Arteriovenous Malformation Model Research Articles

A Microsurgical Arteriovenous Malformation Model on Saphenous Vessels in the Rat.

Arteriovenous malformation (AVM) is an anomaly of blood vessel formation. Numerous models have been established to understand the nature of AVM. These models have limitations in terms of the diameter of the vessels used and the impact on the circulatory system. Our goal was to establish an AVM model that does not cause prompt and significant hemodynamic and cardiac alterations but is feasible for follow-up of the AVM's progression. Sixteen female rats were randomly divided into sham-operated and AVM groups. In the AVM group, the saphenous vein and artery were interconnected using microsurgical techniques. The animals were followed up for 12 weeks. Anastomosis patency and the structural and hemodynamic changes of the heart were monitored. The hearts and vessels were histologically analyzed. During the follow-up period, shunts remained unobstructed. Systolic, diastolic, mean arterial pressure, and heart rate values slightly and non-significantly decreased in the AVM group. Echocardiogram results indicated minor systolic function impact, with slight and insignificant changes in aortic pressure and blood velocity, and minimal left ventricular wall enlargement. The small-caliber saphenous AVM model does not cause acute hemodynamic changes. Moderate but progressive alterations and venous dilatation confirmed AVM-like features. The model seems to be suitable for studying further the progression, enlargement, or destabilization of AVM.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice.

Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

Experimental investigation of transvenous embolization of arteriovenous malformations using different in vivo models

BackgroundTransvenous embolization (TVE) is an emerging technique for the endovascular treatment of cerebral arteriovenous malformations (AVMs). The aim of this study was to investigate two in vivo AVM models and...

Comparison of embolization strategies for mixed plexiform and fistulous brain arteriovenous malformations: a computational model analysis of theoretical risks of nidus rupture

BackgroundHigh-flow fistulas related to plexiform nidi are found in 40% of large brain arteriovenous malformations (AVMs). Endovascular occlusion of intranidal fistulas before plexiform components is empirically considered safe, but potential...

P.191 Development and Testing of a Novel Hydrogel Embolization Treatment for Neurovascular Diseases: Preliminary Animal Results

Background: Embolization represents a minimally invasive treatment modality for arteriovenous malformations (AVMs), tumors, aneurysms, and vessel sacrifice, but can be limited by currently available embolization agents. Discovery of new and improved agents could lead to better treatment outcomes. The goal of this project was to develop and test a novel embolization agent using hydrogels, a class of materials which may be bioengineered to suit a variety of indications. Methods: We devised a method of liquid hydrogel embolization with photo-modulated crosslinking for intravascular solidification, using a custom microcatheter set-up. We tested this in swine blood vessels (n=3), the swine renal arterial trees as a vascular tumor model (n=5), and the swine arterial-arterial networks of the rete mirabile as an AVM model (n=3). Hydrogel embolization was assessed for treatment efficacy and safety. Follow-up angiography was performed at 2-4 week intervals. Results: Hydrogel embolization was technically successful in all animals, with full occlusion of the vascular target immediately following embolization and at follow-up. There were no instances of clinical or angiographic complications. Conclusions: We demonstrated a novel method of dynamic photomodulation and delivery of bioengineered hydrogels to address current limitations of endovascular embolization therapies. This promising technology will be investigated further with longer-term comparative animal trials.

Iterative Metal Artifact Reduction (iMAR) of the Non-adhesive Liquid Embolic Agent Onyx in Computed Tomography

BackgroundA drawback of Onyx, one of the most used embolic agents for endovascular embolization of intracranial arteriovenous malformations (AVM), is the generation of imaging artifacts (IA) in computed tomography (CT). Since these artifacts can represent an obstacle for the detection of periprocedural bleeding, this study investigated the effect of artifact reduction by an iterative metal artifact reduction (iMAR) software in CT in a brain phantom.MethodsTwo different in vitro models with two-dimensional tube and three-dimensional AVM-like configuration were filled with Onyx 18. The models were inserted into a brain imaging phantom and images with (n = 5) and without (n = 10) an experimental hemorrhage adjacent were acquired. Afterwards, the iMAR algorithm was applied for artifact reduction. The IAs of the original and the post-processed images were graded quantitatively and qualitatively. Moreover, qualitative definition of the experimental hemorrhage was investigated.ResultsComparing the IAs of the original and the post-processed CT images, quantitative and qualitative analysis showed a lower degree of IAs in the post-processed images, i.e. quantitative analysis: 2D tube model: 23.92 ± 8.02 Hounsfield units (HU; no iMAR; mean ± standard deviation) vs. 5.93 ± 0.43 HU (with iMAR; p < 0.001); qualitative analysis: 3D AVM model: 4.93 ± 0.18 vs. 3.40 ± 0.48 (p < 0.001). Furthermore, definition of the experimental hemorrhage was better in the post-processed images of both in vitro models (2D tube model: p = 0.004; 3D AVM model: p = 0.002).ConclusionThe iMAR algorithm can significantly reduce the IAs evoked by Onyx 18 in CT. Applying iMAR could thus improve the accuracy of postprocedural CT imaging after embolization with Onyx in clinical practice.

