Name: implantation of human-sized coronary stents into rat abdominal aorta using a trans-femoral access
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Bayan Angela Freund'a gömme ve slayt üretimindeki paha biçilmez teknik yardımı için teşekkür ederiz. Ayrıca Laboratuvar Hayvan Bilimi ve Deneysel Cerrahi Enstitüsü'ndeki Bay Tadeusz Stopinski'ye veterinerlik çalışmalarına yaptığı anlayışlı yardımlar için teşekkür ederiz.

Deneyler, bilimsel amaçlarla kullanılan hayvanların korunmasıyla ilgili Alman hayvan refahı yasası (TSchG) ve Direktifi 2010/63/AB uyarınca gerçek gerçekleştirildi. Bu çalışma için resmi onay Hükümet Hayvan Bakım ve Kullanım Komitesi tarafından verilmiştir (Protokol No.: AZ 87-51.04.2010.A065; Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, Recklinghausen, Almanya). Çalışma protokolü Laboratuvar Hayvanlarının Bakımı ve Kullanımı Kılavuzu'na uygun olarak gerçekleştirildi. Ameliyat sonrası ağrı tedavisi, Alman Laboratuvar Hayvanları Bilimi Derneği'nin (GV-SOLAS) önerilerine ve Girişim Veteriner Ağrı Terapisi'ne dayanmaktadır.
1. Temel teknikler ve ortak prosedürler
<ol><li>Homozigöz apoE-/- Sprague-Dawley sıçanları kullanın. Standart yöntemler kullanarak her hayvanın genotipini tanımlayın17.</li>
	<li>Hayvanları aynı koşullarda (21 °C ± 2 °C, %60 ± %5 nem ve 12 saat açık/karanlık döngü) tutun ve suya ve yiyeceğe ücretsiz erişim sağlayın.</li>
	<li>Tüm prosedürleri temiz ama nonsteril koşullar altında gerçekleştirin.</li>
	<li>Sıçan uyuşturuldıktan sonra, tüm prosedürleri 16x büyütmede cerrahi bir mikroskop altında gerçekleştirin.</li>
	<li>Sıkıştırma hemostazı için pamuklu çubuk kullanın. Laktlı Ringer çözeltisi ile ıslatılmış gazlı bez sürüntüleri (5 cm x 5 cm) kasık nemli tutmak için faydalıdır.</li>
	<li>Kullanılmış malzemeleri bertaraf etmek için atık bertaraf yönetmeliklerine uyun.</li>
</ol>2. Ameliyat öncesi hazırlıklar
<ol><li>Operasyona başlamadan önce veteriner ilaçlarını hazırlayın. Aksi belirtilmedikçe tüm çözümleri oda sıcaklığında tutun.</li>
	<li>
İşlemden otuz dakika önce, 0.03-0.05 mg/kg buprenorfin deri altından uygulayın.
</li>
	<li>Sıçanı 100 mg/kg vücut ağırlığı (BW) (S)-ketamin ve 8 mg/kg BW ksilazin intraperitoneal enjeksiyon ile uyuşturun.</li>
	<li>Bir tartım terazisi kullanarak sıçanın ağırlığını değerlendirin.</li>
	<li>Sıçanı bir ısıtma yastığına yerleştirin ve tıbbi bant kullanarak üst ve alt uzuvları sabitleyin. Sıçanı sol arka uzvu tamamen uzatılmış ve omurgasıyla mümkün olduğunca uyumlu olarak konumlandırın, böylece femoral arter ve aort arasında düz bir çizgi oluşturun. Bu, balona monte stentlerin aort çatallanması yoluyla ilerletilmesini kolaylaştıracaktır.</li>
	<li>2 L/dk akış hızında %97,5 oksijende %1,5 vol izofluran soluma ile anesteziyi koruyun. NOT: Sıçanın entübasyon yapmadan kendiliğinden nefes almasına izin verin.</li>
	<li>Bilinçsizlik sırasında göz hasarlarını önlemek için göz merhemi uygulayın.</li>
	<li>Kürkü sıçanın kasık ve alt karın bölgesinden tıraş edin ve ilgili cildi bir povidone-iyot çözeltisi ile sterilize edin.</li>
	<li>Ameliyata başlamadan önce kuyruk ucunu ve interdigital dokuyu sıkıştırarak yeterli anestezi derinliğini doğrulayın.</li>
</ol>3. Cerrahi
<ol><li>Cildi ve alttaki fasyayı açmak için sol kasıkta ~0,5\u20121 cm medial kesi yapın.</li>
	<li>Titreşen sol uyluk atardamarı tespit edilene kadar derinlikleri künt bir şekilde parçalara ayrılın ve araştırın.</li>
	<li>Çok ince tokmalar kullanarak, çevredeki bağ dokusunu nazikçe çıkararak femoral arteri hazırlayın. Ne femoral sinire ne de artere medial olan femoral damara zarar vermeye dikkat edin.</li>
	<li>Femoral arterin yaklaşık 1 cm'sini hazırlayın. Yavaşça kaldırmak için kabın altına asma ucunu dikkatlice koyun.</li>
	<li>Atardamarın distal ve proksimal kısımlarının altında 4-0 ipek dikiş iplik parçaları ve sapanlar oluşturur. İki iplik sapanının her birinin uçlarını cerrahi kelepçenin dalları arasında sıkıştırın. Atardamarı kontrol etmek için cerrahi kelepçeleri kullanın. Kan akışını geçici olarak kesmek için sapanları hafifçe uzatın ve kaldırın. NOT: Doku hasarına yol açabilecek uzun süreli bir turnikeden kaçınmak için hızlı çalışın.</li>
	<li>Keskin mikro makas kullanarak, femoral arterin ortasında bir arteriotomi gerçekleştirin.</li>
