Use of CT angiography in comparison with other imaging techniques for the determination of embolus and remnant size in experimental aneurysms embolized with hydrogel filaments.

BACKGROUND AND PURPOSE: Beam-hardening artifacts in CTA can be greatly reduced by using metal-free coils for aneurysm embolization. We compared the embolic masses and remnants of experimental rabbit aneurysms coiled with hydrogel filaments by using DSA, CTA and histology. MATERIALS AND METHODS: Embolization of 12 rabbit bifurcation aneurysms was performed with detachable hydrogel filaments. Six aneurysms were embolized as completely as possible, and 6 aneurysms were embolized incompletely to intentionally leave remnants. Three aneurysms in each group underwent follow-up at 4 and 13 weeks. DSA, MRA, and CTA were performed immediately before sacrifice. The harvested aneurysms were evaluated histologically. For each imaging technique, the areas of the embolic mass and remnant were determined by using image analysis. Results were compared by using paired t tests. RESULTS: CTAs were suitable for quantification of the embolus and remnant areas because only small streaking artifacts were evident. The areas of the embolus were larger on CTA compared with DSA and histologic sections. The areas of the remnant were larger on CTA and MRA compared with DSA and histologic sections. Like DSA and MRA, CTA was suitable for determining whether aneurysm retreatment was necessary, provided that loops of hydrogel filaments were not present in the parent artery. CONCLUSIONS: We demonstrated that CTA is a technique with potential for surveillance of aneurysms treated with hydrogel filaments. Additional work is required to determine the accuracy of the technique compared with currently accepted imaging modalities of DSA and MRA.

Angiographic and histologic comparison of experimental aneurysms embolized with hydrogel filaments.

BACKGROUND AND PURPOSE: The embolization of aneurysms with hydrogel filaments allow postprocedural CT and MR imaging studies without artifacts. We compared the performance of 3 hydrogel filament formulations in rabbit experimental aneurysms by using angiography and histologic samples. MATERIALS AND METHODS: Embolization of 35 rabbit elastase or bifurcation aneurysms was performed with 3 different formulations of detachable hydrogel filaments, including 1) polyethylene glycol opacified with aromatic iodine (PEG-I; n = 12), 2) polyethylene glycol opacified with barium sulfate (PEG-B; n = 12), or 3) polypropylene glycol opacified with barium sulfate (PPG-B; n = 11). Follow-up angiography was performed before the rabbits were killed at 2 (n = 7), 6 (n = 9), 10 (n = 8), or 26 (n = 11) weeks. Angiographic occlusion was scored according to the Raymond scale, and interval changes were assessed. The harvested aneurysms were evaluated on histologic examination. From the sections, we determined the percentage of the sac excluded from the vasculature and occupied by embolic devices by using image analysis. We compared results using the analysis of variance/t test or chi(2) test. RESULTS: The mean number of devices used to treat aneurysms in the PPG-B group was significantly greater than that used for the other 2 groups, though aneurysm volumes were similar among groups. Compared with immediate posttreatment occlusion scores, mean angiographic occlusion at follow-up was increased for all 3 hydrogel filament groups. On histologic examination, thrombus organization, neointima formation, and inflammation were similar to that observed in rabbit experimental aneurysms with other embolic devices containing platinum coils. CONCLUSIONS: The embolization of experimental aneurysms with hydrogel filaments resulted in durable angiographic and histologic occlusion from 2 to 26 weeks. With improvements, hydrogel filaments free from metallic coils show promise for endovascular use.

Cartilage and bone neoformation in rabbit carotid bifurcation aneurysms after endovascular coil embolization.

