In vivo cerebral aneurysm models

Free access

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.

ABBREVIATIONS BAPN = β-aminopropionitrile; CA = cerebral aneurysm; CCA = common carotid artery; DOCA = deoxycorticosterone acetate.

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.

Unruptured cerebral aneurysms (CAs) are common in the general population, with an estimated prevalence ranging from 2% to 6%.68 If left untreated, aneurysms can progress and spontaneously rupture, producing a subarachnoid hemorrhage and resulting in significant morbidity and death. The pathophysiology of CA formation and rupture is not fully defined, but risk factors have been identified including increasing age, female sex, hypertension, excessive alcohol intake, and smoking.16,34,68 Studies have suggested that hemodynamic stress is a critical factor in CA pathogenesis17 leading to endothelial dysfunction, inflammatory cell infiltration, and arterial wall remodeling.6–7 Vascular smooth-muscle cells undergo a phenotypic switch, which exacerbates inflammation by expressing inflammatory and matrix remodeling proteins,50 ultimately culminating in histological changes characterized by disruption of the internal elastic lamina, extracellular matrix digestion, thinning of the media, cell loss, and aneurysm formation.

Molecular and histological analysis of human CA specimens has revealed significant information regarding the pathology of CAs. Equally vital to our understanding of CA biology and treatment has been the use of CA animal models, which attempt to replicate the morphological, histological, and hemodynamic features observed in human CAs. These animal models provide a method for investigating aneurysm formation, growth, and rupture while also providing a means of testing new treatment modalities. CA models have been developed in numerous species including mice, rats, rabbits, swine, sheep, canines, and primates, with each model having advantages and limitations such that the model selection depends on the purpose of the study. This review explores some of the more commonly used models of CAs and compares the advantages and disadvantages of each system.

Small Animal CA Models

The theory behind CA formation in rats and mice is that weakening of the cerebral blood vessels combined with hemodynamic stress will induce CA formation. Numerous rat and mouse models of CA formation exist and primarily differ in the mechanisms of vessel wall weakening and hemodynamic stress induction (Fig. 1).

FIG. 1.
FIG. 1.

Cerebral aneurysm formation in rodents, hemodynamic stress, and vessel wall weakening. The procedures used for CA formations in rats and mice vary primarily in the method of inducing hypertension, increasing the flow rate, and weakening the vessel wall. Hypertension can be induced by a combination of a high salt diet, unilateral nephrectomy or bilateral ligation of the posterior branches of the renal arteries (not shown), and subcutaneous placement of DOCA pellets or angiotensin II–filled microosmotic pump (not shown). Increases in flow rate are accomplished by ligation of the left CCA, which causes a compensatory increase in flow rate in the contralateral internal carotid artery. Vessel wall weakening is accomplished by feeding a diet containing 0.12% BAPN, a lysyl oxidase inhibitor, or by a single stereotactic injection of elastase. Copyright Robert Starke. Published with permission.

Hemodynamic Stress and Vessel Wall Weakening

Hemodynamic stress in the cerebral vasculature can be increased by hypertension and/or an increase in flow rate. Using the combination of hypertension and flow rate to induce hemodynamic stress, Hashimoto et al. created the first rodent CA model in rats.31 During a series of surgeries, hemodynamic stress was increased by ligation of the left common carotid artery (CCA) while hypertension was induced by unilateral nephrectomy, followed by subcutaneous injections of deoxycorticosterone acetate (DOCA) and the addition of 1% sodium chloride to the drinking water. Vessel walls were weakened by feeding the rats chow containing 0.12% β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, which prevents collagen and elastin cross-linking, leading to increased vessel fragility and a greater likelihood of aneurysm formation. Morimoto et al. later adapted this method for CA formation in mice and included bilateral ligation of the posterior branches of the renal arteries.51 Four months following surgery, CAs were observed at various stages of formation, located primarily at the bifurcation of the right anterior cerebral artery and the olfactory artery. Histological analysis revealed fragmented elastic laminin and media thinning suggestive of aneurysm formation in 78% of the treated mice. However, the CAs formed by this method are small with a few microaneurysms observable by light microscopy, while other aneurysms require electron microscopy for visualization. This method of CA formation suffers from slow aneurysm formation. Other adaptations to this protocol include ligation of the left renal artery, unilateral nephrectomy, and bilateral ligation of the posterior branches of the renal arteries during the same surgery.3–6,8,10

Elastase and Angiotensin II

Early stages of aneurysm formation are associated with elastic lamina degeneration, which may contribute to aneurysm progression and rupture. Given this histological finding, Nuki et al.54 stereotactically injected elastase into the cerebrospinal fluid of the right basal cistern. To induce hypertension, angiotensin II was continuously administered via a subcutaneously placed microosmotic pump. CA formation was achieved in 77% of the mice within 2 weeks of treatment. Histologically, the aneurysms demonstrated degeneration of the media layer and elastic lamina and infiltration of inflammatory cells.

Intracranial Aneurysm Rupture Model

The spontaneous aneurysm rupture model was introduced by Makino et al.,41 who used a combination of elastase treatment to weaken cerebral blood vessels and hypertension. With this method, in a series of surgeries, hypertension is induced by unilateral nephrectomy, implantation of a DOCA-salt pellet, and the addition of 1% NaCl to the drinking water. During the same surgery as the DOCA-salt pellet implantation, the mice receive a single injection of elastase into the right basal cistern. With this method, CA formation occurs in > 60% of the mice within 28 days of the aneurysm induction surgery. Additionally, spontaneous aneurysm rupture occurs in 50%–60% of mice within 7–11 days following surgery. Hosaka et al. later modified this model with the addition of an increased vessel flow rate and fragility induced by ligating the left CCA and the right renal artery, followed 1 week later by the injection of elastase into the right basal cistern.33 Hypertension and vessel fragility were further enhanced by angiotensin II and by chow containing 8% NaCl and 0.12% BAPN. Using this method with elastase concentrations greater than 50 mU, 100% of the mice develop CAs.