	<li>Arteriotomi yoluyla bir kılavuz tel tanıtın. Proksimal iplik sapanlarına ulaşırken, cerrahi kelepçeyi hareket ettirerek ipliğin gerginliğini serbest bırakın ve kılavuz teli karın aortine doğru daha da ilerletin. NOT: Elleçlemeyi kolaylaştırmak için kılavuz teli bir tel kesici kullanarak kesin.</li>
	<li>Kılavuz telin proksimal ucunu diyafram ve renal arterler arasına yerleştirin. NOT: Kılavuz telin çok ileriye doğru ilerleten aort veya kardiyak yaralanma riski taşır. Kılavuz telin ve stenin en azından ilk birkaç hayvan için yeterli konumlandırılmasını sağlamak için karnın açılmasını öneririz.</li>
	<li>Kılavuz tel üzerinden uyluk atardamarına 2,25 mm x 8 mm (maks. 2,5 mm x 8 mm) ölçülerinde kıvrkıt ve balona monte koroner stent takın ve karın aortuna ilerletin.</li>
	<li>Stetiği aort çatallanmasının hemen üstüne ancak renal arterlerin altına yerleştirin. Balon kateterini şişirerek steni 15 sn için 12 atm'ye şişirerek bir şişirme şırınna sistemi kullanarak dağıtın.</li>
	<li>Balon kateterini söndür ve üreticinin kullanımdaki stent için önerilerine göre negatif basıncı koruyun.</li>
	<li>Sönmüş kateteri yavaşça çekin ve steni yerinde bırakın.</li>
	<li>Kateteri çıkarmadan hemen önce, kan akışını tekrar kesmek için cerrahi kelepçe ile kesiğin üzerindeki iplik halkasında gerginlik yaratın. Daha sonra balon kateterini çıkarın ve damarı proksimally olarak doğrudan lige edin.</li>
	<li>Femoral arteri lige etmek ve arteriotomi yeterli hemostazı doğrulamak için proksimal ve distal iplik döngülerini bağlayın. Kollateral arterler uzuvlara daha fazla perfüzyon sağlayacaktır.</li>
	<li>10-0 resorbable olmayan dikiş kullanarak arterin üzerindeki kası ve cilt kesisini kapatın.</li>
</ol>4. Stent implantasyonundan sonra hayvan bakımı
<ol><li>Ameliyattan hemen sonra, farenin ısınan hava (30\u201235 °C) ve oksijen kaynağı olan özel bir yoğun bakım ünitesi kafesinde 60 dakika boyunca iyileşmesine izin verin.</li>
	<li>Tamamen iyileşene kadar hayvanları dikkatlice izleyin. Daha sonra, sıçanları normal bir kafese taşıyın. Suya ve yiyeneğe reklam libitum erişimi sağlayın.</li>
	<li>Klinik değerlendirme altında toplam 72 saat boyunca 0.03-0.05 mg/kg buprenorfin (s.c., in 500μl NaCl) ile her 6-12 saatte bir postoperatif analjezi uygulamak.</li>
	<li>İmplant edilen stensin trombozdan kaçınmak için yiyecekleri klopidogrel (15 mg/kg) ile karıştırın.</li>
	<li>Hiperkolestemik koşulları ve plak oluşumunu geliştirmek için doğumdan 6\u20128 hafta sonra batı diyet beslenmesine başlayın ve ötanaziye kadar devam edin. İstenirse, normal sıçan yemeğiyle beslenen bir hayvan grubu kontrol görevi görebilirsiniz.</li>
</ol>5. Doku toplama ve işleme
<ol><li>Doku eksplantasyonuna belirlenen zaman noktasında başlamadan önce, hayvanı IACUC yönergelerine göre ötenazi edin. Gözlem süresinin sonunda histolojik analiz için stented aort hasat edin.</li>
	<li>Karnı orta çizgi kesiğiyle açın ve aortun eğimli segmentini ve aortun bitişik olmayan kısımlarını her biri 0,5 cm ölçülerinde çıkarın.</li>
	<li>Dokuyu sabitleme için 24 saat boyunca% 4 tamponlanmış formalin çözeltisine yerleştirin.</li>
	<li>Stented arteriyel dokuyu plastiğe gömün ve standart protokollere göre histolojik ve immünohistokimyasal lekeleme gerçekleştirin18,19.</li>
</ol>6. Histomorfometrik analiz
<ol><li>Uygun bir görüntü analiz yazılımına sahip bir bilgisayara bağlı mikroskop vasıtasıyla, stental aortun proksimal, orta ve distal kısmının sıralı bölümlerinin histoporfometrik analizini yapın.</li>
	<li>Dış elastik lamina (EEL, adventitia ve medya arasında), iç elastik lamina (IEL, medya ve neointima arasında) ve lümen konturlarını bir grafik çizim tableti ile takip edin. Bu değerlerden, yazılımla birlikte EEL alanını, IEL alanını ve lümen alanını hesaplayın.</li>
	<li>Stent restenozunda (ISR) kesitsel alan yüzdesini hesaplayın: <img alt="Equation 1" src="/files/ftp_upload/61442/61442equ01.jpg">
</li>
	<li>Toplam neointimal alanı hesaplayın (Ai): <img alt="Equation 2" src="/files/ftp_upload/61442/61442equ02.jpg">
</li>
	<li>Her stent payandası üzerindeki neointimal kalınlığı (NIT) payanda ve lümen arasındaki mesafe olarak ölçün. Nit'i stent payandaları arasında IEL ve lümen arasındaki mesafe olarak ölçün. NOT: Alternatif olarak, NIT'yi <img alt="Equation 3" src="/files/ftp_upload/61442/61442equ03.jpg"> burada PL ve PIEL sırasıyla lümen ve iç elastik lamina çevresidir20.</li>
	<li>Çalışmanın gerekliliklerine göre ek analizler yapmak.</li>
</ol>

