Intravascular tissue reactions induced by various types of bioabsorbable polymeric materials: correlation between the degradation profiles and corresponding tissue reactions.

INTRODUCTION: Several different bioabsorbable polymeric coil materials are currently used with the goal of improving treatment outcomes of endovascular embolization of intracranial aneurysms. However, little is known about the correlation between polymer degradation profiles and concomitant tissue responses in a blood vessel. The authors describe in vitro degradation characteristics of nine different polymeric materials and their corresponding tissue responses induced in rabbit carotid arteries. METHODS: Mass loss and molecular weight loss of nine commercially available bioabsorbable sutures were evaluated in vitro up to16 weeks. The same nine materials, as well as platinum coils, were implanted into blind-end carotid arteries (n = 44) in rabbits, and their tissue reactions were evaluated histologically 14 days after the implantation. RESULTS: Five of the nine polymers elicited moderate to strong tissue reactions relative to the remaining materials. While polymer mass loss did not correlate with their histologic findings, polymers that showed a faster rate of molecular weight loss had a tendency to present more active tissue reactions such as strong fibrocellular response around the implanted material with a moderate inflammatory cell infiltration. Maxon exhibited the fastest rate of molecular weight loss and poly-l-lactic acid the slowest. CONCLUSIONS: The rate of molecular weight loss may be an important factor that is associated with the degree of bioactivity when bioabsorbable polymers are implanted into blood vessels. For further quantitative analysis, additional experiments utilizing established aneurysm models need to be conducted.

Complete Obliteration of a Foramen Magnum Dural Arteriovenous Fistula by Microsurgery After Failed Endovascular Treatment Using Onyx: Case Report and Literature Review.

BACKGROUND: Foramen magnum dural arteriovenous fistula (DAVF) is a rare disease, with some reported cases of successful treatment. We achieved complete obliteration of the foramen magnum DAVF through microsurgery after complications of endovascular embolization. We reviewed the treatment modalities and outcomes, focusing on pathologic and anatomic features from the literature. CASE DESCRIPTION: A 65-year-old man was admitted to our hospital with sudden diplopia. Magnetic resonance imaging revealed a subarachnoid hemorrhage around the right side of the prepontine cistern, and a foramen magnum DAVF was diagnosed by angiography. Subsequent angiography revealed that the fistula was supplied by the right neuromeningeal trunk of the ascending pharyngeal artery and the right posterior meningeal artery of the vertebral artery (VA), and the veins of the pouch via the fistula were retrogradely draining into the intracranial veins. We aimed to treat complete occlusion endovascularly with balloon-augmented transarterial Onyx injection via the posterior meningeal artery, but Onyx was refluxed to the VA through the anastomosis between the VA and posterior meningeal artery. Onyx subsequently migrated to the top of the basilar artery, causing occlusion, so we urgently removed the Onyx with a stent retriever (Trevo). Several weeks later, we performed complete obliteration of the foramen magnum DAVF via a lateral suboccipital approach with a C1 laminectomy. CONCLUSIONS: Most foramen magnum DAVFs were obliterated completely with only endovascular treatment. Microsurgery is an effective and reliable treatment for incomplete occlusion and complications.

Identification of Metal-Binding Peptides and Their Conjugation onto Nanoparticles of Superparamagnetic Iron Oxides and Liposomes.

Metallic materials are used for clinical medical devices such as vascular stents and coils to treat both ischemic and hemorrhagic vascular diseases. An antiplatelet drug is required to avoid thromboembolic complication until metallic surface is covered with a neo-endothelial cell layer. It is important to identify endothelial cell coverage on the metallic surface. However, it is difficult since there are no selective ligands. Here, we used the phage display method to identify peptide ligands that had high affinity for the metallic surface of Ni-Ti stents, Pt-W coils, and Co-Cr stents. The binding assay using fluorescence labeling revealed that several synthetic peptides could bind onto those surfaces. We also chose some oligopeptides for the conjugation onto superparamagnetic iron oxide (SPIO) nanoparticles and liposome-encapsulating SPIO nanoparticles and studied their ability to bind to the stent and coils. By SEM and fluorophotometry, we found that those modified SPIOs and liposomes were selectively bound onto those surfaces. In addition, both treated stents and coils could be detected by magnetic resonance imaging due to the magnetic artifact through the SPIOs and liposomes that were immobilized onto the surface. Thus, we identified metal-binding peptides which may enable to stop antiplatelet therapy after vascular stenting or coiling.

Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium.

