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Systematic Review

In Vivo Experimental Endovascular Uses of Cyanoacrylate in Non-Modified Arteries: A Systematic Review

by
Kévin Guillen
1,2,
Pierre-Olivier Comby
2,3,
Olivier Chevallier
1,2,
Anne-Virginie Salsac
4 and
Romaric Loffroy
1,2,*
1
Department of Vascular and Interventional Radiology, Image-Guided Therapy Center, François-Mitterrand University Hospital, 14 Rue Paul Gaffarel, BP 77908, 21079 Dijon, France
2
Imaging and Artificial Vision (ImViA) Laboratory-EA 7535, University of Bourgogne/Franche-Comté, 9 Avenue Alain Savary, BP 47870, 21078 Dijon, France
3
Department of Neuroradiology and Emergency Radiology, François-Mitterrand University Hospital, 14 Rue Paul Gaffarel, BP 77908, 21079 Dijon, France
4
Biomechanics and Bioengineering Laboratory, UMR CNRS 7338, Université de Technologie de Compiègne, 60203 Compiègne, France
*
Author to whom correspondence should be addressed.
Biomedicines 2021, 9(9), 1282; https://doi.org/10.3390/biomedicines9091282
Submission received: 22 August 2021 / Revised: 6 September 2021 / Accepted: 15 September 2021 / Published: 21 September 2021
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Review Reports Versions Notes

Abstract

:
Cyanoacrylates were first used for medical purposes during World War II to close skin wounds. Over time, medical applications were developed, specifically in the vascular field. Uses now range from extravascular instillation in vascular grafting to intravascular injection for embolization. These applications were made possible by the conduct of numerous preclinical studies involving a variety of tests and outcome measures, including angiographic and histological criteria. Cyanoacrylates were first harshly criticized by vascular surgeons, chiefly due to their fast and irreversible polymerization. Over the past five years, however, cyanoacrylates have earned an established place in endovascular interventional radiology. Given the irreversible effects of cyanoacrylates, studies in animal models are ethically acceptable only if supported by reliable preliminary data. Many animal studies of cyanoacrylates involved the experimental creation of aneurysms or arteriovenous fistulas, whose treatment by endovascular embolization was then assessed. In clinical practice, however, injection into non-modified arteries may be desirable, for instance, to deprive a tumor of its vascular supply. To help investigators in this field select the animal models and procedures that are most appropriate for their objectives, we have reviewed all published in vivo animal studies that involved the injection of cyanoacrylates into non-modified arteries to discuss their main characteristics and endpoints.

1. Introduction

N-butyl cyanoacrylate (NBCA) is generating considerable interest among interventional radiologists given its good efficacy and biological tolerance when used for endovascular embolization. Practices regarding the clinical uses of NBCAs vary across countries. For instance, Glubran® 2 (GEM, Viareggio, Italy) has obtained the European Conformity (EC) mark, whereas Trufill® (Cordis, Miami Lakes, FL, USA) has been approved by the Food and Drug Administration in the US but is not available elsewhere. Histoacryl® is also an NBCA and is available in the USA and Japan but is normally “off-label” in Europe for endovascular purposes in humans, although it has been used for a long time. Bucrylate®, or isobutyl 2-cyanoacrylate (IBCA), was used in early studies before it was demonstrated that NBCA had a better safety profile and greater tensile strength. General agreement exists about the usefulness, when performing intra-arterial injections of cyanoacrylates, of adding a radio-opaque agent that delays polymerization and provides angiographic guidance for controlling polymerization kinetics [1].
Preclinical studies are one of the available means of increasing our knowledge of NBCAs and identifying their best clinical applications. The adequate conceptualization of relevant experimental models is needed to apply an evidence-based methodology capable of producing a high level of basic science evidence. Most studies of the in vivo uses of endovascular NBCA focused on aneurysms or arteriovenous malformations (AVMs) [2]. Different models have been developed to mimic different clinical situations. Thus, rete mirabile embolization through the ascending pharyngeal artery in swine serves as a model for the treatment of AVMs [3]. Aneurysms, including aortic aneurysms, have been created in rabbits and swine and in arteriovenous fistulas in dogs [4,5,6,7,8]. However, to our knowledge, no review of cyanoacrylate injection into non-modified arteries in animal models is available. Embolization by injection into non-modified arteries is sometimes needed in clinical practice, for instance, to deprive a tumor of its blood supply before surgical excision, or to stop arterial bleeding via the transfemoral approach [9]. Moreover, knowledge of the behavior of cyanoacrylates in non-modified arteries may prove valuable.
When interest in cyanoacrylates—which have been available for many years—was recently rekindled, studies identified several issues requiring further investigation [10]. The objective of this systematic review of the experimental studies of cyanoacrylates injected into non-modified arteries in animal models was to help investigators choose the in vivo model and embolization site most likely to provide the answer to their research questions based on all the data published to date.

