この作品は賞号W81XWH-13-2-0053の下で、AFIRM II努力をサポートするために、陸軍、海軍、NIH、空軍、VAおよび保健省によってサポートされていました。米陸軍医学研究買収活動、820チャンドラーストリート、フォート・デトリックMD 21702から5014までは表彰および管理取得オフィスです。ご意見、解釈、結論と勧告は著者のものであり、必ずしも国防総省によって承認されていません。 著者らは、この研究の間に、その優れた獣医のサポートのためにジェシカイッチ、DVM、キャロライン・ギャレット、DVMとジュリー・ワトソン、DVMに感謝したいと思います。

全ての実験は、国立衛生研究所の実験動物の管理と使用に関する指針（NIH）に従って行ったし、ジョンズ・ホプキンス大学動物実験委員会（JHUACUC）によって承認されました。具体的な手順は、承認されたACUCプロトコルMO13M108下で行いました。 1.ドナー操作<ol><li>手術前に各薬理学的製剤のための適切な時点で鎮痛を管理します。承認された動物の世話のとおりと前皮膚切開にブプレノルフィン皮下に1時間の0.1ミリグラム/キログラムBWプロトコルの使用を使用します。 </li><li>イソフルランで落ち着いたドナーは4％でイソフルラン気化器に取り付けられた室を通って適用しました。ノーズコーンを介して2％で鎮静や麻酔を維持します。手続きの開始に先立って麻酔深度を監視するためにつま先ピンチ撤退反射を実行します。 </li><li>マスク、使い捨ての分離ガウンと手袋を着用してください。 </li><li>外科的ARを剃りますEA、特に後肢と鼠径部、および10％のポビドンで準備を - ヨウ素。 </li><li>滅菌野ドレープ、オートクレーブ処理機器や高倍率顕微鏡（40X）を使用します。 </li><li>半ば腿領域に近位にはさみを使用して、脚の付け根の皮膚切開を行い、円周方向にマウス本体の残りの部分から後肢を画定するために切開部を接続します。 </li><li>大腿動脈、静脈や神経を特定し、解剖。鉗子とマイクロはさみを使用して、すべての3つの構造を分離します。 </li><li>血管茎を解剖したら、マイクロはさみを使用して、鼠径靱帯のレベルで血管を分割します。 </li><li>次に、はさみを使用して、ドナー動物からの移植片を分離するために半ば腿のレベルで近位個々の腹側（薄と大腿内側の筋肉）と背側の筋肉群20を分割し続けます。 </li><li>大腿骨を横断し、はさみを使用して大腿骨シャフトの中間で切断。 </li><li>イソフルラン過剰摂取FOLにより動物を安楽死させます頚椎脱臼が続き。心拍や呼吸の停止を確認してください。 </li><li>注射器に取り付けられた33のGフラッシング針を使用してヘパリン化2ミリリットル（30 IE）の冷（4℃）生理食塩水で手足をフラッシュ（材料表を参照してください）​​。 </li><li>それぞれ、大腿静脈と動脈に1ポリイミドカフを配置します。 </li><li>インセットまで湿った綿ガーゼ、4℃でペトリ皿や店舗内の所定の場所に移植片をラップします。 </li></ol> 2.受信者の操作<ol><li> 後肢の除去 <ol><li>手術前に各薬理学的製剤のための適切な時点で鎮痛を管理します。承認された動物の管理と使用プロトコルを使用ブプレノルフィンSC 1時間前に皮膚切開の0.1ミリグラム/ kg体重あたりとして。 </li><li>イソフルランで落ち着いたドナーは4％でイソフルラン気化器に取り付けられた室を通って適用しました。ノーズコーンを介して2％で鎮静や麻酔を維持します。 DEPTを監視するために、つま先のピンチ撤退の反射を行います手続きの開始に先立って麻酔の時間。 </li><li>麻酔下ながら乾燥を防ぐために、マウスの目に獣医の軟膏を使用してください。 </li><li>特に、10％ポビドンと後肢と脚の付け根と準備を手術領域を剃る - ヨウ素。 </li><li>半ば腿領域に近位にはさみを使用して、脚の付け根の皮膚切開を行い、円周方向にマウス本体の残りの部分から後肢を画定するために切開部を接続します。 </li><li>鉗子とマイクロはさみを使用して、すべての3つの構造を特定し、大腿動脈、静脈や神経を解剖し、分離します。 </li><li>血管茎を解剖したら、鼠径靱帯のレベルで大腿血管をクランプします。 </li><li>浅腹壁動脈のレベルで遠位血管をカットします。 </li><li>次に、ネイティブ後肢リチウムを分離するために、近位に半ば腿のレベルで個々の腹側（薄と大腿内側の筋肉）と背側の筋肉群20を分割し続けますはさみを使用して、レシピエント動物からMB。 </li><li>はさみを使用して大腿骨シャフトの中央に大腿骨を横断。 </li><li>切開部位の出血、したがってレシピエントの血液損失を防止するために、以前に離断大腿部の筋肉を焼灼。 </li></ol></li><li> 移植 <ol><li>温かい生理食塩水（37°C）で術野を灌漑し、操作の前と後の0.3ミリリットル暖かい生理食塩水を注入することにより、流体の損失を最小限に抑えます。 </li><li>受信者の大腿骨と移植片を整列させることによって、ネイティブ後肢の正確な解剖学的位置を反映し、髄内ロッドとして20 G脊髄針を使用してそれらを接続する方法で、移植片を置きます。 </li><li>吸収性縫合糸材料（6-0ポリソーブ）を使用して癒合腹側と背側の筋肉群。 </li><li>非縫合カフ技術を用いて大腿血管を接続します。詳細に、以前グラーフの容器端部に取り付けられたカフの上に容器の受信者側を引っ張りますトン。 10-0ナイロン縫合糸を使用し、袖口に受信者の容器を固定するために、円周ネクタイを行います。 </li><li>次のクランプを解放します。この段階で視覚的にカフ回転および血管の誤回転やねじれを防止するための最適な位置を確認します。 </li><li>筋肉の受信者ドナーインターフェースと骨の両端を中心とした電気メスを使用して細心の止血を行います。 </li><li>非吸収性ナイロン縫合糸（6-0 Ethilon）を用いて皮膚を閉じます。 </li><li>動物は加熱ランプの下で、そのケージに回復できるようにすることで、正常体温条件を確立します。住宅施設に戻す前に、少なくとも4時間、定期的なモニタリングを続けます。 </li><li> 3日間は0.1mg / kgをSC毎に6-8時間の用量でブプレノルフィンと術後鎮痛を提供します。 </li></ol></li></ol>