Additive Fabrication of a Vascular 3D Phantom for Stereotactic Radiosurgery of Arteriovenous Malformations.

In this study, an efficient methodology for manufacturing a realistic three-dimensional (3D) cerebrovascular phantom resembling a brain arteriovenous malformation (AVM) for applications in stereotactic radiosurgery is presented. The AVM vascular structure was 3D reconstructed from brain computed tomography (CT) data acquired from a patient. For the phantom fabrication, stereolithography was used to produce the AVM model and combined with silicone casting to mimic the brain parenchyma surrounding the vascular structure. This model was made with tissues-equivalent materials for radiology. The hollow vascular system of the phantom was filled with a contrast agent usually employed on patients for CT scans. The radiological response of the phantom was tested and compared with the one of the clinical case. The constructed model demonstrated to be a very accurate physical representation of the AVM and its vasculature and good morphological consistency was observed between the model and the patient-specific source anatomy. These results suggest that the proposed method has potential to be used to fabricate patient-specific phantoms for neurovascular radiosurgery applications and medical research.

Imaging Artifacts of Nonadhesive Liquid Embolic Agents in Conventional and Cone-beam CT in a\xa0Novel in Vitro AVM Model

BackgroundA major drawback of liquid embolic agents (LEAs) is the generation of imaging artifacts (IA), which may represent a crucial obstacle for the detection of periprocedural hemorrhage or subsequent radiosurgery of cerebral arteriovenous malformations (AVMs). This study aimed to compare the IAs of Onyx, Squid and PHIL in a novel three-dimensional in vitro AVM model in conventional computed tomography (CT) and cone-beam CT (CBCT).MethodsTubes with different diameters were configured in a container resembling an AVM with an artificial nidus at its center. Subsequently, the AVM models were filled with Onyx 18, Squid 18, PHIL 25% or saline and inserted into an imaging phantom (n = 10/LEA). Afterwards CT and CBCT scans were acquired. The degree of IAs was graded quantitatively (Hounsfield units in a defined region of interest) and qualitatively (feasibility of defining the nidus)—Onyx vs. Squid vs. PHIL vs. saline, respectively.ResultsQuantitative density evaluation demonstrated more artifacts for Onyx compared to Squid and PHIL, e.g. 48.15 ± 14.32 HU for Onyx vs. 7.56 ± 1.34 HU for PHIL in CT (p < 0.001) and 41.88 ± 7.22 density units (DU) for Squid vs. 35.22 ± 5.84 DU for PHIL in CBCT (p = 0.044). Qualitative analysis showed less artifacts for PHIL compared to Onyx and Squid in both imaging modalities while there was no difference between Onyx and Squid regarding the definition of the nidus (p > 0.999).ConclusionIn this novel three-dimensional in vitro AVM model, IAs were higher for the EVOH/tantalum-based LEAs Onyx and Squid compared to iodine-based PHIL. Onyx induced the highest degree of IAs with only minor differences to Squid.

Abstract P495: Aqua Embolic System: Evaluating the Performance of a New Liquid Embolic System Using a Swine AVM Model