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Deviation of man from the usual pattern.</a> Circulation Research. 25 (6), 677-686 (1969).</li><li>Lowe, H. C., James, B., Khachigian, L. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+model+of+in-stent+restenosis:+rat+aortic+stenting.">A novel model of in-stent restenosis: rat aortic stenting.</a> Heart. 91 (3), 393-395 (2005).</li><li>Unthank, J. L., Nixon, J. C., Lash, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Early+adaptations+in+collateral+and+microvascular+resistances+after+ligation+of+the+rat+femoral+artery.">Early adaptations in collateral and microvascular resistances after ligation of the rat femoral artery.</a> Journal of Applied Physiology. 79 (1), 73-82 (1985).</li><li>Nevzati, E., 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=Biodegradable+Magnesium+Stent+Treatment+of+Saccular+Aneurysms+in+a+Rat+Model+-+Introduction+of+the+Surgical+Technique.">Biodegradable Magnesium Stent Treatment of Saccular Aneurysms in a Rat Model - Introduction of the Surgical Technique.</a> Journal of Visualized Experiments. (128), e56359 (2017).</li><li>Aquarius, R., Smits, D., Gounis, M. J., Leenders, W. P. J., de Vries, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flow+diverter+implantation+in+a+rat+model+of+sidewall+aneurysm:+a+feasibility+study.">Flow diverter implantation in a rat model of sidewall aneurysm: a feasibility study.</a> Journal of NeuroInterventional Surgery. 10 (1), 88-92 (2018).</li></ol>

Yazarların açıklayacak bir şeyi yok.

Bu protokol, insan büyüklüğündeki koroner stentlerin apoE-/- sıçanların karın aortuna implantesini açıklar. Birkaç teknik nokta vurgu etmeye değer. İlk olarak, stent boyutu ile aortun büyüklüğü arasında bir uyumsuzluk önlenmelidir. Çok küçük bir stent yerleştirmek stent malappozasyonuna yol açabilirken, aort için çok büyük bir stent takılması damarın aşırı uzamasına, yırtılmasına ve yaralanmasına neden olabilir. Bu nedenle, çapı 2,0 ila 2,5 mm arasında stent kullanm...

Perkütan koroner girişim (PCI), koroner stent dağıtımı ile birlikte koroner arter hastalığının girişimsel tedavisinde altın standardı temsil eder1. Bununla birlikte, stentlerin uzun vadeli başarısı, stent içinde neointimal dokunun aşırı çoğalması ile belirlenen stent istirenozunun (ISR) ortaya çıkması ile sınırlanabilir2,3. ISR koroner arter bypass veya yeniden PCI ile yeniden müdahale gerektirebilir. ISR'nin çalışması için her biri avantaj ve eksiklik içeren çeşitli hayvan modelleri önerilmiştir. En sık kullanılan porcine koroner ve tavşan iliak arter modellerinin en büyük dezavantajları, stent implantasyonu4,5'ten sonra insanlara belirgin bir şekilde benzeyen lezyonlar geliştirmek deolsa,özellikle uzun vadeli çalışmalarda lojistik zorlukların yanı sıra elleçleme ve ekipman sınırlamalarını gündeme getiren büyük hayvan ve barınma maliyetleridir. Ayrıca, domuz ve tavşanların hücresel proteinlerine karşı antikorların mevcudiyeti sınırlıdır. Öte yandan, murine modelleri yüksek verim ve tekrarlanabilirliğin yanı sıra kullanım kolaylığı, konut ve dolayısıyla maliyet etkinliğinin önemli avantajlarını sağlar. Ayrıca, daha fazla sayıda antikor mevcuttur. Bununla birlikte, apolipoprotein E-eksik (apoE-/-) fareler ateroskleroz6,7,8çalışması için yaygın olarak kullanılmış olsa da, stentlerin farelere implante edilmesi için minyatürleştirilmesi ve stentlerin mekanik özelliklerinin potansiyel olarak değiştirilmesi gerektiği için ISR çalışması için uygun değildir. Ayrıca, farelerin aort duvarı genç farelerde 50 μm ile yaşlı farelerde 85 μm arasında ölçülmektedir9ve stentler 2 atm kadar düşük basınç seviyeleri kullanılarak dağıtılmalıdır, bu da stenin malapposition10'ayol açabilir. Bununla birlikte, sıçanlar, ticari olarak mevcut insan koroner stentlerin implantasyonuna izin verir ve ilk olarak Langeveld ve ark.11tarafından bildirilen aort stent implantasyonundan sonra daha büyük hayvanlara benzer bir damar iyileşme kursu gösterir. Bu teknik başlangıçta, kan akışının geçici olarak kesintiye uğraması için aortu fiziksel olarak daraltmayı gerektiren bir trans-abdominal erişim gerektiriyordu. Potansiyel olarak ilişkili damar yaralanmasını ve enflamatuar reaksiyonları önlemek için, teknik daha sonra hayvanların daha yüksek bir hayatta kalma oranına neden olan bir trans-iliak erişimin tanıtılmasıyla rafine edildi12.
Wildtype sıçanlar aterosklerotik lezyonlar geliştirmediği için13, apoE-/- sıçanlar Transkripsiyon Aktivatör Benzeri Efektör Nükleaz (TALEN)14, Kümelenmiş Düzenli Aralıklı Kısa Palindropik Tekrarlar (CRISPR/ Cas9)15ve Çinko Parmak (ZF)16gibi nükleaz teknikleri kullanılarak üretilmiştir. ApoE-/- sıçanlar 2011 yılından beri ticari olarak mevcuttur. Aterojenik bir arka plan sağlayan apoE-/- sıçanlar, özellikle ISR ile ilgili olarak insan büyüklüğündeki koroner stentlerin daha gerçekçi bir şekilde değerlendirilmesini sağlar.
Burada, yöntemi transfemoral erişim yolu üzerinden ve piyasada bulunan ince payanda kobalt-krom ilaç eluting stent (DES) kullanarak açıklıyoruz, ancak çıplak metal stentler (BMS) veya biyolojik olarak parçalanabilir stentler gibi diğer stent türlerinin çalışması için de uygulanabilir.

