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Poly(ethylene glycol) methacrylate hydrolyzable microspheres for transient vascular embolization.

Poly(ethylene glycol) methacrylate (PEGMA) hydrolyzable microspheres intended for biomedical applications were readily prepared from poly(lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-PLGA crosslinker and PEGMA as a monomer using a suspension polymerization process. Additional co-monomers, methacrylic acid and 2-methylene-1,3-dioxepane (MDO), were incorporated into the initial formulation to improve the properties of the microspheres. All synthesized microspheres were spherical in shape, calibrated in the 300-500 μm range, swelled in phosphate-buffered saline (PBS) and easily injectable through a microcatheter. Hydrolytic degradation experiments performed in PBS at 37 °C showed that all of the formulations tested were totally degraded in less than 2 days. The resulting degradation products were a mixture of low-molecular-weight compounds (PEG, lactic and glycolic acids) and water-soluble polymethacrylate chains having molecular weights below the threshold for renal filtration of 50 kg mol(-1) for the microspheres containing MDO. Both the microspheres and the degradation products were determined to exhibit minimal cytotoxicity against L929 fibroblasts. Additionally, in vivo implantation in a subcutaneous rabbit model supported the in vitro results of a rapid degradation rate of microspheres and provided only a mild and transient inflammatory reaction comparable to that of the control group.

A Novel Resorbable Embolization Microsphere for Transient Uterine Artery Occlusion: A Comparative Study with Trisacryl-Gelatin Microspheres in the Sheep Model

PURPOSE To evaluate angiographic recanalization, inflammatory reaction, and uterine damage after sheep uterine artery embolization (UAE) with a novel calibrated resorbable embolization microsphere (REM) and compare the results with control nonresorbable microspheres. MATERIALS AND METHODS Six hormonally artificially cycled sheep underwent bilateral UAE until stasis with either REM or trisacryl-gelatin microspheres (TGMS). At 7 days, control angiograms were obtained to assess the residual vascularization at arterial and parenchymal phases. The animals were then sacrificed for analysis of the presence of microspheres, inflammatory foreign body reaction, and surface areas of uterine damage. RESULTS Mean volume of microspheres injected per uterine artery (UA) or per animal did not differ between groups. At day 7, the flow was normal for six of six UAs that received embolization with REM versus only three of six UAs with TGMS (P = .0455, χ(2) test). Uterine parenchymography showed no defects in six UAs in the REM group versus five defects in six UAs in the TGMS group (P = .0060, χ(2) test). No REM or residual fragments of microspheres were observed on histologic analysis. TGMS were observed in tissues and accompanied by a mild inflammatory response. Necrosis rates were not significantly different between the two products, either in endometrium (REM 23.5% ± 28.8% [median 8.1%] vs TGMS 21.8% ± 23.7% [median 14.6%]) or in myometrium (REM 8.2% ± 22.7% [median 0.0%] vs TGMS 8.8% ± 20.8% [median 0.9%]). Endometrium alteration rate was lower with REM than with TGMS (39.7% ± 25.7% [median 34%] vs 60.6% ± 27.1% [median 71%]; P = .0060, Mann-Whitney test). Myometrium alteration rates were not significantly different between REM (45.7% ± 37.1% [median 63.0%]) and TGMS (37.8% ± 34.0% [median 19.1%]). CONCLUSIONS At 1 week after sheep UAE with REM, the recanalization was complete, the microspheres were completely degraded, and there was no remnant inflammatory response.