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H., Kawai, T., Sykes, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Induction+of+tolerance+through+mixed+chimerism.">Induction of tolerance through mixed chimerism.</a> Cold Spring Harb. Perspect. Med. 4, a015529 (2014).</li><li>Kawai, T., 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=HLA-mismatched+renal+transplantation+without+maintenance+immunosuppression.">HLA-mismatched renal transplantation without maintenance immunosuppression.</a> N. Engl. J. Med. 358, 353-361 (2008).</li><li>Kawai, T., Sachs, D. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tolerance+induction:+hematopoietic+chimerism.">Tolerance induction: hematopoietic chimerism.</a> Curr Opin Organ Transplant. 18, 402-407 (2013).</li><li>Kawai, T., Sachs, D. H., Sykes, M., Cosimi, A. .. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=HLA-mismatched+renal+transplantation+without+maintenance+immunosuppression.">HLA-mismatched renal transplantation without maintenance immunosuppression.</a> N. Engl. J. Med. 368, 1850-1852 (2013).</li><li>Leventhal, J., 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=Chimerism+and+tolerance+without+GVHD+or+engraftment+syndrome+in+HLA-mismatched+combined+kidney+and+hematopoietic+stem+cell+transplantation.">Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.</a> Sci. Transl. Med. 4, 124-128 (2012).</li><li>Cendales, L. C., 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+Banff+2007+working+classification+of+skin-containing+composite+tissue+allograft+pathology.">The Banff 2007 working classification of skin-containing composite tissue allograft pathology.</a> Am. J. Transplant. 8, 1396-1400 (2008).</li></ol>

The authors declare that they have no competing financial interest.

このような壊滅的な組織欠損の再建のための上肢と顔面移植などの血管新生したコンポジット同種移植は、従来の再建手続きに修正可能ではない患者に対する有効な治療法の選択肢として発展してきました。マイクロサージャリーの分野における技術の進歩だけでなく、強力な免疫抑制および固形臓器移植における免疫調節療法と豊富な経験は、今、このユニークな患者集団3,21の長?...

