著者は、博士キャサリン Pietrosimone から編集の貢献を認めます。PLA の足場は、ノースカロライナ州立大学で博士エリザベス Loboa の研究室で製造されました。この作品は、UNC 施設の大学がん研究基金と UNC トランスレーショナルリサーチと臨床科学研究所 (KL2TR001109、UL1TR001111) によって支えられました。

ここで説明するすべての方法は、制度的動物ケアおよび使用委員会 (IACUC) のノースカロライナ大学チャペルヒル校によって承認されています。
注: 開く開頭術、マウスにこの手順を実行 Mostany と・ ポルテラ Cailliau19の摘出は骨組織を破棄する前記によるプロトコルの修正されたバージョンとして設立バリアフリー脳を残して、最終的な糸球体基底膜腫瘍切除術。小沢氏とジェームズの20記載, 開頭手術後腫瘍は定位注入を介して確立されます。我々 インプラント (前から mm) で次の定位座標で 1 × 105 U87 mCh Fl 細胞: (2.5, 0,-0.5)。
1. 細胞培養足場の準備
注: 足場は、マウスに注入する前に 48 h が準備されるべき。以下のボリュームは、足場ごとに基づいて提供しています。追加足場の必要に応じて数量を乗算します。
<ol><li>切除キャビティ サイズ (約 2 mm × 2 mm) に PLA の足場を切る。足場は、はさみを使用してまたは再現性の穴パンチを使用して手でカットできます。</li>
	<li>滅菌 PBS 中に浸漬後 15 分間 70% エタノールに浸漬します。播種用細胞を準備している間 10% 牛胎児血清 (FBS) 1% ペニシリン-ストレプトマイシンを含むダルベッコ変法イーグル培地 (DMEM) に足場を配置します。</li>
	<li>0.05% トリプシン (T75 フラスコの 3-5 mL) を用いた培養 MSCs を持ち上げます。37 ° C、5 分セルが持ち上げたことを確認で孵化させなさい、トリプシンを不活化するフラスコに 7-10 mL DMEM を追加します。</li>
	<li>15 mL 遠心管にフラスコの内容を転送します。診断を使用してセルをカウントします。5 x 105 5 分 100 × g で遠心分離を介して各足場 MSCs をペレットします。</li>
	<li>上清を吸引し、5 x 10 の5セルあたり 5 μ l 添加 DMEM で MSCs を再懸濁します。</li>
	<li>それらの乾燥を叩き、シードの足場を準備します。<ol>
<li>DMEM 浸漬から鉗子で足場を削除し、一時的に 6 ウェル プレートの蓋の上に置きます。過剰な DMEM の液滴を残して、ふたを足場を持ち上げます。</li>
		<li>新しい、乾燥場所で、再び蓋に戻って足場を配置します。3-5 回、繰り返す播種 6 ウェル プレートで部分的に乾燥した足場を配置します。各足場に対して繰り返します。 注: 部分的乾燥足場は、最適な細胞播種結果を提供します。足場が余りにぬれている場合、細胞は足場をオフにスライドし、ウェル プレートの下に従います。足場があまりにも乾燥している場合、液滴が全体の足場は、貧しい人々 の初期細胞配分に終って上普及していません。</li>
	</ol>
</li>
	<li>ピペットを使用して、優しく、底に解決するかもしれないいくつかの細胞懸濁液を均質化する幹細胞のバイアルをミックスします。</li>
	<li>ゆっくりと新鮮な足場では、足場の上に小さな液滴を作成する上で直接 MSC を懸濁液を混合 2.5 μ L をピペットします。</li>
	<li>各井戸の端に 300 μ L DMEM を追加します。これはセル液滴の急速な蒸発を防ぐ。足場に付けるセルを許可する 30 分の 37 ° C で孵化させなさい。</li>
	<li>鉗子、優しくウェル プレートで足場を反転します。シード 2.5 μ L 混合新鮮な MSC に懸濁液 (この結果、足場ごとシード 5 x 10 の5セルの合計)。足場に付けるセルを許可する 30 分の 37 ° C で孵化させなさい。</li>
	<li>6 ウェル プレートの各ウェルに 2 mL を追加して DMEM で足場をカバーしてください。メディアがそれらの下に流れるように足場をそっと持ち上げます。移植手術前に 48 h にこの状態で 37 ° C で孵化させなさい。</li>
	<li>24 h と追加/変更メディア後足場を確認する余分な蒸発または pH の不均衡のため変色したメディアが観察される場合。</li>