Occurrence and histomorphology of cartilage and bone neoformations was retrospectively evaluated in rabbit experimental aneurysms after endovascular coil embolization. During product development, 115 carotid bifurcation aneurysms were treated with hydrogel-containing devices (HydroCoil or target, n=77; HydroSoft or target, n=28; prototype Hydrogel-only, n=10; MicroVentionTerumo, Aliso Viejo, CA). Additional 29 aneurysms were treated with standard (n=22) or with degradable polymer-covered (n=7) platinum coils. After 4 to 52 weeks, the retrieved aneurysms were methylmethacrylate embedded, and ground sections were surface-stained with Rapid Bone Stain and Giemsa solution. Cartilage and/or bone tissue was assessed by light microscopy; respective tissue areas in the aneurysms were determined by computerized histomorphometry. Cartilage neoformation was observed from 26 to 52 weeks. Single chondrocytes to hyaline or fibrous cartilage areas, occupying up to 29% of the aneurysm cavity, were found in 6 aneurysms, treated with HydroCoil (n=4), Hydrogel-only (n=1), and resorbable polymer (n=1) devices. Chondral ossification associated cartilage neoformation in 2 of these 4 HydroCoil-treated aneurysms. Membranous woven and lamellar bone ossicles were observed from 13 to 52 weeks in 7 aneurysms, treated with HydroCoil (n=3) and platinum coil (n=4) devices. Altogether, cartilage and/or bone neoformation was observed in 13 (9%) of 144 rabbit bifurcation aneurysms treated with various embolic devices. Incidence was low until 26 weeks, but increased at 52 weeks in both, HydroCoil and standard platinum coil treated aneurysms. As the neoformations were predominantly located in proximity to the aneurysm neck, they could be related to the long-term mechanobiology of cell differentiation during fibrovascular healing of blood flow-exposed embolized aneurysms.

A tissue sealant based on reactive multifunctional polyethylene glycol.

A rapidly gelling synthetic tissue sealant was developed from tetra-succinimidyl and tetra-thiol-derivatized polyethylene glycol (PEG). The two reagents were dissolved in aqueous buffers at 20% (w/v) solids and sprayed on the tissue site, with the use of a sprayer/mixer device. Good adhesion to collagen membranes, PTFE grafts, and carotid artery was observed in vitro. In a burst test on collagen membranes with a 2-mm orifice defect, the gel sustained fluid pressures of 125 +/- 36 mm Hg (n = 18), fivefold greater than capillary blood pressure and one-half that observed in hypertension. On 0.4-mm-diameter puncture defects in PTFE grafts, pressures of 390-490 mm Hg were sustained, and on 0.6-0.9-mm puncture defects in carotid arteries, pressures of 490 to 840 mm Hg were sustained. In vitro data corresponded to results in vivo, where bleeding in rabbit arteries was stopped immediately in five out of six trials. A significant reduction in time to hemostasis and blood loss, compared to controls, was observed. Carotid artery and subcutaneous implant data in rabbits showed that the formula was compatible with biological tissue. Rapid gelling and effective sealing were dependent on the presence of active succinimidyl ester and thiol groups on PEG. HPLC and chemical substitution methods were useful in predicting whether batches of derivatized PEG would perform satisfactorily.

In vitro and in vivo performance of porcine islets encapsulated in interfacially photopolymerized poly(ethylene glycol) diacrylate membranes.

The usefulness of interfacial photopolymerization of poly(ethylene glycol) (PEG) diacrylate at a variety of concentrations and molecular weights to form hydrogel membranes for encapsulating porcine islets of Langerhans was investigated. The results from this study show in vitro and in vivo function of PEG-encapsulated porcine islets and the ability of PEG membranes to prevent immune rejection in a discordant xenograft model. Encapsulated islets demonstrated an average viability of 85% during the first week after encapsulation, slightly but significantly lower than unencapsulated controls. Encapsulated porcine islets were shown to be glucose responsive using static glucose stimulation and perifusion assays. Higher rates of insulin release were observed for porcine islets encapsulated in lower concentrations of PEG diacrylate (10-13%), not significantly reduced relative to unencapsulated controls, than were observed in islets encapsulated in higher concentrations (25%) of PEG diacrylate. Perifusion results showed biphasic insulin release from encapsulated islets in response to glucose stimulation. Streptozotocin-induced diabetic athymic mice maintained normoglycemia for up to 110 days after the implantation of 5,000-8,000 encapsulated porcine islet equivalents into the peritoneal cavity. Normoglycemia was also confirmed in these animals using glucose tolerance tests. PEG diacrylate-encapsulated porcine islets were shown to be viable and contain insulin after 30 days in the peritoneal cavity of Sprague-Dawley rats, a discordant xenograft model. From these studies, we conclude that PEG diacrylate encapsulation of porcine islets by interfacial photopolymerization shows promise for use as a method of xenoprotection toward a bioartificial endocrine pancreas.