2. Materials and Methods

2.1. Literature Search Strategy

We performed an exhaustive computerized search of the Medline/PubMed and Web of Science databases, which complement each other. The search period was 1950 to 2020. We used the following keywords in all possible paired combinations separated by the Boolean operator AND: “cyanoacrylate”, “lipiodol”, “endovascular”, “in vivo”, “experimental”, “mice”, “sheep”, “dog”, “rabbit”, and “primate”. We then manually checked the reference lists of the articles that were retrieved.
Study inclusion criteria were as follows: English or French language, original research (conferences, letters, abstracts, and editorials were not included), publication after peer review, use of cyanoacrylate for endovascular arterial embolization, and no experimental change to the embolized artery (i.e., no aneurysms or AVMs were created). The second author (P.O.C.) independently assessed the eligibility of the studies and the reproducibility of the computerized search. Disagreements were resolved by having P.O.C. and R.L. review the article together to reach a consensus.

2.2. Outcomes

To our knowledge, no standardized reviewing protocol exists for experimental animal studies. We drew from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR), although it was designed for clinical reviews [11,12]. The data from the selected studies were entered into an electronic spreadsheet listing the following characteristics: publication (first author’s name and country, year, URL); primary study objective; species, number of animals used, and number of models; clinical situations the model was designed to mimic; chemical and commercial names of the cyanoacrylate used; any other compounds used, with the ratio relative to cyanoacrylate; name of the embolized vessels and how they were approached; amount injected; size of the introducer and microcatheters; guiding modality; detailed outcomes (e.g., histological and angiographic findings); and follow-up duration and data. Our findings are reported as a narrative review, with references but without comparisons across studies.

3. Results

3.1. Included Studies

Our exhaustive search strategy retrieved 428 articles. Figure 1 is the flowchart. After the initial screening of the titles and abstracts, we excluded 141 papers, most of which dealt with the NBCA embolization of experimentally produced AVMs or aneurysms. When the same study involved the endovascular treatment of both prepared and non-modified arteries, only the data regarding the non-modified arteries were considered. The crossmatching of reference lists and review articles identified five additional studies, leading to a total of 64 studies. After the examination of the full texts, we found that 20 articles did not meet our selection criteria; for example, eight of them studied intravenous cyanoacrylate.
This left 44 studies for our qualitative analysis of the model characteristics. Their distribution by year of publication is shown in Figure 2. Of the 44 studies, 16 were completed in swine, 17 in dogs, 7 in rabbits, 2 in primates, and 2 in other species. The information needed for a quantitative evaluation of the embolization mixture and procedure characteristics was supplied by 36 of the 44 articles.

