An In Vitro Evaluation of Four Types of Drug-Eluting Embolics Loaded with Idarubicin.

PURPOSE: This study compared loading, elution, and stability of drug-eluting embolic beads (DEBs) loaded with idarubicin. MATERIALS AND METHODS: DC Bead (100-300 µm), HepaSphere (30-60 µm), LifePearl (200 µm), and Tandem (100 µm) DEBs were loaded with 5 mg/mL idarubicin. Loading, elution, diameter changes, loading stability over 2 weeks in storage, and time in suspension were determined for each of the DEBs. RESULTS: Loading of more than 99% of idarubicin was achieved within 15 minutes for LifePearl, DC Bead, and Tandem beads. LifePearl, DC Bead, HepaSphere, and Tandem beads eluted 75% of the total idarubicin released in 13, 24, 42, and 91 minutes, respectively. In vitro elution was completed in 2 hours with 73% ± 3%, 74% ± 3%, 65% ± 6%, and 7% ± 0% of the loaded idarubicin eluted for LifePearl, DC Bead, HepaSphere, and Tandem, respectively. Statistically significant differences were observed at every time point between at least 2 of the products. Overall, in vitro idarubicin elution was rapid and nearly complete for LifePearl, DC Bead, and HepaSphere beads but was minimal and slow from Tandem beads. The average diameter of DEBs after loading was reduced by 5% for LifePearl, whereas it was increased by 9% and 1% for DC Bead and Tandem, respectively. After loading, time in suspension was 11 ± 4 and 10 ± 2 minutes for LifePearl and HepaSphere, respectively, whereas DC Bead and Tandem beads were held in suspension for greater than 20 minutes. CONCLUSIONS: Although all 4 DEBs loaded idarubicin within 15 minutes with minimal changes in diameter, the elution amounts, rates of release, and time in suspension varied.

New Interventional Treatment Model for Pancreatic Neoplasms Using Gemcitabine-Eluting Hydrogel Devices: In Vitro and In Vivo Results.

OBJECTIVES: In vitro and in vivo evaluation of fast- and slow-release gemcitabine-eluting hydrogel (GEH) devices. METHODS: For in vitro elution, the GEH devices were placed in phosphate-buffered saline at 37 °C. Periodically, the solution was analyzed for gemcitabine. The devices consisting of fast release (n = 8), slow release (n = 6), or bland (n = 4) were delivered through a 5-Fr catheter into the gastroduodenal artery of a pig. Additionally, four pigs were treated with intravenous (IV) injection of gemcitabine. Pigs were killed at day 1 (n = 9), day 7 (n = 11), or day 21 (n = 2). Gemcitabine concentrations in the plasma and tissues were determined. RESULTS: In vitro, gemcitabine was completely eluted within 6 h or 30 days for the fast- and slow-release devices, respectively. All 22 pigs were treated without morbidity or mortality. Gemcitabine plasma concentrations peaked at about 105,000 ± 30,000, 252 ± 101, 22 ± 29, and 0 ± 0 ppb for the IV, fast-release, slow-release, and bland treatments, respectively. At days 1 and 7, gemcitabine concentrations were higher in the pancreas for the GEH devices than IV. Gemcitabine delivery to the pancreas was sustained over 21 days in the slow-release group. CONCLUSIONS: Treatment with GEH devices resulted in at least equivalent gemcitabine concentration in the pancreas and reduced concentration in the plasma, heart, liver, and duodenum, at least equivalent to IV injection and reduced concentrations elsewhere. These results show the potential of sustained local delivery of gemcitabine to treat pancreatic neoplasms with reduced side effects.

An In Vitro Evaluation of Four Types of Drug-Eluting Microspheres Loaded with Doxorubicin.

