembolic events can be directly measured.
Introduction
Intracranial stenting, used either for treatment of intracranial stenosis mainly due to atherosclerosis or as an adjunctive technique to coiling for the treatment of saccular aneurysms, has evolved. Recently, a trend towards lower-profile devices has emerged aiming for safer deployment with smaller microcatheters, improved wall apposition, and the ability to reach smaller diameter vessels in distal locations.1 2 Additionally, devices with special coatings able to reduce thrombogenicity and potentially the need for dual antiplatelet therapy,3 or even reduce cell proliferation and consequently the rates of vessel restenosis,4 5 have been described.
The safety and efficacy of new technology is initially tested in large animal models in the extracranial circulation. Given the substantive differences between the structure of the cerebrovasculature versus the peripheral or coronary arteries,6 vascular response to these devices may vary as a function of vessel composition. Furthermore, testing of devices in vascular beds not supplying the target organ hinders the validity of pathophysiological findings, which might not be translated to clinical practice.
The absence of a rete mirabile, present in commonly used laboratory animals (sheep and pigs), makes dogs excellent models for neuro-endovascular procedures. Although the posterior circulation with access to the vertebral or basilar artery7 8 has been more commonly used, microcatheter access to the anterior circulation and the middle cerebral artery (MCA) specifically, has been performed successfully for either occlusion or mechanical thrombectomy purposes.9–11
The purpose of this study was to assess the feasibility of intracranial anterior circulation stenting in a canine model—specifically the MCA—to investigate device patency and device-related ischemic complications based on imaging findings, functional outcomes, and histopathologic vascular response to implant.
Materials and methods
Animal preparation
All animal procedures performed were approved by the University of Massachusetts Chan Medical School Institutional Animal Care and Use Committee (#PROTO202100059). We used six dogs (mean weight: 19.4 kg, 6 female) to assess the technical feasibility of bilateral MCA stenting. All stents were nitinol self-expanding stents delivered through an 0.0165″ microcatheter (made per order by Admedes GmbH, Pforzheim, Germany). Six stents had a length of 12 mm and the remaining six a length of 10 mm, and were very similar in construct/profile to commercially available 0.017″ deliverable stents. All procedures (stent implantation, non-invasive imaging, and invasive terminal follow-up angiography) were performed under general anesthesia. The animals were pre-anesthetized by an intramuscular injection of acepromazine (0.06 mg/kg), glycopyrrolate (0.01 mg/kg) and buprenorphine (0.02 mg/kg). Anesthesia was induced by an intravenous injection of propofol (3–4 mg/kg) and all animals were intubated with an endotracheal tube and maintained with mechanical ventilation of 1–4% isoflurane in oxygen. The physiological status of each animal was assessed every 15 min using continuous monitoring of respiration rate, heart rate, oxygen saturation level, end-tidal carbon dioxide level, invasive blood pressure, and temperature.
Half of the animals received dual antiplatelet therapy (DAPT) 3 days prior to the procedure (40.5 mg aspirin, 37.5 clopidogrel orally once per day) and until termination, and the remainder received only aspirin 3 days prior and for 10 days postoperatively (40.5 mg, orally once per day). Aspirin-only therapy was included in our design since it is well known that dogs are fibrinolytic.12
Stent deployment
The animals were heparinized with an initial heparin bolus (100 U/kg), and heparin levels were monitored throughout the procedure to maintain an activated clotting time over 300 s.
The femoral arteries bilaterally were surgically exposed, and arterial access was achieved via direct arterial puncture and placement of an 8 F sheath. Fluoroscopic guidance (Philips FD20, Best, The Netherlands) was used throughout the procedure for material guidance and device deployment.
