Ulrike Stampfl

Biocompatibility and Recanalization Characteristics of Hydrogel Microspheres with Polyzene-F as Polymer Coating

The objective of this study was to evaluate inflammatory response and recanalization after embolization with a new spherical embolic agent based on a core and shell design with a hydrogel core of polymethylmethacrylate (PMMA) and a Polyzene-F nanoscale coating in a porcine kidney model. Thirty-six minipigs were enrolled for superselective renal embolization. Polyzene-F-coated PMMA particles and uncoated PMMA particles with a diameter of 300–600xa0μm were used. Either 4 or 12 weeks post-embolization, arteriography of the embolized kidneys was performed and then compared with pre- and immediate post-embolization arteriograms using a specific recanalization score to determine the extent of recanalization. Using a microscopic inflammation score (Banff classification), the embolized organs were examined for local inflammatory effects which occurred in response to the embolic agent. In Polyzene-F-coated particles, the Banff classification showed an average inflammation score of 0.26xa0±xa00.58 at 4 weeks and of 0.08xa0±xa00.28 at 12 weeks. In uncoated particles, the Banff score measured 0.37xa0±xa00.6 at 4 weeks, which was higher, but without a statistically significant difference. According to the recanalization score used in this study, mild angiographic recanalization was evident in all groups, without statistically significant differences (3.0xa0±xa00.71 in coated particles, 3.09xa0±xa00.81 in uncoated particles; pxa0=xa00.74). We conclude that both uncoated hydrogel particles and Polyzene-F-coated embolic agents triggered virtually no inflammatory response and effectively occluded target arteries. This study demonstrates good biocompatibility of the new embolic material. As in other spherical embolic agents, recanalization can occur to some degree.

Arterial Distribution Characteristics of Embozene Particles and Comparison with Other Spherical Embolic Agents in the Porcine Acute Embolization Model

PURPOSEnTo determine the arterial distribution pattern of the embolic agent Embozene within the porcine kidney and compare it with those of other spherical embolic agents.nnnMATERIALS AND METHODSnEmbozene, Embosphere, Bead Block, and Contour SE in size classes of 100-300 microm, 500-700 microm, and 700-900 microm and Embozene and Embosphere in the size class of 40-120 microm were used for total arterial occlusion in minipig kidneys. Organs were evaluated microscopically regarding vascular distribution of the different embolic agents and particle sizes.nnnRESULTSnThe following variations of arterial distribution were identified. In the 40-120-microm size class, Embosphere particles penetrated significantly deeper compared with Embozene (P = .04). In the 100-300-microm size class, Bead Block showed a significantly deeper distribution as microscopy identified particles in arteries much smaller than their nominal size. In the 500-700-microm size class, Embosphere and Contour SE showed a deeper distribution. The most uniform arterial distribution was observed in the 700-900 microm size class,. However, few Embosphere and Contour SE particles were found in arcuate arteries, also indicating a distal distribution.nnnCONCLUSIONSnThroughout the four most-used size classes, from very small (40-120 microm) to large (700-900 microm), the distribution characteristics of the four tested materials vary substantially. Particularly, small Embosphere particles and small Bead Block particles showed a more distal distribution, as did medium-sized Embosphere and Contour SE particles. In the largest investigated size class, the distribution was more uniform. In general, the Embozene particles are very uniform in size, and they seem to reach vessels closely corresponding to their nominal size.

Experimental Evaluation of Early and Long-Term Effects of Microparticle Embolization in Two Different Mini-Pig Models. Part I: Kidney

PurposeUsing a pig model: (1) to evaluate the vascular distribution pattern, including the homogeneity and completeness of the intra-arterial microsphere distribution, of 40–120-μm trisacryl-gelatin microspheres (Embospheres) in acute whole-kidney embolization; (2) to evaluate the durability and biocompatibility of 40–120-μm trisacryl-gelatin microspheres (Embospheres) in chronic partial kidney embolization.MethodsTwenty-two animals were divided into four groups: group 1 (nxa0=xa04) underwent total arterial renal occlusion with immediate euthanasia. Groups 2–4 had chronic superselective and partial renal embolization with increasing follow-up times: group 2 (nxa0=xa02), 1 week; group 3 (nxa0=xa07), 4 weeks; and group 4 (nxa0=xa09), 14 weeks. Key endpoints in group 1 were homogeneity and completeness of acute embolizations. In groups 2–4 the key endpoints were durability of embolization and particle-related inflammation in chronic partial embolizations as assessed by quantitative angiography or histomorphometry. A numerical angiographic occlusion score (0.0 to 4.0, where 3.0 is optimal) was developed to assess and quantify the angiographic durability of superselective embolizations (groups 2–4).ResultsIn group 1, a relatively homogeneous distribution of the particles from segmental arteries to the precapillary level was shown by histomorphometry. Some particles reached the glomerular vas afferens (10xa0μm diameter). In groups 2–4, a mild recanalization appeared during follow-up. The immediate average postembolization occlusion score of 3.18xa0±xa00.73 was reduced to 1.44xa0±xa00.73 (statistically significant). Microscopy revealed subtotal necrosis but no foreign body granuloma formation. The intra-arterial appearance of giant cells closely attaching to the surface of the embolic spheres inside the vessel lumen was noted. Vessel walls showed major ischemic reactions.ConclusionMicrospheres 40–120xa0μm in diameter might achieve total occlusion of the arterial kidney vasculature when injected centrally as a result of their fairly homogeneous distribution. Segmental renal infarction occurs after chronic partial embolization despite recanalizations during follow-up. Only mild specific intra-arterial foreign body reactions were found.