With elastase, CAs are made and also rupture at predictable time points. With 25–30 mU of elastase, the majority of mice form aneurysms at 1 week without signs of rupture.61–64 However, approximately 80% of animals will have subarachnoid hemorrhage by 4 weeks. Similar to the histological changes observed in human CAs, the aneurysms formed by elastase display disruption of the elastic lamina, macrophage infiltration, loss or reduction of the endothelium, and smooth-muscle cell hyperplasia. This model is utilized extensively in the literature and has been used to test pharmacological inhibitors that decrease the incidence of aneurysm progression and rupture.54,62

Surgically Created Saccular Aneurysms

The small animal size and the intracranial aneurysms formed preclude the use of rodent CA models for endovascular device testing. To circumvent this issue, Frösen et al.21 and Marbacher et al.43 surgically created saccular aneurysms using a donor thoracic aorta, which was surgically ligated end-to-side to the abdominal aorta in both mice and rats. These saccular aneurysms display inflammatory cell infiltration, endothelial denudation, thrombus formation, and intimal hyperplasia. Marbacher et al.44 expanded on this model with sodium dodecyl sulfate–induced decellularization of the donor thoracic aorta prior to aneurysm creation. The loss of mural cells led to an unorganized luminal thrombus, increased inflammation, and wall damage resulting in aneurysm growth and rupture.44 Although mice are too small, studies have been successfully conducted using the rat saccular aneurysm model for testing stents11,27 and coils.45

Perspectives and Limitations

Rodent CA models offer a powerful tool for the investigation of aneurysm biology at a molecular, cellular, and physiological level. Excluding surgically created saccular aneurysms, rodent CA models do not require direct vessel manipulation and have an intracranial location. This leads to the question of what constitutes an aneurysm. In the early studies, aneurysm formation produced small microaneurysms that were rarely visible and only detectable by light or electron microscopy or histological alterations of the vessel wall. Some scientists do not believe these “microaneurysms” recapitulate human CA disease. In contrast, elastase treatment results in clear and defined outward bulging of the vessel walls of the circle of Willis and its major branches. Starke et al.61 defined an aneurysm as a bulge in the vessel wall whose diameter is > 150% of the diameter of the parent artery. Similarly, Nuki et al.54 defined an aneurysm as a bulging of the vessel wall > 150% of the diameter of the basilar artery.

Although rodent CA models replicate many of the histological and molecular changes found in human CAs, there are certain pathologies observed in human CAs but not in the rodent CA models. For example, in human saccular CAs, lipids and oxidized lipids accumulate in the aneurysm wall and are associated with cell death, vessel wall weakening, and aneurysm rupture.22,55 Similarly, the complement inflammatory system is activated in human saccular CAs and is involved in aneurysm wall degradation and rupture.65

The commercial availability of genetically modified mice has made rodent CA models a vital tool in investigating the molecular underpinnings of CA formation, progression, and rupture. Transgenic mice allow for the investigation of particular proteins that are altered in human CA disease. For example, tumor necrosis factor (TNF)–α,61 monocyte chemoattractant protein (MCP)–1,4 and nuclear factor (NF)–κB p50 subunit7 knockout reduces CA formation, whereas endothelial nitric oxide synthase (eNOS)9 and SOX1740 knockout predisposes mice to CA formation. The cited studies are just a few of the many using transgenic mice to better understand CA biology in preclinical studies.

Large Animal CA Models

Large animal CA models have been made in numerous species but are primarily formed in rabbits, dogs, and swine.15 Aneurysm formation in large animals requires direct vessel manipulation through either microsurgical or endovascular intervention, and these aneurysms are typically formed using the CCA. Therefore, these models are extracranial in location and suffer from the effects of surgical creation at the aneurysm neck and dome.15 Despite these weaknesses, each model has particular characteristics that are either advantageous for or detrimental to the purposes of a particular study.

Rabbit Aneurysm Models

Venous Graft Aneurysm

To simulate arterial bifurcation aneurysms, a technique was developed to create venous pouch aneurysms using a jugular venous graft at a surgically induced bifurcation at the end-to-side anastomosis of the left CCA to the right CCA.20 Marbacher et al.42 modified this technique to create a more complicated aneurysm by grafting large, wide-necked, bilobar, and bisaccular venous pouches to this surgically created bifurcation. Most recently, a very broad-necked aneurysm model was developed by longitudinally opening a segment of the jugular vein and grafting this patch to the CCA.59 A limitation of these venous pouch models is their inability to replicate the histological changes observed in human aneurysms. A beneficial quality of this model is the ability to tailor aneurysms in terms of both dome and neck size.

Arterial Aneurysms

The most common model of aneurysm creation in rabbits is the saccular aneurysm created by enzymatic weakening of the arterial wall. A reliable method was developed whereby aneurysms were produced by occluding the CCA with an endovascular balloon and incubating the aortic arch–brachiocephalic trunk bifurcation with elastase.18 Subsequently, the same group refined their technique whereby the CCA was surgically exposed, cannulated, and occluded with an endovascular balloon, and then the CCA was incubated with elastase above the balloon prior to its distal ligation (Fig. 2).1 While early techniques for endovascular incubation with elastase were effective at producing aneurysms with adequate patency duration, the retrograde flow of elastase would often cause damage to the trachea and other organs. To curtail this complication, the technique was modified further so that a microcatheter was introduced distal to the balloon and proximal to the CCA ligation to prevent retrograde elastase flow.38 Finally, to dissolve the collagen in the tunica media, collagenase was added to the elastase in endovascular models, which resulted in aneurysms that are nearly histologically identical to human CAs, showing fragmentation and diminution of the internal elastic lamina and increased levels of smooth-muscle cells.36,37,44,45 Although aneurysms created with this method show long-term patency more than 24 months, these aneurysm fail to grow and rupture and demonstrate a homogeneity in vessel wall makeup and thickness. Therefore, it fails to replicate the more complex, heterogenic aneurysm vessel environment of atherosclerosis and wall thinning, as well as the inflammatory cell infiltration and de-endothelialization associated with aneurysm rupture.

FIG. 2.
FIG. 2.