The common carotid arteries were bilaterally accessed with a 6 F long sheath (Flexor, Shuttle, Cook Medical, Bloomington, Indiana, USA). Baseline angiograms and 3D-rotational angiograms were acquired, which were used to approximately determine the implant site with use of virtual stenting. Access to the MCA was achieved either through the internal carotid arteries (ICAs) or an anastomotic channel consistently present between the external carotid artery (ECA) and the intracranial ICA, described in further detail in the results. A distal access catheter (DAC 3.9 or 4.3F, Stryker Neurovascular, Fremont, California, USA) was advanced in the proximal ICA or internal maxillary artery (IMAX) depending on the access path for support, and a 1.6 F microcatheter (Headway Duo, Microvention, Aliso Viejo, California, USA) with a 0.014" microwire (Asahi Chikai, Asahi Intecc Co, Aichi, Japan) or 0.010" (Synchro, Stryker Neurovascular) was navigated into the distal M2 segment of the MCA. A distal access 5 F catheter (Catalyst, Stryker Neurovascular) was placed in the contralateral ICA for contrast delivery during the procedure when needed.
After completion of the interventional procedure, final control digital-subtraction angiograms (DSAs) and high-resolution, contrast-enhanced cone-beam CT scans were performed to assess satisfactory deployment and vessel patency. The devices were removed, the femoral arteries ligated, and the wound was closed.
MRI protocol
MRI assessment was performed immediately following the procedure, and weekly for 1 month to track the evolution of ischemia and/or hemorrhage using a Phillips Ingenia 3T MRI (Phillips) with a 16-channel knee coil. The protocol included time-of-flight vascular imaging (TR/TE 20/4 ms, FA=20o, matrix=332×212), diffusion-weighted imaging (TR/TE 2000/76 ms, FA=90o, b-values=0, 1000 s/mm2, NSA=6, matrix=144×144), susceptibility weighted imaging (SWI) (TR/TE 32/7.2 ms, FA=17 o, NSA=2, matrix=268×268, slice thickness=0.5 mm), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) (TR/TE=11 000/125 ms, TI=2800 ms, FA=90o, NSA=2, matrix=160×156, slice thickness 1.5 mm) and, T1-weighted magnetization-prepared rapid acquisition of a gradient echo (T1w-MPRAGE) (TR/TE=10/4.75 ms, TI=900 ms, acceleration=161, FA = 8o, NSA=2, matrix=172×169, slice thickness=0.75 mm). Following the conclusion of the MRI examination, the dog was recovered from anesthesia.
Neurological assessment
Immediately postoperatively and after recovery from anesthesia animals were assessed neurologically and daily thereafter until termination by experienced members of our laboratory. Neurological examination included evaluation of mentation; evaluation of posture and gait, including assessment for head tilt, ataxia, weakness, paresis, motor function assessment, postural reaction assessment using the paw replacement test and the hopping test; vision assessment using the menace response, pupillary light reflexes and size, eye movements, eyelids for ptosis, facial sensation and expression, nasal mucosa testing, corneal and palpebral reflexes, tongue movement, ability to keep saliva, water and food. The animals were also assessed for presence of nystagmus or neglect, and basic reflexes like biceps, triceps, patellar and gastrocnemius reflexes were evaluated. In animals with loss of motor function, pain reception was also assessed with pinching of the toe web or periosteum.
Terminal angiography and histology
After the final MRI study at 30 days, the animals were returned to the angiosuite for DSA and cone-beam CT. In one case, intravascular high-frequency optical coherence tomography was performed, as previously described.13 After completion of imaging, the animals were maximally heparinized (500 U/kg) and 10 min later euthanized by an overdose of sodium pentobarbital (150 mg/kg). After cardiac perfusion of chilled heparinized saline followed by 4% paraformaldehyde under physiological pressure (~100 mm Hg), the brains were explanted for histological assessment.
The brains containing implanted vessels were radiographed at two incidences, the MCAs were excised, and implants were radiographed at two incidences. The in-stent portion of the vessel was processed and embedded in Spurr’s resin. Resulting blocks were sectioned to acquire three in-stent levels (ie, proximal, middle, and distal). From each level, two slides were generated; one slide was stained with hematoxylin and eosin (H&E) and the remaining slide with elastin trichrome or Movat pentachrome. The brains were breadloafed and evaluated grossly. Brain slices from two animals were selected based on brain MRI images. Selected slices were collected, paraffin processed, and embedded. Paraffin blocks were microtomed, sections were mounted on glass slides and stained with H&E, and immunohistochemically labeled with ionized calcium binding molecule 1 and glial fibrillar acidic protein.