The late nineties heralded the pioneering days of reconstructive transplantation with the first successful hand transplant performed in France in 1998. Since then, the use of VCAs for reconstruction of devastating tissue defects has been successfully employed in a wide spectrum of patients. To date, the world counts 76 recipients of 112 upper extremities as well as 31 faces 1-3. In addition, several other types of VCAs such as abdominal wall 4, larynx 5, trachea 6, vascularized joints 7, and even penis 8 have been performed. Furthermore, the live birth of a baby was recently reported after uterus transplantation 9. This growing world experience is indicative for how reconstructive transplantation has become a valid therapeutic option for patients suffering of significant functional tissue defects not amendable to conventional reconstructive and restorative surgery and treatment. 
While the idea of replacing "like with like" sparked clinical enthusiasm, initial skepticism still prevails with regards to side effects of conventional high-dose immunosuppression required to maintain allografts and their function 10,11. However, as shown by seminal work of Lee et al., these composite grafts are less likely to reject than its individual components, and furthermore, some of the tissue components such as the vascularized bone compartment have fueled optimism as they might exert unique immunological effects onto the balance of immune acceptance and rejection 12. 
Our group pioneered several microsurgical animal models for solid organ transplantation, as well as vascularized composite allotransplantation 13-19. Here we describe a novel surgical procedure using a non-suture cuff technique to perform super micro-vascular anastomosis in an orthotopic mouse hind limb transplantation model. This transplant model provides a useful tool for investigating immune acceptance and rejection mechanisms, as well as the role of individual tissue components, such as the vascularized bone marrow compartment, towards tolerance induction in the immunologically versatile setting of the mouse species. Additionally, the orthotopic placement of the limb opens the possibilities for nerve regeneration and functional outcome studies, which are critically important to the setting of VCA.

<table>
	<tbody>
		<tr>
			<td>Suture, 6-0 Nylon</td>
			<td>MWI</td>
			<td>31849</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture, 6-0 Polysorb</td>
			<td>MWI</td>
			<td>72667</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture, 10-0 Nylon</td>
			<td>Aero Surgical</td>
			<td>TK-107038</td>
			<td></td>
		</tr>
		<tr>
			<td>Polyimide Tubing, Size 25</td>
			<td>Vention Medical</td>
			<td>141-0023</td>
			<td></td>
		</tr>
		<tr>
			<td>Polyimide Tubing, Size 27</td>
			<td>Vention Medical</td>
			<td>141-0015</td>
			<td></td>
		</tr>
		<tr>
			<td>Microvascular Clamps (Single)</td>
			<td>Synovis</td>
			<td>00396</td>
			<td></td>
		</tr>
		<tr>
			<td>Microvascular Clamps (Double)</td>
			<td>Synovis</td>
			<td>00414</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Scissors</td>
			<td>Synovis</td>
			<td>SAS-18</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Forceps</td>
			<td>Synovis</td>
			<td>FRS-15 RM-8</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Dilators</td>
			<td>Synovis</td>
			<td>FRS-15 RM-8d.1</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Needledriver</td>
			<td>Synovis</td>
			<td>C-14</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Clamp Applicator</td>
			<td>Synovis</td>
			<td>CAF-4</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro-Flushing Needle</td>
			<td>Hamilton</td>
			<td>N/A</td>
			<td>10MM, 30&#176;, 33G</td>
		</tr>
		<tr>
			<td>Lactated Ringers Solution</td>
			<td>Fisher Scientific</td>
			<td>NC9968051</td>
			<td></td>
		</tr>
		<tr>
			<td>Buprenorphine</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>DEA Number required; Obtained from hosptial pharmacy.</td>
		</tr>
		<tr>
			<td>Enrofloxacin; Baytril</td>
			<td>Bayer Health Care</td>
			<td>186599</td>
			<td></td>
		</tr>
		<tr>
			<td>Heparin</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Obtained from hosptial pharmacy</td>
		</tr>
	</tbody>
</table>