</ol>2. 蛍光ガイド下切除と足場注入
注: 手術の初期化前にすべてのツールを滅菌します。機関 IACUC プロトコルに従って、予防的鎮痛を管理します。
<ol><li>解剖顕微鏡蛍光の段階の脳定位固定装置のフレームを配置します。</li>
	<li>誘導室における吸入イソフルランの下にマウスを麻酔します。一度麻酔、イソフルラン ノーズコーン アダプターを介して連続的な吸入麻酔供給脳定位固定装置のフレームでマウスを固定します。加熱パッドやプローブの体温を維持します。 注: 4-5% イソフルランは誘導に適した 2-3% 維持のために適して、この適応および各マウスの監視が必要であります。</li>
	<li>角膜の乾燥を防ぐために目に眼軟膏を適用します。3 つのアルコールや betadine ワイプの 3 つのシリーズで頭皮の切開部位を消毒します。</li>
	<li>各肢のつま先ピンチ反射テストを実行し、適切な anesthetization を確保するための否定応答を確認します。約 55 65 呼吸/分で安定した呼吸率を確保します。</li>
	<li>鉗子を使用して、ピンチ、優しく頭皮を持ち上げます。外科はさみで正中線の線形の吻側尾側切開を作る。PBS の切開部位に水を引くし、ブラッシングの円運動で綿の先端アプリケータと皮下脂肪を除去します。以前に確立した頭蓋ウィンドウが完全に表示されるよう、皮膚を配置します。</li>
	<li>優しくだけ 18 G 針を用いて頭蓋のウィンドウの境界線の内側の硬膜を穿刺します。切開完全トレース ウィンドウの内部までを繰り返します。</li>
	<li>硬膜を削除するには、離れて明らかに基になる柔組織と腫瘍の微細鉗子を使用してそれを剥離します。</li>
	<li>部屋のライトをオフにして、実体顕微鏡蛍光モードをオンにして U87 mCh フロリダ腫瘍を見つけます。真空ポンプのチューブの端に 1-200 μ L ピペット チップを読み込むことによって切除の準備します。</li>
	<li>真空ポンプをオンにします。信号がなくなるまで優しく蛍光組織を吸引によって腫瘍を切除します。真空ポンプの電源を切り、ピペット チップを破棄します。オン オフ蛍光と部屋のライトを入れます。 注: 出血を制御するため冷 PBS で灌漑し、綿の先端アプリケータと着実に圧力を適用します。深刻なケースで切除空洞も一時的にパックできます止血剤で出血が別の PBS の灌漑に続いて停止した後削除されます限り。</li>
	<li>注入直前にゆっくりと不要なメディアおよび関連コンポーネントを削除する PBS の PLA の MSC シード足場を浸しなさい。切除空洞に足場を注入します。必要な場合は、場所に 1 μ L フィブリノゲン (67 106 mg/mL) 1 μ L トロンビン、足場を確保する (400 625 な U/mL) に続いてを追加します。</li>
	<li>削除硬膜と骨フラップ既に破棄頭蓋の] ウィンドウから、皮膚を閉じるし、手術用の接着剤を適用するだけで傷をシールします。吸入麻酔薬から動物を外し、加熱面に回復することができます。</li>
	<li>ケージに戻り、一度歩行マウス。IACUC 承認スケジュールで鎮痛剤を管理します。各マウスの手順を繰り返します。</li>
</ol>3. 術後画像
<ol><li>28 G インスリン注射用の針を使用して、D-ルシフェリン (150 mg/kg 腹腔内投与) でマウスを注入します。</li>
	<li>10 分を待ちます。これは体全体を循環し、ピークの式を取得する脳内ルシフェラーゼ発現がん細胞と反応するルシフェリンをできるようになります。</li>
	<li>(前述のように) として、イソフルラン麻酔下で生物発光イメージング腫瘍を可視化する (結合) システムでマウスをイメージします。必要な (数秒から数分) 腫瘍の大きさに応じて、露出時間は異なります。</li>
	<li>腫瘍の成長速度を決定するため必要に応じて画像検査手順を繰り返します。動物の健康を監視し続けます。 注: 治療上の MSCs 恒常トレイル、がん細胞を殺すと全体的な腫瘍の成長を抑制することを表明します。2-5 日ごとのイメージングは、この目的のため十分な頻度を提供します。</li>
	<li>IACUC プロトコルで説明されている定義済みのエンドポイントが満たされているとき、transcardial 潅流によってマウスを犠牲にし解析のためのティッシュを収集します。</li>
</ol>