3.2. General Characteristics

Most of the publications were by North American authors (USA and Canada), although Japan and China also made substantive contributions (Figure 3). The total number of animals used was 1042, with 454 rats in 4 studies. The main objectives fell into two groups: the evaluation of polymerization kinetics or other characteristics (33 studies, including 11 with Histoacryl® (B/Braun, Tuttlingen, Germany), 8 with Bucrylate®, and 1 with Glubran® 2), and the development of models that replicated clinical situations, such as ischemia (six studies, half of which used Histoacryl® and none Glubran® 2). In five other studies, cyanoacrylates were used to document the characteristics of a new tool (e.g., a balloon-microcatheter) or the effects of embolization on the neighboring tissues. Overall, the mean model follow-up was 31 days, the median was 3 days, and the range was 0 to 180 days (with the longest follow-up in mongrel dogs); of the 44 studies, 15 involved euthanasia on the same day as the endovascular intervention.

3.3. Procedures

Most of the procedures were completed under fluoroscopic guidance (41/44, 93%) via the transfemoral approach. In the remaining three studies, the microcatheter was inserted directly into the target artery.
Table 1, Table 2 and Table 3 report the main quantitative data in studies of dogs, swine, and rabbits, respectively. Three articles, on primate and rat models, were not considered for the quantitative evaluation, which thus relied on 33 articles [8,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45].
The ranges of end-tip external diameters for dog, swine, and rabbit models were 1.0–4.2 French (Fr), 2.0–4.1 Fr, and 1.5–3.6 Fr, respectively. The cyanoacrylate absolute concentrations in the injected substance ranged from 10% to 100%. Figure 4 is a histogram showing the frequencies of arterial sites used for embolization. In 19 (57%) of the 33 studies, the renal artery was embolized. When radio-opaque agents were added to allow real-time control of the embolization while also adjusting the polymerization time, Lipiodol was chosen in 47% and iophendylate in 22% of the cases. Importantly, iophendylate was used in the earliest studies, and Lipiodol was used in the more recent work. Tantalum powder was the third most commonly used contrast agent and had no effect on cyanoacrylate polymerization characteristics.