Rabbit elastase aneurysm model. Aneurysm formation in rabbits consists of exposing the right CCA. After gaining arterial access, a balloon is advanced to the origin of the CCA (A). As the balloon is inflated, elastase is simultaneously injected, filling the artery (B). The artery is incubated with elastase for 20 minutes. The elastase and balloon are then removed, and the distal portion of the CCA is ligated, forming the aneurysm. Residual elastase and hemodynamic forces will cause the aneurysm to maturate over a period of several weeks following surgery. A digital subtraction angiography study shows a newly formed aneurysm (C). Copyright Robert Starke. Published with permission.

Hemodynamic Stress–Induced Aneurysms of the Posterior Circulation

Studies by Hassler in 196332 and later by Gao et al.23 demonstrated that aneurysms can be formed in the posterior circulation of rabbits using hemodynamic stress alone without hypertension or vessel wall weakening. In this model, hemodynamic stress is increased in the basilar artery by unilateral or bilateral ligation of the carotid arteries. Using this technique, Hassler and Gao found histological changes in the arterial wall of the basilar terminus resembling nascent aneurysm formation characterized by a loss of internal elastic lamina, media thinning, and an outward bulge of the vessel lumen. This model has been expanded with the addition of the aneurysm risk factors of hypertension and estrogen deficiency.66 Hypertension is induced by unilateral nephrectomy combined with a high salt diet, and estrogen deficiency is induced by bilateral oophorectomy. The combining of hemodynamic stress with hypertension and estrogen deficiency induced changes in the circle of Willis, such as vessel length and tortuosity, as well as aneurysm lesion formation and vascular damage.

Fusiform Aneurysm

Recently, Avery et al.12 developed a carotid artery fusiform aneurysm in rabbits. In this model, the right CCA is exposed and wrapped in gauze and isolated from surrounding tissue by placing the CCA-wrapped section into a cradle. The gauze is then soaked in elastase and CaCl2 for 20 minutes. With this method, fusiform aneurysms, which were defined as vessel dilations greater than 50% of the proximal artery diameter, were formed in 100% of the animals at 6 weeks after aneurysm creation surgery. Histologically, these aneurysms demonstrate an almost complete loss of the internal elastic lamina, a reduction in the tunica media, and a thickening of the tunica intima. The long-term patency of this model was not investigated past 6 weeks.

Canine Aneurysm Models

Venous Pouch Model

The first reliable aneurysm model was developed in 1954 by German and Black, who used a venous pouch graft to create saccular aneurysms in dogs.24 This technique has remained in use to date.62,70 The technique involves exposing the external jugular vein and sectioning a suitable length; one side of the venous segment is closed with a suture to create a venous pouch, which is then sutured to an arteriotomy created at any location of the investigator’s choice. Several modifications of this technique have been described including those for giant, wide-necked, and fusiform aneurysm creation (Fig. 3).29,35,57,71,72

FIG. 3.
FIG. 3.

Venous pouch aneurysms. Illustration depicting the surgical creation of sidewall, bifurcation, and terminal aneurysms using the left and right CCA and a segment of the external jugular vein (EJV). Copyright Robert Starke. Published with permission.

Generally, the CCA or cervical internal carotid artery is selected for the creation of aneurysms because of their similarity in caliber and blood flow to human cerebral vessels and the ability of the animal to tolerate the surgical procedure.26,47,60,69 The canine’s CCA is approximately 4 mm in diameter, similar to the human internal carotid artery, and the relatively long CCA in dogs (10–12 cm) affords easy surgical access.

Hemodynamic Stress and Arterial Wall Injury

More recently, Wang et al. described a novel method of CA formation by inducing hemodynamic stress in combination with arterial wall weakening.67 In this model, a new branch in the CCA is surgically constructed by attaching the proximal segment of one CCA to the proximal sidewall of the contralateral CCA.49,61,67 Hypertension is induced, and elastase is delivered externally to the apex of the newly created bifurcation.

Swine Aneurysm Models

The procedure for aneurysm production in swine is similar to that described by German and Black for aneurysm formation in canines.24 This method was slightly modified by using a longer venous segment and a side-to-side anastomosis to construct giant aneurysms, which were more prone to rupture if left untreated than smaller sized aneurysms.56

Elastase was introduced by Goericke et al.25 to create saccular aneurysms. As in rabbit models, the CCA is exposed and occluded at the origin, and elastase is injected into the CCA and incubated for a period of time. As in both the rodent and rabbit CA models, elastase weakens the arterial wall, triggering an initial inflammatory response as well as activation of endogenous proteinases to break down elastin and collagen, resulting in vascular dilation.30

Perspectives and Limitations

Large animal CA models offer broad utility for investigating endovascular therapeutic interventions, healing, and endovascular training. Among the large animal models, the venous pouch aneurysm model allows for the selection of aneurysm size, morphology, and location, and the aneurysm can be created in vessels with a caliber and blood flow similar to those of human cerebral vessels. However, the venous pouch model suffers in terms of the surgical trauma and suture material involved in aneurysm formation, nonarterial aneurysm composition, and an artificial neck. Despite these drawbacks, large animal models allow for testing of endovascular devices as well as endovascular training. However, the preferred CA model for endovascular training is still up for debate.

A major disadvantage of the rabbit elastase aneurysm model is that it lacks an inflammatory response and does not spontaneously rupture, but it does have coagulation and thrombolysis profiles similar to those of humans, which is critical for testing new materials for use in endovascular devices for aneurysm occlusion.13 A major disadvantage of the swine CA venous graft model is a tendency for spontaneous thrombosis and healing with or without embolization.28,39,52,58 Another disadvantage of the large animal models is the presence of viable mural vascular smooth-muscle cells, which are significantly reduced or absent in human CA tissue. Marbacher et al.44 demonstrated that decellularized aneurysm grafts formed an unorganized luminal thrombus and had increased inflammation and wall damage resulting in aneurysm growth and rupture. Therefore, the healing response in CA models with normal cellularization of the aneurysm wall would be enhanced and thereby potentially enhance the healing response in device studies.

Silicone Aneurysm Models

The recent advancement in and accessibility to 3D printed technologies has allowed for the fabrication of patient-specific true-to-scale arterial replicas.19,37,46 These 3D printed models serve as education tools for presurgical assessment or can be further processed using silicone-casting technology to form a hollow, silicone-walled artificial vasculature. There is an increasing volume of literature in which artificial CA models have been used for endovascular device testing and training, surgical clip ligation training, presurgical assessment, and fluid dynamics studies,2 and they have also been surgically implanted into swine and cadaveric human heads for neurosurgical training.14,53 Although this model offers an excellent alternative to animals in endovascular training, it does not fully replicate the natural arterial biology, which may greatly affect testing results.

