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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/265392992 A Novel Resorbable Embolization Microsphere for Transient Uterine Artery Occlusion: A Comparative Study with... Article in Journal of vascular and interventional radiology: JVIR · September 2014 DOI: 10.1016/j.jvir.2014.06.025 · Source: PubMed CITATIONS 3 READS 51 9 authors, including: Some of the authors of this publication are also working on these related projects: Drug Delivery Systems for mini-invasive treatments View project Valentin Verret French National Institute for Agricultural Res… 33 PUBLICATIONS 69 CITATIONS SEE PROFILE Mchel Wassef Hôpital Lariboisière - Fernand-Widal (Hôpita… 276 PUBLICATIONS 4,346 CITATIONS SEE PROFILE Laurent Bédouet Occlugel 58 PUBLICATIONS 692 CITATIONS SEE PROFILE Alexandre Laurent APHP - Hopital Lariboisière, 2 rue A.Paré, 750… 152 PUBLICATIONS 2,147 CITATIONS SEE PROFILE All content following this page was uploaded by Laurent Bédouet on 07 May 2015. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
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  • Seediscussions,stats,andauthorprofilesforthispublicationat:https://www.researchgate.net/publication/265392992

    ANovelResorbableEmbolizationMicrosphereforTransientUterineArteryOcclusion:AComparativeStudywith...

    ArticleinJournalofvascularandinterventionalradiology:JVIRSeptember2014

    DOI:10.1016/j.jvir.2014.06.025Source:PubMed

    CITATIONS

    3

    READS

    51

    9authors,including:

    Someoftheauthorsofthispublicationarealsoworkingontheserelatedprojects:

    DrugDeliverySystemsformini-invasivetreatmentsViewproject

    ValentinVerret

    FrenchNationalInstituteforAgriculturalRes

    33PUBLICATIONS69CITATIONS

    SEEPROFILE

    MchelWassef

    HpitalLariboisire-Fernand-Widal(Hpita

    276PUBLICATIONS4,346CITATIONS

    SEEPROFILE

    LaurentBdouet

    Occlugel

    58PUBLICATIONS692CITATIONS

    SEEPROFILE

    AlexandreLaurent

    APHP-HopitalLariboisire,2rueA.Par,750

    152PUBLICATIONS2,147CITATIONS

    SEEPROFILE

    AllcontentfollowingthispagewasuploadedbyLaurentBdoueton07May2015.

    Theuserhasrequestedenhancementofthedownloadedfile.Allin-textreferencesunderlinedinblue

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    https://www.researchgate.net/publication/265392992_A_Novel_Resorbable_Embolization_Microsphere_for_Transient_Uterine_Artery_Occlusion_A_Comparative_Study_with_Trisacryl-Gelatin_Microspheres_in_the_Sheep_Model?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_2&_esc=publicationCoverPdfhttps://www.researchgate.net/project/Drug-Delivery-Systems-for-mini-invasive-treatments?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_9&_esc=publicationCoverPdfhttps://www.researchgate.net/?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_1&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Valentin_Verret?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_4&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Valentin_Verret?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_5&_esc=publicationCoverPdfhttps://www.researchgate.net/institution/French_National_Institute_for_Agricultural_Research?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_6&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Valentin_Verret?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_7&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Mchel_Wassef?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_4&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Mchel_Wassef?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_5&_esc=publicationCoverPdfhttps://www.researchgate.net/institution/Hopital_Lariboisiere-Fernand-Widal_Hopitaux_Universitaires_Sant-Louis_Lariboisiere_Fernand-Widal?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_6&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Mchel_Wassef?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_7&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Laurent_Bedouet?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_4&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Laurent_Bedouet?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_5&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Laurent_Bedouet?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_7&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Alexandre_Laurent2?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_4&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Alexandre_Laurent2?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_5&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Alexandre_Laurent2?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_7&_esc=publicationCoverPdfhttps://www.researchgate.net/profile/Laurent_Bedouet?enrichId=rgreq-d7aca9fca4c328bff4974b0ae0642b4c-XXX&enrichSource=Y292ZXJQYWdlOzI2NTM5Mjk5MjtBUzoyMjY1ODU0OTcwODM5MDRAMTQzMTAzMzYwMDg1MA%3D%3D&el=1_x_10&_esc=publicationCoverPdf