Results
Access to the canine MCA
Standard access from the ipsilateral ICA was used in eight vessels. Access from the contralateral ICA through the anterior communicating artery was used in one vessel. In the remaining three vessels, access was achieved through the ECA (online supplemental figure). Different approaches are illustrated in figure 1 and figure 2.
Supplemental material
Selective injection of the left internal carotid artery (ICA). Digital subtraction angiograms (DSAs) in (A) anteroposterior (AP), (B) lateral, and (C) oblique views. The severely tortuous anatomy of the ICA can be well appreciated. Unsubtracted AP view of the ICA with the microcatheter positioned in the left middle cerebral artery (MCA) (D) oblique (E) view where the stent in the left MCA has been deployed (red circle) and the microcatheter is in place in the right MCA for deployment of the second stent. Right sided arteriovenous fistula (AVF) at the level of ICA-looping before the ICA enters the skull. DSA and unsubtracted image of a right common carotid artery injection, where the right ICA and its relationship to the bony structures (red circle) can be seen (F, G) .Subtracted and unsubtracted image of an iatrogenic AVF caused by the microcatheter and/or microwire during microcatheterization of the right ICA (H, I). The exact level of the fistula is better appreciated on the unsubtracted image (I), where the relationship with the bony structures is shown (red circle).
Standard access from the ipsilateral ICA
The ICA originates from the common carotid artery, usually as the first main branch just before the origin of the occipital, ascending pharyngeal, and lingual arteries followed by the rest of the external carotid branches. It has a diameter of approximately 2 mm and for the first few centimeters exhibits a relatively straight course. Consecutively, the vessel takes an almost 90 degree course towards the anterior aspect of the skull base before looping again at an extreme and complex 90-180-90-degree configuration in the depths of the temporal bone,14 after which the ICA finally enters intracranially through the carotid canal.
This tortuous segment of the ICA can be difficult to navigate. A soft-tip microwire able to form a tight J shape is probably the easiest and least traumatic way to reach the ICA lumen proximal to the posterior communicating artery (PComA) before further advancing the microcatheter over the wire. Once the microcatheter has navigated past the extracranial segment of the ICA, the microwire will usually advance more easily and will enter the MCA. Occasionally, the microwire alone will smoothly find its way directly into the MCA and then the microcatheter can reach the target vessel in one step. Another technique we like to use is the so called ‘step-ladder’ technique, where the microwire and microcatheter follow each other in small intervals while navigating through the ICA loops, and at the same time releasing tension accumulated in the system whenever necessary (figure 1).
Pitfall: Aggressive manipulations at the level of extreme ICA looping, just before the vessels enters the skull base can result into a benign arteriovenous fistula between the ICA and neighboring venous structures (figure 1). Although these arteriovenous fistulas remain asymptomatic and resolve spontaneously, with concomitant ICA occlusion or not, at the acute phase they make further access distal to the fistula cumbersome or impossible.
Contralateral access from the ICA
In a similar fashion, as described above, the intracranial ICA before the terminus is accessed. The microcatheter/microwire combination in the ICA lumen usually has the tendency to enter the ipsilateral MCA. An oblique or lateral view with injection through the microcatheter or through a second access (vertebral or contralateral ICA) can be helpful in identifying the origin of the A1 segment. Multiple manipulations are usually not well tolerated, and the resulting vasospasm can delay the procedure or even render the procedure unsuccessful. Once the microwire has entered the A1 segment, cross-over to the contralateral A1 can easily be achieved, due to lack of a true anterior communicating artery. Subsequently, the microcatheter is advanced to gain support, secure position and the contralateral MCA can be selected (figure 2).
