Material Requirements for Therapeutic Embolization of Intracranial Vascular Malformations
The last of a three-part series on diagnosing, treating, and researching management options for intracranial malformations.
Definitive treatment of vascular malformations often requires surgery or radiosurgery. Various embolization techniques, however, have come to enhance and, sometimes, replace surgical methods by occluding the lesions.1-5 Current trends in research are focused on refining imaging modalities to identify lesions earlier, to allow for close monitoring and risk stratification. In therapeutics, liquid embolics are being adapted to accommodate cerebrovascular anatomy and minimize unnecessary ischemic damage to neural tissue. Customization of catheters used in delivery of these embolics is also concurrently being done to optimize delivery. In the final section of this series, we elaborate on these developments in the management of cerebrovascular malformations.
TECHNOLOGIES IN RESEARCH
Collaborative efforts among researchers in neurosurgery, radiosurgery, vascular surgery, and neurology have significantly advanced our understanding of neuroendovascular intervention, particularly for arteriovenous malformations (AVMs), dural arteriovenous fistulas, and tumors. Imaging modalities such as CT scans and magnetic resonance imaging (MRI) continue to be highly utilized in detection and treatment of AVMs. The introduction of noninvasive and highly sensitive neuroimaging devices such as MRI and CT angiography have resulted in earlier detection of unruptured cerebral lesions in patients and provides valuable information such as the topography and localization of an AVM.6,7 Through early detection, the morbidity and mortality associated with hemorrhage and stroke can be reduced. Vascularization of tumors and sites of rupture are assessed via angiography of the vessels, specifically neurovascular digital subtraction angiography and magnetic resonance angiography. Currently, it is highly recommended to obtain an MRI study and a four-vessel angiogram to examine the course and features of an AVM.7
The testing of new embolic agents, performed only in animal models in the past, is continuously being translated into the clinical setting. In general, the field has seen the development of novel materials that precipitate or augment blood coagulation and were initially tested in a variety of in vitro models.8,9 Typically, material characterization with rheology, microcatheter delivery, radiopacity, and cytocompatibility precede in vitro hemocompatibility evaluation.9-11 Subsequent to demonstration of safety in vitro, materials are then evaluated in simple embolization models to show occlusive potential. These include embolization of rabbit kidneys, swine rete mirabilia, and even creation of saccular aneurysms from adjacent vasculature.12-16 The first-inhuman clinical trials that typically followed identified a select number of potential materials that have suitable flow and catheter delivery characteristics, suitable carrier/ solvent systems that cause minimal toxicity, and safety with minimal nontarget side effects.17-22
Adjunct technologies have augmented the use and delivery of liquid embolics. For example, there have been major advances in catheter technology to aid in material delivery.23-29 Early microcatheters were unbraided and prone to distortion as they passed around sharp curves. Braided microcatheters with hydrophilic coatings were subsequently developed to increase tracking ability and convey resistance.30
Flow-directed microcatheters, which are braided except at the tip, have been invaluable for embolization of AVMs in the brain because they can advance into long feeders toward the site of embolization.31 However, the flow-directed catheters are limited by which embolic agents, particularly coils, can pass due to size restrictions.32 Microwires have similarly been optimized for use in embolization procedures.33 Catheter cerebral arteriography is commonly used to confirm the presence, size, and location of intracranial aneurysms.34 However, the wide variation in clinical presentation and low incidence of AVMs has been a major obstacle in developing diagnostic and therapeutic modalities.
From a materials and surgical perspective, achieving high biocompatibility and low immunogenicity of materials is imperative in the design of next-generation materials.35,36 An understanding of the human tissue response to embolization is essential in the development of successful embolic materials. Several liquid embolic agents that use a carrier solvent such as dimethyl sulfoxide, which is displaced to allow precipitation of the material, cause vasospasm, acute cytotoxicity, and potential necrosis.28,37-40 However, much is still unknown about in vivo reactions to embolic agents, including long-term consequences for both AVMs and various tumors.28,41 The delicate balance that is maintained between sufficient embolization to prevent recanalization and overfilling to prevent inadvertent end-organ embolization is a constant challenge.42 Although these therapeutic modalities have come a long way, the full benefit can only be extracted through increased collaborative efforts between the material scientists and surgeons.