Inflammation and Recanalization of Four Different Spherical Embolization Agents in the Porcine Kidney Model

PURPOSEnTo evaluate the pattern of recanalization and specific inflammatory reaction after superselective embolization with four commercially available spherical embolic agents of different sizes in the mini pig kidney model.nnnMATERIALS AND METHODSnIn 40 mini pigs, the lower poles of both kidneys were superselectively embolized with Embozene, Embosphere, Bead Block, and Contour SE particles in sizes of 40-120 mircom (Embozene, Embosphere) and 100-300 microm, 500-700 microm, and 700-900 microm (Embozene, Embosphere, Bead Block, Contour SE). After a follow-up time of 4 or 12 weeks, recanalization was determined with angiography. Pathologic and histologic evaluation of the kidneys was performed, and the Banff 97 classification was used to evaluate the extent of vessel wall inflammation. Macroscopically visible ischemic changes were evaluated by using a specific ischemia score.nnnRESULTSnAfter embolization with Embozene microspheres, larger Embosphere particles, and Bead Block and Contour SE particles, the absence of inflammation or a low inflammation score was observed. Significantly elevated inflammation scores were evident with small Embosphere particles after 4 weeks (mean score, 1.21 +/- 1.0). Distinct recanalization occurred with Contour SE particles (100% recanalization with 100-300-microm particles at 12 weeks, 500-700-microm particles at 4 and 12 weeks, and 700-900-microm particles at 4 weeks). Ischemia scores were highest in the target area in all specimens. Mildly elevated ischemia scores in nontarget tissue areas were indicative of minor nontarget embolization.nnnCONCLUSIONSnExcept for small Embosphere particles at 4 weeks, the absence of inflammatory reaction to the embolization procedure or only low inflammatory changes were observed with all embolic agents, particle sizes, and follow-up intervals. Recanalization was evident with all embolic agents; however, it was pronounced with Contour SE particles.

Experimental Liver Embolization with Four Different Spherical Embolic Materials: Impact on Inflammatory Tissue and Foreign Body Reaction

We sought to describe and compare material specific inflammatory and foreign body reactions after porcine liver embolization with spherical embolic agents. In 40 animals, superselective liver embolization was performed with four different spherical embolic agents of various sizes: 40–120xa0μm (Embozene, Embosphere), and 100–300xa0μm, 500–700xa0μm, and 700–900xa0μm (Embozene, Embosphere, Bead Block, and Contour SE, respectively). After 4 or 12xa0weeks, inflammatory reactions were evaluated microscopically according to the Banff 97 classification. For investigation of foreign body reactions, a newly designed giant cell score was applied. Banff 97 and giant cell scores closely correlated. At 4xa0weeks, small Embosphere particles (100–300xa0μm) had a significantly higher Banff 97 score than Embozene, Bead Block, and Contour SE of the corresponding size. After 12xa0weeks, the calculated differences were not statistically significant. Comparison between the 4-week results and the 12-week results revealed a statistically higher Banff 97 score for Embosphere 100–300xa0μm after 4xa0weeks than after 12xa0weeks (Pxa0=xa00.02). The overall foreign body reaction was pronounced after embolization with smaller particles, especially in small Embosphere particles. Giant cell numbers with Embosphere 100–300xa0μm were statistically higher compared with the other materials of corresponding size (Pxa0<xa00.0001). Inflammatory and giant cell reactions after embolization procedures depend on the embolic material. The overall inflammatory reaction was low. However, marked inflammation was associated with small Embosphere particles at 4xa0weeks, a finding that might be caused by the allogeneic overcoat. Correspondingly, giant cells indicating a foreign body reaction were more frequently associated with small particle sizes, especially after embolization with small Embosphere particles.