Clinical Translation and Conclusions

Animal models of CA have been and continue to be an invaluable tool for investigating the molecular, cellular, and physiological aspects of CA pathophysiology as well as for testing novel endovascular devices. Ideally, the CA model will replicate the hemodynamic forces, wall sheer stresses, and cellular and tissue responses observed in human CAs. However, no animal model perfectly replicates the human disease being investigated. Therefore, each investigator must consider the strengths and weaknesses of each model in order to best replicate the aspect of CAs that is being investigated. In general, rodent CA models are useful for investigating the molecular and cellular mechanisms of aneurysm formation, growth, and rupture with the goal of finding druggable targets for therapeutic intervention and translational potential. In contrast, large CA animal models are primarily used in the development and refinement of new endovascular therapies and in the assessment of novel therapeutic interventions, as was done with Gamma Knife radiosurgery.48 Large animal models also allow for the investigation of aneurysm healing following therapy. No current CA model perfectly replicates human CA disease. Therefore, further work is needed to create a CA model that more closely replicates the histological and pathophysiological features of human CA disease.

Acknowledgments

This work was supported by a National Research and Education Foundation (NREF) Young Clinician Investigator Award, Joe Niekro Research Grant, Bee Foundation Award, Brain Aneurysm Foundation Award, and Miami Clinical and Translational Science Institute Award (R.M.S.). The project described was supported by grant no. UL1TR002736, Miami Clinical and Translational Science Institute, from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Disclosures

Dr. Snelling has direct stock ownership in RIST Neurovascular.

Author Contributions

Conception and design: Starke, Thompson. Drafting the article: Thompson, Elwardany, McCarthy, Sheinberg, Alvarez, Nada, Snelling, Chen, Sur.

References

  • 1

    Altes TACloft HJShort JGDeGast ADo HMHelm GA: Creation of saccular aneurysms in the rabbit: a model suitable for testing endovascular devices. AJR Am J Roentgenol 174:3493542000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Amili OSchiavazzi DMoen SJagadeesan BVan de Moortele PFColetti F: Hemodynamics in a giant intracranial aneurysm characterized by in vitro 4D flow MRI. PLoS One 13:e01883232018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Aoki TFukuda MNishimura MNozaki KNarumiya S: Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation. Acta Neuropathol Commun 2:342014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Aoki TKataoka HIshibashi RNozaki KEgashira KHashimoto N: Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40:9429512009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Aoki TKataoka HIshibashi RNozaki KHashimoto N: Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms. Stroke 39:260326102008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Aoki TKataoka HMoriwaki TNozaki KHashimoto N: Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 38:233723452007

  • 7

    Aoki TKataoka HShimamura MNakagami HWakayama KMoriwaki T: NF-κB is a key mediator of cerebral aneurysm formation. Circulation 116:283028402007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Aoki TNishimura MKataoka HIshibashi RNozaki KHashimoto N: Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox-/- mice. Lab Invest 89:7307412009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Aoki TNishimura MKataoka HIshibashi RNozaki KMiyamoto S: Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS. Lab Invest 91:6196262011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Aoki TNishimura MMatsuoka TYamamoto KFuruyashiki TKataoka H: PGE2-EP2 signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB. Br J Pharmacol 163:123712492011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Aquarius RSmits DGounis MJLeenders WPJde Vries J: Flow diverter implantation in a rat model of sidewall aneurysm: a feasibility study. J Neurointerv Surg 10:88922018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Avery MBAlaqeel ABromley ABChen YXWong JHEesa M: A refined experimental model of fusiform aneurysms in a rabbit carotid artery. J Neurosurg 131:88952019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Bavinzski Gal-Schameri AKiller MSchwendenwein IGruber ASaringer W: Experimental bifurcation aneurysm: a model for in vivo evaluation of endovascular techniques. Minim Invasive Neurosurg 41:1291321998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Benet APlata-Bello JAbla AAAcevedo-Bolton GSaloner DLawton MT: Implantation of 3D-printed patient-specific aneurysm models into cadaveric specimens: a new training paradigm to allow for improvements in cerebrovascular surgery and research. BioMed Res Int 2015:9393872015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Bouzeghrane FNaggara OKallmes DFBerenstein ARaymond J: In vivo experimental intracranial aneurysm models: a systematic review. AJNR Am J Neuroradiol 31:4184232010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Brinjikji WZhu YQLanzino GCloft HJMurad MHWang Z: Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol 37:6156202016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Chalouhi NHoh BLHasan D: Review of cerebral aneurysm formation, growth, and rupture. Stroke 44:361336222013

  • 18

    Cloft HJAltes TAMarx WFRaible RJHudson SBHelm GA: Endovascular creation of an in vivo bifurcation aneurysm model in rabbits. Radiology 213:2232281999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    D’Urso PSThompson RGAtkinson RLWeidmann MJRedmond MJHall BI: Cerebrovascular biomodelling: a technical note. Surg Neurol 52:4905001999

  • 20

    Forrest MDO’Reilly GV: Production of experimental aneurysms at a surgically created arterial bifurcation. AJNR Am J Neuroradiol 10:4004021989

    • Search Google Scholar
    • Export Citation
  • 21

    Frösen JMarjamaa JMyllärniemi MAbo-Ramadan UTulamo RNiemelä M: Contribution of mural and bone marrow-derived neointimal cells to thrombus organization and wall remodeling in a microsurgical murine saccular aneurysm model. Neurosurgery 58:9369442006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Frösen JTulamo RHeikura TSammalkorpi SNiemelä MHernesniemi J: Lipid accumulation, lipid oxidation, and low plasma levels of acquired antibodies against oxidized lipids associate with degeneration and rupture of the intracranial aneurysm wall. Acta Neuropathol Commun 1:712013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Gao LHoi YSwartz DDKolega JSiddiqui AMeng H: Nascent aneurysm formation at the basilar terminus induced by hemodynamics. Stroke 39:208520902008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    German WJBlack SP: Experimental production of carotid aneurysms. N Engl J Med 250:1041061954