Contralateral access: oblique (A) and anteroposterior (B) digitally subtracted angiograms of a super-selective injection of the right middle cerebral artery (MCA) delivered through the left internal carotid artery (ICA). The microcatheter tip is located at the origin of the right MCA after crossing over from the left anterior cerebral artery (ACA) to the right ACA. The outline of the microcatheter (A) shows the course of the vessel. After removing the slack from the system and tension has been released, the left ICA straightens, as seen by the configuration of the microcatheter (B). Unsubtracted image (frontal projection) with the microcatheter positioned in the right MCA (distal tip in M2 segment). (C) A stent is being delivered through the microcatheter. The stent is at the level of the M1 segment and the markers are located between the markers of the microcatheter. Access to left MCA through the anastomotic network of the external carotid artery internal maxillary artery injection with opacification of the anastomotic artery and ICA. The anastomotic artery (circle) with opacification of the ICA (open arrowhead), ACA (arrow), MCA (arrowhead) is depicted (D). The microcatheter is advanced into the anastomotic artery (arrow) and selective injection is performed (E). A second smaller anastomosis is also revealed (arrowhead in E). The microcatheter has entered the cavernous segment of the ICA (F). The ICA (arrowhead) and MCA (arrow) are well opacified (F). Unsubtracted image showing the microcatheter inside the MCA, with its distal tip in the superior division prior to stent deployment (G).
Pitfall: Stress overload with stretching of the ICA after the microcatheter is in place can cause asymptomatic ICA occlusion. The extensive anastomotic network from the ECA and circle of Willis fully compensates for the occlusion, but re-access to the vessel, at a later time if needed, will not be possible unless the ICA recanalizes spontaneously.
Access from the anastomotic network of the ECA
Multiple anastomotic channels exist between the ICA and ECA, and the ECA is functionally important in perfusing the brain in dogs.15 The anastomotic artery originating from the internal maxillary artery is the largest single anastomosis between ICA and ECA,16 with sufficient caliber to accommodate a microcatheter. The nomenclature used in the literature for different arteries in this area is somewhat inconsistent, so the most appropriate in our opinion will be adopted here. The IMAX after leaving the alisphenoid canal of the sphenoid bone gives rise to the orbital artery, from which the external ophthalmic, external ethmoidal artery arise and in proximity the middle meningeal artery and the anastomotic artery also originate. Variations of origins of the aforementioned vessels do exist but the anastomotic artery is always present connecting the IMAX to the ICA. It enters through the foramen ovale and runs within the cavernous sinus.14 Although the artery is large enough for microcatheterization, the presence of more than one anastomotic channel is possible, leading in such cases to decreased caliber and increased tortuosity of this anastomosis. For stability and support a distal access catheter should be advanced into the internal maxillary artery just proximal to the origin of the orbital artery. Navigation through the vessel will allow access to the cavernous segment of the ICA, in this way bypassing the proximal challenging looping. Once the microcatheter is safely placed into the ICA, further navigation distally to the MCA or anterior cerebral artery (ACA) is usually uneventful (figure 2).
Pitfall: Small diameter and tapering of the anastomotic channel or acute angulation, can prevent the microcatheter from advancing into the ICA lumen, even if the microwire is able to select the ICA.
Stenting of the canine MCA
Twelve stents were successfully deployed in 12 MCA arteries by the same operator (VA). The MCA diameters ranged approximately between 1 and 1.2 mm. In one artery (8.3%) the stent was deployed in the M1, in five arteries (41.7%) in the M1–M2 segment, in five arteries (41.7%) the proximal end of the stent extended into the distal ICA, and in one artery (8.3%) the stent was deployed from M1 to M2 with stent intussusception forming a double stent layer.
Immediate post-deployment DSAs showed patent stents (figure 3), no acute thrombus formation or distal vessel occlusions in all animals, and normal anterograde filling with no imaging findings of retrograde collateral filling due to occlusion or high-grade stenosis. In 7 of 12 vessels (58.3%), periprocedural vasospasm occurred, which was treated with intra-arterial injection of verapamil (2.5 mg). By the end of the procedure the vasospasm regressed but did not completely resolve. Periprocedural complications were not encountered, other than two cases of a benign iatrogenic carotid fistula at the base of the skull during catheterization of the ICA, which resolved spontaneously.