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夫妻のシート、Bagó、および Hingtgen の諸相幹細胞と足場技術 UNC チャペルヒルからライセンスを取得しているファルコン治療で公平があります。

次の点を考慮に入れて精度を最大化し、時間のかかる落とし穴を避けることを考えれば通常マウスあたり 30 分以内で手術を完了できます。まず、正しく手順を開始する前に脳定位固定装置でマウスを確認します。不要な頭の動きは、開頭手術の手術の精度、腫瘍移植と腫瘍切除の程度の位置に制限されます。切除前、硬膜腫瘍の部分を完全に削除します。それを吸引中にステータス退避とタ...

膠芽腫 (GBM) は、成人、陰気な生存期間中央値は 12-15 ヶ月1,2,3,4、5の最も一般的な脳腫瘍の症例です。2005 現在の放射線と併用し、補助のテモゾロマイド化学療法に続いて最大の外科的切除の臨床標準の頃6,7を採用したので生存率は、大幅に改善しません。この治療法は、患者の症状の一時的な救済を提供しながら治療の標準に必ず結果再発浸潤癌病巣切除を回避するし、血液脳関門 (BBB) によって全身療法から保護されます。この積極的な衰弱させる病気に対するトラクションを得るためには、BBB を回避しながら腫瘍浸潤巣を対象とする戦略が急務します。
ヒト間葉系幹細胞 (MSCs) は、そのネイティブの腫瘍親和性8,9による糸球体基底膜の配送車薬として約束を示します。MSCs の受容体を持っているし、間質細胞由来因子 1 α など、腫瘍が分泌する可溶性因子への移行 (自衛隊 1 α)、マトリックス マトリックスメタロプロテアーゼ 1 (MMP 1)、および単球走化性因子タンパク質-1 (MCP-1) 他の人の間で10,11,12,13。 工学 MSCs 表現および細胞毒性薬を分泌する腫瘍ホーミング薬物送達車として活かされることができます。設計された MSCs は、腫瘍浸潤巣に向かって移動、治療用タンパク質を提供します。このアプローチは、さまざまな臨床糸球体基底膜モデル9,14の可能性を実証しています。しかし、これらのモデルの大半はこのコンポーネントの臨床関連性にもかかわらず外科的切除を含めないでください。切除の新しいモデルを用いた研究を新たな外科的摘出が摘出腔15に直接注入される幹細胞の永続性を減少させることを明らかにしました。実行可能性の損失結果減少効果、腫瘍浸潤病巣に線量そして薬剤の持続期間の減少により可能性が配信されました。
幹細胞と薬剤投与を増やす、注入前に足場に MSCs をシードできます。このプロトコルでは生体親和性と吸収性のエレクトロスピニング ナノ poly(lactic acid))、MSCs PLA 折り曲げとインプラント治療のカバレッジを最大化、最小化時に切除キャビティの形状に適合のための足場として使用されます、。MSCs の距離は、腫瘍細胞に到達する旅行する必要があります。MSCs は、注入中に足場上に残ります、注入16,17後腫瘍細胞へ足場を移行します。MSCs と彼らを運ぶ、細胞傷害性薬剤は腫瘍巣に蓄積されます。腫瘍への薬剤の配達には、MSC 生存率および足場の注入による支援の永続化が必要です。
この手順でレンチウイルスベクターを使用 (体外追跡) 蛍光と発光 (生体内での追跡) を安定に発現を誘導するがんと幹細胞ラインのマーカー。ヒト糸球体基底膜ライン U87 は mCherry とホタルのルシフェラーゼ (U87 母子-フロリダ州) と GFP および renilla ルシフェラーゼ (MSC GFP Rluc) と非治療の MSCs に感染しています。MSCs の治療のバリエーションは、tnf α 関連アポトーシス誘導リガンド (TRAIL-MSC) を表現します。近くの癌の死の受容体にバインド トレイル、構成的分泌蛋白質、細胞およびカスパーゼ - アポトーシス18を開始。
ここでは、前臨床画像誘導 GBM の外科的切除と MSC シード足場の注入のためのプロトコルを提供します。簡単に言えば、ヌードマウスに開頭手術 3 日後に原発腫瘍を確立する U87 mCh フロリダの定位の同所性注入が続きますが与えられています。明らかな移植腫瘍は、約 1 週間の期間が増加します。PLA の足場は、切除手術する前に MSCs 48 h にシードされます。蛍光の指導の下で腫瘍は切除し、MSC ロード足場が切除キャビティ内に注入されます。腫瘍の負担とマウスの生存率は、生物発光イメージング (結合) の手術後、追跡されます。これらのプロシージャのタイムラインを (図 1) を以下に示します。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57452/57452fig1.jpg"> 図 1: プロシージャのタイムライン。マウスは、当初頭蓋ウィンドウ (0 日) を受け取る。腫瘍は、3 日間の回復期間後 (日 3) を注入し、約 1 週間の成長します。足場は、腫瘍の切除と移植の手順 (10 日) の前に 2 日間 MSCs (8 日) にシードされます。腫瘍の進行と治療効果は、術後その後イメージング (日 10 +) を介して評価されます。<a href="//cloudflare.jove.com/files/ftp_upload/57452/57452fig1large.jpg" target="_blank">この図の拡大版を表示するのにはここをクリックしてください</a>。

