Name: Auteur in de schijnwerpers: gebruik van het venoplastiekballonmodel bij knaagdieren om chirurgische ingrepen voor diepe aderen te simuleren
Uploaded: 2024-05-24T14:30:00
Description: Balloon venoplasty is a commonly used clinical technique to treat deep vein stenosis and occlusion as a consequence of trauma, congenital anatomic ...

Deze studie wordt ondersteund door de American Venous Forum (AVF) 2023 Basic Science Research Grant en Surmodics, Inc.

Het volgende protocol volgt het beleid en de richtlijnen van het Institutional Animal Care and Use Committee (IACUC) van de Universiteit van Michigan (UMICH), de principes van de Amerikaanse overheid voor het gebruik en de verzorging van gewervelde dieren die worden gebruikt bij testen, onderzoek en training, en de ARRIVE-richtlijnen 2.0. De UMICH Animal Welfare Assurance-overeenkomst is in overeenstemming met OLAW en USDA en is volledig geaccrediteerd door AAALAC International. Dit protocol is goedgekeurd met het ID-num...

Het Model van de de Venoplastiekballon van het knaagdier voor Studies van de Diepe Behandeling van de ader

<ol>
	<li>Prandoni, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+long-term+clinical+course+of+acute+deep+venous+thrombosis.">The long-term clinical course of acute deep venous thrombosis.</a> Ann Inter Med. 125 (1), 1-7 (1996).</li><li>Prandoni, P., Kahn, S. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Post-thrombotic+syndrome:+prevalence,+prognostication+and+need+for+progress.">Post-thrombotic syndrome: prevalence, prognostication and need for progress.</a> Br J Haematol. 145 (3), 286-295 (2009).</li><li>Gloviczki, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+2023+Society+for+Vascular+Surgery,+American+Venous+Forum,+and+American+Vein+and+Lymphatic+Society+clinical+practice+guidelines+for+the+management+of+varicose+veins+of+the+lower+extremities.+Part+II.">The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II.</a> J Vas Surg Venous Lymph Diso. 12 (1), 101670 (2024).</li><li>Henke, P., Sharma, S., Wakefield, T., Myers, D., Obi, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Insights+from+experimental+post-thrombotic+syndrome+and+potential+for+novel+therapies.">Insights from experimental post-thrombotic syndrome and potential for novel therapies.</a> Transl Res. 225, 95-104 (2020).</li><li>Diaz, J. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Choosing+a+mouse+model+of+venous+thrombosis:+A+consensus+assessment+of+utility+and+application.">Choosing a mouse model of venous thrombosis: A consensus assessment of utility and application.</a> Arterioscl Thrombo Vasc Biol. 39 (3), 311-318 (2019).</li><li>Lee, Y. U., Lee, A. Y., Humphrey, J. D., Rausch, M. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Histological+and+biomechanical+changes+in+a+mouse+model+of+venous+thrombus+remodeling.">Histological and biomechanical changes in a mouse model of venous thrombus remodeling.</a> Biorheology. 52 (3), 235-245 (2015).</li><li>Xie, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Correspondence+of+ultrasound+elasticity+imaging+to+direct+mechanical+measurement+in+aging+DVT+in+rats.">Correspondence of ultrasound elasticity imaging to direct mechanical measurement in aging DVT in rats.</a> Ultrasound Med Biol. 31 (10), 1351-1359 (2005).</li><li>Moini, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Venoplasty+and+stenting+in+post-thrombotic+syndrome+and+non-thrombotic+iliac+vein+lesion.">Venoplasty and stenting in post-thrombotic syndrome and non-thrombotic iliac vein lesion.</a> Minim Invasive Ther Allied Technol. 29 (1), 35-41 (2020).</li><li>Chaitidis, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+post-thrombotic+syndrome:+A+comprehensive+review.">Management of post-thrombotic syndrome: A comprehensive review.</a> Curr Pharma Des. 28 (7), 550-559 (2022).</li><li>Dangas, G. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In-stent+restenosis+in+the+drug-eluting+stent+era.">In-stent restenosis in the drug-eluting stent era.</a> J Am Coll Cardiol. 56 (23), 1897-1907 (2010).</li><li>Negl&#233;n, P., Berry, M. A., Raju, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endovascular+surgery+in+the+treatment+of+chronic+primary+and+post-thrombotic+iliac+vein+obstruction.">Endovascular surgery in the treatment of chronic primary and post-thrombotic iliac vein obstruction.</a> Euro J Vas Endovas Surg. 20 (6), 560-571 (2000).</li><li>Sharifi, M., Mehdipour, M., Bay, C., Smith, G., Sharifi, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endovenous+therapy+for+deep+venous+thrombosis:+The+TORPEDO+trial.">Endovenous therapy for deep venous thrombosis: The TORPEDO trial.</a> Catheter Cardiovasc Interv. 76 (3), 316-325 (2010).</li><li>Nicklas, J. M., Gordon, A. E., Henke, P. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Resolution+of+deep+venous+thrombosis:+Proposed+immune+paradigms.">Resolution of deep venous thrombosis: Proposed immune paradigms.</a> Int J Mol Sci. 21 (6), 2080 (2020).</li><li>Li, J., Kim, S. G., Blenis, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapamycin:+One+drug,+many+effects.">Rapamycin: One drug, many effects.</a> Cell Metabol. 19 (3), 373-379 (2014).</li><li>Chen, X., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapamycin+regulates+Akt+and+ERK+phosphorylation+through+mTORC1+and+mTORC2+signaling+pathways.">Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways.</a> Mol Carcinogen. 49 (6), 603-610 (2010).</li><li>Diaz, J. A., Farris, D. M., Wrobleski, S. K., Myers, D. D., Wakefield, T. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inferior+vena+cava+branch+variations+in+C57BL/6+mice+have+an+impact+on+thrombus+size+in+an+IVC+ligation+(stasis)+model.">Inferior vena cava branch variations in C57BL/6 mice have an impact on thrombus size in an IVC ligation (stasis) model.</a> J Thromb Haemo. 13 (4), 660-664 (2015).</li><li>Sch&#246;nfelder, T., J&#228;ckel, S., Wenzel, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mouse+models+of+deep+vein+thrombosis.">Mouse models of deep vein thrombosis.</a> Gef&#228;sschirurgie. 22 (1), 28-33 (2017).</li><li>de Barros, R. S. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Morphometric+analysis+of+rat+femoral+vessels+under+a+video+magnification+system.">Morphometric analysis of rat femoral vessels under a video magnification system.</a> J Vasc Bras. 16 (1), 73-76 (2017).</li></ol>