  • 25

    Goericke SLParohl NAlbert JDudda MForsting M: Elastase-induced aneurysm in swine: proof of feasibility in a first case. A technical note. Interv Neuroradiol 15:4134162009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Graves VBAhuja AStrother CMRappe AH: Canine model of terminal arterial aneurysm. AJNR Am J Neuroradiol 14:8018031993

  • 27

    Grüter BETäschler DStrange FRey Jvon Gunten MGrandgirard D: Testing bioresorbable stent feasibility in a rat aneurysm model. J Neurointerv Surg [epub ahead of print] 2019

    • Search Google Scholar
    • Export Citation
  • 28

    Guglielmi GJi CMassoud TFKurata ALownie SPViñuela F: Experimental saccular aneurysms. II. A new model in swine. Neuroradiology 36:5475501994

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Guo SJiang PLiu JYang XJiang CLi Y: A comparative CFD analysis of common carotid fusiform aneurysm in canine models and vertebrobasilar fusiform aneurysm in human patients. Int Angiol 37:32402018

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Halpern VJNackman GBGandhi RHIrizarry EScholes JVRamey WG: The elastase infusion model of experimental aortic aneurysms: synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response. J Vasc Surg 20:51601994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Hashimoto NHanda HHazama F: Experimentally induced cerebral aneurysms in rats. Surg Neurol 10:381978

  • 32

    Hassler O: experimental carotid ligation followed by aneurysmal formation and other morphological changes in the circle of Willis. J Neurosurg 20:171963

  • 33

    Hosaka KDownes DPNowicki KWHoh BL: Modified murine intracranial aneurysm model: aneurysm formation and rupture by elastase and hypertension. J Neurointerv Surg 6:4744792014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J Med 339:172517331998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Jiang YZLan QWang QHWang SZLu HWu WJ: Creation of experimental aneurysms at a surgically created arterial confluence. Eur Rev Med Pharmacol Sci 19:424142482015

    • Search Google Scholar
    • Export Citation
  • 36

    Kang WConnor JYan XNeely BCarney EEllwanger J: A modified technique improved histology similarity to human intracranial aneurysm in rabbit aneurysm model. Neuroradiol J 23:6166212010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Kimura TMorita ANishimura KAiyama HItoh HFukaya S: Simulation of and training for cerebral aneurysm clipping with 3-dimensional models. Neurosurgery 65:7197262009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Krings TMöller-Hartmann WHans FJThiex RBrunn AScherer K: A refined method for creating saccular aneurysms in the rabbit. Neuroradiology 45:4234292003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Lee DYuki IMurayama YChiang ANishimura IVinters HV: Thrombus organization and healing in the swine experimental aneurysm model. Part I. A histological and molecular analysis. J Neurosurg 107:941082007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Lee SKim IKAhn JSWoo DCKim STSong S: Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm. Circulation 131:99510052015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Makino HTada YWada KLiang EIChang MMobashery S: Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke 43:245024562012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Marbacher SErhardt SSchläppi JAColuccia DRemonda LFandino J: Complex bilobular, bisaccular, and broad-neck microsurgical aneurysm formation in the rabbit bifurcation model for the study of upcoming endovascular techniques. AJNR Am J Neuroradiol 32:7727772011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Marbacher SFrösén JMarjamaa JAnisimov AHonkanen Pvon Gunten M: Intraluminal cell transplantation prevents growth and rupture in a model of rupture-prone saccular aneurysms. Stroke 45:368436902014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Marbacher SMarjamaa JBradacova Kvon Gunten MHonkanen PAbo-Ramadan U: Loss of mural cells leads to wall degeneration, aneurysm growth, and eventual rupture in a rat aneurysm model. Stroke 45:2482542014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Marjamaa JTulamo RFrösen JAbo-Ramadan UHernesniemi JANiemelä MR: Occlusion of neck remnant in experimental rat aneurysms after treatment with platinum- or polyglycolic-polylactic acid-coated coils. Surg Neurol 71:4584652009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Mashiko TOtani KKawano RKonno TKaneko NIto Y: Development of three-dimensional hollow elastic model for cerebral aneurysm clipping simulation enabling rapid and low cost prototyping. World Neurosurg 83:3513612015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Massoud TFGuglielmi GJi CViñuela FDuckwiler GR: Experimental saccular aneurysms. I. Review of surgically-constructed models and their laboratory applications. Neuroradiology 36:5375461994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Meadowcroft MDCooper TKRupprecht SWright TCNeely EEFerenci M: Gamma Knife radiosurgery of saccular aneurysms in a rabbit model. J Neurosurg 129:153015402018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Meng HWang ZHoi YGao LMetaxa ESwartz DD: Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 38:192419312007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Mérei FTGallyas F: Role of the structural elements of the arterial wall in the formation and growth of intracranial saccular aneurysms. Neurol Res 2:2833031980

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Morimoto MMiyamoto SMizoguchi AKume NKita THashimoto N: Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke 33:191119152002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Murayama YViñuela FSuzuki YAkiba YUlihoa ADuckwiler GR: Development of the biologically active Guglielmi detachable coil for the treatment of cerebral aneurysms. Part II: an experimental study in a swine aneurysm model. AJNR Am J Neuroradiol 20:199219991999

    • Search Google Scholar
    • Export Citation
  • 53

    Namba KMashio KKawamura YHigaki ANemoto S: Swine hybrid aneurysm model for endovascular surgery training. Interv Neuroradiol 19:1531582013