PURPOSE: To compare in vitro properties of 4 drug-eluting embolic agents loaded with doxorubicin. MATERIALS AND METHODS: DC Bead (100-300 µm), LifePearl (200 µm), HepaSphere (30-60 µm), and Tandem (100 µm) microspheres were loaded with 40 mg/20 mL of doxorubicin per milliliter of microspheres. Loading, elution, diameter changes after loading, changes in the amount of doxorubicin loaded over 2 weeks in storage, and time in suspension were evaluated. RESULTS: All microspheres loaded > 99% doxorubicin within 1 hour. In vitro elution reached a plateau by 6 hours, with 30% ± 5, 21% ± 2, 8% ± 3, and 6% ± 0 of the loaded doxorubicin eluted for LifePearl, DC Bead, HepaSphere, and Tandem microspheres, respectively, with at least 1 statistically significant difference between at least 2 of the products in doxorubicin eluted at every time point. The times to elute 75% of the total released doxorubicin were 197, 139, 110, and 77 min for DC Bead, LifePearl, HepaSphere, and Tandem microspheres, respectively. The average diameters of LifePearl, DC Bead, and Tandem microspheres were reduced after loading by 24%, 20%, and 9%, respectively. After suspension in contrast medium, no changes were observed in doxorubicin loading over 2 wk. After loading, times in suspension were 8.4 min ± 0.2, 6.0 min ± 0.1, 3.1 min ± 0.2, and 2.9 min ± 0.3 for Tandem, LifePearl, DC Bead, and HepaSphere microspheres, respectively. CONCLUSIONS: Although drug-eluting embolic agents universally loaded doxorubicin within 1 hour, the elution amounts, rates of release, diameter shrinkage, and times in suspension varied by product.

An in-vitro evaluation of three types of drug-eluting microspheres loaded with irinotecan.

To compare the mechanical and chemical properties of three commercially available microspheres loaded with irinotecan. LifePearl (200 µm), DC Bead (100-300 µm), and Tandem (100 µm) microspheres were loaded with irinotecan. For loading, elution, and stability determinations, irinotecan concentrations were quantified using validated high-performance liquid chromatography methods. In-vitro elution was performed over 24 h using a USP 4 dissolution apparatus. Diameter measurements were performed using light microscopy. Time in suspension was considered as the time required for the microspheres to vacate 1/3 of the volume. All three microsphere types rapidly loaded irinotecan, with more than 95% loading at 1 h. In-vitro elution of irinotecan was rapid for LifePearl and DC Bead microspheres, with more than 98% elution at 1 h, and delayed for Tandem microspheres, with about 70% elution at 6 h. After loading with irinotecan, the average diameter of LifePearl and DC Bead microspheres was reduced by 9 and 18%, respectively, and was unchanged for Tandem microspheres. All three microsphere types lost 4-6% of the loaded irinotecan almost immediately upon placement in contrast: water and contrast: 5% dextrose, but further losses were minimal over 2 weeks. LifePearl microspheres remained longer in suspension (392±23 s) compared with DC Bead (154±13 s, P<0.001) and Tandem (198±19 s, P<0.001) microspheres. All three microsphere types load irinotecan rapidly. LifePearl and DC Bead microspheres elute irinotecan rapidly. Elution is delayed with Tandem microspheres. LifePearl microspheres show the longest time in suspension.

Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up.

BACKGROUND: Surgical clipping of intracranial aneurysms is the gold standard for the prevention of rupture. However, the biological processes that occur following clipping are poorly understood. To better understand these effects, retrieved and clipped human intracranial aneurysms were examined histologically. METHODS: At autopsy, 17 aneurysms from 10 patients were retrieved 3-21 days after clipping. The tissues were embedded in paraffin, and microtome sections were stained using hematoxylin-eosin and Movat pentachrome. Using light microscopy, clip placement relative to the internal elastic lamina of the parent artery, endothelialization of the aneurysm neck, thrombus organization inside the aneurysm sac, inflammation in the sac, wall, and parent artery, and atherosclerotic changes were determined. RESULTS: Despite complete reconstruction of the artery with the clip, diseased vessel wall was frequently observed outside the clip. By 10 days postsurgery, the beginnings of endothelialization and neointima formation were observed at the neck. However, the neck coverage was variable and incomplete at these early time points. Thrombus organization inside the aneurysm sac was rarely observed, and inflammatory cells were not present inside the aneurysm sac. Inflammatory cells were commonly observed in the aneurysm wall, and atherosclerotic change was present in each sample. CONCLUSIONS: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation. SUMMARY: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.

Angiographic and histologic comparison of injectable, expansile hydrogel embolic and pushable AZUR embolic devices in porcine arteries.