Introduction: Liquid embolic material (LEM) plays an essential role in the treatment of hemorrhagic stroke caused by vascular malformation such as arteriovenous malformations (AVMs). However, currently available non-adhesive LEMs has the problem of catheter entrapment, and also known to have cytotoxicity due to the organic solvents such as Dimethyl Sulfoxide (DMSO). Aqua Embolic System (AES) is a new liquid embolic material, which is mainly composed of multiple polysaccharides. AES, when injected via a microcatheter, immediately forms a solid and elastic hydrogel cast upon exposure to Ca2+ in the bloodstream. The use of organic solvents, e.g., DMSO, is not required. The performance of AES was evaluated using an established AVM model utilizing swine rete-mirabile. Methods: Under general anesthesia, the left ascending pharyngeal artery (APA) of Yorkshire swine (40 kg) was catheterized using a microcatheter (ID:0.013 inches), and AES was slowly injected into the rete-mirabile under fluoroscopy. The following parameters were assessed to evaluate the embolization performance of the AES; 1) the amount of AES required for the complete occlusion of the feeding artery, 2) injection speed, 3) radiopacity during the deployment, and 4) incidence of catheter entrapment after the injection. The same evaluation was performed on the contralateral rete-mirabile and the left renal artery as well. Results: 12 arteries in 4 swine were treated, and all arteries were completely occluded without technical complications. The injected materials immediately formed AES cast in all vessels, followed by the reflux over the tip of the microcatheter. All catheters were withdrawn without any sign of catheter entrapment. The AES mixed with tantalum based contrasts medium showed sufficient radiopacity under fluoroscopy. With the injection speed of 0.02ml/sec, the average volume required was 0.85mL for the APA and 2.9mL for the renal artery. No increased thrombogenicity or vasospasm near the treated lesion was observed during the procedure. Conclusions: AES, which is a DMSO free, non-adhesive polysaccharides-based LEM, may be used as an embolic material for the treatment of hemorrhagic stroke caused by cerebrovascular diseases, such as brain AVM.

Simulation Model of Arteriovenous Malformation Embolization Using Onyx.

Although Onyx has made effective embolization possible in the endovascular treatment of arteriovenous malformation (AVM), its infusion requires a high level of skill and experience. The purpose of this study is to create a simulation model that will help to solve this technical issue. Using data of 3D DSA images of a clinical case, an acrylonitrile-butadiene-styrene (ABS) resin model of the AVM was created with a 3D printer. Then, a hollow elastic model was created by applying silicone and eluting the ABS resin, which was finally connected to the human vascular model. Simulation of angiography and Onyx embolization using the model showed similar angiographic features and flow dynamics of contrast media and Onyx. During Onyx embolization, the plug and push technique could be performed as in a clinical case. 3D AVM model created with 3D printer enabled us to stimulate Onyx embolization of AVM.

Combination of Alcohol and EVOH as a New Embolic Agent: Midterm Tissue and Inflammatory Effects in a Swine Model.

Objective To evaluate the vascular occlusion and midterm tissue toxicity properties of a combination of ethylene-vinyl alcohol (EVOH) (Squid 18®) (75%) and alcohol (25%)—Alco-Squid 18—in a swine model. Materials and Methods Alco-Squid 18 (75% Squid 18® mixed with 25% alcohol) (AS18) was compared to embolization with 96% alcohol alone and to embolization with Squid 18® (S18®) alone. An arteriovenous malformation (AVM) model was created in group 1 (n = 2). Each AVM model was then embolized with AS18 or S18® alone with evaluation of a ratio between the volume of embolic agent divided by the volume of the AVM (evaluated by CT). For group 2 (n = 5), each agent was tested on three different kidneys (upper pole kidney artery). Pre- and postinterventional CTs, angiographies, blood alcohol content dosages, and histological studies (3 months postintervention) were performed. Results AS18 has better distal distribution than S18® alone, both in the kidneys (mean capsule-S18® distance: 3.9 mm (±0.23) and mean capsule-AS18 distance: 2.3 mm (±0.11) (p=0.029) and in the AVM model. Histological exploration found a higher rate of tubular necrosis with AS18 compared with S18® alone and alcohol alone (3.78 ± 0.44 compared to 2.33 ± 1.22 (p = 0.012) and 1.22 ± 0.67 (p < 0 .0001)). The blood alcohol content was negligible in all cases. Conclusion AS18 can suggest a better distal sclerotic and embolic character as compared with S18® alone without systemic toxicity.

In Vitro Modeling of Human Brain Arteriovenous Malformation for Endovascular Simulation and Flow Analysis

Current invitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed invitro AVM model for embolic material testing, preclinical training, and flow analysis. Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI. The manufacture of 3D invitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the invitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis. An invitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials.