Targeting and Recanalization after Embolization with Calibrated Resorbable Microspheres versus Hand-cut Gelatin Sponge Particles in a Porcine Kidney Model

PURPOSE To report on polyethylene glycol hydrogel-based resorbable embolization microspheres (REM) that were synthesized to resorb in < 24 hours, before inflammation and vascular remodeling, to achieve a complete arterial recanalization and to compare targeting and recanalization of REM of 300-500 µm, 500-700 µm, and 700-900 µm with hand-cut gelatin sponge particles (GSP). MATERIALS AND METHODS Eight pigs underwent polar renal artery embolization with REM or GSP. Angiograms were obtained before embolization and 10 minutes and 7 days after embolization before pigs were sacrificed to determine the occlusion level, the percentage of occlusion, and the recanalization rate for each product. The distribution of embolic material was assessed in pathology, and infarction rate of the kidneys was measured. RESULTS REM of 300-500 µm occluded more distal vessels than REM of 500-700 µm and 700-900 µm. At day 7, the recanalization rate was complete for the larger REM, whereas it was about 60% for the two smaller sizes. REM were completely degraded, with no residual material or inflammation. GSP occluded more proximal arteries than REM of 700-900 µm, were partly degraded at day 7, and were accompanied by a foreign body reaction in proximal and distal arteries. GSP recanalized at 79%. The infarction rate was higher with the two smaller sizes of REM and with GSP than with the largest REM. CONCLUSIONS REM of different sizes targeted different occlusion levels in kidney arteries. GSP provided an extended occlusion level without actual targeting. Regardless of embolic material used, angiographic recanalization of renal arteries depended on the extent of necrosis. REM of 700-900 µm demonstrated the lowest infarction rate and the best recanalization rate.

Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: An in vitro study with sunitinib and bevacizumab

Anti-angiogenic (AA) drugs are proposed as novel agents for targeted therapies in hepatocellular carcinoma (HCC). Loading of AA drugs into drug delivery systems for local delivery would reduce their side effects. The present study investigated the loading and the delivery of two AA drugs, sunitinib and bevacizumab, from one day-resorbable embolization microspheres (REM). REM were prepared with 10 or 20% of methacrylic acid (MA) as active drug binding monomer. Sterilized beads (100-300 μm) were analyzed for cytotoxicity, AA loading and in vitro release. REM modified with MA were not cytotoxic and extemporaneous drug loading was significantly higher on REM containing 20% of MA. The drug release in saline buffer was sustained for several hours before complete REM degradation. MA content had low effect on drug release profile. When eluted from REM, sunitinib and bevacizumab reduced viability of tumoral VX2 cells, and proliferation of human endothelial cells, respectively. Deliverability of REM via microcatheter was not impaired by the loaded drugs. As conclusion, the loading values of sunitinib and bevacizumab on REM were close to those achieved for cytotoxic drugs onto non-degradable MS used in chemoembolization of HCC. Transcatheter delivery to liver tumors of anti-angiogenics could be achieved with REM.

Tunable delivery of niflumic acid from resorbable embolization microspheres for uterine fibroid embolization

Uterine arteries embolization (UAE) is a recent technique that aims, by means of particles injected percutaneously, to stifle fibroids (leiomyomas). This treatment is non-invasive, compared with uterine ablation, but generates pelvic pain for a few days. A strategy to reduce the post-embolization pain would be to use calibrated embolization microspheres preloaded with a non-steroidal inflammatory drug (NSAID). In this study, we first compared four drugs, all active at low concentration on cyclooxygenase-2, i.e. ketoprofen, sodium diclofenac, flurbiprofen and niflumic acid (NFA), for their capacity to be loaded on resorbable embolization microspheres (REM) 500-700μm. NFA had the highest capacity of loading (5mg/mL) on resorbable microspheres. Then, we evaluated in vitro the NFA release profiles from REM having various degradation times of one, two or five days. NFA release was biphasic, with an initial burst (about 60% of the loading) followed by a sustained release that correlated significantly to REMs hydrolysis (rho=0.761, p<0.0001). For each group of beads, the size distribution was not modified by the loading of NFA and their delivery through microcatheter was not impaired by the drug. NFA eluted from REM inhibited the synthesis of prostaglandin E2 from rabbit uterus explants. In summary, NFA is loadable on REM in significant amount and its delivery can be tuned according to the degradation rate of REM to provide an antalgic effect for a few days after UAE.