PURPOSE: To compare an injectable hydrogel embolic device with a pushable AZUR device procedurally, angiographically, and histologically in the embolization of porcine arteries. MATERIALS AND METHODS: In 12 pigs, embolization of renal, gluteal, and hepatic or thoracic arteries was performed with either injectable hydrogel embolic devices (two arteries per pig) or an AZUR device (one artery per pig). Follow-up angiography was performed before sacrifice in five pigs at 7 days after embolization and seven pigs at 90 days after embolization. The harvested tissues were evaluated histologically. Continuous and ordinal results were compared using analysis of variance and χ(2) tests. RESULTS: For the sites with embolization performed with injectable hydrogel, complete angiographic occlusion was obtained in 21 of 24 (88%) sites after treatment, 10 of 10 (100%) sites at 7 days, and 10 of 14 (72%) sites at 90 days. For the sites with embolization performed with AZUR devices, complete angiographic occlusion was obtained in 10 of 12 (83%) sites after treatment, 4 of 5 (80%) sites at 7 days, and 5 of 7 (72%) sites at 90 days. Statistically significant differences in angiographic occlusion were not observed at 7 days (P = .13) or 90 days (P = .35). The embolization time of the injectable hydrogel group (14 minutes ± 8) was significantly reduced (P = .02) compared with the AZUR group (22 minutes ± 12). Differences between the groups in arterial wall damage were not evident at either 7 days or 90 days, although greater damage was observed in both groups at 90 days. In both groups, inflammation was nonexistent to minimal at 7 days and minimal to mild at 90 days. CONCLUSIONS: Embolization of porcine arteries was as effective with injectable hydrogel embolic devices as pushable AZUR devices, as evidenced by the procedural, angiographic, and histologic results.

MR imaging of hydrogel filament embolic devices loaded with superparamagnetic iron oxide or gadolinium.

INTRODUCTION: We evaluated hydrogel filaments loaded with barium sulphate and either gadolinium or superparamagnetic iron oxide (SPIO) in an effort to develop an embolic material that is visible with fluoroscopic and magnetic resonance imaging. METHODS: Hydrogel filaments were prepared with gadolinium and iron concentrations ranging from 1,500 to 7,500 and 500 to 2,500 ppm, respectively. The filaments were encased in agar and imaged using an MR scanner. Embolisation of eight aneurysms (seven bifurcation, one sidewall) in seven rabbits was performed using hydrogel filaments loaded with gadolinium (n = 4) or SPIO (n = 4). Angiographic evaluations occurred immediately post-treatment and at 13 weeks. Magnetic resonance angiography (MRA) evaluations occurred immediately post-treatment or 13 weeks post-treatment. RESULTS: Based on the in vitro results, we selected 4,500 and 2,000 ppm for gadolinium and iron loadings, respectively, for the in vivo experiments. Loading the filaments with gadolinium or SPIO did not affect the angiographic results, as embolic masses were readily evident with some distinguishing of individual filaments. In MRA, the hydrogel filaments loaded with SPIO were hypointense, and the hydrogel filaments loaded with Gd were hyperintense. The hyperintensity of the Gd-loaded filaments confounded the ability to distinguish between flow and the embolic devices. The hypointensity of the hydrogel filaments loaded with SPIO provided sufficient contrast between the embolic devices and the blood flow to allow of aneurysm occlusion evaluation using MRA. CONCLUSION: Based on these results, we are focusing on loading hydrogel filaments with SPIO in an effort to provide adequate visualisation for use in MR-guided interventions.

Histomorphology of thrombus organization, neointima formation, and foreign body response in retrieved human aneurysms treated with hydrocoil devices.

Biological processes, such as thrombus organization, endothelialization, and foreign body response, that occur following embolization of intracranial aneurysms are poorly understood. We examined 13 human aneurysms (retrieved at autopsy 1-74 days postembolization) treated with hybrid hydrogel-platinum coil devices and platinum coils. The specimens were embedded in methyl methacrylate and ground sections were surface stained. Using light microscopy, thrombus organization in the sac, endothelialization of the neck, and foreign body response to the embolic devices were determined. The area percentages of the sac occupied by embolic devices and unorganized thrombus were quantified using image analysis. Thrombus organization increased over time, but was incomplete up to 74 days post-treatment. Neointima formation had started at 5 days upon dense fibrin depositions and progressed to form a new vessel wall at 74 days. The foreign body response to the hydrogel was characterized by mononuclear macrophages, while platinum coils were surrounded by multinuclear foreign body giant cells. Histometric aneurysm occlusion ranged from 89 to 100% and embolic devices occupied 31-64% of the aneurysm sac. These findings showed that the hydrogel-based devices occupied a large percentage of the aneurysm sac, provided a framework for thrombus organization to occur, and elicited less severe foreign body response than platinum coils.

Angiographic and artefact-free computed tomography imaging of experimental aneurysms embolised with hydrogel filaments.