4. Discussion

This review aimed to identify all of the studies that involved cyanoacrylate injection into non-modified arteries of animal models and were published between the early 1970s and now. We did not consider studies of aneurysm embolization as the methods used to produce aneurysms are associated with multiple sources of confounding. More specifically, the need to infuse a heparin sulfate solution and the induced local inflammation of the artery influence the reproducibility of aneurysm models [46]. Furthermore, although successful in vivo animal experiments do not necessarily predict clinical efficacy, they are of interest for developing embolic agents given the physicochemical similarities between experimental animals and humans [17,47].
Animal experimentation has a number of drawbacks. First, sophisticated and costly tools that are appropriate for the species that is used are needed. Moreover, all in vivo imaging studies and interventions require controlled analgesia and monitoring in an accredited laboratory. The relevance of the experiment to everyday clinical practice must be demonstrated before starting the study. Thus, financial and ethical limitations are substantial obstacles to conducting in vivo animal studies.
Cyanoacrylate is emerging as an effective agent for permanent embolization, with a low rate of recanalization [10,36,48]. Many studies have established that cyanoacrylate glues have a broad spectrum of indications, ranging from skin-wound closure to the treatment of varicose veins [49,50]. The low viscosity of cyanoacrylate that allows for injection through a microcatheter is among the main features of considerable interest for endovascular applications [17]. Furthermore, the low viscosity allows the embolization of small distal arteries beyond the reach of the microcatheter tip. Moreover, the rapid polymerization of cyanoacrylate results in a smaller radiation dose to the patient when angiographic guidance is used compared to the use of particulate or solid embolization devices, such as plugs or coils.
The effects of cyanoacrylate glues on body tissues have been extensively studied. The deposition of cyanoacrylate within a vessel results in an acute inflammatory reaction in the wall and surrounding tissues. This progresses to a chronic and granulomatous process after approximately one month, with foreign body giant cells and fibrosis. Several studies from this review provided interesting histopathologic considerations that are listed in Table 4.
The main challenge in using cyanoacrylate results from the fast polymerization, which is linked to the multiple reactions involved, including initiation and propagation phases. The low viscosity may increase the risk of reflux with non-target embolization. Finally, cyanoacrylate is radiolucent. In vitro and in vivo studies have been performed to modulate polymerization, for instance, by adding glacial acetic acid [39,43,51], to induce radio-opacity by adding tantalum powder or a contrast agent [26,52], or to decrease vessel adhesivity by adding absolute ethanol [53]. In vivo assessments can help to understand the mechanisms underlying cyanoacrylate polymerization. They are also performed to characterize new liquid embolic agents, such as precipitating hydrophobic injectable liquid (PHIL®, Culpan Medical, Victoria, Australia) or ethylene–vinyl alcohol copolymer (EVOH and tantalum, Squid®, Emboflu, Gland, Switzerland) [54].
We focused on studies of non-modified arteries, which are more reliable for characterizing polymerization and for designing models of ischemia. Recent studies chiefly used rabbits and swine for both ethical and financial reasons. Swine have interesting resemblances to humans in terms of vessel diameter, hemodynamics, and coagulation [55]. The main drawbacks are the need for dedicated instruments to perform the procedure and the fairly high cost of these large animals. Rabbits are available in most preclinical laboratories and exhibit blood-clotting properties similar to those of humans, although other characteristics show greater differences compared to swine. Rabbit models are less costly and seem to allow medium- to long-term follow-up [43,56]. Canine models are intermediate between swine and rabbits regarding vessel diameter, coagulation properties, and cost. However, the use of dogs has declined over time, probably due to changes in basic science practices. It is worth noting that animal models of non-modified arteries have also been used to test new tools, such as new types of microcatheters [23].
The cyanoacrylate glue most widely used today for endovascular interventions is Histoacryl®, i.e., NBCA, with Lipiodol as the radio-opaque agent. This probably explains why most of the recent preclinical studies were completed with Histoacryl®. The two countries with the largest number of publications on Histoacryl® identified by our search are the USA and Japan, where this product has been widely available for many years. Bucrylate®, or isobutyl 2-cyanoacrylate, was used more often in the 1990s, before studies showed that Histoacryl® (NBCA) had a better safety profile, with notably less inflammation and greater tensile strength [22,57,58]. Glubran® 2, composed of NBCA mixed with the monomer metacryloxysulfolane, was the first cyanoacrylate to receive the EC mark for endovascular use. Although Glubran® 2 is commonly used in Europe for endovascular interventions, it was used in a single animal study identified by our review, with promising results [36].
The tools needed for endovascular interventions using cyanoacrylates vary according to the model used. For instance, narrower introducers are needed for rats and rabbits than for dogs, swine, and primates. Furthermore, the microcatheter, particularly the external diameter of the distal tip, must be appropriate not only for the animal species but also for the embolization site. Our review showed that the renal arteries were most often used in animal studies of cyanoacrylates. Obvious technical reasons explain this preference. Furthermore, the terminal vascularization of the kidneys allows the target embolization of a theoretically restricted area devoid of anastomoses, with better tolerance of the resulting ischemia compared to other organs. These characteristics allow for the monitoring of the vascular reaction over time, which typically consists of acute local inflammation followed by a foreign-body giant-cell reaction and fibrosis [26,59].

5. Conclusions

We aimed to provide an exhaustive review of the preclinical animal experiments that used cyanoacrylates for endovascular interventions on non-modified arteries. We assessed the study designs, models, and endovascular procedures performed. Such studies are scarce compared to studies of embolic agents in general, and most of them used Histoacryl® or Bucrylate®. Canine, rabbit, and swine models predominated, and the renal arteries were by far the most common embolization site.
Additional work is needed to better understand the mechanism of action of liquid cyanoacrylate glues that are used for endovascular interventions.