<table><tbody><tr><td>&lt;strong&gt;Diet&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>SNIFF High Fat diet + Clopidogrel (15 mg/kg)</td><td>SNIFF Spezialdi&amp;auml;ten GmbH, Soest</td><td>custom prepared</td><td>Western Diet</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Drugs and Anesthetics&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Buprenorphine</td><td>Essex Pharma</td><td>997.00.00</td><td></td></tr><tr><td>ISOFLO (Isoflurane Vapor) vaporiser</td><td>Eickemeyer</td><td>4802885</td><td></td></tr><tr><td>Isoflurane</td><td>Forene Abbott</td><td>B 506</td><td></td></tr><tr><td>Isotonic (0.9%) NaCl solution</td><td>DeltaSelect GmbH</td><td>PZN 00765145</td><td></td></tr><tr><td>Ringer&#039;s lactate solution</td><td>Baxter Deutschland GmbH</td><td>3775380</td><td></td></tr><tr><td>(S)-ketamine</td><td>CEVA Germany</td><td></td><td></td></tr><tr><td>Xylazine</td><td>Medistar Germany</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Consumable supplies&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>10 mL syringes</td><td>BD Plastipak</td><td>4606108V</td><td></td></tr><tr><td>2 mL syringes</td><td>BD Plastipak</td><td>4606027V</td><td></td></tr><tr><td>6-0 prolene suture</td><td>ETHICON</td><td>N-2719K</td><td></td></tr><tr><td>4-0 silk suture</td><td>Seraflex</td><td>IC 158000</td><td></td></tr><tr><td>Bepanthen Eye and Nose Ointment</td><td>Bayer Vital GmbH</td><td>6029009.00.00</td><td></td></tr><tr><td>Cotton Gauze swabs</td><td>Fuhrmann GmbH</td><td>32014</td><td></td></tr><tr><td>Durapore silk tape</td><td>3M</td><td>1538-1</td><td></td></tr><tr><td>Poly-Alcohol Skin Desinfection Solution</td><td>Antiseptica GmbH</td><td>72PAH200</td><td></td></tr><tr><td>Sterican needle 18 G</td><td>B. Braun</td><td>304622</td><td></td></tr><tr><td>Sterican needle 27 3/4 G</td><td>B.Braun</td><td>4657705</td><td></td></tr><tr><td>Tissue Paper</td><td>commercially available</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Surgical instruments&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Graefe forceps curved x1</td><td>Fine Science Tools Inc.</td><td>11151-10</td><td></td></tr><tr><td>Graefe forceps straight</td><td>Fine Science Tools Inc.</td><td>11050-10</td><td></td></tr><tr><td>Needle holder Mathieu</td><td>Fine Science Tools Inc.</td><td>12010-14</td><td></td></tr><tr><td>Scissors</td><td>Fine Science Tools Inc.</td><td>14074-11</td><td></td></tr><tr><td>Semken forceps</td><td>Fine Science Tools Inc.</td><td>11008-13</td><td></td></tr><tr><td>Small surgical scissors curved</td><td>Fine Science Tools Inc.</td><td>14029-10</td><td></td></tr><tr><td>Small surgical scissors straight</td><td>Fine Science Tools Inc.</td><td>14028-10</td><td></td></tr><tr><td>Standard pattern forceps</td><td>Fine Science Tools Inc.</td><td>11000-12</td><td></td></tr><tr><td>Vannas spring scissors</td><td>Fine Science Tools Inc.</td><td>15000-08</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Equipment&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Dissecting microscope</td><td>Leica MZ9</td><td></td><td></td></tr><tr><td>Temperature controlled heating pad</td><td>Sygonix</td><td>26857617</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Equipment for stent implantation&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Drug-eluting stent Xience 2,25mm x 8mm</td><td>Abbott Vascular USA</td><td>1009544-18</td><td></td></tr><tr><td>Guide wire Fielder XT PTCA guide wire: 0.014&quot; x 300cm</td><td>ASAHI INTECC CO., LTD Japan</td><td>AGP140302</td><td></td></tr><tr><td>Inflation syringe system</td><td>Abbott 20/30 Priority Pack</td><td>1000186</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>&lt;strong&gt;Tissue processing and analysis&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>30% H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;</td><td>Roth</td><td>9681</td><td>Histology</td></tr><tr><td>Ethanol</td><td>Roth</td><td>K928.1</td><td>Histology</td></tr><tr><td>Giemsas Azur-Eosin-Methylenblau</td><td>Merck</td><td>109204</td><td>Histology</td></tr><tr><td>Graphic Drawing Tablet</td><td>WACOM Europe GmbH</td><td>CTL-6100WLK-S</td><td></td></tr><tr><td>Roti Histofix, Formaldehyd 4% buffered</td><td>Roth</td><td>P087</td><td>Histology</td></tr><tr><td>Technovit 9100</td><td>Morphisto</td><td>12225.K1000</td><td>Histology</td></tr></tbody></table>