<table>
	<tbody>
		<tr>
			<td>Just for mouse stereotaxic instrument</td>
			<td>Stoelting</td>
			<td>51730</td>
			<td>Maintains steady head positioning during surgery</td>
		</tr>
		<tr>
			<td>Fluorescence dissecting stereomicroscope</td>
			<td>Leica</td>
			<td>M165 FC&#160;</td>
			<td>Allows real-time imaging of tumor during resection</td>
		</tr>
		<tr>
			<td>Motorized integrated stereotaxic injector (ISI) system</td>
			<td>Stoelting</td>
			<td>53315</td>
			<td>Allows precise tumor cell injection volume and rate</td>
		</tr>
		<tr>
			<td>Vetbond tissue adhesive</td>
			<td>3M</td>
			<td>1469</td>
			<td>Sugical glue to close skin wound</td>
		</tr>
		<tr>
			<td>Artificial tears</td>
			<td>Akorn</td>
			<td>664268</td>
			<td>Prevents eyes from drying during surgery</td>
		</tr>
		<tr>
			<td>Webcol alcohol preps</td>
			<td>Covidien</td>
			<td>6818</td>
			<td>Sterilize incision site</td>
		</tr>
		<tr>
			<td>Betadine surgical scrub</td>
			<td>Purdue Fredick Company</td>
			<td>6761815117</td>
			<td>Sterilize incision site</td>
		</tr>
		<tr>
			<td>Cotton-tipped applicators</td>
			<td>Fisherbrand</td>
			<td>23-400-115</td>
			<td>Surgery tool</td>
		</tr>
		<tr>
			<td>E-vac aspirating system</td>
			<td>Argos</td>
			<td>EV310</td>
			<td>Vacuum pump used to resect tumor</td>
		</tr>
		<tr>
			<td>Fibrinogen and thrombin extracted from as-received TISSEEL</td>
			<td>Baxter</td>
			<td></td>
			<td>To temporarily secure the scaffold in the resection cavity</td>
		</tr>
		<tr>
			<td>IVIS Kinetic in vivo optical imaging system</td>
			<td>Caliper Life Science</td>
			<td></td>
			<td>Bioluminescent Imager</td>
		</tr>
		<tr>
			<td>D-Luciferin potassium salt</td>
			<td>PerkinElmer</td>
			<td>122799</td>
			<td>In vivo imaging agent</td>
		</tr>
	</tbody>
</table>

