この研究は、American Venous Forum (AVF) 2023 Basic Science research grant と Surmodics, Inc. の支援を受けています。

次のプロトコルは、ミシガン大学(UMICH)の施設内動物管理および使用委員会(IACUC)のポリシーとガイドライン、試験、研究、および訓練で使用される脊椎動物の利用とケアに関する米国政府の原則、およびARRIVEガイドライン2.0に従います。UMICH動物福祉保証契約は、OLALおよびUSDAに準拠しており、AAALACインターナショナルによって完全に認定されています。このプロトコルは、ID番号PRO00010841で承...

深部静脈治療研究のためのげっ歯類静脈形成術バルーンモデル

<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>

利益相反は宣言されていません。

VBMは、2.5〜3.5mmの範囲のバルーンを使用して、250g≥ラットに対して実行できます。750 gを超えるラットの場合、この技術は、IVC直径の変化ではなく、腹腔内の脂肪組織の量と臓器のサイズが多いことによって制限されます。私たちの経験から、静脈壁タンパク質分析または活性アッセイと組織学のためにグループ間の統計的有意性を得るためには、グループごとに10匹以上の動物が必要である...

未解決の血栓による深部静脈閉塞は、深部静脈血栓症(DVT)の一般的な結果であり、血栓後症候群(PTS)の原因の1つであり、医療に数十億ドルの費用がかかり、生活の質に大きな影響を与えています1,2,3。PTSは、小動物のDVTモデル5,6,7では完全に捕捉されていない結果として生じる静脈壁線維症4を伴う独特の炎症性病理であり、さらに重要なことに、以前のモデルは治療介入に対する反応を評価できません。血栓性静脈閉塞は、ステント留置術やバルーン静脈形成術によって治療されることがよくあります8,9;このような介入は、再狭窄と閉塞による高い再介入率によって妨げられます 10,11,12。
動脈特異的な狭窄/閉塞に対処するための薬剤コーティングバルーンが利用可能であるにもかかわらず、深部静脈には存在しません。再狭窄の背後にある分子メカニズムは、静脈内ではよく理解されておらず、直接的な治療法はありません4。したがって、私たちの目標は、深部静脈の血栓後閉塞をシミュレートする静脈形成バルーンを介して局所的に送達される治療薬をテストできる動物モデルを提示することです。このモデルは、血栓形成後の状態を再現し、さまざまな種類の静脈形成バルーンが 生体内で静脈壁にどのように影響するかを評価します。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3-0 DemeCRYL</td>
			<td>DemeTech</td>
			<td>G183019F4P</td>
			<td>12 per box</td>
		</tr>
		<tr>
			<td>5-0 DemeCRYL</td>
			<td>DemeTech</td>
			<td>G285017B0P</td>
			<td>12 per box</td>
		</tr>
		<tr>
			<td>7-0 DemeLENE</td>
			<td>DemeTech</td>
			<td>PM197011F13M</td>
			<td>12 per box</td>
		</tr>
		<tr>
			<td>8-0 DemeLON</td>
			<td>DemeTech</td>
			<td>NL868007C7P</td>
			<td>12 per box</td>
		</tr>
		<tr>
			<td>Angled Clip Applier</td>
			<td>SCANLAN</td>
			<td>3795-01A</td>
			<td>7-1/4&#8243; (18.5 cm)</td>
		</tr>
		<tr>
			<td>Baxter 0.9% Sodium Chloride Irrigation Bottle</td>
			<td>Baxter</td>
			<td>SKU: 195-7124</td>
			<td>1000mL Bottle</td>
		</tr>
		<tr>
			<td>Bovie Cautery Low Temperature Fine Tip</td>
			<td>Symmetry Surgical Inc</td>
			<td>AA00</td>
			<td>10/bx</td>
		</tr>
		<tr>
			<td>Buprenorphine</td>
			<td>Fidelis Animal Health</td>
			<td>SKU- 099114</td>
			<td>1.3mg/mL, 3mL</td>
		</tr>
		<tr>
			<td>CD (Sprague Dawley) Rats</td>
			<td>Charles River</td>
			<td>Strain Code 001</td>
			<td>Male, 400 gm</td>
		</tr>
		<tr>
			<td>Clip-It Traceable Timer</td>
			<td>TRACEABLE PRODUCTS</td>
			<td>Cat. No. 5046</td>
			<td></td>
		</tr>
		<tr>
			<td>Cotton-Tip Applicator 3&#34;</td>
			<td>Dukal Corporation</td>
			<td>922-00037BX100</td>
			<td>1000/BOX</td>
		</tr>
		<tr>
			<td>Enzymatic Surgical Instrument Detergent and Presoak</td>
			<td>Medline</td>
			<td>MDS88000B9</td>
			<td>1 Gal</td>
		</tr>
		<tr>
			<td>Eye Lube</td>
			<td>Optixcare</td>
			<td>SKU-065441</td>
			<td>20gm&#160;</td>
		</tr>
		<tr>
			<td>Gaymar T/Pump Stryker Localized Warming/Cooling Therapy System</td>
			<td>Stryker</td>
			<td>TP700</td>
			<td></td>
		</tr>
		<tr>
			<td>Heifetz Microclips 12mmx2.25mm</td>
			<td>SCANLAN</td>
			<td>3795-20</td>
			<td>Straight</td>
		</tr>
		<tr>
			<td>Heifetz Microclips 12mmx2.25mm</td>
			<td>SCANLAN</td>
			<td>3795-28</td>
			<td>Curved</td>
		</tr>
		<tr>
			<td>Heifetz Microclips 8mmx1.75mm&#160;</td>
			<td>SCANLAN</td>
			<td>3795-14</td>
			<td>Straight</td>
		</tr>
		<tr>
			<td>Heifetz Microclips 8mmx1.75mm&#160;</td>
			<td>SCANLAN</td>
			<td>3795-18</td>
			<td>Curved</td>
		</tr>
		<tr>
			<td>Inflation device&#160;</td>
			<td>Merit Medical</td>
			<td>IN4130</td>
			<td>BasixCOMPAK with Analog Display</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>MFR VETONE</td>
			<td>SKU-501017</td>
			<td>100mL, Liquid for Inhalation</td>
		</tr>
		<tr>
			<td>Microsurgery kit containing tweezers and forceps</td>
			<td>Customized</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Oxygen, E-tank</td>
			<td>Medline</td>
			<td>MDM1630</td>
			<td></td>
		</tr>
		<tr>
			<td>Sharpened Guidewire</td>
			<td>Customized</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sterile Glad Press-n-Seal</td>
			<td>Glad</td>
			<td>SKU # PSS-140</td>
			<td>ETO Exposed</td>
		</tr>
		<tr>
			<td>Sterile Nonwoven Gauze Sponges 2s 4ply 4x4&#160;</td>
			<td>Medline</td>
			<td>SKU PRM21444H</td>
			<td>100Ct</td>
		</tr>
		<tr>
			<td>Surgical microscope&#160;</td>
			<td>Zeiss</td>
			<td>S100 / OPMI pico</td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical Scrub &#38; Handwash</td>
			<td>Vetoquinol</td>
			<td>NDC: 17030-003-16</td>
			<td>16 oz</td>
		</tr>
		<tr>
			<td>Ultrasound Gel</td>
			<td>Medline</td>
			<td>CTR001305</td>
			<td>8.5 oz, 12/CS</td>
		</tr>
		<tr>
			<td>Ultrasound system</td>
			<td>Siemens</td>
			<td>ACUSON Antares</td>
			<td>3-D, Color, Continuous wave (CW), Pulsed wave (PW), Power CW/CW Spectral</td>
		</tr>
		<tr>
			<td>Venoplasty Balloon</td>
			<td>Customized</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