Author Contributions

Conceptualization, K.G. and R.L.; Methodology, K.G., P.-O.C. and R.L.; Software, K.G. and O.C.; Validation, O.C. and R.L.; Formal analysis, A.-V.S.; Investigation, K.G. and P.-O.C.; Resources, O.C.; Data curation, K.G.; Writing—original draft preparation, K.G., P.-O.C., O.C., A.-V.S. and R.L.; Writing—review and editing, K.G., P.-O.C., O.C., A.-V.S. and R.L.; Visualization, R.L.; Supervision, R.L.; Project administration, K.G.; Funding acquisition, O.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded solely by institutional and departmental resources: no external funding was used.

Institutional Review Board Statement

Ethical review and approval were waived for this study, as it consisted in the retrospective assessment of experimental data for a review article.

Informed Consent Statement

Not applicable since this study did not involve humans.

Data Availability Statement

All the study data are reported in this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Biomedicines 09 01282 g001 550
Figure 1. Flow chart. WOS, Web of Science; AVM, arteriovenous malformation.
Figure 1. Flow chart. WOS, Web of Science; AVM, arteriovenous malformation.
Biomedicines 09 01282 g001
Biomedicines 09 01282 g002 550
Figure 2. Percentage of studies identified during consecutive 8-year periods from 1972 to 2020.
Figure 2. Percentage of studies identified during consecutive 8-year periods from 1972 to 2020.
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Biomedicines 09 01282 g003 550
Figure 3. Geographical distribution of the first authors of the included studies (graphic indicates the number of publications of each country).
Figure 3. Geographical distribution of the first authors of the included studies (graphic indicates the number of publications of each country).
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Biomedicines 09 01282 g004 550
Figure 4. Percentages of studies that used each embolization site; the denominator was the total number of studies with quantitative data (n = 36).
Figure 4. Percentages of studies that used each embolization site; the denominator was the total number of studies with quantitative data (n = 36).
Biomedicines 09 01282 g004
Table
Table 1. Quantitative data from studies of dog models.
Table 1. Quantitative data from studies of dog models.
Cyanoacrylate
Glue Used		Radiopaque AgentOther ComponentsAbsolute Cyanoacrylate Concentration (%)Amount (mL)Embolization SiteMicrocatheter Distal Tip-External Diameter (French)Introducer Size
(French)		AuthorsPublication Year
Commercial cyanoacrylateNoneNone0.960.05Superior cerebral artery and anterior communicating arteryDPDPGuo et al. [13]1995
Histoacryl® (NBCA)Ethiodized oilTantalum powder0.17–0.330.5–1Coronary arteryNR7.0Matos et al. [14]2005
Histoacryl® (NBCA)LipiodolNone0.250.1–0.3Superior mesenteric artery3.05.0Jae et al. [15]2008
Bucrylate® (IBCA)Tantalum powder aloneNone10.3–0.5Left gastric artery, gastroduodenal artery, inferior pancreatico-duodenal artery, and branches of the superior mesenteric artery3.06.7Dotter et al. [16]1975
Histoacryl® (NBCA)LipiodolNone0.1–0.50.43Renal artery2.08.0Takasawa et al. [17]2012
Bucrylate® (IBCA)Iophendylate oilNone0.5NRRenal arteryDPDPCromwell et al. [18]1986