  • 54

    Nuki YTsou TLKurihara CKanematsu MKanematsu YHashimoto T: Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension 54:133713442009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Ollikainen ETulamo RLehti SLee-Rueckert MHernesniemi JNiemelä M: Smooth muscle cell foam cell formation, apolipoproteins, and ABCA1 in intracranial aneurysms: implications for lipid accumulation as a promoter of aneurysm wall rupture. J Neuropathol Exp Neurol 75:6896992016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Raymond JDarsaut TEKotowski MMakoyeva AGevry GBerthelet F: Thrombosis heralding aneurysmal rupture: an exploration of potential mechanisms in a novel giant swine aneurysm model. AJNR Am J Neuroradiol 34:3463532013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Raymond JSalazkin IGeorganos SGuilbert FDesfaits ACGevry G: Endovascular treatment of experimental wide neck aneurysms: comparison of results using coils or cyanoacrylate with the assistance of an aneurysm neck bridge device. AJNR Am J Neuroradiol 23:171017162002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Raymond JVenne DAllas SRoy DOliva VLDenbow N: Healing mechanisms in experimental aneurysms. I. Vascular smooth muscle cells and neointima formation. J Neuroradiol 26:7201999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Sherif CHerbich EPlasenzotti RBergmeister HWindberger UMach G: Very large and giant microsurgical bifurcation aneurysms in rabbits: Proof of feasibility and comparability using computational fluid dynamics and biomechanical testing. J Neurosci Methods 268:7132016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Sorteberg ASorteberg WRappe AStrother CM: Effect of Guglielmi detachable coils on intraaneurysmal flow: experimental study in canines. AJNR Am J Neuroradiol 23:2882942002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Starke RMChalouhi NJabbour PMTjoumakaris SIGonzalez LFRosenwasser RH: Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. J Neuroinflammation 11:772014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Starke RMThompson JWAli MSPascale CLMartinez Lege ADing D: Cigarette smoke initiates oxidative stress-induced cellular phenotypic modulation leading to cerebral aneurysm pathogenesis. Arterioscler Thromb Vasc Biol 38:6106212018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Tada YWada KShimada KMakino HLiang EIMurakami S: Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:5795862014

  • 64

    Tada YWada KShimada KMakino HLiang EIMurakami S: Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension 63:133913442014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Tulamo RFrösen JJunnikkala SPaetau APitkäniemi JKangasniemi M: Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59:106910772006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Tutino VMMandelbaum MTakahashi APope LCSiddiqui AKolega J: Hypertension and estrogen deficiency augment aneurysmal remodeling in the rabbit circle of Willis in response to carotid ligation. Anat Rec (Hoboken) 298:190319102015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Wang JTan HQZhu YQLi MHLi ZZYan L: Complex hemodynamic insult in combination with wall degeneration at the apex of an arterial bifurcation contributes to generation of nascent aneurysms in a canine model. AJNR Am J Neuroradiol 35:180518122014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Weir B: Unruptured intracranial aneurysms: a review. J Neurosurg 96:3422002

  • 69

    Yan LZhu YQLi MHTan HQCheng YS: Geometric, hemodynamic, and pathological study of a distal internal carotid artery aneurysm model in dogs. Stroke 44:292629292013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Yang XJLi LWu ZX: A novel arterial pouch model of saccular aneurysm by concomitant elastase and collagenase digestion. J Zhejiang Univ Sci B 8:6977032007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Yapor WJafar JCrowell RM: One-stage construction of giant experimental aneurysms in dogs. Surg Neurol 36:4264301991

  • 72

    Ysuda RStrother CMAagaard-Kienitz BPulfer KConsigny D: A large and giant bifurcation aneurysm model in canines: proof of feasibility. AJNR Am J Neuroradiol 33:5075122012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence Robert M. Starke: Miami University, Lois Pope LIFE Center, Miami, FL. rstarke@med.miami.edu.

INCLUDE WHEN CITING DOI: 10.3171/2019.4.FOCUS19219.

Disclosures Dr. Snelling has direct stock ownership in RIST Neurovascular.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Cerebral aneurysm formation in rodents, hemodynamic stress, and vessel wall weakening. The procedures used for CA formations in rats and mice vary primarily in the method of inducing hypertension, increasing the flow rate, and weakening the vessel wall. Hypertension can be induced by a combination of a high salt diet, unilateral nephrectomy or bilateral ligation of the posterior branches of the renal arteries (not shown), and subcutaneous placement of DOCA pellets or angiotensin II–filled microosmotic pump (not shown). Increases in flow rate are accomplished by ligation of the left CCA, which causes a compensatory increase in flow rate in the contralateral internal carotid artery. Vessel wall weakening is accomplished by feeding a diet containing 0.12% BAPN, a lysyl oxidase inhibitor, or by a single stereotactic injection of elastase. Copyright Robert Starke. Published with permission.

  • View in gallery

    Rabbit elastase aneurysm model. Aneurysm formation in rabbits consists of exposing the right CCA. After gaining arterial access, a balloon is advanced to the origin of the CCA (A). As the balloon is inflated, elastase is simultaneously injected, filling the artery (B). The artery is incubated with elastase for 20 minutes. The elastase and balloon are then removed, and the distal portion of the CCA is ligated, forming the aneurysm. Residual elastase and hemodynamic forces will cause the aneurysm to maturate over a period of several weeks following surgery. A digital subtraction angiography study shows a newly formed aneurysm (C). Copyright Robert Starke. Published with permission.

  • View in gallery

    Venous pouch aneurysms. Illustration depicting the surgical creation of sidewall, bifurcation, and terminal aneurysms using the left and right CCA and a segment of the external jugular vein (EJV). Copyright Robert Starke. Published with permission.

References

  • 1

    Altes TACloft HJShort JGDeGast ADo HMHelm GA: Creation of saccular aneurysms in the rabbit: a model suitable for testing endovascular devices. AJR Am J Roentgenol 174:3493542000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Amili OSchiavazzi DMoen SJagadeesan BVan de Moortele PFColetti F: Hemodynamics in a giant intracranial aneurysm characterized by in vitro 4D flow MRI. PLoS One 13:e01883232018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Aoki TFukuda MNishimura MNozaki KNarumiya S: Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation. Acta Neuropathol Commun 2:342014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Aoki TKataoka HIshibashi RNozaki KEgashira KHashimoto N: Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40:9429512009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Aoki TKataoka HIshibashi RNozaki KHashimoto N: Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms. Stroke 39:260326102008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Aoki TKataoka HMoriwaki TNozaki KHashimoto N: Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 38:233723452007