rodent inferior vena cava venoplasty balloon model

バルーン静脈形成術は、外傷、先天性解剖学的異常、急性深部静脈血栓症(DVT)、またはステント留置術の結果としての深部静脈狭窄症および閉塞を治療するために一般的に使用される臨床技術です。慢性深部静脈閉塞は、組織病理学的に血栓症、線維症、またはその両方によって特徴付けられます。現在、これらの病理学的プロセスを標的とする直接的な治療法はありません。したがって、新しい介入をテストするための信頼性の高い in vivo 動物モデルが必要です。げっ歯類生存率下大静脈 (IVC) 静脈形成術バルーン モデル (VBM) は、複数の時点にわたる非血栓性および血栓後の状態におけるバルーン静脈形成術の研究を可能にします。コーティングされた静脈形成術およびコーティングされていない静脈形成術バルーンの局所的および全身的な影響は、リアルタイムポリメラーゼ連鎖反応(RT-PCR)、ウェスタンブロット、酵素結合免疫吸着アッセイ(ELISA)、ザイモグラフィー、静脈壁および血栓細胞分析、全血および血漿アッセイ、組織学的分析などの組織、血栓、および血液アッセイによって定量化できます。VBMは再現性があり、外科的なヒト介入を再現し、局所静脈壁血栓タンパク質の変化を特定でき、同じサンプルからの複数の分析を可能にするため、グループごとに必要な動物の数が減少します。

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.

著者スポットライト:げっ歯類の静脈形成術バルーンモデルを利用して、深部静脈の外科的介入をシミュレートする

げっ歯類の下大静脈静脈形成術バルーンモデル

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.

VBMは、完全な止血制御における静脈形成バルーンの効果を評価するモデルです。まず、 図1に示すように、正しいバルーンサイジングのためにIVC(中低腎部)の直径を定量化しました。次に、開発された段階的なマイクロサージュリー技術を 図2に示し、 図3に重要なステップの例も示しています。鋭利なガイドワイヤーを使用?...

このプロトコルは、非血栓性、血栓性、および血栓性後の深部静脈における静脈形成バルーン (VB) 介入をテストするための生存げっ歯類モデルを提示します。

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

327 Views.  University of Michigan. 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 lea...