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    LABORATORY INVESTIGATION

    A Novel Resorbable Embolization Microsphere forTransient Uterine Artery Occlusion: A Comparative

    Study with Trisacryl-Gelatin Microspheres in theSheep Model

    Valentin Verret, Eng MSc, Jean Pierre Pelage, MD, Michel Wassef, MD,Stphanie Louguet, PhD, Emeline Servais, PhD, Laurent Bdouet, PhD,

    Thomas Beaulieu, Eng MSc, Laurence Moine, PhD, andAlexandre Laurent, MD, PhD

    ABSTRACT

    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 nonresorbablemicrospheres.

    Materials and Methods: Six hormonally cycled sheep underwent bilateral UAE until stasis with either REM or trisacryl-gelatinmicrospheres (TGMS). At 7 days, control angiograms were obtained to assess the residual vascularization at arterial and parenchymalphases. The animals were then sacrificed for analysis of the presence of microspheres, inflammatory foreign body reaction, and surfaceareas of uterine damage.

    Results: Mean volume of microspheres injected per uterine artery (UA) or per animal did not differ between groups. At day 7, theflow was normal for six of six UAs that received embolization with REM versus only three of six UAs with TGMS (P .0455, 2test). Uterine parenchymography showed no defects in six UAs in the REM group versus five defects in six UAs in the TGMS group(P .0060, 2 test). No REM or residual fragments of microspheres were observed on histologic analysis. TGMS were observed intissues 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 (REM8.2% 22.7% [median 0.0%] vs TGMS 8.8% 20.8% [median 0.9%]). Endometrium alteration rate was lower with REM than withTGMS (39.7% 25.7% [median 34%] vs 60.6% 27.1% [median 71%]; P .0060, Mann-Whitney test). Myometrium alterationrates 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.

    ABBREVIATIONS

    PEG = polyethylene glycol, PLGA = polylactic-glycolic acid, REM = resorbable embolization microsphere, TGMS = trisacryl-gelatinmicrospheres, UA = uterine artery, UAE = uterine artery embolization

    58596061626364656667686970

    & 2014 Published by Elsevier, Inc., on behalf of the SIR.

    J Vasc Interv Radiol 2014; XX:]]]]]]

    http://dx.doi.org/10.1016/j.jvir.2014.06.025

    V.V., S.L., L.B., E.S., and T.B. receive salaries from Occlugel SAS. A.L., L.M.,and M.W. are shareholders in Occlugel SAS. J.P.P. is a paid consultant ofOcclugel SAS. This research work was funded by Occlugel SAS.

    From Occlugel SAS (V.V., S.L., E.S., L.B., T.B.), Jouy en Josas; Service deRadiologie (J.P.P.), Centre Hospitalier Universitaire de Caen, Caen; Departe-ment de Pathologie (M.W.) and Departement de Neuroradiologie Interven-tionnelle (A.L.), APHP, Hpital Lariboisire, 2 rue Ambroise Par, 75010 Paris,France; UMR CNRS 8612 Institut Galien Paris-Sud (L.M.), Chatenay Malabry;Universit Ren Diderot (M.W., A.L.), Paris; and Laboratoire MSC (A.L.), Paris,France. Received March 5, 2014; final revision received June 11, 2014;accepted June 25, 2014. Address correspondence to A.L.; E-mail: [email protected]

    For uterine fibroid embolization, nonbiodegradable par-ticles are not ideal. After having played their occlusive role,they persist as remnant foreign bodies in the uterus andgenerate an inflammatory response, which sometimes maylast months (13). Uterine arteries (UAs) that receivedembolization may recanalize, but this is inconstant andpartial (2,4). It has been found in the sheep model thatembolization particles could constitute a durable obstacleto flow in UAs, even after a partial recanalization, reducingfertility or lowering birth weight (4).By contrast, biodegradable embolization materials are

    designed to generate an inflammatory reaction that is

    dx.doi.org/10.1016/j.jvir.2014.06.025dx.doi.org/10.1016/j.jvir.2014.06.025dx.doi.org/10.1016/j.jvir.2014.06.025mailto:[email protected]:[email protected] Textgivenname

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    Original TextAU: Please approve shortened running head title or provide one that is 60 characters, including spaces.