Prior to stent deployment, virtual stenting was used on 3D angiography to determine the ideal landing location (A). Final angiography after both stents were deployed in the left and right middle cerebral arteries (MCAs) (B). Vasospasm, especially of the right proximal M1 (arrow), is seen (B). Initial diffusion weighted imaging postoperatively (C) and consecutive fluid-attenuated inversion recovery MR imaging at 1 (D), 2 (E), and 4 (F) weeks depicting the evolution of the ischemic lesions of the left MCA territory. No new lesions are present.
Immediate postprocedure MRI revealed no ischemic lesions in five cases (41.7%), and in four cases (33.3%) small acute ischemic lesions were present (defined as either small MCA-territory cortical single lesion or small caudate nucleus lesion) (figure 3), and in the remaining three cases (25%) larger areas of acute MCA-territorial ischemia were encountered (defined as multiple areas of patchy, mostly cortical, lesions). In one case additional ACA-territory ischemia was present. MR angiography showed indirect signs of patent stents with patent peripheral intracranial vessels in all animals, with no obvious distal occlusions or absent branches.
One animal showed significant neurologic deficit with right-sided paresis after recovery, and the remaining animals were clinically asymptomatic.
Post-stenting surveillance
During the follow-up period, only one animal showed at 1 week postoperatively new MCA-territory ischemic lesions with new FLAIR abnormalities and no corresponding diffusion-weighted imaging lesion, compatible with early postoperative new lesions (table 1). All other animals showed normal evolution of ischemic lesions, with complete regression of initial FLAIR abnormalities (figure 3) and small gliotic lesions at the corresponding areas at 1 month.
Summary of animals
At final DSA imaging all stented vessel segments were patent with no significant stenosis. In three animals, three ICA occlusions were observed. In all three animals, injections through the vertebral arteries showed patency of the ICA terminus, PComAs and all proximal stented segments. No thromboembolic findings were present. Spontaneous healing of the two iatrogenic fistulas was also observed (figure 4).
Final angiogram at 4 weeks with anteroposterior (A, C) and lateral (B, D) projections of the right and left middle cerebral arteries (MCAs), respectively. Both stents and MCA branches are seen patent. High-frequency optical coherence tomography (inset) shows minimal intimal hyperplasia that is confirmed with histology (E and F, Movat pentachrome stain). Immunohistochemistry (ionized calcium binding molecule-1, (G) Photomicrographs of a brain section at the level of the caudate in the right hemisphere depict areas of extensive microglial response (dark brown stain, rectangle), whereas mostly normal brain (circle) was seen. High magnification of the area in the rectangle shows a focal subacute infarct (H, encircled by dotted line) with hemorrhage, neuropil loss, and infiltration of microglial cells (arrows). Scale bars in E, F, G, and H are 200 µm, 100 µm, 1 mm (top right), and 250 µm, respectively.
The neurologic examination revealed no new neurologic deficits in any of the animals. The one animal with right-sided paresis improved during the first week and had only minimal residual hind-limb monoparesis after 30 days, exhibiting as a slightly longer than normal stride of the pelvic limb.
In five out of six cases on DAPT, ischemic lesions were present (83.3%), while only in two out of six cases on monotherapy (33.3%).
Histopathology
Macroscopic, radiographic, microscopic, and morphometric evaluation of six middle cerebral arteries implanted in a total of three canines euthanized at 28±2 days, post implantation demonstrated the following salient findings:
No stent fractures were detected in any of the implanted devices, and vessel wall injury (eg, focal disruption of the internal elastic lamina) was detected in one vessel, most probably procedure related (figure 4). No other mural injuries were present in the rest of the vessels. No malapposition or thrombosis was present. The vessels were intact with wide stent expansion. All stents showed excellent biocompatibility, with almost no, or minimal, inflammation of the vessel walls. Minimal inflammatory response was present in association with focal vessel injury and interpreted as procedure-associated. Healing was excellent in all vessels, with complete endothelialization on histopathology and nearly mature fibromuscular neointima. Lumen area stenosis was minimal with a median of 10.95% (SD 5.69%). Although histological assessments of the brain parenchyma found no thromboembolisms, focal areas of microgliosis, focal subacute infarction, hemorrhage, and neuropil loss were detected (figure 4).