orthotopic hind limb transplantation in the mouse

In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and translational research in the field of transplantation medicine. A vast array of reagents is available exclusively in this setting, including mono- and polyclonal antibodies for both diagnostic and interventional applications. In addition, a vast number of genotyped, inbred, transgenic, and knock out strains allow detailed investigation of the individual contributions of humoral and cellular components to the complex interplay of an immune response and make the mouse the gold standard for immunological research. 
Vascularized Composite Allotransplantation (VCA) delineates a novel field of transplantation using allografts to replace "like with like" in patients suffering traumatic or congenital tissue loss. This surgical methodological protocol shows the use of a non-suture cuff technique for super-microvascular anastomosis in an orthotopic mouse hind limb transplantation model. The model specifically allows for comparison between established paradigms in solid organ transplantation with a novel form of transplants consisting of various different tissue components. Uniquely, this model allows for the transplantation of a viable vascularized bone marrow compartment and niche that have the potential to exert a beneficial effect on the balance of immune acceptance and rejection. This technique provides a tool to investigate alloantigen recognition and allograft rejection and acceptance, as well as enables the pursuit of functional nerve regeneration studies to further advance this novel field of transplantation.

非縫合カフ技術を用いて、マウスモデルにおいて血管新生複合同種移植を行うと、 図1に示すように優れ、長期間の移植および動物の生存を達成することができる。また、血管新生合成の緩やかな同種移植片拒絶反応の再現可能な結果を得るための信頼できる方法を表します。などの同種移植は、 図2に示されている画像によって文書化。拒?...

Watch this Scientific Journal Video about Orthotopic Hind Limb Transplantation in the Mouse at JoVE.com

Orthotopic Hind Limb Transplantation in the Mouse

超微小血管吻合のための非縫合カフ技術を適用したマウスにおける同所後肢移植のためのこの新規モデルは、血管新生複合同種移植（VCA）に関連したin vivoでのメカニズムの免疫学的研究のための強力なツールを提供します。

マウスで同所後肢移植

In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and ...

orthotopic-hind-limb-transplantation-in-the-mouse

Universidad de Cartagena UDEC

Research

JoVE Journal

Medicine

11.6K ビュー.  Johns Hopkins University School of Medicine. 超微小血管吻合のための非縫合カフ技術を適用したマウスにおける同所後肢移植のためのこの新規モデルは、血管新生複合同種移植（VCA）に関連したin vivoでのメカニズムの免疫学的研究のための強力なツールを提供します。 

ビデオ: Orthotopic Hind Limb Transplantation in the Mouse

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.

同所性大動脈移植：慢性血管障害の発生研究のラットモデル

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

医学

Longitudinal Evaluation of Mouse Hind Limb Bone Loss After Spinal Cord Injury using Novel, in vivo, Methodology

Spinal cord injury (SCI) is often accompanied by osteoporosis in the sublesional regions of the pelvis and lower extremities, leading to a higher frequency of fractures 1. As these fractures often occur in regions that have lost normal sensory function, the patient is at a greater risk of fracture-dependent pathologies, including death. SCI-dependent loss in both bone mineral density (BMD, grams/cm2) and bone mineral content (BMC, grams) has been attributed to mechanical disuse 2, aberrant neuronal signaling 3 and hormonal changes 4. The use of rodent models of SCI-induced osteoporosis can provide invaluable information regarding the mechanisms underlying the development of osteoporosis following SCI as well as a test environment for the generation of new therapies 5-7 (and reviewed in 8). Mouse models of SCI are of great interest as they permit a reductionist approach to mechanism-based assessment through the use of null and transgenic mice. While such models have provided important data, there is still a need for minimally-invasive, reliable, reproducible, and quantifiable methods in determining the extent of bone loss following SCI, particularly over time and within the same cohort of experimental animals, to improve diagnosis, treatment methods, and/or prevention of SCI-induced osteoporosis.
An ideal method for measuring bone density in rodents would allow multiple, sequential (over time) exposures to low-levels of X-ray radiation. This study describes the use of a new whole-animal scanner, the IVIS Lumina XR (Caliper Instruments) that can be used to provide low-energy (1-3 milligray (mGy)) high-resolution, high-magnification X-ray images of mouse hind limb bones over time following SCI. Significant bone density loss was seen in the tibiae of mice by 10 days post-spinal transection when compared to uninjured, age-matched control (na&iuml;ve) mice (13% decrease, p&lt;0.0005). Loss of bone density in the distal femur was also detectable by day 10 post-SCI, while a loss of density in the proximal femur was not detectable until 40 days post injury (7% decrease, p&lt;0.05). SCI-dependent loss of mouse femur density was confirmed post-mortem through the use of Dual-energy X-ray Absorptiometry (DXA), the current "gold standard" for bone density measurements. We detect a 12% loss of BMC in the femurs of mice at 40 days post-SCI using the IVIS Lumina XR. This compares favorably with a previously reported BMC loss of 13.5% by Picard and colleagues who used DXA analysis on mouse femurs post-mortem 30 days post-SCI 9. Our results suggest that the IVIS Lumina XR provides a novel, high-resolution/high-magnification method for performing long-term, longitudinal measurements of hind limb bone density in the mouse following SCI.