    Original TextAU: Are all author degrees correct as added?

    Original TextPlease confirm that given names and surnames have been identified correctly and are presented in the desired order.

    Original TextAU: Editing of Purpose to conform to journal style OK?

    Original TextAU: Need to explain the phrase "hormonally cycled"?

    Original TextAU: Correct to add "%" to median values?

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    Verret et al JVIR2 Novel REM for Transient UterineQ3 Artery Occlusion

    limited to their period of resorption to insure a full andconstant recanalization of UA. The resorption time ofdegradable particles is long and associated with vasculardamage and remodeling that delay and limit recanaliza-tion. Gelatin sponge particles undergo a prolongeddegradation that lasts for weeks or months and isaccompanied by a chronic inflammatory response, vesselremodeling, and a fibrotic reaction (5,6). Collagen-coated polylactic-glycolic acid (PLGA) microspheresdegrade slowly over several months, they generate alocal inflammatory response, and the UAs remain fullyoccluded by fibrous connective tissue at 6 months (7).The persistence of particles in the vessel wall and theremodeling of the UA could act as an obstacle to bloodflow. The dilation of the UA that occurs duringpregnancy, which is important for gestation (810),could be compromised.To remedy these drawbacks, we have conceived

    a resorbable embolization microsphere (REM) thatwould satisfy two imperatives. First, it should occludethe vessel for a short timebetween a few hours and afew daysto achieve ischemia of fibroids. Second, itshould subsequently be quickly and completely elimi-nated, before the onset of a chronic inflammatoryresponse and vessel wall remodeling. We postulated thatthe UA recanalization and the absence of chronicinflammation would facilitate the healing process ofthe uterus, which could sustain collateral damage duringfibroid embolization. UA recanalization would be bene-ficial to changes in UA diameter during hormonalcycling and pregnancy.We designed the REM from a polyethylene glycol

    (PEG) hydrogel cross-linked with hydrolyzable bridges(11). PEG hydrogel was chosen because it is usedin many biomedical applications for its hydrophili-city, elasticity, and biocompatibility (11). The resorptionspeed of PEG hydrogel REM can be controlled byadjusting the polymer chemistry of the hydrolyzablecross-link. The components were chosen to generate, afterhydrolysis, macromolecules that are water-soluble toavoid any accumulation in the organism leading toinflammatory reactions (12). Hydrolyzable linkages wereincorporated into the hydrogel backbone to shorten thesize of the polymer degradation products (o 50 kg/mol),facilitating renal elimination (13,14).PEG hydrogel microspheres with high water content

    ( 90%) have been synthesized with sizes ranging from1001,000 mm. Their biocompatibility was assessedin vitro by cytotoxicity tests of the microspheres andtheir degradation products on various cells in cultureand in vivo by subcutaneous implantation in rabbits (15).Degradation of the microspheres by hydrolysis inphosphate-buffered saline is achieved in o 24 hours.An in vivo study demonstrated that this REM allowedtargeted and efficient occlusion of renal arteries andangiographic recanalization at 1 week with no residualinflammation in tissue (16). The purpose of the present

    study was to evaluate recanalization, inflammation, anduterine damage with REM 7 days after uterine arteryembolization (UAE) in the sheep model by comparisonwith a nonresorbable reference microsphere.

    MATERIALS AND METHODS

    MicrospheresREM (ResMic; Occlugel SAS, Jouy-en-Josas, France)were made by suspension polymerization of a PEGhydrogel cross-linked with PLGA-PEG-PLGA hydro-lyzable bridges (15). The formulation was adjusted toobtain a resorption time of 24 hours in phosphate-buffered saline. Hydrated REM were soft and containedabout 90% of water. After sieving at the size range of500700 mm, REM were freeze-dried and sterilized by -irradiation (IONISOS, Chaumesnil, France). REM werecompared with trisacryl-gelatin microspheres (TGMS)(Embosphere; Merit Medical Systems, Salt Lake City,Utah) at the nominal range 500700 mm, which is themost common diameter used for uterine fibroid embo-lization in clinical practice.