Discussion
In development of the next generation intracranial stents, including novel surface modifications, the choice of animal model and experiment design is crucial in reaching valid conclusions. The appropriate animal model would be one with vessels of appropriate caliber to accommodate the necessary catheters and optimally, one where all technical aspects of a procedure—from catheter navigation to device deployment—could be replicated within the intended target organ. Thromboembolic and ischemic events can be better assessed and thereafter clinically translated when the target territory is relevant. The potential consequences and adverse events of new devices can only be better understood if testing is performed in vessels supplying an equivalent organ, which in this case is the brain.
In dogs, access to the posterior circulation has been more commonly used;7 8 however, an improvement to the model would be to position a control and test device in the same animal, which is not possible when using the basilar artery. The pathway to reach the basilar artery is relatively easy, with no severe anatomical obstacles. Access to the MCA or ACA on the other hand poses more challenges, mostly due to the more tortuous nature and extreme looping of the ICA just before entering the cranial cavity, compared with the straight basilar artery. The delicate nature, small diameter, and tortuous course of the ICA in the dog, coupled with the propensity to spasm, can make distal access challenging and leaves little room for error. Furthermore, due to the small vessel size microcatheter size can be restrictive, necessitating a 0.017" or smaller microcatheter as well as an appropriate stent size and length.
We have shown in our current experimental study that stenting of anterior circulation vessels is feasible and reproducible. In our cohort, all procedures were technically feasible with successful deployments in all selected vessels. As this was a feasibility study to determine the access and stent delivery to the MCA, the small number of animals and variations in the interventional protocol do not allow for conventional statistical analysis and this limits estimation of complication rates or specific details of a given approach. Furthermore, the proper antiplatelet regimen in dogs for intracranial stenting is not known due to the strong fibrinolytic profile. The procedures performed in the initial three animals were part of a learning curve. Intracranial periprocedural times in the first three animals were significantly longer than in the last three, with the microcatheter in an occlusive/subocclusive position in the MCA for longer periods of time. As a result, ischemic lesions in the first three animals were more extensive, although the animals were receiving DAPT. We attributed the immediate postprocedure ischemic lesions in that group as procedure-related and not device-related. This was further reinforced by the fact that no new ischemic lesions occurred during the follow-up period, indicating that DAPT was effective. This finding emphasizes the importance of technical adequacy and shows how technique can have significant implications on procedure outcome. With refinements in our technique, in our future confirmatory study, monotherapy will be used.
We have shown in the present study that access to the anterior circulation and specifically the MCA can be performed through different routes. We described three possibilities, the ipsilateral ICA approach, the contralateral ICA approach, and the use of the ICA–ECA anastomotic network. These different routes can be useful either as a bailout technique or as the main pathway to the MCA. The ICA anatomy is consistent compared with the ECA–ICA anastomotic network, where the size, number of connections, and tortuosity in our experience can vary substantially among animals. For both the contralateral approach and the IMAX-anastomosis, 3D angiography might be valuable to understand anatomy and use appropriate projections in order to access the target vessels and navigate more easily in areas of bifurcations or acute angulations. Access to the MCA through the PComA and the posterior circulation is also possible and has been used in some of our other experimental work but not in the present study, mainly because we did not want to put a different territory at risk since we did not know the extent of possible ischemia from the anterior circulation intervention and each animals’ compensatory mechanism.
Conclusion
As a device developed for neurointerventional procedures is constantly evolving, refined preclinical modeling is needed. We have shown that it is technically feasible to implant stents in the MCAs of dogs, providing a viable model for preclinical testing of new generations of intracranial stents.
Supplemental material
Data availability statement
Data are available upon reasonable request. Data are available by contacting the corresponding author.
Ethics statements
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Ethics approval
Not applicable.