Characterization of permeability and network structure of interfacially photopolymerized poly(ethylene glycol) diacrylate hydrogels.

Hydrogel membranes formed by interfacially photopolymerizing poly(ethylene glycol) (PEG) diacrylate precursor solution were prepared from PEG diacrylate of molecular weights (MW) ranging from 2000 (2K) to 20000 (20K) with concentrations ranging from 10% to 30% w/w. The effects of PEG diacrylate MW and concentration in the membrane precursor solution upon the diffusivities of vitamin B12, myoglobin, ovalbumin, albumin, and IgG were determined. Regardless of the concentration of the PEG diacrylate in the precursor solution, hydrogels prepared with PEG 2K, 4K, and 8K diacrylate were impermeable to proteins with a size equal to or larger than myoglobin (22 kDa), while hydrogels prepared with PEG 20K diacrylate were impermeable to proteins with a size equal to or larger than ovalbumin (45 kDa). Similarities between hydrogels formed from PEG 2K, 4K, and 8K diacrylates were also seen in calculations of the molecular weight between crosslinks and the mesh size, with values in the range of 150-750 g/mol and 15-35 A, respectively, depending on PEG diacrylate concentration. In contrast, hydrogels formed from PEG 20K diacrylate had molecular weight between crosslinks ranging from 1150 to 2000 g/mol and mesh sizes ranging from 45-70 A, with larger values being observed in membranes polymerized from more dilute PEG diacrylate precursor.

A sensitivity study of the key parameters in the interfacial photopolymerization of poly(ethylene glycol) diacrylate upon porcine islets.

A method has been defined to interfacially photopolymerize poly(ethylene glycol) diacrylates (PEG diacrylates) to form a crosslinked hydrogel membrane upon the surfaces of porcine islets of Langerhans to serve as an immune barrier for allo- and xenotransplantation. A sensitivity study of six key parameters in the interfacial photopolymerization process was performed to aid in determination of the optimal encapsulation conditions, leading to the most uniform hydrogel membranes and viable islets. The key parameters included the concentrations of the components of the initiation scheme, namely eosin Y, triethanolamine, and 1-vinyl 2-pyrrolidinone. Other parameters investigated included the duration and flux of laser irradiation and the PEG diacrylate molecular weight. Each parameter was doubled and halved from the standard conditions used in the encapsulation process while holding all the remaining parameters at the standard conditions. The effects of changing each parameter on islet viability, encapsulation efficiency, and gel thickness were quantified. Islet viability was sensitive to the duration of laser illumination, viability significantly increasing as the duration was reduced. Encapsulation efficiency was sensitive to the concentrations of eosin Y, triethanolamine, and 1-vinyl 2-pyrrolidinone, to the laser flux, and to the PEG diacrylate molecular weight. Increasing the concentration of eosin Y significantly improved the encapsulation efficiency, while decreasing the concentration of 1-vinyl 2-pyrrolidinone and increasing the concentration of triethanolamine had the greatest effects in significantly reducing the encapsulation efficiency. Gel thickness was sensitive to the concentrations of triethanolamine and 1-vinyl 2-pyrrolidinone, to the duration of laser illumination, and to the PEG diacrylate molecular weight. Increasing the PEG diacrylate molecular weight significantly increased the gel thickness, while decreasing the concentration of 1-vinyl 2-pyrrolidinone and increasing the concentration of triethanolamine had the greatest effects in significantly reducing the gel thickness. From this sensitivity study, conditions were determined to encapsulate porcine islets, resulting in greater than 90% islet viability and greater than 90% encapsulation efficiency.

Immunoisolation of adult porcine islets for the treatment of diabetes mellitus. The use of photopolymerizable polyethylene glycol in the conformal coating of mass-isolated porcine islets.

Functional porcine islets, free of known pathogens, can serve as a source of insulin producing cells for the treatment of experimentally induced insulin dependent Diabetes Mellitus. Porcine islets can be conformally coated (microencapsulated) with a covalently linked, stable permselective membrane while maintaining islet viability and function. The PEG conformal coating is immunoprotective in a discordant xenograft animal model (porcine islets to rat).