    AnimalsAll experiments were approved by the institutionalanimal care and use committee. Embolization (threeprocedures per type of embolic agent) was performedon six adult Pralpes Sheep (54 kg 3, 48 mo 22).For each animal, the type of embolic agent used wasrandomly assigned.

    Embolization ProcedureSheep were artificially cycled 16 days before the embo-lization procedure to obtain a maximal dilation of UAs(17). Sheep were not fed for 24 hours before theprocedure. Anesthesia was induced by intramuscularinjection of 15 mg thiopental sodium (Nesdonal) perkilogram of body weight. Each animal was placed insupine position, intubated, anesthetized with a mixtureof 1.5% isoflurane (Vetflurane; Virbac, Carros, France)and 98.5% oxygen (Linde, Paris, France), and ventilatedusing a Primus workstation (Drger Medical, Antony,France). End-tidal carbon dioxide levels were measuredcontinuously and maintained at 2636 mm Hg with amonitor (Infinity Gamma XXL; Drger Medical).Peripheral arterial oxygen saturation, maintained at495%, was monitored with a probe applied to the ear.Aliquots of 2 mL of embolization microspheres weresuspended in a solution of contrast agent (Telebrix35, 350 mg I/mL; Guerbet, Villepinte, France) and saline(Versol; Laboratoires Aguettant, Lyon, France) follow-ing the manufacturers instructions for use (REM, 12mL saline 6 mL contrast agent; TGMS, 8 mL saline 10 mL contrast agent). Animals were randomly assignedto receive REM or TGMS. A 5-F vascular sheath wasplaced in the femoral artery by using the standard

    Original TextAU: Is "6 months" correct as added?

    Original TextAU: Addition of the phrase "which is important for gestation" OK?

    Original TextAU: Need to define or clarify the phrase "Sheep were artificially cycled"?

    Original TextAU: Please add manufacturer name and location for Nesdonal.

    Original TextAU: Is addition of the phrase "using a Primus workstation" correct?

    Original TextAU: Location for Laboratoires Aguettant correct as added?

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    Volume XX Number X Month 2014 3

    Seldinger technique under sterile conditions. Selectiveembolization of both internal iliac arteries was achievedusing a Cobra-type catheter, and superselective emboli-zation of both UAs was performed with a 2.7-F micro-catheter (Progreat, inner diameter 0.027 inch [0.65 mm];Terumo). The tip of the microcatheter was placed 4 cmdistally into the UA at the level of the uterine arch. Theinjection was performed slowly (1 mL/min) under fluo-roscopic control using 3-mL syringes. After injection ofthe embolic agent, the catheter was flushed with 3 mL ofsaline. Embolization was stopped when stasis of contrastmedium was observed in the UA. The stasis was assessed3 minutes later to ensure that no secondary redistrib-ution of embolization microspheres occurred. Theamount of microspheres injected to obtain stasis wasrecorded.

    Follow-up and Sacrifice after EmbolizationVeterinary follow-up evaluation (behavior, appetite,complete blood count) was performed for each ewebefore sacrifice. In accordance with the protocol, ananimal with any abnormal behavior or in pain would besacrificed immediately. Otherwise, sacrifices were sched-uled at 7 days after embolization. On the day of sacrifice,bilateral control angiography of the UAs was per-formed. Sheep were sacrificed by pentobarbital injection(Dolethal; Vetoquinol, Paris, France) under anesthesia.

    Angiographic ControlAngiography was performed before embolization toassess the vascular anatomy of each sheep. Embolizationwas considered successful if stasis was present in themain UA on angiography performed after embolization.Recanalization was assessed for each UA 7 days afterembolization and compared with initial angiography.The blood flow in the UA was evaluated using a three-grade scale: normal flow, reduced flow (defined ascontrast material visible during five heart beats beforedisappearing), and stasis (defined as the blockade of thecontrast column in the UA). Parenchymography wasassessed as normal (without defect of opacification), withdefects of opacification, or absent when there was noopacification of the parenchyma.Each uterus was sampled by cutting 10-mm-thick

    slices in the body, in the left and right horns, and inthe ovaries. For each animal, two to three specimens ofthe body, five to six specimens of the horns, and onespecimen of each ovary were dehydrated in a series ofalcohols, set in xylene, embedded in paraffin, cut intoradial 4- to 5-mm-thick sections, and mounted on glassslides. Each section was stained with hematoxylin-eosin-saffron.