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @AjitSPuri1
Contributors VA, MJG: planning, conception, and design of the study, acquisition of data, analysis, interpretation of data, and drafting the manuscript. They are guarantors of the report. RMK, LG, JL, JDB, RV: data acquisition, protocol development, and all technical aspects of animal modeling and pathology. Provided critical editing of the manuscript. ASP, AHS: major contributions to study design and model development. Provided critical editing of the manuscript. All authors approved the final version of this manuscript to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding This study was sponsored by Imperative Care.
Competing interests MJG: 1. Consultant on a fee-per-hour basis for Alembic LLC, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, Jacob’s Institute, Medtronic Neurovascular, Mivi Neurosciences, phenox GMbH, Q’Apel, Route 92 Medical, Scientia, Stryker Neurovascular, Stryker Sustainability Solutions, Wallaby Medical; holds stock in Imperative Care, InNeuroCo, Galaxy Therapeutics and Neurogami; 2. Research support from the NIH, the United States – Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Balt, Cerenovus, Ceretrieve, CereVasc LLC, Cook Medical, Galaxy Therapeutics, Gentuity, Gilbert Foundation, Imperative Care, InNeuroCo, Insera, Jacob’s Institute, Magneto, MicroBot, Microvention, Medtronic Neurovascular, MIVI Neurosciences, Naglreiter MDDO, Neurogami, Philips Healthcare, Progressive Medical, Pulse Medical, Rapid Medical, Route 92 Medical, Scientia, Stryker Neurovascular, Syntheon, ThrombX Medical, Wallaby Medical, the Wyss Institute and Xtract Medical; 3. Associate editor of basic science on the JNIS editorial board. RV: grants from the NIH, Leducq Foundation, 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions, Absorption Systems, Advanced NanoTherapies, Aerwave Medical Inc, Alivas, Amgen Inc, Asahi Medical, Aurios Medical, Avantec Vascular, BD Bioscences, Biosensors, Biotronik, Biotyx Medical, Bolt Medical Inc, Boston Scientific, Canon Inc, Cardiac Implants LLC, Cardiawave, CardioMech, Cardionomic, CeloNova BioSciences Inc, Cerus Endovascular Inc, Chansu Vascular Technologies LLC, Children’s National Medical Center, Concept Medical, Cook Medical, Cooper Health, Cormaze Technologies GmbH, CRL/AccelLab, CroíValve, CSI, DexCom Inc, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies Inc, Emboline Inc, Endotronix, Envision, Filterlex, Imperative Care Inc, Innovative Cardiovascular Solutions LLC, Intact Vascular Inc, Interface Biolgics, InterShunt Technologies Inc, Invatin Technologies, Lahav CRO, LimFlow, L & J Biosciences, Lutonix, Lyra Therapeutics Inc, Mayo Clinic, Maywell, MD Start, MedAlliance, Medanex Clinic, Medtronic plc, Mercator Limited, MicroPort, MicroVention, Neovasc Inc, Nephronyx Ltd, Nova Vascular, Nyra Medical, Occultech, Olympus Therapeutics, OhioHealth, OrbusNeich, Ossio, phenox Inc, Pi-Cardia, Polares Medical, PolyVascular, Profusa Inc, ProKidney LLC, Protembis, Pulse Biosciences Inc, Qool Therapeutics, Recombinetics, ReCor Medical Inc, Regencor Inc, Renata Medical, Restore Medical Ltd, Ripple Therapeutics, Rush University, Sanofi SA, Shockwave Medical, Sahajanand Medical Technologies Limited, SoundPipe, Spartan Micro, SpectraWAVE Inc, Surmodics Inc, Terumo Corporation, Jacobs Institute, Transmural Systems LLC, Transverse Medical Inc, TruLeaf Medical, University of California, San Francisco, University of Pennsylvania Medical Center, Vascudyne Inc, Vesper, Vetex Medical, WhiteSwell, WL Gore and Associates Inc, and Xeltis