Longitudinal Evaluation of Mouse Hind Limb Bone Loss After Spinal Cord Injury using Novel, in vivo, Methodology

A longitudinal examination of bone loss in the femurs and tibiae of adult mice was performed following spinal cord injury using sequential low-dose X-ray scans. Tibia bone loss was detected throughout the study, while bone loss in the femur was not detected until 40 days post injury.

小説を使用して、脊髄損傷後のマウス後肢の骨の損失の経時的評価、 in vivoで、方法論

Spinal cord injury (SCI) is often accompanied by osteoporosis in the sublesional regions of the pelvis and lower extremities, leading to a higher ...

Orthotopic Small Bowel Transplantation in Rats

Small bowel transplantation has become an accepted clinical option for patients with short gut syndrome and failure of parenteral nutrition (irreversible intestinal failure). In specialized centers improved operative and managing strategies have led to excellent short- and intermediate term patient and graft survival while providing high quality of life 1,3. Unlike in the more common transplantation of other solid organs (i.e. heart, liver) many underlying mechanisms of graft function and immunologic alterations induced by intestinal transplantation are not entirely known6,7. Episodes of acute rejection, sepsis and chronic graft failure are the main obstacles still contributing to less favorable long term outcome and hindering a more widespread employment of the procedure despite a growing number of patients on home parenteral nutrition who would potentially benefit from such a transplant. The small intestine contains a large number of passenger leucocytes commonly referred to as part of the gut associated lymphoid system (GALT) this being part of the reason for the high immunogenity of the intestinal graft. The presence and close proximity of many commensals and pathogens in the gut explains the severity of sepsis episodes once graft mucosal integrity is compromised (for example by rejection). To advance the field of intestinal- and multiorgan transplantation more data generated from reliable and feasible animal models is needed. The model provided herein combines both reliability and feasibility once established in a standardized manner and can provide valuable insight in the underlying complex molecular, cellular and functional mechanisms that are triggered by intestinal transplantation. We have successfully used and refined the described procedure over more than 5 years in our laboratory 8-11. The JoVE video-based format is especially useful to demonstrate the complex procedure and avoid initial pitfalls for groups planning to establish an orthotopic rodent model investigating intestinal transplantation.

Small bowel transplantation has become an accepted treatment option for patients with irreversible intestinal failure. Our experimental model of orthotopic small bowel transplantation in rats serves as a reliable tool to address underlying immunologic and inflammatory processes that complicate intestinal transplantation.

ラット同所性小腸移植

Small  bowel transplantation has become an accepted clinical option for patients with  short gut syndrome and failure of parenteral nutrition ...

Orthotopic Liver Transplantation in Rats

Clinical progress in the field of liver transplantation has been largely supported by animal models1,2. Since the publication of the first orthotopic rat liver transplantation in 1979 by Kamada et al.3, this model has remained the gold standard despite various proposed alternative techniques4. Nevertheless, its broader use is limited by its steep learning curve5.
In this video paper, we show a simple and easy-to-establish revision of Kamada's two-cuff technique. The suprahepatic vena cava anastomosis is performed manually with a running suture, and the vena porta and infrahepatic vena cava anastomoses are performed utilizing a quick-linker cuff system6. Manufacturing the quick-linker kit is shown in a separate video paper.

We present an easy-to-establish revision of the classical two-cuff technique for orthotopic liver transplantation in rat.

ラット同所性肝移植

Clinical progress in the field of liver transplantation has been largely supported by animal models1,2. Since the publication of the first orthotopic rat ...