    Histologic AnalysisHistologic slides were digitalized with a NanoZoomer2.0-HT slide scanner at a 20 objective (Hamamatsu,

    Hamamatsu, Japan). Measurements were performedwith CaloPix (TRIBVN, Chtillon, France). Occludedvessels were analyzed on histologic sections for each typeof embolization material. The presence or absence ofrecanalization was assessed based on the presence orabsence of a vascular lumen with red blood cells orplasma in the area of the occluded vessel. Microscopicevaluation of the area of endometrial and myometriallesions was performed on each section. The two layers ofthe myometrium (ie, inner [circular muscle cells] andouter [longitudinal muscle cells]) were measured sepa-rately. Lesions were classified according to a three-gradescale: grade 0, normal tissue; grade 1, altered tissue (ie,tissues modified by fibrosis or cells with a modifiednucleus or cytoplasm); and grade 2, necrosis withdisappearance of nuclei. The percentage of normal,altered, or necrotized tissues was calculated as follows:percent of grade x in the region (sum of areas of gradex tissues in the region/total area of the region) * 100 (x is0, 1, or 2, and region is either the myometrium or theendometrium). All sections were reviewed to detectinflammatory cells such as macrophages, neutrophils,lymphocytes, and foreign body giant cells.

    Statistical AnalysisStatistical analyses were performed on StatView SAS2000 (SAS Institute Inc, Cary, North Carolina). Becausethe continuous values measured mainly followed a non-Gaussian distribution, nonparametric Mann-Whitney or2 tests were performed for comparisons. Continuousvariables were expressed as median and mean SD.

    RESULTS

    EmbolizationBilateral UAE was successful in all animals. The desiredangiographic endpoint (ie, arterial stasis) was obtainedin all cases (Figs 1ad, 2ad, 3ad). There was no diffe-rence between TGMS and REM in terms of buoyancyafter mixing with contrast media and saline and no diffe-rence of injectability. For REM, a mean volume of 1.0mL 0.5 of microspheres was injected per UA (range,0.52 mL) for a total of 2.1 mL 0.8 per animal (range,1.53 mL). For TGMS, the mean volume was 1.6 mL 0.9 (range, 0.52.5 mL) for a total of 3.2 mL 1.9 peranimal (range, 14.5 mL). No statistical difference bet-ween the two groups was found in terms of mean volumeof microspheres injected per UA (P .3785, Mann-Whitney) or per animal (P .5635, Mann-Whitney).During the follow-up period after embolization, therewas no abnormal behavior, no limping, and no pain. Noabnormal blood count was observed.

    Angiographic RecanalizationArterial blood flow was graded normal for all UAarteries that received embolization with REM (six of

    Original TextAU: Please add city, country location for Terumo?

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    299300301302303304305306307308309310311312313314315316317318319320321322323324325326327328329330331332333334335336337338339340341342343344345346347348349350351352353354355

    356357358359360361362363364365366367368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399400401402403404405406407408409410411412

    Figure 1. Example of full UA recanalization and complete parenchyma opacification after embolization with REM. (a) Angiogramobtained before embolization. UA (arrow) and parenchyma (star) are opacified. (b) Angiogram obtained 10 minutes after embolization.

    Q24 Flow is interrupted at the level of the descending UA (arrow). (c) Angiogram obtained 7 days after embolization. Opacification of UA andits branches (arrow) at arterial phase. (d) Angiogram obtained 7 days after embolization. Opacification of parenchyma (star).

    Verret et al JVIR4 Novel REM for Transient UterineQ3 Artery Occlusion

    six) and in only three of six UAs that received emboli-zation with TGMS. A reduced blood flow was observedin the remaining three of six UAs, making a significantdifference between REM and TGMS (P .0455, 2)(Figs 1ad, 2ad, 3ad). Uterine parenchymography inthe animals with embolization with REM was normal insix of six UAs (Fig 1ad). With TGMS, parenchymo-graphy was normal in one of six UAs, and five of sixUAs showed defects of opacification corresponding to asignificant difference between REM and TGMS (P .0060, 2).