This final article of a three-part series on cerebral AVMs and dural arteriovenous fistulas aimed to summarize the technologies under development and what novel therapies are being developed. With technological advances, further interdisciplinary collaboration between material scientists, physicians, and surgical specialists will pave the way for clinical applicability and ultimately improve patient outcomes. This concludes a review on our understanding of cerebrovascular lesions, current treatment paradigms, and anticipated developments in research.
Ravi R. Vissapragada, MD, is with the Department of Surgery, Tufts Medical Center in Boston, Massachusetts. He has stated that he has no financial interests related to this article.
Vivek A. Kumar, PhD, is with the Department of Chemistry, Rice University in Houston, Texas. He has stated that he has no financial interests related to this article. Dr. Kumar may be reached at firstname.lastname@example.org.
Omar F. Merchant, MD, is with Baylor College of Medicine in Houston, Texas. He has stated that he has no financial interests related to this article.
Lyahn K. Hwang, BS, is with the University of Texas Southwestern Medical School in Dallas, Texas. She has stated that she has no financial interests related to this article.
Matthew R. Fusco, MD, is with the Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts. He has stated that he has no financial interests related to this article.
Christopher S. Ogilvy, MD, is with the Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts. He has stated that he has no financial interests related to this article.
Ajith J. Thomas, MD, is with the Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts. He has disclosed that he is on the data safety monitoring board for Boston Biomedical Associates. Dr. Thomas may be reached at email@example.com; (617) 632- 9785.
- Katsaridis V, Papagiannaki C, Aimar E. Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology. 2008;50:589-597.
- Jayaraman MV, Marcellus ML, Hamilton S, et al. Neurologic complications of arteriovenous malformation embolization using liquid embolic agents. AJNR Am J Neuroradiol. 2008;29:242-246.
- Howington JU, Kerber CW, Hopkins LN. Liquid embolic agents in the treatment of intracranial arteriovenous malformations. Neurosurg Clin N Am. 2005;16:355-363, ix-x.
- Terada T, Nakamura Y, Tsuura M, et al. Embolization of arteriovenous malformations with peripheral aneurysms using ethylene vinyl alcohol copolymer. Report of three cases. J Neurosurg. 1991;75:655-660.
- Fournier D, TerBrugge KG, Willinsky R, et al. Endovascular treatment of intracerebral arteriovenous malformations: experience in 49 cases. J Neurosurg. 1991;75:228-233.
- UCAS Japan Investigators, Morita A, Kirino T, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med. 2012;366:2474-2482.
- Ogilvy CS, Stieg PE, Awad I, et al; Stroke Council, American Stroke Association. Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Circulation. 2001;103: 2644-2657.
- Takasawa C, Seiji K, Matsunaga K, et al. Properties of N-butyl cyanoacrylate-iodized oil mixtures for arterial embolization: in vitro and in vivo experiments. J Vasc Interv Radiol. 2012;23:1215-1221.
- Horak D, Sitnikov A, Guseinov E, et al. Poly(HEMA)–based embolic material in endovascular surgery of liver. Polim Med. 2002;32:48-62.
- Jeynes BJ, Gunnlaugson B. Assessment, in vitro, of the thrombogenicity of embolic homologous arterial thrombus material and of cholesterol crystals. Artery. 1983;12:156-169.
- Sharma KV, Dreher MR, Tang Y, et al. Development of “imageable” beads for transcatheter embolotherapy. J Vasc Interv Radiol. 2010;21:865-876.
- Haussen DC, Ashour R, Johnson JN, et al. Direct continuous measurement of draining vein pressure during Onyx embolization in a swine arteriovenous malformation model. J Neurointerv Surg. 2015;7:62
- Arakawa H, Murayama Y, Davis CR, et al. Endovascular embolization of the swine rete mirabile with Eudragit-E 100 polymer. AJNR Am J Neuroradiol. 2007;28: 1191-1196.
- Becker TA, Preul MC, Bichard WD, et al. Calcium alginate gel as a biocompatible material for endovascular arteriovenous malformation embolization: six-month results in an animal model. Neurosurgery. 2005;56:793- 801; discussion 793-801.
- Becker TA, Kipke DR, Preul MC, et al. In vivo assessment of calcium alginate gel for endovascular embolization of a cerebral arteriovenous malformation model using the Swine rete mirabile. Neurosurgery. 2002;51:453-458; discussion 458-459.
- Gobin YP, Vinuela F, Vinters HV, et al. Embolization with radiopaque microbeads of polyacrylonitrile hydrogel: evaluation in swine. Radiology. 2000;214:113-119.
- Makower D, Rozenblit A, Kaufman H, et al. Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res. 2003;9:693-702.