De VBM kan worden uitgevoerd bij ratten ≥ 250 g met behulp van ballonnen in het bereik van 2,5-3,5 mm. Voor ratten van meer dan 750 g wordt de techniek beperkt door een grotere hoeveelheid vetweefsel in de buikholte en de orgaangrootte in plaats van veranderingen in de IVC-diameter. Uit onze ervaring hebben we ontdekt dat 10 of meer dieren per groep nodig zijn om statistische significantie tussen de groepen te verkrijgen voor aderwandeiwitanalyse of activiteitstesten en histologie. Periodieke temperatuurcontrole en bew...

Diepe veneuze obstructies van onopgeloste trombi zijn een veelvoorkomend gevolg van diepe veneuze trombose (DVT) en zijn een van de oorzaken van posttrombotisch syndroom (PTS), dat miljarden dollars kost aan gezondheidszorg en een aanzienlijke invloed heeft op de kwaliteit van leven 1,2,3. PTS is een unieke inflammatoire pathologie met als gevolg aderwandfibrose4 die niet volledig is vastgelegd in DVT-modellenvoor kleine dieren 5,6,7, en wat nog belangrijker is, eerdere modellen kunnen de respons op therapeutische interventies niet evalueren. Trombotische veneuze obstructies worden vaak behandeld door stenting en ballonvenoplastiek 8,9; Dergelijke interventies worden belemmerd door een hoog herinterventiepercentage als gevolg van restenose en occlusie 10,11,12.
Ondanks de beschikbaarheid van met medicijnen beklede ballonnen om arteriële-specifieke stenose/occlusies aan te pakken, bestaan er geen voor diepe aders. Het moleculaire mechanisme achter restenose is slecht begrepen in aderen en heeft geen directe therapie4. Daarom is ons doel om een diermodel te presenteren dat lokaal toegediende therapieën kan testen via venoplastiekballonnen die posttrombotische obstructies van diepe veneuze simuleren. Dit model reproduceert de posttrombotische aandoening en evalueert hoe verschillende soorten venoplastiekballonnen de aderwand in vivo beïnvloeden.