    HistologyAt gross examination, brownish areas of ischemicdamage to the endometrium and myometrium werefound in all uteri. Fibrinous exudates were found in

    lumens of uteri. No abnormality was seen in the ovaries.There were 59 histologic sections analyzed. No REMwere found in the specimens, whereas 998 TGMS wereassociated with occlusion of 223 arterial branches. AllUAs that received embolization with REM were patent,with no residual fragments of microspheres in the tissues.Arteries exhibited a normal aspect, without arterial wallmodification (Fig 4).TGMS were found in organized thrombi, and 79% of

    the arteries occluded by TGMS showed evidence ofrecanalization, characterized by a new endothelium,fresh blood flow, or plasma in a lumen (Fig 5). TGMSwere surrounded by some layers of macrophages,neutrophils, and sometimes foreign body giant cells.Such cell types have not been identified in the arterialwall of vessels that received embolization with REM.

    Original TextAU: Correct to add "after embolization" for fig 1b?

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    Figure 2. Example of complete UA recanalization and parenchymal defects after embolization with TGMS. (a) Angiogram obtained beforeembolization. UA and its branches (arrow) and parenchyma (star) are opacified. (b) Angiogram obtained 10 minutes after embolization.

    Q25 Flow is interrupted at the level of UA ascending branches (arrow). (c) Angiogram obtained 7 days after embolization. Opacification of UA(arrow) at arterial phase. (d) Angiogram obtained 7 days after embolization. Defects of opacification of parenchyma (arrows).

    Volume XX Number X Month 2014 5

    Histologic grade 2 (necrosis) and grade 0 (normaltissues) specimens were not significantly different bet-ween the two products in the myometrium and in theendometrium (each P 4 .05, Mann-Whitney) (Table).There were significantly more grade 1 (altered) tissues inthe endometrium with TGMS than with REM (P .0060, Mann-Whitney), but this was not the case in themyometrium (P 4 .05, Mann-Whitney).

    519520521522523524525526

    DISCUSSION

    The first major finding of the present study is that REMinjected in UAs disappear, and a complete recanaliza-tion is rapidly obtained. The rapid resorption of REM isnot surprising because the constituting biomaterial has

    been specifically designed to be fully hydrolyzed within12 days in contact of fluids. Hydrolytic degrada-tion experiments performed in vitro have demonstratedthat REM were totally degraded within 24 hours (15).Logically, vessels that received embolization using REMwere fully patent on angiography 7 days after emboli-zation. At that time, the angiographic aspect of theuterus was similar to angiography performed beforeembolization, both in terms of arterial flow and interms of uterine parenchymography (16). The rapidresorption of the biomaterial was not associated withany structural alteration of the arterial wall of vessels.Conversely, with TGMS, arterial blood flow reductionand defects of parenchymography were present. Suchincomplete recanalization after 7 days was expectedbecause it is a common feature of nonresorbable

    Original TextAU: Correct to add "after embolization" for fig 2b?

    Original TextAU: Per journal style, it is preferable to avoid subheadings in the Discussion; OK to remove all subheadings?

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    527528529530531532533534535536537538539540541542543544545546547548549550551552553554555556557558559560561562563564565566567568569570571572573574575576577578579580581582583

    584585586587588589590591592593594595596597598599600601602603604605606607608609610611612613614615616617618619620621622623624625626627628629630631632633634635636637638639640

    Figure 3. Example of absence of recanalization and reduced parenchymal opacification after embolization with TGMS. (a) Angiogramobtained before embolization. UA and its branches (arrow) and parenchyma (star) are opacified. (b) Angiogram obtained 10 minutesafter embolization. Flow is interrupted at the level of UA ascending branches (arrow). (c) Angiogram obtained 7 days after embolization.UA flow is interrupted (arrow). (d) Angiogram obtained 7 days after embolization. Slight, incomplete opacification of parenchyma (star).