Promising cell therapies using mesenchymal stem cells (MSCs) is proposed for stroke patients. Therefore, we aimed to efficiently accumulate human MSC (hMSC) to damaged brain area to improve the therapeutic effect using poly(ethylene glycol) (PEG)-conjugated phospholipid (PEG-lipid) carrying an oligopeptide as a ligand, specific for E-selectin which is upregulated on activated endothelial cells under hypoxia-like stroke. Here we synthesized E-selectin-binding oligopeptide (ES-bp) conjugated with PEG spacer having different molecular weights from 1 to 40 kDa. We found that ES-bp can be immobilized onto the hMSC surface through PEG-lipid without influence on cell growth and differentiation into adipocytes and osteocytes, respectively. It is also possible to control the immobilization of ES-bp on hMSC surface (<108 ES-bp per cell). Immobilized ES-bp can be continuously immobilized at the outside of cell membrane when PEG-lipids with PEG 5 and 40 kDa were used. In addition, the modified hMSC can specifically attach onto E-selectin-immobilized surface as a model surface of activated endothelium in human blood, indicating the sufficient number of immobilized ES-bp onto hMSC. Thus, this technique is one of the candidates for hMSC accumulation to cerebral infarction area. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1779-1792, 2019.

Thrombus organization and healing in an experimental aneurysm model. Part II. The effect of various types of bioactive bioabsorbable polymeric coils.

OBJECT: Bioabsorbable polymeric material coils are being used in the endovascular treatment of aneurysms to achieve better thrombus organization than is possible using bare platinum coils. We used immunohistochemical and molecular biological analysis techniques in experimental aneurysms implanted with three different bioabsorbable polymer coils and platinum coils. METHODS: The degradation kinetics of nine polymer candidates for further analysis were first analyzed in vitro, and three materials with different degradation rates were selected. Seventy-four aneurysms were created in 37 swine using the venous pouch technique. The aneurysms were surgically implanted with one of the materials as follows (time points = 3, 7, and 14 days): Group 1, Guglielmi detachable coils (platinum); Group 2, Polysorb (90:10 polyglycolic acid [PGA]/polylactic acid); Group 3, Maxon (PGA/trimethylene carbonate); and Group 4, poly-l-lactic acid. Histological, immunohistochemical, and cDNA microarray analyses were performed on tissue specimens. RESULTS: Groups 1 and 4 showed minimal inflammatory response adjacent to the coil mass. In Group 2, Polysorb elicited a unique, firm granulation tissue that accelerated intraaneurysmal thrombus organization. In Group 3 intermediate inflammatory reactions were seen. Microarray analysis with Expression Analysis Sytematic Explorer software showed functional-cluster-gene activation to be increased at Day 7, preceding the histologic manifestation of polymer-induced granulation tissue at Day 14. A profile of expression changes in cytokine-related and extracellular membrane-related genes was compiled. CONCLUSIONS: Degradation speed was not the only factor determining the strength of the biological response. Polysorb induced an early, unique granulation tissue that conferred greater mechanical strength to the intraaneurysmal coilthrombus complex. Enhancing the formation of this polymer-induced granulation tissue may provide a new direction for improving long-term anatomical outcomes in cases involving aneurysms embolized with detachable coils.

Initial clinical experience with matrix detachable coils for the treatment of intracranial aneurysms.

OBJECT: The Matrix detachable coil is a new bioactive, bioabsorbable coil used in the endovascular embolization of intracranial aneurysms. It has a platinum core covered with a bioactive, bioabsorbable polymer (polyglycolic acid/lactide). The authors report on their initial midterm clinical experience with the first-generation Matrix detachable coil. METHODS: One hundred twelve patients harboring 118 aneurysms were treated using Matrix coils. Forty-nine aneurysms (41.5%) were associated with acute subarachnoid hemorrhage (SAH). Twenty-four lesions (49%) were harbored by patients with Hunt and Hess Grade I, 11 (23.4%) by patients with Grade II, eight (16.3%) by those with Grade III, and six (12.2%) by those with Grade IV. Four aneurysms (3.4%) were harbored by patients who had presented with nonacute SAH. Sixty-five aneurysms (55%) were unruptured. Fifty-seven lesions (48.3%) were small with a small neck, 29 (24.6%) were small with a wide neck, 30 (25.4%) were large, and two (1.7%) were giant. All patients were followed up to obtain angiography and clinical outcome data. Technical complications occurred in six patients: two thromboembolic complications and four aneurysm perforations. Of these six patients, the status of two deteriorated because of aneurysm perforation and another two because of thrombus formation (morbidity 3.6%). There were five deaths--one due to rerupture after embolization. Angiography follow-up studies of 87 aneurysms were obtained. Seventy aneurysms demonstrated progressive occlusion or a stable neck (80.5%), and 17 had some degree of recanalization (19.5%). The aneurysms originally diagnosed as a neck remnant showed a 15% rate of recanalization. CONCLUSIONS: Matrix coils can be delivered into aneurysms with technical complications similar to those encountered using GDCs. Midterm anatomical outcomes to date have shown moderate improvement in the recanalization rate when compared with those realized using the GDC system. Because of the increased friction associated with the first-generation Matrix coil, the packing density in most aneurysms was less than that achieved with GDCs. Prolonged angiography follow-up evaluations are needed to document long-term efficacy.