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rodent inferior vena cava venoplasty balloon model

Ballonvenoplastiek is een veelgebruikte klinische techniek voor de behandeling van diepe veneuze stenose en occlusie als gevolg van trauma, aangeboren anatomische afwijkingen, acute diepe veneuze trombose (DVT) of stenting. Chronische diepe veneuze obstructie wordt histopathologisch gekenmerkt door trombose, fibrose of beide. Momenteel is er geen directe behandeling beschikbaar om deze pathologische processen aan te pakken. Daarom is een betrouwbaar in vivo diermodel nodig om nieuwe interventies te testen. Het knaagdieroverleving inferieure vena cava (IVC) venoplastiekballonmodel (VBM) maakt de studie van ballonvenoplastiek bij niet-trombotische en post-trombotische aandoeningen op meerdere tijdstippen mogelijk. Het lokale en systemische effect van gecoate en ongecoate venoplastiekballonnen kan worden gekwantificeerd via weefsel-, trombus- en bloedtesten zoals real-time polymerasekettingreactie (RT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), zymografie, aderwand- en trombuscelanalyse, volbloed- en plasmatesten en histologische analyse. De VBM is reproduceerbaar, repliceert chirurgische menselijke ingrepen, kan lokale veranderingen in de aderwand-trombi-eiwit identificeren en maakt meerdere analyses van hetzelfde monster mogelijk, waardoor het aantal dieren dat per groep nodig is, wordt verminderd.

Deep vein obstructions from unresolved thrombi are a common consequence of deep vein thrombosis (DVT) and are one of the causes of post-thrombotic syndrome (PTS), costing billions of dollars in healthcare and significantly impacting the quality of life1,2,3. PTS is a unique inflammatory pathology with consequent vein wall fibrosis4 not fully captured in small animal DVT models5,6,7, and more importantly, previous models cannot evaluate the response to therapeutic interventions. Thrombotic venous obstructions are often treated by stenting and balloon venoplasty8,9; such interventions are hampered by a high reintervention rate due to restenosis and occlusion10,11,12.
Despite the availability of drug-coated balloons to address arterial-specific stenosis/occlusions, none exist for deep veins. The molecular mechanism behind restenosis is poorly understood in veins and has no direct therapy4. Therefore, our goal is to present an animal model that can test locally delivered therapeutics via venoplasty balloons simulating deep vein post-thrombotic obstructions. This model reproduces the post-thrombotic condition and evaluates how different types of venoplasty balloons affect the vein wall in vivo.

Auteur in de schijnwerpers: gebruik van het venoplastiekballonmodel bij knaagdieren om chirurgische ingrepen voor diepe aderen te simuleren

Knaagdier Inferieure Vena Cava Venoplastiek Ballon Model

In our laboratory, led by Dr.Andrea Obi, we study a type of abnormal blood clotting, venous thrombosis. In fact, we're one of the very few laboratories in the world working in this promising discovery area. Our goal is to take our findings and translate them into new, safer, more effective approaches to treat venous thrombosis.Our work has led us to look more closely at the role of the immune system, including the presence of infection in thrombus formation, as well as the pathways leading to clot resolution, venous fibrosis, including vein wall scarring and post-thrombotic syndrome. No previous animal model has been able to replicate the complex immune interactions that occur in venous thromboembolism in humans. Additionally, no model has been able to characterize the response to endovascular treatments followed by ultrasound.We are making important contributions to understand how different types of immune cells interact with environment around a blood clot, and how those interactions can lead to changes in the expression of cell's genetics code, a process now as epigenetic regulation. We believe that Inferior Vena Cava Venoplasty Balloon Model will accelerate the development of novel balloon angioplasty prototypes for the treatment of venous thrombosis, and the possibility for prevention of post-thrombotic syndrome.

De VBM is een model dat het effect van venoplastiekballonnen evalueert bij volledige hemostasecontrole. Eerst hebben we de diameter van de IVC (mid-infrarenale sectie) gekwantificeerd, zoals weergegeven in figuur 1, voor de juiste grootte van de ballon. Ten tweede wordt de ontwikkelde stap-voor-stap microchirurgische techniek geïllustreerd in figuur 2, en laten we ook voorbeelden zien van de kritieke stappen in figuur 3. Let op de ...