Bucrylate® (IBCA)Iophendylate oilTantalum powder, Glacial acetic acid0.75NRRenal artery and polar arteries3.6–4.27.0Spiegel et al. [19]1986
Bucrylate® (IBCA)Tantalum powder aloneWith or without nitrocellulose0.96–14–5.4Renal artery3.05.0Sadato et al. [20]2000
Histoacryl® (NBCA)Lipiodol, Urogranoic acidNone0.33–0.70.5-2Renal artery and polar arteries3.0DISzmigielski et al. [21]1981
Histoacryl® (NBCA)Tantalum powder aloneNone0.11–0.26NRRenal artery3.6NROowaki et al. [22]2000
Bucrylate® (IBCA)NoneNone10.15Left renal artery1.5–2.6NRZanetti et al. [8]1972
Bucrylate® (IBCA)Iophendylate oilTantalum powder0.75NRBranch of renal artery, branch of external carotid artery, and vertebral artery3.6–4.27.0Debrun et al. [23]1982
Bucrylate® (IBCA)Iophendylate oilNone0.5NRRenal and visceral arteries1.06.5Khangure et al. [24]1981
Bucrylate® (IBCA)Iophendylate oilTantalum powder0.750.13Renal artery, splenic artery, and anterior spinal artery via the vertebral artery3.04.1–5.0ApSimon et al. [25]1984
Histoacryl® (NBCA)Iophendylate oil, LipiodolNone0.2–0.5NRRenal artery, intercostal and lumbar arteries, vertebral arteries, and superior mesenteric arteryNR5.0Stoesslein et al. [26]1982
NR, not reported; DP, direct puncture of the target artery; DI, direct insertion of the microcatheter without using an introducer; IBCA, iso-butyl cyanoacrylate; NBCA, N-butyl-cyanoacrylate.
Table
Table 2. Quantitative data from studies of swine models.
Table 2. Quantitative data from studies of swine models.
Cyanoacrylate
Glue Used		Radioopaque AgentOther ComponentsAbsolute Cyanoacrylate Concentration (%)Amount
(mL)		Embolization SiteMicrocatheter Distal Tip-External Diameter (French)Introducer Size (French)AuthorsPublication Year
Alpha-hexil-cyanoacrylateLipiodolNone0.33NRRenal artery and polar arteries (ascending pharyngeal artery and rete mirabile)2.46.0Izaaryene et al. [27]2016
Histoacryl® (NBCA)LipiodolNone0.5NRCommon hepatic artery and internal inguinal artery2.25.0Tanaka et al. [28]2015
Histoacryl® (NBCA)LipiodolNone0.50.3–0.7Intercostal artery2.74.0Hamaguchi et al. [29]2015
Histoacryl® (NBCA)LipiodolNone0.670.5Superior mesenteric artery or one of its main branches2.96.0Bruhn et al. [30]2013
Histoacryl® (NBCA)LipiodolNone0.13–0.50.11–0.16Uterine artery2.24.0Sonomura et al. [31]2013
Histoacryl® (NBCA)LipiodolNone0.5–0.10.67Dorsal pancreatic artery2.15.0Okada et al. [32]2012
Histoacryl® (NBCA)LipiodolNone0.1250.2Bronchial artery2.54.0Tanaka et al. [33]2012
Histoacryl® (NBCA)LipiodolNone0.20.1–0.4Sigmoid-rectal branch artery, right colic branch, and middle colic branch2.55.0Ikoma et al. [34]2010
Histoacryl® (NBCA)LipiodolNone0.17NRRenal and splenic arteries2.55.0Yonemitsu et al. [35]2010
Histoacryl® (NBCA)LipiodolNone0.5–0.220.2Renal arterial branches and ascending pharyngeal artery2.0–2.65.0Levrier et al. [36]2003
Histoacryl® (NBCA)LipiodolNone0.55Superior mesenteric artery3.08.0Klein et al. [37]1996
Avacryl® (NBCA)Iophendylate oilNone0.2–0.50.2–0.05Renal artery, hepatic artery, gastro-splenic artery, internal iliac artery, gluteal artery, posterior and anterior deep femoral arteries, popliteal artery, anterior tibial artery, and jejunal artery3.07.0Widlus et al. [38]1992
Histoacryl® (NBCA)Iophendylate oilGlacial acetic acid0.50–0.750.15Internal carotid artery (rete mirabile)4.15.0Brothers et al. [39]1989