  • 7

    Aoki TKataoka HShimamura MNakagami HWakayama KMoriwaki T: NF-κB is a key mediator of cerebral aneurysm formation. Circulation 116:283028402007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Aoki TNishimura MKataoka HIshibashi RNozaki KHashimoto N: Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox-/- mice. Lab Invest 89:7307412009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Aoki TNishimura MKataoka HIshibashi RNozaki KMiyamoto S: Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS. Lab Invest 91:6196262011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Aoki TNishimura MMatsuoka TYamamoto KFuruyashiki TKataoka H: PGE2-EP2 signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB. Br J Pharmacol 163:123712492011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Aquarius RSmits DGounis MJLeenders WPJde Vries J: Flow diverter implantation in a rat model of sidewall aneurysm: a feasibility study. J Neurointerv Surg 10:88922018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Avery MBAlaqeel ABromley ABChen YXWong JHEesa M: A refined experimental model of fusiform aneurysms in a rabbit carotid artery. J Neurosurg 131:88952019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Bavinzski Gal-Schameri AKiller MSchwendenwein IGruber ASaringer W: Experimental bifurcation aneurysm: a model for in vivo evaluation of endovascular techniques. Minim Invasive Neurosurg 41:1291321998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Benet APlata-Bello JAbla AAAcevedo-Bolton GSaloner DLawton MT: Implantation of 3D-printed patient-specific aneurysm models into cadaveric specimens: a new training paradigm to allow for improvements in cerebrovascular surgery and research. BioMed Res Int 2015:9393872015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Bouzeghrane FNaggara OKallmes DFBerenstein ARaymond J: In vivo experimental intracranial aneurysm models: a systematic review. AJNR Am J Neuroradiol 31:4184232010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Brinjikji WZhu YQLanzino GCloft HJMurad MHWang Z: Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol 37:6156202016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Chalouhi NHoh BLHasan D: Review of cerebral aneurysm formation, growth, and rupture. Stroke 44:361336222013

  • 18

    Cloft HJAltes TAMarx WFRaible RJHudson SBHelm GA: Endovascular creation of an in vivo bifurcation aneurysm model in rabbits. Radiology 213:2232281999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    D’Urso PSThompson RGAtkinson RLWeidmann MJRedmond MJHall BI: Cerebrovascular biomodelling: a technical note. Surg Neurol 52:4905001999

  • 20

    Forrest MDO’Reilly GV: Production of experimental aneurysms at a surgically created arterial bifurcation. AJNR Am J Neuroradiol 10:4004021989

    • Search Google Scholar
    • Export Citation
  • 21

    Frösen JMarjamaa JMyllärniemi MAbo-Ramadan UTulamo RNiemelä M: Contribution of mural and bone marrow-derived neointimal cells to thrombus organization and wall remodeling in a microsurgical murine saccular aneurysm model. Neurosurgery 58:9369442006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Frösen JTulamo RHeikura TSammalkorpi SNiemelä MHernesniemi J: Lipid accumulation, lipid oxidation, and low plasma levels of acquired antibodies against oxidized lipids associate with degeneration and rupture of the intracranial aneurysm wall. Acta Neuropathol Commun 1:712013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Gao LHoi YSwartz DDKolega JSiddiqui AMeng H: Nascent aneurysm formation at the basilar terminus induced by hemodynamics. Stroke 39:208520902008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    German WJBlack SP: Experimental production of carotid aneurysms. N Engl J Med 250:1041061954

  • 25

    Goericke SLParohl NAlbert JDudda MForsting M: Elastase-induced aneurysm in swine: proof of feasibility in a first case. A technical note. Interv Neuroradiol 15:4134162009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Graves VBAhuja AStrother CMRappe AH: Canine model of terminal arterial aneurysm. AJNR Am J Neuroradiol 14:8018031993

  • 27

    Grüter BETäschler DStrange FRey Jvon Gunten MGrandgirard D: Testing bioresorbable stent feasibility in a rat aneurysm model. J Neurointerv Surg [epub ahead of print] 2019

    • Search Google Scholar
    • Export Citation
  • 28

    Guglielmi GJi CMassoud TFKurata ALownie SPViñuela F: Experimental saccular aneurysms. II. A new model in swine. Neuroradiology 36:5475501994

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Guo SJiang PLiu JYang XJiang CLi Y: A comparative CFD analysis of common carotid fusiform aneurysm in canine models and vertebrobasilar fusiform aneurysm in human patients. Int Angiol 37:32402018

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Halpern VJNackman GBGandhi RHIrizarry EScholes JVRamey WG: The elastase infusion model of experimental aortic aneurysms: synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response. J Vasc Surg 20:51601994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Hashimoto NHanda HHazama F: Experimentally induced cerebral aneurysms in rats. Surg Neurol 10:381978

  • 32

    Hassler O: experimental carotid ligation followed by aneurysmal formation and other morphological changes in the circle of Willis. J Neurosurg 20:171963

  • 33

    Hosaka KDownes DPNowicki KWHoh BL: Modified murine intracranial aneurysm model: aneurysm formation and rupture by elastase and hypertension. J Neurointerv Surg 6:4744792014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J Med 339:172517331998

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Jiang YZLan QWang QHWang SZLu HWu WJ: Creation of experimental aneurysms at a surgically created arterial confluence. Eur Rev Med Pharmacol Sci 19:424142482015