Het protocol presenteert een overlevingsmodel voor knaagdieren om interventies met een venoplastiekballon (VB) te testen in niet-trombotische, trombotische en posttrombotische diepe aders.

Balloon venoplasty is a commonly used clinical technique to treat deep vein stenosis and occlusion as a consequence of trauma, congenital anatomic ...

rodent-inferior-vena-cava-venoplasty-balloon-model

Research

JoVE Journal

Medicine

Rodent Inferior Vena Cava Venoplasty Balloon Model

Balloon venoplasty is a commonly used clinical technique to treat deep vein stenosis and occlusion as a consequence of trauma, congenital anatomic abnormalities, acute deep vein thrombosis (DVT), or stenting. Chronic deep venous obstruction is histopathologically characterized by thrombosis, fibrosis, or both. Currently, no direct treatment is available to target these pathological processes. Therefore, a reliable in vivo animal model to test novel interventions is necessary. The rodent survival inferior vena cava (IVC) venoplasty balloon model (VBM) allows the study of balloon venoplasty in non-thrombotic and post-thrombotic conditions across multiple time points. The local and systemic effect of coated and uncoated venoplasty balloons can be quantified via tissue, thrombus, and blood assays such as real-time polymerase chain reaction (RT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), zymography, vein wall and thrombus cellular analysis, whole blood and plasma assays, and histological analysis. The VBM is reproducible, replicates surgical human interventions, can identify local vein wall-thrombi protein changes, and allows multiple analyses from the same sample, decreasing the number of animals required per group.

The protocol presents a survival rodent model to test venoplasty balloon (VB) interventions in non-thrombotic, thrombotic, and post-thrombotic deep veins.

Developing a Rodent Venoplasty Balloon Model for Researching Deep Vein Stenosis Treatments

To begin, position the anesthetized rat for the ultrasound scanning of the inferior vena cava or IVC. Apply a conducting gel to the abdomen and orient the transducer in a transverse position. Using two-dimensional imaging mode or B mode, lower the 10 megahertz linear probe on the center of the abdomen.When the abdominal vessels come into view, differentiate the IVC from the abdominal aorta with compressibility and flow assessment. Once the IVC is located, identify the midsection in the middle third portion inferior to the renal veins and superior to the IVC bifurcation. At the midsection IVC, measure the wall to wall diameter in the transverse view using the cross-sectional B mode image, recording the widest diameter of the vessel.Store the data using compact disks as DICOM files. Clean the abdomen with gauze-soaked chlorhexidine scrub and chlorhexidine solution three times. Place the sterilized cling film as a surgical wrap to cover the rat thorax and abdominal area.Using iris scissors, make a three centimeter ventral midline incision approximately two centimeters below the xiphoid process through the skin and abdominal wall. With a sterile saline-soaked gauze, reflect the intestines to the animal's right side. Place a wire speculum in the incision to allow IVC visualization.Then using a sterile cotton tipped applicator, perform a blunt dissection. Employing a low temperature fine tip cautery, cauterize all IVC lumbar branches from the renal veins to the iliac bifurcation, and ligate side branches with 7-0 non-absorbable polypropylene sutures. Place a proximal curved vascular micro clip on the IVC, which is separated from the aorta and is inferior to the renal veins.Place a straight micro clip on the distal IVC superior to the iliac bifurcation. Place an 8-0 nylon U-stitch suture caudal to the left renal vein centered on the anterior surface of the IVC. Insert a 0.014 millimeter sharpened guide wire with the venoplasty balloon backloaded retrograde to blood flow into the infrarenal IVC caudal to the curved micro clip.Advance the balloon into the mid IVC using the Seldinger technique. Remove the sharpened guidewire and using a 20 milliliter inflation syringe, inflate the venoplasty balloon for three minutes with a 10 to 15%IVC overstretch. Flush sterile saline to all the systems before IVC cannulation to avoid air embolism.Tighten the U-stitch upon venoplasty balloon deflation and removal. Then remove the micro clips and close the laparotomy site in a two-layer fashion using a 3-0 polyglactin absorbable synthetic suture. Close both the abdominal wall and skin in a continuous pattern.Recover the rat in an individual cage and observe it for 30 minutes under a heating lamp placed 24 inches away from the cage before returning it to its original housing unit. Average pulsed wave doppler flow velocity in the inferior vena cava of the rats after clip placement of the vessel was significantly reduced.