Bucrylate® (IBCA)Tantalum powder aloneTantalum powder0.13.3Internal iliac artery3.57.0Miller et al. [40]1978
NR, not reported; IBCA, iso-butyl cyanoacrylate; NBCA, N-butyl-cyanoacrylate.
Table
Table 3. Quantitative data from studies of rabbit models.
Table 3. Quantitative data from studies of rabbit models.
Cyanoacrylate Glue UsedRadiopaque AgentOther ComponentsAbsolute Cyanoacrylate Concentration (%)Amount
(mL)		Embolization SiteMicrocatheter Distal Tip-External Diameter (French)Introducer Size (French)AuthorsPublication Year
Histoacryl® (NBCA)LipiodolNone0.50.1–0.2Femoral arteryDPDPWang et al. [41]2006
Histoacryl® (NBCA)Iobenzene esterNone0.50.2–0.3Right carotid artery2.0–2.7DIShi et al. [42]2002
Histoacryl® (NBCA)LipiodolGlacial acetic acid0.2–0.5NRSubclavian and femoral arteries1.8–2.74.0Gounis et al. [43]2002
Histoacryl® (NBCA)EthiodolEthiodol0.5–0.20.2Renal artery2.7DISadato et al. [20]2000
Isostearyl-2-cyanoacrylate (derived from IBCA), Histoacryl® (NBCA)LipiodolNone0.50.5Renal artery1.5NROowaki et al. [22]1999
Bucrylate® (IBCA)Tantalum powder aloneWith or without nitrocellulose0.96–0.990.4–0.8Renal artery3.0DISalomonowitz et al. [44]1983
Histoacryl® (NBCA)Tantalum powder aloneNone0.11–0.25NRRenal artery3.0–3.6NRGünther et al. [45]1978
NR, not reported; DP, direct puncture of the target artery; DI, direct insertion of the microcatheter without using an introducer; IBCA, iso-butyl cyanoacrylate; NBCA, N-butyl-cyanoacrylate.
Table
Table 4. Main histopathologic findings from studies of animal models [3,4,5,6,8,13,14,15,17,27,28,29,32,33,34,35,36,39,40,41,45,46,57,59].
Table 4. Main histopathologic findings from studies of animal models [3,4,5,6,8,13,14,15,17,27,28,29,32,33,34,35,36,39,40,41,45,46,57,59].
Histopathologic
Findings		Minimal Delay between Embolization and Description (Days)Animal
Models
Sponge-like matrix with entrapped erythrocytes in its interstices1Swine, dog, rabbit
Desquamation of adjacent to the endothelial cells1Swine, dog
Infiltration of neutrophils into the adventitial layer1Dog
Infiltration of neutrophils into the intermediate layer2Swine, rat
Hyperplasia of adjacent elastic fibrils7Dog
Foreign body giant cells adjacent to the polymer7Swine, dog, rabbit, rat
Tissue necrosis7Swine, dog, rabbit, rat
Infarcted region calcification21Rabbit
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Guillen, K.; Comby, P.-O.; Chevallier, O.; Salsac, A.-V.; Loffroy, R. In Vivo Experimental Endovascular Uses of Cyanoacrylate in Non-Modified Arteries: A Systematic Review. Biomedicines 2021, 9, 1282. https://doi.org/10.3390/biomedicines9091282

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Guillen K, Comby P-O, Chevallier O, Salsac A-V, Loffroy R. In Vivo Experimental Endovascular Uses of Cyanoacrylate in Non-Modified Arteries: A Systematic Review. Biomedicines. 2021; 9(9):1282. https://doi.org/10.3390/biomedicines9091282

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Guillen, Kévin, Pierre-Olivier Comby, Olivier Chevallier, Anne-Virginie Salsac, and Romaric Loffroy. 2021. "In Vivo Experimental Endovascular Uses of Cyanoacrylate in Non-Modified Arteries: A Systematic Review" Biomedicines 9, no. 9: 1282. https://doi.org/10.3390/biomedicines9091282

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