and personal fees from Abbott Vascular, Boston Scientific, CeloNova BioSciences Inc, OrbusNeich, Terumo Corporation, W. L. Gore and Associates Inc, Edwards Lifesciences, Cook Medical, CSI, ReCor Medical, Sino Medical Sciences Technology Inc, Surmodics Inc, Bard BD, Medtronic plc, and Xeltis outside the submitted work. ASP: 1. Consultant for Medtronic Neurovascular, Stryker NeurovascularBalt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc and Arsenal Medical; 2. Research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular and Stryker Neurovascular; 3. Stockholder: InNeuroCo, Agile, Perfuze, Galaxy, and NTI. AHS: consulting fees: Amnis Therapeutics, Apellis Pharmaceuticals, Inc., Boston Scientific, Canon Medical Systems USA, Inc., Cardinal Health 200, LLC, Cerebrotech Medical Systems, Inc., Cerenovus, Cerevatech Medical, Inc., Cordis, Corindus, Inc., Endostream Medical, Ltd, Imperative Care, Integra, IRRAS AB, Medtronic, MicroVention, Minnetronix Neuro, Inc., Penumbra, Q’Apel Medical, Inc., Rapid Medical, Serenity Medical, Inc., Silk Road Medical, StimMed, LLC, Stryker Neurovascular, Three Rivers Medical, Inc., VasSol, Viz.ai, Inc., W.L. Gore and Associates. Leadership or fiduciary role in other board, society, committee or advocacy group: Past secretary of the board of the Society of NeuroInterventional Surgery (2020-2021), chair of the Cerebrovascular Section of the AANS/CNS. Stock or stock options: Adona Medical, Inc., Amnis Therapeutics, Bend IT Technologies, Ltd., BlinkTBI, Inc, Buffalo Technology Partners, Inc., Cardinal Consultants, LLC, Cerebrotech Medical Systems, Inc, Cerevatech Medical, Inc., Cognition Medical, CVAID Ltd., E8, Inc., Endostream Medical, Ltd, Imperative Care, Inc., Instylla, Inc., International Medical Distribution Partners, Launch NY, Inc., NeuroRadial Technologies, Inc., Neurotechnology Investors, Neurovascular Diagnostics, Inc., PerFlow Medical, Ltd., Q’Apel Medical, Inc., QAS.ai, Inc., Radical Catheter Technologies, Inc., Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp), Rist Neurovascular, Inc. (purchased 2020 by Medtronic), Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, Adona Medical, Inc., Amnis Therapeutics, Bend IT Technologies, Ltd., BlinkTBI, Inc, Buffalo Technology Partners, Inc., Cardinal Consultants, LLC, Cerebrotech Medical Systems, Inc, Cerevatech Medical, Inc., Cognition Medical, CVAID Ltd., E8, Inc., Endostream Medical, Ltd, Imperative Care, Inc., Instylla, Inc., International Medical Distribution Partners, Launch NY, Inc., NeuroRadial Technologies, Inc., Neurotechnology Investors, Neurovascular Diagnostics, Inc., PerFlow Medical, Ltd., Q’Apel Medical, Inc., QAS.ai, Inc., Radical Catheter Technologies, Inc., Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp), Rist Neurovascular, Inc. (Purchased 2020 by Medtronic), Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, SongBird Therapy, Spinnaker Medical, Inc., StimMed, LLC, Synchron, Inc., Three Rivers Medical, Inc., Truvic Medical, Inc., Tulavi Therapeutics, Inc., Vastrax, LLC, VICIS, Inc., Viseon, Inc. Other financial or non-financial interests: National PI/Steering Committees: Cerenovus EXCELLENT and ARISE II Trial; Medtronic SWIFT PRIME, VANTAGE, EMBOLISE and SWIFT DIRECT Trials; MicroVention FRED Trial and CONFIDENCE Study; MUSC POSITIVE Trial; Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial, MIVI neuroscience EVAQ Trial; Rapid Medical SUCCESS Trial; InspireMD C-GUARDIANS IDE Pivotal Trial.
Provenance and peer review Not commissioned; externally peer reviewed.
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