implantation of human-sized coronary stents into rat abdominal aorta using a trans-femoral access

Perkütan koroner girişim (PCI), koroner stent dağıtımı ile birlikte koroner arter hastalığının girişimsel tedavisinde altın standardı temsil eder. Stent içi restenoz (ISR), stent içindeki neointimal dokunun aşırı çoğalması ile belirlenir ve stentlerin uzun süreli başarısını sınırlar. Steno-in-stent restenozunun (ISR) altında yatan patofizyolojik süreçlerin aydınlatılması için çeşitli hayvan modelleri kullanılmıştır, porsin koroner ve tavşan iliak arter modelleri en sık kullanılanlardır. Murine modelleri, yüksek verim, kullanım ve gövde kolaylığı, tekrarlanabilirlik ve moleküler belirteçlerin geniş bir kullanılabilirliği avantajları sağlar. Apolipoprotein E eksikliği (apoE-/- ) fare modeli kardiyovasküler hastalıkları incelemek için yaygın olarak kullanılmıştır. Bununla birlikte, stentlerin farelere yerleştirilmek için minyatürleştirilmesi gerekir, mekanik ve (potansiyel olarak) biyolojik özelliklerinin önemli değişikliklerini içeren. ApoE-/- sıçanların kullanımı, apoE-/- sıçanlar insan büyüklüğünde koroner stentlerin değerlendirilmesine izin verirken aynı zamanda aterojenik bir fenotip sağlarken bu eksikliklerin üstesinden gelebilir. Bu, stent implantasyonundan sonra ISR'yi araştırmak için mükemmel ve güvenilir bir model haline getirir. Burada, ticari olarak mevcut insan koroner stentlerinin trans-femoral erişim kullanarak apoE-/- arka plan ile sıçanların karın aortuna implante edilmesi ayrıntılı olarak açıklanmaktadır.

Bu protokol, trans-femoral erişim yolu kullanan sıçanların karın aortunda stent implantasyonunu açıklar (Şekil 1). Bu hayvan modelinin ilk merkezi noktası, insan büyüklüğünde koroner stentlerin yerleştirilmesine izin veriyor olmasıdır. Piyasada bulunan kıvraklı ve balona monte koroner stent, sıçanların karın aortuna yerlenebilir. Böylece, ek olarak, insanlarda olduğu gibi aynı stent dağıtım prensibi uygulanabilir. Sıçan kullanımının bir başka avantajı, tic...

Watch this Scientific Journal Video about Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access at JoVE.com

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

Bu protokol, insan koroner stentlerin trans-femoral erişim kullanılarak apoE-/- arka plan ile sıçanların karın aortuna implantesini açıklar. Diğer hayvan modelleriyle karşılaştırıldığında, murine modelleri yüksek verim, tekrarlanabilirlik, kullanım ve muhafaza kolaylığı ve moleküler belirteçlerin geniş bir kullanılabilirliği avantajlarını taşır.

Trans-Femoral Erişim Kullanılarak İnsan Büyüklüğünde Koroner Stentlerin Rat Abdominal Aort'a yerleştirilmesi

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of ...

implantation-human-sized-coronary-stents-into-rat-abdominal-aorta

Research

JoVE Journal

Medicine

4.1K Görüntüleme.  University Hospital RWTH Aachen. Bu protokol, insan koroner stentlerin trans-femoral erişim kullanılarak apoE-/- arka plan ile sıçanların karın aortuna implantesini açıklar. Diğer hayvan modelleriyle karşılaştırıldığında, murine modelleri yüksek verim, tekrarlanabilirlik, kullanım ve muhafaza kolaylığı ve moleküler belirteçlerin geniş bir kullanılabilirliği avantajlarını taşır.