OBJECTIVES: We compared experimental rabbit carotid bifurcation aneurysms embolised with platinum coils or hydrogel filaments by using digital subtraction angiography (DSA) and computed tomography angiography (CTA). METHODS: Embolisation was performed using platinum coils (n = 2), hydrogel filaments loaded with iodine (n = 3) and hydrogel filaments loaded with barium sulphate (n = 3). In one case, a stent was deployed in the parent vessel to determine the effect of hydrogel filaments on stent visualisation. DSA evaluations occurred immediately post-treatment. CTA evaluations occurred at 0-13 weeks post-treatment. The DSA and CTA images were evaluated for the lack of artefacts and the visibilities of the embolic mass, individual coils and residual flow in the aneurysm sac and neck. RESULTS: The DSA results were largely concordant among the three groups. The embolic masses were readily evident with some individual coils being distinguished. In the aneurysms embolised with hydrogel filaments, visualisation of the individual coils, residual flow and stent with minor or no artefacts was possible using CTA. On the other hand, the beam hardening artefacts precluded analysis of aneurysms embolised with platinum coils. CONCLUSION: CTA-compatible embolic devices could have wide applications in diverse locations throughout the vasculature, particularly in combination with stents or stent grafts.

A comparison of experimental aneurysm occlusion determination by angiography, scanning electron microscopy, MICROFIL perfusion, and histology.

In clinical practice, occlusion of embolized, intracerebral aneurysms is evaluated using angiography. Standard, two-dimensional digital subtract angiography (DSA) is unable to quantify irregular aneurysm remnants, and even three-dimensional rotational angiography cannot quantify the degree of occlusion. To better understand occlusion at the aneurysm neck, we compared angiographic results with MICROFIL perfusion, histology, and scanning electron microscopy (SEM) results in 20 elastase-induced saccular aneurysms in rabbits. Aneurysms were embolized with HydroCoil devices (n = 12) or platinum coils (n = 8). Aneurysm follow-up occurred at 2 (n = 10) and 6 (n = 10) weeks. Aneurysm occlusion was evaluated using DSA, MICROFIL perfusion, histological ground sections, and SEM. Groups were compared statistically using ANOVA and chi(2) tests. The MICROFIL perfusion results were not concordant with the angiographic results for the HydroCoil and platinum coil groups. Both increased and decreased occlusion was observed on the MICROFIL-perfused aneurysms when compared with angiography. The histologic occlusion results of the HydroCoil group were concordant with the angiographic results; however, unoccluded areas not visible on angiography were routinely observed on the ground sections in the platinum coil group. SEM imaging of the aneurysm neck consistently showed decreased occlusion than angiographic results for both the HydroCoil and platinum coil groups. Although histology and MICROFIL-perfusion analyses provided additional details of aneurysm occlusion when compared with angiography, complete visualization of the entire neck of the aneurysm and accurate assessment of aneurysm occlusion was possible only with SEM.

Preparation, characterization, and evaluation of radiopaque hydrogel filaments for endovascular embolization.

Radiopaque hydrogel filaments were prepared, characterized, and evaluated for potential use as implants for endovascular embolization of vascular defects. Three hydrogel formulations were prepared by free radical polymerization: (i) poly(ethylene glycol) diacrylate with 2,4,6-triiodophenyl penta-4-enoate (PEG-I), (ii) poly(ethylene glycol) diacrylamide with barium sulfate (PEG-B), and (iii) poly(propylene glycol) diacrylate with barium sulfate (PPG-B). The PEG-B and PPG-B hydrogels exhibited radiopacity comparable with clinically used platinum coils, whereas the PEG-I hydrogel did not. In the dry state, the average ultimate tensile strength and strain of the hydrogels ranged from 37 to 128 gf and 21% to 72%, respectively. The PEG-B hydrogel had significantly higher tensile strength compared with the PEG-I hydrogel. In the hydrated state, the average ultimate tensile strength and strain ranged from 5 to 15 gf and 7% to 30%, respectively. Statistically significant differences in tensile strength were not present when hydrated. Compared with poly(ethylene) after 4-week implantation into the subcutaneous space of rabbits, the PEG-I hydrogel elicited slightly more inflammation, whereas the PEG-B and PPG-B hydrogels elicited less inflammation. All three hydrogel formulations elicited less fibrous encapsulation than poly(ethylene). With further development, these materials have potential as embolization devices.