Midterm Results of Uterine Artery Embolization Using Narrow-Size Calibrated Embozene Microspheres

PurposeTo evaluate safety and efficacy of uterine artery embolization using narrow-size-range polyphosphazene-coated hydrogel microspheres (Embozene, CeloNova Biosciences, Newnan, GA).MethodsBetween May 2006 and September 2008, a total of 121 consecutive patients (meanxa0±xa0SD age 42.1xa0±xa05.4xa0years, range 30.5–51.5xa0years) were enrolled onto this single-center study. The primary study endpoint was safety as assessed by the society of interventional radiology (SIR) classification. The secondary endpoint was efficacy, which was based on a 1-year magnetic resonance imaging study and relief of symptoms documented by the Medical Outcomes Study 36-Item Short-Form Health Survey questionnaire over a 2-year interval.ResultsThe meanxa0±xa0SD diameter of the dominant fibroid was 6.4xa0±xa02.6 (range, 2.9–13.9) cm and the mean volume 137.2xa0±xa0245.1 (range, 5.3–1184) ml. Most patients had multiple fibroids with 11% more than 10. A total of 240 of 242 interventions were completed as planned, a technical success rate of 99.2%. According to the SIR classification, one type A, eight type C, and one type D complication occurred. Total devascularization was noted in 96% (116 of 121) of dominant fibroids. Volume decrease was 4% at 2xa0weeks, 52% (Pxa0<xa00.001) at 3xa0months, 78% (Pxa0<xa00.001) at 6xa0months, and 91% at 12xa0months (Pxa0<xa00.001). The latter difference was statistically significant (Pxa0=xa00.007). A total of 92% had improved hypermenorrhea at 1xa0year and 94% at 2xa0years. Dysmenorrhea was improved in 96% at 1xa0year and in 95% at 2xa0years. The overall health status score was 60.4xa0±xa026.2 points at baseline and 96.9xa0±xa03.8 after 1xa0year (Pxa0=xa00.0019).ConclusionUterine artery embolization with Embozene microspheres is a safe procedure. Its efficacy is demonstrated by high fibroid devascularization and volume reduction rates and significant improvements of clinical symptoms and quality-of-life scores during follow-up.

Restenosis of the CYPHER-Select, TAXUS-Express, and Polyzene-F nanocoated cobalt-chromium stents in the minipig coronary artery model.

PurposeTo date no direct experimental comparison between the CYPHER-Select and TAXUS-Express stents is available. Therefore, we investigated late in-stent stenosis, thrombogenicity, and inflammation, comparing the CYPHER-Select, TAXUS-Express, and custom-made cobalt chromium Polyzene-F nanocoated stents (CCPS) in the minipig coronary artery model.MethodsThe three stent types were implanted in the right coronary artery of 30 minipigs. The primary endpoint was in-stent stenosis assessed by quantitative angiography and microscopy. Secondary endpoints were inflammation and thrombogenicity evaluated by scores for inflammation and immunoreactivity (C-reactive protein and transforming growth factor beta). Follow-up was at 4 and 12xa0weeks.ResultsStent placement was successful in all animals; no thrombus deposition occurred. Quantitative angiography did not depict statistically significant differences between the three stent types after 4 and 12xa0weeks. Quantitative microscopy at 4xa0weeks showed a statistically significant thicker neointima (pxa0=xa00.0431) for the CYPHER (105.034xa0±xa062.52xa0μm) versus the TAXUS (74.864xa0±xa066.03xa0μm) and versus the CCPS (63.542xa0±xa039.57xa0μm). At 12xa0weeks there were no statistically significant differences. Inflammation scores at 4xa0weeks were significantly lower for the CCPS and CYPHER compared with the TAXUS stent (pxa0=xa00.0431). After 12xa0weeks statistical significance was only found for the CYPHER versus the TAXUS stent (pxa0=xa00.0431). The semiquantitative immunoreactivity scores for C-reactive protein and transforming growth factor beta showed no statistically significant differences between the three stent types after 4 and 12xa0weeks.ConclusionsThe CCPS provided effective control of late in-stent stenosis and thrombogenicity in this porcine model compared with the two drug-eluting stents. Its low inflammation score underscores its noninflammatory potential and might explain its equivalence to the two DES.

Retrospective Study in 23 Patients of the Self-Expanding Sinus-XL Stent for Treatment of Malignant Superior Vena Cava Obstruction Caused by Non–Small Cell Lung Cancer