Orthotopic Aortic Transplantation in Mice for the Study of Vascular Disease

Vascular procedures involving anastomoses in the mouse are generally thought to be difficult and highly dependent on the skill of the individual surgeon. This is largely true, but there are a number of important principles that can reduce the difficulty of these procedures and enhance reproducibility. Orthotopic aortic transplantation is an excellent procedure in which to learn these principles because it involves only two end-to-end anastomoses, but requires good suturing technique and handling of the vessels for consistent success. This procedure begins with the procurement of a length of abdominal aorta from a donor animal, followed by division of the native aorta in the recipient. The procured aorta is then placed between the divided ends of the recipient aorta and sutured into place using end-to-end anastomoses. To accomplish this objective successfully requires a high degree of concentration, good tools, a steady hand, and an appreciation of how easily the vasculature of a mouse can be damaged, resulting in thrombosis. Learning these important principles is what occupies most of the beginner's time when learning microsurgery in small rodents. Throughout this protocol, we refer to these important points. This model can be used to study vascular disease in a variety of different experimental systems1-8. In the context shown here, it is most often used for the study of post-transplant vascular disease, a common long-term complication of solid organ transplantation in which intimal hyperplasia occurs within the allograft. The primary advantage of the model is that it facilitates quantitative morphometric analyses and the transplanted vessel lies contiguous to the endogenous vessel, which can serve as an additional control9. The technique shown here is most often used for mice weighing 18-25 grams. We have accumulated most of our experience using the C57BL/6J, BALB/cJ, and C3H/HeJ strains.

We describe a technique in which a section of the abdominal aorta from a mouse is transplanted orthotopically to just below the renal arteries in an allogeneic or syngeneic recipient. This technique can be useful in studies in which transplantation of large arteries of uniform size is deemed advantageous.

血管疾患の研究のためのマウスにおける同所性大動脈移植

Vascular procedures involving anastomoses in the mouse are generally thought to be difficult and highly dependent on the skill of the individual surgeon. ...

A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation (VCA) Research

Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma and devastating tissue loss. Despite favorable and highly encouraging early and intermediate functional outcomes, rejection of the highly immunogenic skin component of a VCA and potential adverse effects of chronic multi-drug immunosuppression continue to hamper widespread clinical application of VCA. Therefore, research in this novel field needs to focus on translational studies related to unique immunologic features of VCA and to develop novel immunomodulatory strategies for immunomodulation and tolerance induction following VCA without the need for long term immunosuppression.
This article describes a reliable and reproducible translational large animal model of VCA that is comprised of an osteomyocutaneous flap in a MHC-defined swine heterotopic hind limb allotransplantation. Briefly, a well-vascularized skin paddle is identified in the anteromedial thigh region using near infrared laser angiography. The underlying muscles, knee joint, distal femur, and proximal tibia are harvested on a femoral vascular pedicle. This allograft can be considered both a VCA and a vascularized bone marrow transplant with its unique immune privileged features. The graft is transplanted to a subcutaneous abdominal pocket in the recipient animal with a skin component exteriorized to the dorsolateral region for immune monitoring.
Three surgical teams work simultaneously in a well-coordinated manner to reduce anesthesia and ischemia times, thereby improving efficiency of this model and reducing potential confounders in experimental protocols. This model serves as the groundwork for future therapeutic strategies aimed at reducing and potentially eliminating the need for chronic multi-drug immunosuppression in VCA.

A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation VCA Research

Vascularized Composite Allotransplantations (VCA) have become a clinical reality. However, broad clinical application of VCA is limited by chronic multi-drug immunosuppression. The authors present a reliable and reproducible large animal model to translate novel immunomodulatory strategies that can minimize or potentially eliminate the need of immunosuppression in VCA.

トランスレーショナル血管柄コンポジット同種移植（VCA）研究用に修正異豚後肢移植モデル

Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma ...

Mouse Kidney Transplantation: Models of Allograft Rejection

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

Here, we present a protocol to study the immunology of rejection. The surgical model presented reports a short operating time and a concise technique. Depending on the donor-recipient strain combination, the transplanted kidney may develop acute cellular rejection or chronic allograft damage, defined by interstitial fibrosis and tubular atrophy.

マウス腎臓移植：同種移植片拒絶のモデル

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely ...