Healing of intracranial aneurysms with bioactive coils.

Inadequate healing is an important mechanism for aneurysm development and recanalization after embolization. Matrix coils have been shown by experimental studies to enhance vascular repair and fibrosis, thus reducing the risk of recanalization. The clinical application of Matrix coils represents the transition from pure mechanical occlusion to adjunct biologic healing of aneurysms. Our preliminary clinical experience reveals evidence of a healing response in aneurysms treated with Matrix coils. This technology can be further improved through the incorporation of new knowledge on the molecular pathogenesis of aneurysms and the cellular and molecular mechanisms of healing.

Matrix and bioabsorbable polymeric coils accelerate healing of intracranial aneurysms: long-term experimental study.

BACKGROUND AND PURPOSE: Acceleration of intra-aneurysmal clot organization and fibrosis may be a solution to preventing aneurysm recanalization after endovascular treatment. The purpose of this study was to evaluate the short-term efficacy and long-term safety of the new Matrix coil system. METHODS: Matrix coils consist of thin platinum coils covered with a bioabsorbable, polymeric material (polyglycolic acid/lactide). Fifty-two experimental aneurysms were created in 26 swine. All of the aneurysms were tightly packed with Matrix or Guglielmi detachable coils (GDC). Comparative angiographic and histopathologic data were analyzed at 2 weeks (n=14), 3 months (n=6), and 6 months (n=6) after embolization. RESULTS: Three aneurysms treated with GDC ruptured despite tight packing. No recanalization or rupturing was observed in the aneurysms embolized with Matrix coils. At 14 days after embolization, the aneurysms treated with Matrix coils exhibited a more extensive area of organized thrombus when compared with the aneurysms treated with GDC (87% versus 75%, P=0.008, n=11). At 3 months, both Matrix and GDC-treated aneurysms demonstrated complete clot organization. Neck tissue thickness was higher in Matrix-treated aneurysms at 14 days and 3 months, but not at 6 months. No untoward parent artery stenosis was observed in aneurysms treated with Matrix during follow-up. The angiographic cross-sectional area of the Matrix-treated aneurysms was smaller than those treated with GDC at the 3 months. CONCLUSIONS: Matrix accelerated aneurysm fibrosis and neointima formation without parent artery stenosis. The Matrix system might prevent aneurysmal recanalization after endovascular treatment of cerebral aneurysms.

Cellular responses of bioabsorbable polymeric material and Guglielmi detachable coil in experimental aneurysms.

BACKGROUND AND PURPOSE: Acceleration of healing mechanisms is a promising approach to improve current limitations of endovascular aneurysm therapy with the use of platinum coils. We evaluated a new endovascular therapeutic, bioabsorbable polymeric material (BPM), which may promote cellular reaction in the aneurysms. METHODS: Four different concentrations of lactide/glycolic acid copolymer [poly(D-L-lactic-co-glycolic acid)] (PLGA), 85/15, 75/25, 65/35, and 50/50, were used as BPMs. Sixteen experimental aneurysms were created in 8 swine. Eight-millimeter-long spiral-shaped BPMs were surgically implanted in the aneurysms without tight packing (n=3 for each BPM). Guglielmi detachable coils (GDCs) were used as control (n=4). The animals were killed 14 days after embolization, and angiographic, histological, and immunohistochemical analyses were performed. RESULTS: Despite loose packing of aneurysms with BPMs, faster BPMs such as 50/50 or 65/35 PLGA demonstrated more mature collagen formation and fibrosis in the sac and neck of the aneurysm. One aneurysm treated with 65/35 PLGA, 1 treated with 75/25 PLGA, and all 3 treated with 85/15 PLGA showed a neck remnant on angiography. There was a linear relationship between collagen levels and polymer degradation properties (r=-0.9513). CONCLUSIONS: This preliminary animal study indicates that acceleration of aneurysm healing with the use of BPM is feasible. This concept can be applied to decrease and perhaps prevent aneurysmal recanalization after endovascular treatment of cerebral aneurysms.