- Hecht JR, Bedford R, Abbruzzese JL, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res. 2003;9:555- 561.
- Pelz DM. Advances in interventional neuroradiology. Stroke. 2003;34:357-358.
- Cohen EE, Rudin CM. ONYX-015. Onyx pharmaceuticals. Curr Opin Investig Drugs. 2001;2:1770-1775.
- Ries S, Korn WM. ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer. 2002;86:5-11.
- Tolleson TR, Harrington RA. Recent clinical trials in acute coronary syndromes without persistent ST elevation. Curr Opin Cardiol. 1999;14:403-411.
- Park S, Hwang SM, Lim OK, et al. Compliant neurovascular balloon catheters may not be compatible with liquid embolic materials: intraprocedural rupture of the protecting balloon during tumor embolization using n-butyl cyanoacrylate and lipiodol mixture. J Neurointerv Surg. 2014. doi: 10.1136/neurintsurg-2014-011331. [Epub ahead of print]
- Zhao LB, Shim JH, Lee DG, Suh DC. Two microcatheter technique for embolization of arteriovenous fistula with liquid embolic agent. Neurointervention 2014;9:32-38.
- Bearat HH, Preul MC, Vernon BL. Cytotoxicity, in vitro models and preliminary in vivo study of dual physical and chemical gels for endovascular embolization of cerebral aneurysms. J Biomed Mater Res A. 2013;101:2515- 2525.
- Simon SD, Reig AS, Archer KJ, Mericle RA. Biomechanical attributes of microcatheters used in liquid embolization of intracranial aneurysms. J Neurointerv Surg. 2012;4:211-214.
- Vanninen RL, Manninen I. Onyx, a new liquid embolic material for peripheral interventions: preliminary experience in aneurysm, pseudoaneurysm, and pulmonary arteriovenous malformation embolization. Cardiovasc Intervent Radiol. 2007;30:196-200.
- Kerber CW, Wong W. Liquid acrylic adhesive agents in interventional neuroradiology. Neurosurg Clin N Am. 2000;11:85-99, viii-ix.
- Eberhart RC, Clagett CP. Catheter coatings, blood flow, and biocompatibility. Semin Hematol. 1991;28:42- 48; discussion 66-48.
- Gudino N, Heilman JA, Derakhshan JJ, et al. Control of intravascular catheters using an array of active steering coils. Med Phys. 2011;38:4215-4224.
- Carey J, Fahim A, Munro M. Design of braided composite cardiovascular catheters based on required axial, flexural, and torsional rigidities. J Biomed Mater Res B Appl Biomater. 2004;70:73-81.
- Abe T, Hirohata M, Tanaka N, et al. Distal-tip shape-consistency testing of steam-shaped microcatheters suitable for cerebral aneurysm coil placement. AJNR Am J Neuroradiol. 2004;25:1058-1061.
- Krysl J, Kumpe DA. Embolization agents: a review. Tech Vasc Interv Radiol. 2000;3:158-161.
- Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103-110.
- Grundfest-Broniatowski S. What would surgeons like from materials scientists? Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013;5:299-319.
- Palmaz JC. New advances in endovascular technology. Tex Heart Inst J. 1997;24: 156-159.
- Chaloupka JC, Huddle DC, Alderman J, et al. A reexamination of the angiotoxicity of superselective injection of DMSO in the swine rete embolization model. AJNR Am J Neuroradiol. 1999;20:401-410.
- Mottu F, Gailloud P, Massuelle D, et al. In vitro assessment of new embolic liquids prepared from preformed polymers and water-miscible solvents for aneurysm treatment. Biomaterials. 2000;21:803-811.
- Sugiu K, Kinugasa K, Mandai S, et al. Direct thrombosis of experimental aneurysms with cellulose acetate polymer (CAP): technical aspects, angiographic follow up, and histological study. J Neurosurg. 1995;83:531- 538.
- Nitsch A, Pabyk A, Honig JF, et al. Cellular, histomorphologic, and clinical characteristics of a new octyl- 2-cyanoacrylate skin adhesive. Aesthetic Plast Surg. 2005;29:53-58.
- Laurent A. Materials and biomaterials for interventional radiology. Biomed Pharmacother. 1998;52:76-88.
- Guo WY, Karlsson B, Ericson K, Lindqvist M. Even the smallest remnant of an AVM constitutes a risk of further bleeding. Case report. Acta Neurochir (Wien). 1993;121:212-215.