Abstract TP492: Novel in vitro Model of Arteriovenous Malformation for Endovascular Embolization and Flow Analysis

Introduction: 3D printed human vascular in vitro models of aneurysms and acute stroke have been utilized for training, simulation and device development. However, there are no realistic in vitro arteriovenous malformation (AVM) models. Current experimental models analyzing the efficacy of embolic materials or flow conditions are limited by their simplistic design, lacking complex AVM nidus anatomic features. The purpose of this study is to develop a new in vitro AVM model for embolic material testing and flow analysis. Methods: 3D images of the AVM nidus were extracted from 3D rotational angiography from a patient. Artificial feeders and drainers were added to the nidus and an inner vascular mold was printed using a 3D printer. The inner mold was coated with polydimethylsiloxanes. The inner plastic mold was removed by acetone, leaving a hollow AVM model. ONYX injection and 4DFlow MRI (Phase Contrast MRA) were performed using the AVM models. In addition, computational fluid dynamics (CFD) analysis was performed to compare flow rate with 4DFlow MRI. Results: An in vitro AVM model with realistic representation of nidus vasculature and complexity was successfully created. Liquid onyx injection performed in the in vitro model successfully replicated real-life treatment conditions. The model effectively simulated plug and push technique before penetration of the ONYX into the AVM nidus. 4DFlow MRI flow rates were similar to the CFD analysis. Conclusions: An in vitro AVM model using 3D printing technology was successfully created. The model demonstrated realistic pliability during ONYX injection. This in vitro AVM model may represent a useful tool for training and development of new materials, and have potential of highly-resolved flow quantifications.

Computational Network Modeling of Intranidal Hemodynamic Compartmentalization in a Theoretical Three-Dimensional Brain Arteriovenous Malformation.

There are currently no in vivo techniques to accurately study dynamic equilibrium of blood flow within separate regions (compartments) of a large brain arteriovenous malformation (AVM) nidus. A greater understanding of this AVM compartmentalization, even if theoretical, would be useful for optimal planning of endovascular and multimodal AVM therapies. We aimed to develop a biomathematical AVM model for theoretical investigations of intranidal regions of increased mean intravascular pressure (Pmean) and flow representing hemodynamic compartments, upon simulated AVM superselective angiography (SSA). We constructed an AVM model as a theoretical electrical circuit containing four arterial feeders (AF1–AF4) and a three-dimensional nidus of 97 interconnected plexiform and fistulous components. We simulated SSA by increases in Pmean in each AF (with and without occlusion of all other AFs), and then used network analysis to establish resulting increases in Pmean and flow within each nidus vessel. We analyzed shifts in hemodynamic compartments consequent to increasing AF injection pressures. SSA simulated by increases of 10 mm Hg in AF1, AF2, AF3, or AF4 resulted in dissipation of Pmean over 38, 66, 76, or 20% of the nidus, respectively, rising slightly with simultaneous occlusion of other AFs. We qualitatively analyzed shifting intranidal compartments consequent to varying injection pressures by mapping the hemodynamic changes onto the nidus network. Differences in extent of nidus filling upon SSA injections provide theoretical evidence that hemodynamic and angioarchitectural features help establish AVM nidus compartmentalization. This model based on a theoretical AVM will serve as a useful computational tool for further investigations of AVM embolotherapy strategies.

Large-scale ensemble simulations of biomathematical brain arteriovenous malformation models using graphics processing unit computation

BackgroundTheoretical modeling allows investigations of cerebral arteriovenous malformation (AVM) hemodynamics, but current models are too simple and not clinically representative. We developed a more realistic AVM model based on graphics processing unit (GPU) computing, to replicate highly variable and complex nidus angioarchitectures with vessel counts in the thousands—orders of magnitude greater than current models. MethodsWe constructed a theoretical electrical circuit AVM model with a nidus described by a stochastic block model (SBM) of 57 nodes and an average of 1000 plexiform and fistulous vessels. We sampled and individually simulated 10,000 distinct nidus morphologies from this SBM, constituting an ensemble simulation. We assigned appropriate biophysical values to all model vessels, and known values of mean intravascular pressure (Pmean) to extranidal vessels. We then used network analysis to calculate Pmean and volumetric flow rate within each nidus vessel, and mapped these values onto a graphic representation of the nidus network. We derived an expression for nidus rupture risk and conducted a model parameter sensitivity analysis. ResultsSimulations revealed a total intranidal volumetric blood flow ranging from 268 mL/min to 535 mL/min, with an average of 463 mL/min. The maximum percentage rupture risk among all vessels in the nidus ranged from 0% to 60%, with an average of 29%. ConclusionThis easy to implement biomathematical AVM model, allowed by parallel data processing using advanced GPU computing, will serve as a useful tool for theoretical investigations of AVM therapies and their hemodynamic sequelae.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