Thermoreversible gelation polymer as an embolic material for aneurysm treatment: a delivery device for dermal fibroblasts and basic fibroblast growing factor into experimental aneurysms in rats.

BACKGROUND: This study evaluates whether thermoreversible gelation polymer (TGP) can be used as a delivery device to deploy dermal fibroblasts and cytokines into experimental aneurysms in rats. METHODS: The right common iliac artery of rats was surgically ligated and an experimental aneurysm was created by applying exogenous elastase. Seven days later, two aneurysms were harvested and used as controls (Group A), two were embolized with pure TGP (Group B), two were embolized with TGP and basic fibroblast growth factor (bFGF) (Group C) and two were embolized with TGP loaded with rat dermal fibroblasts (Group D). The aneurysms were also embolized with TGP mixed with dermal fibroblasts and bFGF at different concentrations (10 ng/ml: Group E (n=2), 100 ng/ml: Group F (n=2), 1000 ng/ml: Group G (n=2)). Each aneurysm sample was harvested after 7 days and histologic analyses were performed. RESULTS: The most advanced thrombus organization in the aneurysm, such as prominent fibroblast proliferation and collagen deposition, was observed in Groups E, F and G, although there was no noticeable difference between the groups. Moderate thrombus organization was seen in Group D and minimal thrombus organization was seen in Groups B and C. CONCLUSIONS: TGP mixed with both dermal fibroblasts and bFGF induced the most advanced thrombus organization in the experimental aneurysms followed by TGP mixed only with dermal fibroblasts. TGP may be useful as a delivery device to deploy fibroblasts and cytokines into aneurysms.

A rabbit model for efficacy evaluation of endovascular coil materials.

BACKGROUND: To investigate biomaterials seeking for their possible use for aneurysm treatment, in vivo screening tests using a number of potential materials are required. However, there is no established animal model that is suitable for such purpose. Some models require special preparation of tested materials for transcatheter delivery and others are inappropriate in view of their cost-effectiveness. The purpose of this study is to establish an animal model that overcomes these limitations and help us select potential materials before the preclinical evaluation. METHODS: Bilateral CCAs in a rabbit were surgically ligated, and a 2-cm segment of either a bare platinum coil or a polymeric coil (a platinum coil coated with PLGA 10/90) was implanted into each blind-ended arterial segment (n = 26). They were harvested at day 1, 7, 10, 14, or 30, respectively. Angiographic and histologic evaluations as well as quantitative analysis on the development of the organized thrombus were performed. RESULTS: One day after the implantation, both platinum and PLGA coils were surrounded by immature thrombus that was induced by blood flow stagnation in the arterial segment. At day 7, minimal thrombus organization was observed around both types of materials. At postimplantation days 10 and 14, fibrocellular responses, the early findings of the thrombus organization process, were observed in both material groups. Such histologic findings were more prominent in the PLGA coil group as compared to the platinum coil group (day 10, P = .051; day 14, P = .011). Well-organized thrombus was observed in both material groups at day 30 without showing statistical difference (P = .12). CONCLUSION: Given the cost-effectiveness, the simple material preparation process, and its feasible histologic evaluation methods, this new animal model can be useful in screening other potential biomaterials for the development of new coil devices.

Endovascular treatment of experimental aneurysms using a combination of thermoreversible gelation polymer and protection devices: feasibility study.

OBJECTIVE: We developed a new liquid embolic agent, an aqueous solution of thermoreversible gelation polymer (TGP) for the treatment of cerebral aneurysms. This polymer solution has the unique characteristics that allow it to solidify at a specific temperature without solvent. We performed an experimental aneurysm embolization using this liquid embolic agent with and without different protective devices to evaluate its technical feasibility for the treatment of aneurysms. METHODS: Fourteen side-wall aneurysms were surgically constructed on 14 common carotid arteries of 7 swine. Embolizations were conducted in combination with balloon protection (balloon group, n = 4), microstent protection (stent group, n = 4), and microcoil and microstent protection (stent-coil group, n = 4). Two aneurysms were used as controls. One control aneurysm was not embolized, and the other received control stent placement only. Angiographic follow-up was performed on day 14 and was followed by histopathological evaluation. RESULTS: Successful TGP solution delivery was conducted in all cases. Complete aneurysm occlusion was achieved in all cases without TGP migration. Follow-up angiograms demonstrated complete occlusion in the stent and stent-coil groups. A small recurrence was observed in the balloon group. Histopathological findings demonstrated neoendothelialization across the necks of the aneurysms. CONCLUSION: Experimental aneurysms were safely embolized using TGP. Further modifications related to mechanical stability and long-term safety evaluation results are necessary before clinical application.