Video: Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant vasculopathy (TVP).
The commonly used animal model for cardiovascular chronic rejection studies is the heterotopic heart transplant model performed in laboratory rodents. This model is used widely in experiments since Ono and Lindsey (3) published their technique. To analyze the findings in the blood vessels, the heart has to be sectioned and all vessels have to be measured.
Another method to investigate chronic rejection in cardiovascular questionings is the aortic transplant model (1, 2). In the orthotopic aortic transplant model, the aorta can easily be histologically evaluated (2). The PVG-to-ACI model is especially useful for CAV studies, since acute vascular rejection is not a major confounding factor and Cyclosporin A (CsA) treatment does not prevent the development of CAV, similar to what we find in the clinical setting (4). A7-day period of CsA is required in this model to prevent acute rejection and to achieve long-term survival with the development of TVP.
This model can also be used to investigate acute cellular rejection and media necrosis in xenogeneic models (5).

This video demonstrates the orthotopic aortic transplant model as a simple model to study the development of transplant vasculopathy (TVP) in rats.

Ortotopik Aort Nakli: Rat Modeli Kronik Vaskülopati Geliştirme Çalışması

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant ...

Tıp

Human Internal Mammary Artery (IMA) Transplantation and Stenting: A Human Model to Study the Development of In-Stent Restenosis

Preclinical in vivo research models to investigate pathobiological and pathophysiological processes in the development of intimal hyperplasia after vessel stenting are crucial for translational approaches1,2.
The commonly used animal models include mice, rats, rabbits, and pigs3-5. However, the translation of these models into clinical settings remains difficult, since those biological processes are already studied in animal vessels but never performed before in human research models6,7. In this video we demonstrate a new humanized model to overcome this translational gap. The shown procedure is reproducible, easy, and fast to perform and is suitable to study the development of intimal hyperplasia and the applicability of diverse stents.
This video shows how to perform the stent technique in human vessels followed by transplantation into immunodeficient rats, and identifies the origin of proliferating cells as human.

Human Internal Mammary Artery IMA Transplantation and Stenting: A Human Model to Study the Development of In-Stent Restenosis

This video shows a model to study the development of intimal hyperplasia after stent deployment using a human vessel (IMA) in an immunodeficient rat model.

İnsan internal meme arter (İMA) Transplantasyon ve Stent: In-Stent Restenozis Geliştirme Eğitim Bir İnsan Modeli

Preclinical in vivo research models to investigate pathobiological and pathophysiological processes in the development of intimal hyperplasia after vessel ...

Implantation of Engineered Tissue in the Rat Heart

Rodent surgery is often an important component in assessing the utility of engineered tissues. A wide variety of surgical procedures can be performed in common laboratory rats or mice and these quite frequently serve as an intermediate step between bench-top experiments and large animal testing or human trials. Given that rodents provide an established, cost-effective, and physiologically-relevant model system in which to test novel combinations of scaffolding materials and cells, they are particularly well-suited for cardiovascular tissue engineering studies. Presently, we describe an open-heart surgical procedure to implant engineered tissue containing myogenic progenitor cells in the atrioventricular (AV) groove of a rat heart. These implants are intended to create an electrical conduit between the right atrium and right ventricle with the ultimate goal of providing an alternative treatment to conventional pacemaker implantation in pediatric patients with complete heart block[1]. The engineered tissue is implanted in the AV-groove by means of a thoracotomy. For our purposes, Lewis rats are anesthetized and invasively ventilated to maintain positive airway pressure during the sterile surgical procedure. The approach to the heart is performed by a right thoracotomy through an antero-lateral incision at the 5th intercostal space. The tissue construct is fixed in the AV groove using a single 7-0 Prolene suture and positioned between the right ventricle and atrium at the ventral portion of the heart. The epicardium is partially removed to allow direct contact between the recipient myocardial cells and those contained in the engineered tissue. Following implantation, the chest wall is closed in layers, any pneumothorax is evacuated, and the animal is extubated and treated with analgesic.

Here, we describe a cardiac surgical procedure to implant engineered tissue in the atrioventricular (AV)-groove of an adult Lewis rat.

Sıçan Kalp Engineered Doku implantasyonu

Rodent surgery is often an important component in assessing the utility of engineered tissues. A wide variety of surgical procedures can be performed in ...

Biyoloji

A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis

Despite the considerable progress made in the stent development in the last decades, cardiovascular diseases remain the main cause of death in western countries. Beside the benefits offered by the development of different drug-eluting stents, the coronary revascularization bears also the life-threatening risks of in-stent thrombosis and restenosis. Research on new therapeutic strategies is impaired by the lack of appropriate methods to study stent implantation and restenosis processes. Here, we describe a rapid and accessible procedure of stent implantation in mouse carotid artery, which offers the possibility to study in a convenient way the molecular mechanisms of vessel remodeling and the effects of different drug coatings.

A model of stent implantation in mouse carotid artery is described. Compared to other similar methods, this procedure is very rapid, simple and accessible, offering the possibility to study in a convenient way the vascular wall reaction to different drug-eluting stents and the molecular mechanisms of restenosis.

Restenoz Çalışmaları Karotis Arter Stent İmplantasyonu bir murin Modeli

Despite  the considerable progress made in the stent development in the last decades,  cardiovascular diseases remain the main cause of death in western ...