    Verret et al JVIR6 Novel REM for Transient UterineQ3 Artery Occlusion

    particles (14). Incomplete recanalization has also beendescribed with slowly resorbable particles of gelatin orPLGA and has been related to a chronic remodelingprocess followed by stenosis or fibrosis or both (57).To achieve necrosis of fibroids, the occlusion time

    induced by a degradable material has to be sufficient toobtain adequate ischemia, and this remains to bedemonstrated in patients. It is commonly accepted thatfibroids are sensitive to ischemia and that necrosis can beobtained following reduced blood perfusion of the tissuefor a short duration of time. The immediate reduction infibroid perfusion after bilateral UAE correlates withuterine fibroid necrosis and with a favorable clinicaloutcome several months later (1820). However, theduration of occlusion required to obtain fibroid necrosisis not strictly defined. Few data are available from thetemporary UA occlusion by Doppler-guided transvagi-nal clamp, which has been proposed as a surgical

    alternative to UAE (2123) to obtain clinical improve-ment and reduction of uterine fibroids. The clamp timeranges from 57 hours according to the reported series(2123). Temporary clamping of the UA for 5170minutes generates a decrease in pH of the uterus inassociation with pain, which can be attributed toanaerobic metabolism (22). Lichtinger et al (24)observed by laparoscopy that bilateral UA clampingfor 26 minutes (range, 1059 min) resulted in a completeblanching of the uterus, which was reversible on clampopening. Our findings show that there was a similardegree of uterine necrosis in myometrium and endome-trium after embolization with REM and TGMS,suggesting that the duration of arterial occlusion withREM was sufficient to achieve the same ischemic effectsas TGMS. Clinical trials are needed to estimate the im-pact of REM resorption on the results of uterine fibroidembolization. However, because the uterine necrosis

    Original TextAU: Is change of "fibroids and uterus" to "uterine fibroids" correct?

    Original TextAU: Is the sentence "Temporary clamping of the UA for 5170 minutes generates a decrease in pH of the uterus in association with pain, which can be attributed to anaerobic metabolism" correct as edited?

    Original TextAU: Is "UFE" correctly spelled out?

  • 641642643644645646647648649650651652653654655656657658659660661662663664665666667668669670671672673674675676677678679680681682683684685686687688689690691692693694695696697

    698699700701702703704705706707708709710711712713714715716717718719720721722723724725726727728729730731732733734735736737738739740741

    Figure 5. Histologic view of arteries after embolization withREM 7 days before. All the lumens are patent, devoid of anyREM residue or organizing thrombus. The arterioles are partlyflattened because they contain no microspheres that coulddeform them, in contrast to what is observed with TGMS (Fig 4).

    PRINT&WEB4C/FPO

    Figure 4. Histologic view of UAs that received embolizationwith TGMS 7 days before. The vessels contain TGMS, organiz-ing thrombus, and small channels of recanalization (arrows).TGMS are surrounded by a foreign body reaction containingmacrophages, neutrophils, and giant cells.

    PRINT&WEB4C/FPO

    Table . Percentages of Grade of Lesions of the Endometrium and My

    Grade of Lesions REM

    Endometrium

    GradeQ26 2 necrosis 23.5% 28.8% (median 8.1%) 21

    Grade 1 altered 39.7% 25.7% (median 34.7%) 60

    Grade 0 normal 36.7% 36.9% (median 22.1%) 17

    Myometrium

    Grade 2 necrosis 8.2% 22.7% (median 0.0%) 8.

    Grade 1 altered 45.7% 37.1% (median 63.0%) 37

    Grade 0 normal 46.1% 39.3% (median 26.7%) 53

    REM resorbable embolization microsphere; TGMS trisacryl-gel

    Volume XX Number X Month 2014 7

    resulting from REM occlusion is similar to that ofcontrol group, one can expect that the ischemic timeinduced by REM will be sufficient to achieve necrosis ofthe fibroids.There was a smaller amount of nonnecrotized but