    • Search Google Scholar
    • Export Citation
  • 36

    Kang WConnor JYan XNeely BCarney EEllwanger J: A modified technique improved histology similarity to human intracranial aneurysm in rabbit aneurysm model. Neuroradiol J 23:6166212010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Kimura TMorita ANishimura KAiyama HItoh HFukaya S: Simulation of and training for cerebral aneurysm clipping with 3-dimensional models. Neurosurgery 65:7197262009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Krings TMöller-Hartmann WHans FJThiex RBrunn AScherer K: A refined method for creating saccular aneurysms in the rabbit. Neuroradiology 45:4234292003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Lee DYuki IMurayama YChiang ANishimura IVinters HV: Thrombus organization and healing in the swine experimental aneurysm model. Part I. A histological and molecular analysis. J Neurosurg 107:941082007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Lee SKim IKAhn JSWoo DCKim STSong S: Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm. Circulation 131:99510052015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Makino HTada YWada KLiang EIChang MMobashery S: Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke 43:245024562012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Marbacher SErhardt SSchläppi JAColuccia DRemonda LFandino J: Complex bilobular, bisaccular, and broad-neck microsurgical aneurysm formation in the rabbit bifurcation model for the study of upcoming endovascular techniques. AJNR Am J Neuroradiol 32:7727772011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Marbacher SFrösén JMarjamaa JAnisimov AHonkanen Pvon Gunten M: Intraluminal cell transplantation prevents growth and rupture in a model of rupture-prone saccular aneurysms. Stroke 45:368436902014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Marbacher SMarjamaa JBradacova Kvon Gunten MHonkanen PAbo-Ramadan U: Loss of mural cells leads to wall degeneration, aneurysm growth, and eventual rupture in a rat aneurysm model. Stroke 45:2482542014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Marjamaa JTulamo RFrösen JAbo-Ramadan UHernesniemi JANiemelä MR: Occlusion of neck remnant in experimental rat aneurysms after treatment with platinum- or polyglycolic-polylactic acid-coated coils. Surg Neurol 71:4584652009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Mashiko TOtani KKawano RKonno TKaneko NIto Y: Development of three-dimensional hollow elastic model for cerebral aneurysm clipping simulation enabling rapid and low cost prototyping. World Neurosurg 83:3513612015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Massoud TFGuglielmi GJi CViñuela FDuckwiler GR: Experimental saccular aneurysms. I. Review of surgically-constructed models and their laboratory applications. Neuroradiology 36:5375461994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Meadowcroft MDCooper TKRupprecht SWright TCNeely EEFerenci M: Gamma Knife radiosurgery of saccular aneurysms in a rabbit model. J Neurosurg 129:153015402018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Meng HWang ZHoi YGao LMetaxa ESwartz DD: Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 38:192419312007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Mérei FTGallyas F: Role of the structural elements of the arterial wall in the formation and growth of intracranial saccular aneurysms. Neurol Res 2:2833031980

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Morimoto MMiyamoto SMizoguchi AKume NKita THashimoto N: Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke 33:191119152002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Murayama YViñuela FSuzuki YAkiba YUlihoa ADuckwiler GR: Development of the biologically active Guglielmi detachable coil for the treatment of cerebral aneurysms. Part II: an experimental study in a swine aneurysm model. AJNR Am J Neuroradiol 20:199219991999

    • Search Google Scholar
    • Export Citation
  • 53

    Namba KMashio KKawamura YHigaki ANemoto S: Swine hybrid aneurysm model for endovascular surgery training. Interv Neuroradiol 19:1531582013

  • 54

    Nuki YTsou TLKurihara CKanematsu MKanematsu YHashimoto T: Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension 54:133713442009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Ollikainen ETulamo RLehti SLee-Rueckert MHernesniemi JNiemelä M: Smooth muscle cell foam cell formation, apolipoproteins, and ABCA1 in intracranial aneurysms: implications for lipid accumulation as a promoter of aneurysm wall rupture. J Neuropathol Exp Neurol 75:6896992016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Raymond JDarsaut TEKotowski MMakoyeva AGevry GBerthelet F: Thrombosis heralding aneurysmal rupture: an exploration of potential mechanisms in a novel giant swine aneurysm model. AJNR Am J Neuroradiol 34:3463532013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Raymond JSalazkin IGeorganos SGuilbert FDesfaits ACGevry G: Endovascular treatment of experimental wide neck aneurysms: comparison of results using coils or cyanoacrylate with the assistance of an aneurysm neck bridge device. AJNR Am J Neuroradiol 23:171017162002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Raymond JVenne DAllas SRoy DOliva VLDenbow N: Healing mechanisms in experimental aneurysms. I. Vascular smooth muscle cells and neointima formation. J Neuroradiol 26:7201999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Sherif CHerbich EPlasenzotti RBergmeister HWindberger UMach G: Very large and giant microsurgical bifurcation aneurysms in rabbits: Proof of feasibility and comparability using computational fluid dynamics and biomechanical testing. J Neurosci Methods 268:7132016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Sorteberg ASorteberg WRappe AStrother CM: Effect of Guglielmi detachable coils on intraaneurysmal flow: experimental study in canines. AJNR Am J Neuroradiol 23:2882942002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Starke RMChalouhi NJabbour PMTjoumakaris SIGonzalez LFRosenwasser RH: Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. J Neuroinflammation 11:772014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Starke RMThompson JWAli MSPascale CLMartinez Lege ADing D: Cigarette smoke initiates oxidative stress-induced cellular phenotypic modulation leading to cerebral aneurysm pathogenesis. Arterioscler Thromb Vasc Biol 38:6106212018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Tada YWada KShimada KMakino HLiang EIMurakami S: Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:5795862014

  • 64

    Tada YWada KShimada KMakino HLiang EIMurakami S: Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension 63:133913442014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Tulamo RFrösen JJunnikkala SPaetau APitkäniemi JKangasniemi M: Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59:106910772006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Tutino VMMandelbaum MTakahashi APope LCSiddiqui AKolega J: Hypertension and estrogen deficiency augment aneurysmal remodeling in the rabbit circle of Willis in response to carotid ligation. Anat Rec (Hoboken) 298:190319102015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Wang JTan HQZhu YQLi MHLi ZZYan L: Complex hemodynamic insult in combination with wall degeneration at the apex of an arterial bifurcation contributes to generation of nascent aneurysms in a canine model. AJNR Am J Neuroradiol 35:180518122014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Weir B: Unruptured intracranial aneurysms: a review. J Neurosurg 96:3422002

  • 69

    Yan LZhu YQLi MHTan HQCheng YS: Geometric, hemodynamic, and pathological study of a distal internal carotid artery aneurysm model in dogs. Stroke 44:292629292013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Yang XJLi LWu ZX: A novel arterial pouch model of saccular aneurysm by concomitant elastase and collagenase digestion. J Zhejiang Univ Sci B 8:6977032007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Yapor WJafar JCrowell RM: One-stage construction of giant experimental aneurysms in dogs. Surg Neurol 36:4264301991

  • 72

    Ysuda RStrother CMAagaard-Kienitz BPulfer KConsigny D: A large and giant bifurcation aneurysm model in canines: proof of feasibility. AJNR Am J Neuroradiol 33:5075122012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 148 148 148
PDF Downloads 230 230 230
EPUB Downloads 0 0 0

PubMed

Google Scholar