Contralateral Transfalcine Versus Ipsilateral Anterior Interhemispheric Approach for Midline Arteriovenous Malformations: Surgical and Anatomical Assessment

The contralateral anterior interhemispheric approach (CAIA) is considered to provide surgical advantages to access deep midline lesions: wider working angle, gravity enhanced dissection and retraction, more efficient lighting, and ergonomics. Our team has previously published on the merits of using a contralateral trajectory for medial frontoparietal arteriovenous malformations (AVMs) compared with the conventional anterior interhemispheric approach (IAIA). In this article, we compare the IAIA and CAIA for the resection of medial frontoparietal AVMs using quantitative surgical and anatomical analysis. Two models were designed mimicking the most common features of midline AVMs. The CAIA and IAIA were performed bilaterally in 10 specimens. Variables to compare technical feasibility (surgical window [SW] and surgical freedom [SF], target exposure, and angle of attack) were independently assessed using stereotactic navigation. The average SW, SF, and angle of attack were compared with the Student t test. Significance threshold was set at 0.05. The CITA and IAIA were similar in terms of SW, target exposure, and SF in the superior aspect of the AVM. In the depth of the interhemispheric fissure, the CAIA was significantly superior to IAIA in both AVM models: 77% wider AA for the inferior aspect of the AVM (P < 0.01) and greater SF for the draining vein (54%, P= 0.01), ipsilateral (98%, P= 0.02), and contralateral ACA (117%, P < 0.01). This study suggests technical superiority of the CAIA for the resection of deep midline AVMs. No objective difference was noted in the superficial areas of our models, denoting that IAIA is a safer choice for superficial AVMs. Our results set the foundation for further clinical analysis comparing both approaches.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Development of three-dimensional brain arteriovenous malformation model for patient communication and young neurosurgeon education

Purpose: Rapid prototyping technology is used to fabricate three-dimensional (3D) brain arteriovenous malformation (AVM) models and facilitate presurgical patient communication and medical education for young surgeons.Methods: Two intracranial AVM cases were selected for this study. Using 3D CT angiography or 3D rotational angiography images, the brain AVM models were reconstructed on personal computer and the rapid prototyping process was completed using a 3D printer. The size and morphology of the models were compared to brain digital subtraction arteriography of the same patients. 3D brain AVM models were used for preoperative patient communication and young neurosurgeon education.Results: Two brain AVM models were successfully produced. By neurosurgeons’ evaluation, the printed models have high fidelity with the actual brain AVM structures of the patients. The patient responded positively toward the brain AVM model specific to himself. Twenty surgical residents from residency programs tested the brain AVM models and provided positive feedback on their usefulness as educational tool and resemblance to real brain AVM structures.Conclusions: Patient-specific 3D printed models of brain AVM can be constructed with high fidelity. 3D printed brain AVM models are proved to be helpful in preoperative patient consultation, surgical planning and resident training.

In vivo imaging of endothelial cell adhesion molecule expression after radiosurgery in an animal model of arteriovenous malformation.

Focussed radiosurgery may provide a means of inducing molecular changes on the luminal surface of diseased endothelium to allow targeted delivery of novel therapeutic compounds. We investigated the potential of ionizing radiation to induce surface expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells (EC) in vitro and in vivo, to assess their suitability as vascular targets in irradiated arteriovenous malformations (AVMs). Cultured brain microvascular EC were irradiated by linear accelerator at single doses of 0, 5, 15 or 25 Gy and expression of ICAM-1 and VCAM-1 measured by qRT-PCR, Western, ELISA and immunocytochemistry. In vivo, near-infrared (NIR) fluorescence optical imaging using Xenolight 750-conjugated ICAM-1 or VCAM-1 antibodies examined luminal biodistribution over 84 days in a rat AVM model after Gamma Knife surgery at a single 15 Gy dose. ICAM-1 and VCAM-1 were minimally expressed on untreated EC in vitro. Doses of 15 and 25 Gy stimulated expression equally; 5 Gy was not different from the unirradiated. In vivo, normal vessels did not bind or retain the fluorescent probes, however binding was significant in AVM vessels. No additive increases in probe binding were found in response to radiosurgery at a dose of 15 Gy. In summary, radiation induces adhesion molecule expression in vitro but elevated baseline levels in AVM vessels precludes further induction in vivo. These molecules may be suitable targets in irradiated vessels without hemodynamic derangement, but not AVMs. These findings demonstrate the importance of using flow-modulated, pre-clinical animal models for validating candidate proteins for vascular targeting in irradiated AVMs.