    altered endometrium with REM compared with TGMS;this may be related to the rapid arterial recanalizationin tissue that received embolization with REM associ-ated with earlier endometrial healing. The ability of theuterus to recover from ischemic injury has been alreadyreported (19). Although ischemic fibroids undergo ir-reversible infarction, complete reperfusion of myometrialtissue is generally obtained within 4872 hours (19).There were fewer endometrial lesions with REM. Casesof myometrial damage associated with amenorrhea havebeen reported after UAE with nonresorbable particles(25,26).Because there was no ovarian damage in either group,

    no conclusion can be drawn. However, we cannot ruleout that ovarian damage could result after embolizationwith REM, as for other embolization agents.There appeared to be some relationship between the

    arterial flow on control angiography and the histologicdamage in each group. With resorbable microspheres,full UA recanalization and absence of parenchymadefect were associated with a low rate of endometrialalteration. With nonresorbable microspheres, there was50% UA blockade, parenchymal defects in most cases(five of six UAs), and significantly larger myometriumalteration than for resorbable microspheres. Similarfindings have been reported with degradable micro-spheres in a sheep kidney embolization modeltherewas less parenchymal damage when the recanalizationwas total. This finding supports the hypothesis that earlyrecanalization could attenuate the tissular damageresulting from ischemia (16). Recanalization couldfavor the repair of uterine parts damaged by ischemicstress. However, there is no strict parallel between angio-graphy and the histologic findings. The parenchymaopacification 7 days after embolization could appearnormal while the histologic damage is present.The second important result of the present study

    is the absence of residual inflammation in tissuethat received REM embolization, presumably secondary

    742743744745746747748749750751752753754

    ometrium Caused by REM versus TGMS

    TGMS P Value (Mann-Whitney)

    .8% 23.7% (median 14.6%) .3786

    .6% 27.1% (median 71.5%) .006 Q270

    .6% 25.4% (median 8.3%) .1011

    8% 20.8% (median 0.9%) .2846

    .8% 34.0% (median 19.1%) .8258

    .4% 36.9% (median 73.1%) .7672

    atin microspheres.

    Original TextAU: Correct to expand "Med" as "median" and to add "%" in Table?

    Original TextAU: Please remove bold from table body and add a footnote with asterisk to indicate the significance of this entry.

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    Verret et al JVIR8 Novel REM for Transient UterineQ3 Artery Occlusion

    to the rapid resorption of the biomaterial. No inflam-matory cells of foreign body type have been seen in theuteri that received embolization with REM, whichconfirms previous in vivo findings (15,16). The absenceof IRFB, consistent with the complete disappearance ofthe material in tissue, clearly distinguishes REM from allother embolic agents. Slowly resorbable materials areassociated with the presence of inflammatory cellsinfiltrated in the vessel wall, vessel remodeling, anda fibrotic reaction (57), so the functional vasculariza-tion of the organ is often limited (7). That no IRFBoccurs with REM is an improvement over existing em-bolic agents, including nondegradable and degradableagents such as absorbable gelatin sponge (Gelfoam),because the chronic inflammation that contributes to thepostembolization syndrome is circumvented. Conversely,a limited IRFB comprising macrophages, neutrophils,and sometimes foreign body giant cells was observedaround TGMS, as previously described (2,3).This study has some limitations. First, TGMS and

    REM were assessed at a size range commonly used forUAE in clinical practice, but the results may not beextrapolated to other size ranges. Second, no uterinefibroid was present in our animal model, which limits theapplications of our results to the clinical situation. Third,results of angiographic recanalization were obtained 7days after embolization, and the time point for achievinga complete recanalization, presumably o 7 days, has notbeen precisely defined. Fourth, the results were obtainedon a small sample size. The present findings have to beconfirmed experimentally on larger animal cohorts andultimately in clinical trials comparing REM with otherdegradable agents used as controls.In conclusion, keeping the aforementioned limitations

    in mind, it can be reasonably expected that such arapidly resorbable and calibrated material may become apromising embolization material for uterine fibroidembolization.

    850851852853854

    UNCITED REFERENCE

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    868

    Original TextAU: Please spell out IRFB here at first mention and at 2 subsequent mentions in this paragraph.

    Original TextAU: Correct to add "and" before "a fibrotic reaction"?

    Original TextAU: Please add a manufacturer and location for Gelfoam.

    Original TextAU: Please provide Ref. 27 is not cited in the text.

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