Large animals in neurointerventional research: A systematic review on models, techniques and their application in endovascular procedures for stroke, aneurysms and vascular malformations

Abstract

Neuroendovascular procedures have led to breakthroughs in the treatment of ischemic stroke, intracranial aneurysms, and intracranial arteriovenous malformations. Due to these substantial successes, there is continuous development of novel and refined therapeutic approaches. Large animal models feature various conceptual advantages in translational research, which makes them appealing for the development of novel endovascular treatments. However, the availability and role of large animal models have not been systematically described so far. Based on comprehensive research in two databases, this systematic review describes current large animal models in neuroendovascular research including their primary use. It may therefore serve as a compact compendium for researchers entering the field or looking for opportunities to refine study concepts. It also describes particular applications for ischemic stroke and aneurysm therapy, as well as for the treatment of arteriovenous malformations. It focuses on most promising study designs and readout parameters, as well as on important pitfalls in endovascular translational research including ways to circumvent them.

Keywords: Endovascular; aneurysm; arteriovenous malformations; large animal models; stroke.

Figure 1.

Study data. (a) PRISMA flow chart of selection process; systematic research in Medline and Web of Science databases, inclusion of studies that address neurointerventional research, test endovascular techniques and were performed in large animals (b) Study numbers show a continuous increase from 1990 until 2005, followed by a slight decline and a recent increase to all-time highs.

Figure 2.

Illustration of the different techniques for model induction and utilization of clinical imaging procedures. (a) There are three different ways to induce an aneurysm model: elastase-induced aneurysms (aneurysm develops in a closed vessel by elastase infusion), venous pouches aneurysms (preparation of a venous pouch and suturing to artery, usually CCA) and use of artificial implants. Abbreviations: CCA: common carotid artery. (b) AVM models can be created by a carotid-jugular fistula (shunt between CCA and JV), use of RM in pigs and sheep, and use of autologous implants. Abbreviations: JV: jugular vein; ECA: external carotid artery. (c) Ischemic stroke models are based on transient or permanent occlusion of cerebral arteries. Extravascular and intravascular occlusion methods can be discriminated. Extravascular occlusion comprises electrocoagulation and the use of ligation, or occluding devices such as aneurysm clips. Intravascular occlusion can be induced by intravascular devices, such as aneurysm coils, blood clots, thrombin infusion or artificial emboli. (d) A major advantage of large animal models is the compatibility with clinical imaging technologies. Sample images were taken in a sheep after transient MCAO by a surgical clip (3-h occlusion time). Abbreviations: MTT: mean transit time; DWI: diffusion-weighted imaging; T2w: T2-weighted imaging. False color scale indicates MTTS from 0 (purple) to 10 s (red). All images were taken on standard clinical scanner during an in-house study (data not published).

Figure 3.

Applied therapies in analyzed studies. (a) Aneurysms: main focus was on coils, stents and flow diverter stents (b) stroke: dominant therapy was mechanical thrombectomy, a recognized alternative to intravenous thrombolysis (c) AVMs: majority of studies investigated liquid embolic agents; unspecified conditions (e.g. “intracranial lesions,” “abnormalities in central nervous system” or “brain injury”): focus was on hypothermia and endovascular devices; carotid occlusive diseases: all studies investigated stents. Information about animals: (d) Number of animals: almost half of the studies used only up to 10 animals. (e) Occurrence of different species: most commonly used species were pigs and dogs, followed by rabbits (f) Animal characteristics: only a minority of studies reported all four items – strain, weight, sex and age.

Figure 4.

Overview of endpoint assessment in analyzed studies. (a) Evaluation process: frequent use of imaging (reflecting uncomplicated use in large animals) and histology. Only 16.5% evaluated physiological parameters. Behavioral tests are applied in stroke research (b) Data about imaging: clearly dominated by angiography (well qualified for use in neurointerventional research). Most common use for imaging was to prove efficacy and for procedural process. (c) Presentation of physiological parameters: dominated by blood pressure, temperature, heart rate and electrocardiogram. CT: computed tomography; MRI: magnetic resonance imaging; OCT: optical coherence tomography.