PURPOSEnTo evaluate retrospectively the self-expanding nitinol Sinus-XL stent (OptiMed, Ettlingen, Germany) for the treatment of superior vena cava (SVC) obstruction caused by non-small cell lung cancer (NSCLC).nnnMATERIALS AND METHODSnBetween October 2009 and December 2012, 23 patients (7 women and 16 men; age, 62.5 y ± 8.5) with stage IIIA (1 patient), IIIB (4 patients) or IV (18 patients) NSCLC and acute SVC obstruction were scheduled for urgent stent implantation. The primary study endpoints were technical success (defined as accurate stent placement with complete coverage of the obstructed SVC), residual stenosis < 30%, and clinical efficacy. Complications were assessed as a secondary study endpoint.nnnRESULTSnThere were 26 stents implanted in 23 patients. The technical success was 100%. Stent dilation was performed after deployment in 18 cases (78%). Stent migration into the right atrium occurred immediately after deployment in one patient; however, this stent was successfully repositioned and stabilized by a second stent. The clinical symptoms improved at least one category according to the International Consensus Committee on Chronic Venous Disease after stent implantation in all but one patient. The mean clinical follow-up was 66 days ± 83 (range, 1-305 d). Three minor complications (13%) and one major complication (4%) occurred.nnnCONCLUSIONSnImplantation of the self-expanding Sinus-XL stent for treatment of SVC obstruction caused by NSCLC is a safe and effective urgent treatment in this palliative setting.

Immunohistochemical Characterization of Specific Inflammatory Tissue Reactions following Embolization with Four Different Spherical Agents in the Minipig Kidney Model

PURPOSEnTo evaluate the immunohistochemical inflammatory reaction after porcine renal embolization with the new spherical embolic agent Embozene and to compare it with other spherical embolic agents.nnnMATERIALS AND METHODSnAfter superselective porcine renal embolization (40 pigs) with different sizes of embolic agents (Embozene, Embosphere, Bead Block, Contour SE), tissue arrays were obtained (size ranges, 40-120 microm, 100-300 microm, 500-700 microm, 700-900 microm). After immunostaining for CD subtyping (CD45 and CD68) and cytokines (C-reactive protein [CRP] and interleukin-1 beta), a semiquantitative immunoreactivity score was calculated for each marker: intensity of staining was scored between 0 (negative) and 3 (intensive) and extent of staining between 0 and 4 (>80%), indicating the percentage of positive staining. The intensity score (0-3) was multiplied by the extent of staining score (0-4), resulting in a semiquantitative immunoreactivity score (0-12).nnnRESULTSnAnalysis of cellular expression profiles (ie, CD45, CD68) revealed a significantly higher inflammatory score 4 weeks after embolization with Embosphere 100-300 microm particles than after embolization with Embozene, Bead Block, and Contour SE. After 12 weeks, the Embosphere 100-300 microm score decreased. Analysis of CRP expression showed similar results, with a significantly higher score 4 weeks after embolization with Embosphere 100-300 microm. In the size class used most frequently for uterine artery emboliation (500-700 microm), all scores were low (<2.5) and there was no significant difference among particle types.nnnCONCLUSIONSnPronounced immunomarker expression was seen 4 weeks after embolization with small Embosphere particles. However, in general, modern spherical embolic agents cause a fairly low level of inflammatory reaction. In the present experimental setting, which is highly sensitive for specific tissue-to-agent reactivity, Embozene presented with low inflammatory results.

Reduction of Late In-Stent Stenosis in a Porcine Coronary Artery Model by Cobalt Chromium Stents with a Nanocoat of Polyphosphazene (Polyzene-F)

The purpose of this study was to investigate the potential of nanoscale coating with the highly biocompatible polymer Polyzene-F (PZF), in combination with cobalt chromium and stainless steel stents, to reduce in-stent stenosis, thrombogenicity, and vessel wall injury and inflammation. One bare cobalt chromium, PZF-nanocoated stainless steel or PZF-nanocoated cobalt chromium stent was implanted in right coronary artery of 30 mini-pigs (4- or 12-week follow-up). Primary study end points were in-stent stenosis and thrombogenicity. Secondary study end points were vessel wall injury and inflammation as evaluated by microscopy and a new immunoreactivity score applying C-reactive protein (CRP), tumor-necrosis factor alpha (TNFα), and TGFβ. At 12xa0weeks, angiography showed a significantly lower average loss in lumen diameter (2.1%xa0±xa03.05%) in PZF-nanocoated cobalt chromium stents compared with stents in the other groups (9.73%xa0±xa04.93% for bare cobalt chromium stents and 9.71%xa0±xa07% for PZF-nanocoated stainless steel stents; pxa0=xa00.04), which was confirmed at microscopy (neointima 40.7xa0±xa016xa0μm in PZF-nanocoated cobalt chromium stents, 74.7xa0±xa057.6xa0μm in bare cobalt chromium stents, and 141.5xa0±xa0109xa0μm in PZF-nanocoated stainless steel stents; pxa0=xa00.04). Injury and inflammation scores were low in all stents and were without significant differences. PZF-nanocoated cobalt chromium stents provided the highest efficacy in reducing in-stent stenosis at long-term follow-up. The PZF nanocoat proved to be biocompatible with respect to thromboresistance and inflammation. Our data suggest that its combination with cobalt chromium stents might provide an interesting passive stent platform.