A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis

The majority of cancer-related deaths are caused by the metastasis of the cancer rather than the primary tumor itself. Yet, the underlying mechanisms of cancer metastasis are still unclear. Animal models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of metastatic cancers. Here, an in-depth description of a &#8220;patient-like&#8221; orthotopic syngeneic mouse model for exploring the mechanisms of metastasis of solid organ tumors is provided. The survival surgical implantation of BNL 1ME A.7R.1 mouse hepatocellular carcinoma cells directly into the liver (the organ of origin) of the inbred wild-type immune competent laboratory mouse strain, BALB/c is described. The success and reproducibility of this methodology recommends it for widespread use in elucidating the biological mechanisms of solid organ cancer metastasis.

The metastatic spread of cancer is the major cause of cancer-related deaths. We provide an in-depth description of our survival surgery methodology for establishing a &#8220;patient-like&#8221; orthotopic syngeneic mouse model system for studying the mechanisms of metastasis in solid organ tumors.

肝細胞癌転移の「患者様」同所同系マウスモデル

The majority of cancer-related deaths are caused by the metastasis of the cancer rather than the primary tumor itself. Yet, the underlying mechanisms of ...

Preclinical Model of Hind Limb Ischemia in Diabetic Rabbits

Peripheral vascular disease is a widespread clinical problem that affects millions of patients worldwide. A major consequence of peripheral vascular disease is the development of ischemia. In severe cases, patients can develop critical limb ischemia in which they experience constant pain and an increased risk of limb amputation. Current therapies for peripheral ischemia include bypass surgery or percutaneous interventions such as angioplasty with stenting or atherectomy to restore blood flow. However, these treatments often fail to the continued progression of vascular disease or restenosis or are contraindicated due to the overall poor health of the patient. A promising potential approach to treat peripheral ischemia involves the induction of therapeutic neovascularization to allow the patient to develop collateral vasculature. This newly formed network alleviates peripheral ischemia by restoring perfusion to the affected area. The most frequently employed preclinical model for peripheral ischemia utilizes the creation of hind limb ischemia in healthy rabbits through femoral artery ligation. In the past, however, there has been a strong disconnect between the success of preclinical studies and the failure of clinical trials regarding treatments for peripheral ischemia. Healthy animals typically have robust vascular regeneration in response to surgically induced ischemia, in contrast to the reduced vascularity and regeneration in patients with chronic peripheral ischemia. Here, we describe an optimized animal model for peripheral ischemia in rabbits that includes hyperlipidemia and diabetes. This model has reduced collateral formation and blood pressure recovery in comparison to a model with a higher cholesterol diet. Thus, the model may provide better correlation with human patients with compromised angiogenesis from the common co-morbidities that accompany peripheral vascular disease.

We describe a surgical procedure used to induce peripheral ischemia in rabbits with hyperlipidemia and diabetes. This surgery acts as a preclinical model for conditions experienced in peripheral artery disease in patients. Angiography is also described as a means to measure the extent of introduced ischemia and recovery of perfusion.

糖尿病性ウサギにおける後肢虚血の前臨床モデル

Peripheral vascular disease is a widespread clinical problem that affects millions of patients worldwide. A major consequence of peripheral vascular ...

A Pre-Clinical Porcine Model of Orthotopic Heart Transplantation

Fifty-years following the first successful report, cardiac transplantation remains the gold-standard treatment for eligible patients with advanced heart failure. Multiple small-animal models of heart transplantation have been used to study the acute and long-term effects of novel therapies. However, few are tested and demonstrated success in clinical trials. It is of critical importance to evaluate new therapies in a clinically relevant large-animal model for efficient and reliable translation of basic studies&#39;&#160;findings. Here, we describe a pre-clinical large-animal (porcine) model of orthotopic heart transplantation that has been firmly established and previously used to investigate novel cardioprotective strategies. This procedure focuses on acute ischemia-reperfusion injury and is a reliable method to investigate novel interventions which have been tested and validated in smaller experimental models, such as the murine model. We demonstrate its usefulness in assessing cardiac performance during the early post-transplantation period and other potential possibilities enabled by the model.

Here, we describe a pre-clinical large-animal (porcine) model of orthotopic heart transplantation that has been firmly established and utilized to investigate novel cardioprotective strategies.

オルソトピック心臓移植の前臨床ブタモデル

Fifty-years following the first successful report, cardiac transplantation remains the gold-standard treatment for eligible patients with advanced heart ...