A New Murine Model of Endovascular Aortic Aneurysm Repair

Endovascular aneurysm exclusion is a validated technique to prevent aneurysm rupture. Long-term results highlight technique limitations and new aspects of Abdominal aortic aneurysm (AAA) pathophysiology. There is no abdominal aortic aneurysm endograft exclusion model cheap and reproducible, which would allow deep investigations of AAA before and after treatment. We hereby describe how to induce, and then to exclude with a covered coronary stentgraft an abdominal aortic aneurysm in a rat. The well known elastase induced AAA model was first reported in 19901 in a rat, then described in mice2. Elastin degradation leads to dilation of the aorta with inflammatory infiltration of the abdominal wall and intra luminal thrombus, matching with human AAA. Endovascular exclusion with small covered stentgraft is then performed, excluding any interactions between circulating blood and the aneurysm thrombus. Appropriate exclusion and stentgraft patency is confirmed before euthanasia by an angiography thought the left carotid artery. Partial control of elastase diffusion makes aneurysm shape different for each animal. It is difficult to create an aneurysm, which will allow an appropriate length of aorta below the aneurysm for an easy stentgraft introduction, and with adequate proximal and distal neck to prevent endoleaks. Lots of failure can result to stentgraft introduction which sometimes lead to aorta tear with pain and troubles to stitch it, and endothelial damage with post op aorta thrombosis. Giving aspirin to rats before stentgraft implantation decreases failure rate without major hemorrhage. Clamping time activates neutrophils, endothelium and platelets, and may interfere with biological analysis.

Histological and biochemical modifications after aneurysm endograft exclusion are still unclear. We describe a new model of endograft implantation on a murine aneurysm. Through thrombus analysis with and without persistant circulating blood stream interface, and new endovascular biomaterials evaluation, this model will help to better understand endovascular aneurysm exclusion pathobiology.

Endovasküler Aort Anevrizma Onarımı Yeni Bir murin Modeli

Endovascular aneurysm exclusion is a validated technique to prevent aneurysm rupture. Long-term results highlight technique limitations and new aspects of ...

Imaging In-Stent Restenosis: An Inexpensive, Reliable, and Rapid Preclinical Model

Preclinical models of restenosis are essential to unravel the pathophysiological processes that lead to in-stent restenosis and to optimize existing and future drug-eluting stents.
A variety of antibodies and transgenic and knockout strains are available in rats. Consequently, a model for in-stent restenosis in the rat would be convenient for pathobiological and pathophysiological studies. 
In this video, we present the full procedure and pit-falls of a rat stent model suitable for high throughput stent research. We will show the surgical procedure of stent deployment, and the assessment of in-stent restenosis using the most elegant technique of OCT (Optical Coherence Tomography). This technique provides high accuracy in assessing plaque CSAs (cross section areas) and correlates well with histological sections, which require special and time consuming embedding and sectioning techniques. OCT imaging further allows longitudinal monitoring of the development of in-stent restenosis within the same animal compared to one-time snapshots using histology.

This video demonstrates how to use a preclinical inexpensive and reliable model to study pathobiological and pathophysiological processes of in-stent restenosis development. Longitudinal in vivo monitoring using OCT (Optical Coherence Tomography) and analysis of OCT images are also demonstrated.

Görüntüleme-stent restenoz: Ucuz, güvenilir ve hızlı bir Preklinik Modeli

Preclinical models of restenosis are essential to unravel the pathophysiological processes that lead to in-stent restenosis and to optimize existing and ...

Biodegradable Magnesium Stent Treatment of Saccular Aneurysms in a Rat Model - Introduction of the Surgical Technique

The steady progess in the armamentarium of techniques available for endovascular treatment of intracranial aneurysms requires affordable and reproducable experimental animal models to test novel embolization materials such as stents and flow diverters. The aim of the present project was to design a safe, fast, and standardized surgical technique for stent assisted embolization of saccular aneurysms in a rat animal model.
Saccular aneurysms were created from an arterial graft from the descending aorta.The aneurysms were microsurgically transplanted through end-to-side anastomosis to the infrarenal abdominal aorta of a syngenic male Wistar rat weighing &#62;500 g. Following aneurysm anastomosis, aneurysm embolization was performed using balloon expandable magnesium stents (2.5 mm x 6 mm). The stent system was retrograde introduced from the lower abdominal aorta using a modified Seldinger technique.
Following a pilot series of 6 animals, a total of 67 rats were operated according to established standard operating procedures. Mean surgery time, mean anastomosis time, and mean suturing time of the artery puncture site were 167 &#177; 22 min, 26 &#177; 6 min and 11 &#177; 5 min, respectively. The mortality rate was 6% (n=4). The morbidity rate was 7.5% (n=5), and in-stent thrombosis was found in 4 cases (n=2 early, n=2 late in stent thrombosis).
The results demonstrate the feasibility of standardized stent occlusion of saccular sidewall aneurysms in rats - with low rates of morbidity and mortality. This stent embolization procedure combines the opportunity to study novel concepts of stent or flow diverter based devices as well as the molecular aspects of healing.

Reproducable experimental animal models are needed for the testing of novel embolization materials, which have been designed to treat endovascular occlusion of intracranial aneurysms (IA). The present study aims to develop a safe and standardized surgical technique for stent assisted embolization of saccular aneurysms in a rat animal model.

Bir sıçan modelinde - cerrahi tekniğin getirilmesi Saccular Anevrizmalarının biyobozunur magnezyum Stent tedavisi

The steady progess in the armamentarium of techniques available for endovascular treatment of intracranial aneurysms requires affordable and reproducable ...

Nörobilim

Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally (3D) printed coronary implants can be employed to percutaneously create a focal coronary stenosis. However, reliable delivery of the implants can be difficult without the use of ancillary equipment. We describe the use of a mother-and-child coronary guide catheter for stabilization of the implant and for effective delivery of the 3D printed implant to any desired location along the length of the coronary vessel. The focal coronary narrowing was confirmed under coronary cineangiography and the functional significance of the coronary stenosis was assessed using gadolinium-enhanced first-pass cardiac perfusion MRI. We showed that reliable delivery of 3D printed coronary implants in swine models (n = 11) of ischemic heart disease can be achieved through repurposing mother-and-child coronary guide catheters. Our technique simplifies the percutaneous delivery of coronary implants to create closed-chest swine models of focal coronary artery stenosis and can be performed expeditiously, with a low procedural failure rate.

We describe a novel, cost-effective, and efficient technique for percutaneous delivery of three-dimensionally printed coronary implants to create closed-chest swine models of ischemic heart disease. The implants were fixed in place using a mother-and-child extension catheter with high success rate.

İskemik Kalp Hastalığının Domuz Modellerinde 3D Baskılı Koroner Stenoz İmplantlarının Konuşlandırılmasında Yeni Perkütan Yaklaşım

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally ...

Using a Cell-Tracer Injection to Investigate the Origin of Neointima-Forming Cells in a Rat Saccular Side Wall Model

Microsurgical clipping creates a subsequent barrier of blood flow into intracranial aneurysms, whereas endovascular treatment relies on neointima and thrombus formation. The source of endothelial cells covering the endoluminal layer of the neointima remains unclear. Therefore, the aim of the present study was to investigate the origin of neointima-forming cells after cell-tracer injection in the already well-established Helsinki rat microsurgical sidewall aneurysm model.
Sidewall aneurysms were created by suturing decellularized or vital arterial pouches end-to-side to the aorta in male Lewis rats. Before arteriotomy with aneurysm suture, a cell-tracer injection containing CM-Dil dye was performed into the clamped aorta to label endothelial cells in the adjacent vessel and track their proliferation during follow-up (FU). Treatment followed by coiling (n = 16) or stenting (n = 15). At FU (7 days or 21 days), all rats underwent fluorescence angiography, followed by aneurysm harvesting and macroscopic and histological evaluation with immunohistological cell counts for specific regions of interest. 
None of the 31 aneurysms had ruptured upon follow-up. Four animals died prematurely. Macroscopically residual perfusion was observed in 75.0% coiled and 7.0% of stented rats. The amount of cell-tracer-positive cells was significantly elevated in decellularized stented compared to coiled aneurysms with respect to thrombus on day 7 (p = 0.01) and neointima on day 21 (p = 0.04). No significant differences were found in thrombus or neointima in vital aneurysms. 
These findings confirm worse healing patterns in coiled compared to stented aneurysms. Neointima formation seems particularly dependent on the parent artery in decellularized aneurysms, whereas it is supported by the recruitment from aneurysm wall cells in vital cell-rich walls. In terms of translation, stent treatment might be more appropriate for highly degenerated aneurysms, whereas coiling alone might be adequate for aneurysms with mostly healthy vessel walls.

We performed a one-point, lipophilic cell-tracer injection to track endothelial cells, followed by an arteriotomy and suturing of sidewall aneurysms on the abdominal rat aorta. Neointima formation seemed dependent on the parent artery in decellularized aneurysms and was promoted by the recruitment from aneurysm wall cells in vital cell-rich walls.

Bir Sıçan Sakküler Yan Duvar Modelinde Neointima Oluşturan Hücrelerin Kökenini Araştırmak için Bir Hücre İzleyici Enjeksiyonu Kullanma

Microsurgical clipping creates a subsequent barrier of blood flow into intracranial aneurysms, whereas endovascular treatment relies on neointima and ...

Implantation of Electrospun Vascular Grafts with Optimized Structure in a Rat Model

Here, we present a protocol to fabricate macroporous PCL vascular graft and describe an evaluation protocol by using a rat model of abdominal aorta replacement. The electrospun vascular grafts often possess relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the neo-arteries. In this study, PCL vascular grafts with thicker fibers (5 - 6 &#181;m) and larger pores (~30 &#181;m) were fabricated by using a modified processing technique. The long-term performance of the graft was evaluated by implantation in a rat abdominal aorta model. Ultrasound analysis showed that the grafts remained patent without aneurysm or stenosis occurring even after 12 months of implantation. Macroporous structure improved the cell ingrowth and thus promoted tissue regenerated at 3 months. More importantly, there was no sign of adverse remodeling, such as calcification within the graft wall after 12 months. Therefore, electrospun PCL vascular grafts with modified macroporous processing hold potential to be an artery substitute for long-term implantation.

Here, we present a modified electrospinning method to fabricate PCL vascular grafts with thick fibers and large pores, and describe a protocol to evaluate the in vivo performance in a rat model of abdominal aorta replacement.

Bir sıçan modelinde en iyi duruma getirilmiş yapısı ile Electrospun vasküler greft implantasyonu

Here, we present a protocol to fabricate macroporous PCL vascular graft and describe an evaluation protocol by using a rat model of abdominal aorta ...