image-guided resection of glioblastoma and intracranial implantation of therapeutic stem cell-seeded scaffolds

膠芽腫 (GBM)、最も一般的で積極的な脳腫瘍の症例は 12-15 ヶ月の余命を運ぶ。余命の短いは、侵襲性の腫瘍巣を除去するために続いて放射線と化学療法、外科的切除から成る現在の治療のできない一部予定です。これらの病巣の治療は、抗腫瘍ヒト間葉系幹細胞 (MSCs) によって改善されること。MSCs では、強力な腫瘍親和性を展示し、腫瘍細胞を殺す表現治療タンパク質を設計することができます。前臨床モデルの進歩を示すその切除早期 MSC 喪失を誘導し、治療効果を低減します。MSC 治療の有効性は、生分解性 poly(lactic acid)) 足場に播種 MSCs によって改善できます。PLA 足場に外科的切除空洞に MSC 配信は、セルの保持、保存、および腫瘍の殺害を復元します。糸球体基底膜の PLA の MSC シード注入の効果を研究、正確な前臨床モデルが必要です。ここで注入後 MSC シード足場免疫欠損マウスにおける糸球体基底膜の画像ガイド下腫瘍切除のため前臨床外科プロトコルを提供します。MSCs は、構成を表現し、蛍光の追跡を許可する緑色蛍光タンパク質 (GFP) と同様、治療 tnf α 関連アポトーシス誘導リガンド (TRAIL) を分泌するレンチ ウイルスの構造に設計されています。同様に、U87 腫瘍細胞は、エクスプレス mCherry とホタルのルシフェラーゼ、デュアル蛍光/発光の追跡を提供する設計されています。現在、治療の幹細胞を介した配信を調査に使用、このプロトコルは糸球体基底膜の他の介入に外科的切除の影響を調査する変更でした。

U87 腫瘍細胞は、高速 mCherry しホタルのルシフェラーゼ (U87 母子-フロリダ州)、注入前と画像誘導切除および発光 (図 2 a・ C) を追跡できるように設計されました。幹細胞同様に診断 GFP-Rluc (MSC GFP) または治療の GFP 試み (MSC 歩道) で設計されて, 添付ファイル (図 2 Dの-F) の増殖を確認する PLA 足場上.</...

Watch this Scientific Journal Video about Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds at JoVE.com

Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds

膠芽腫の治療の幹細胞シード足場の頭蓋内注入画像誘導切除

腫瘍を求めて治療間葉系幹細胞 (MSCs) 侵襲神経膠芽腫のための処置として約束を示します。最適な移植には、足場に腫瘍切除キャビティへの MSCs の配信が含まれます。ここでは、神経膠芽腫の MSC 治療を研究する臨床技術を含んで提供される: 画像ガイド下腫瘍切除;MSC シード足場; の注入術後療法を追跡します。

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in ...

image-guided-resection-glioblastoma-intracranial-implantation

Research

JoVE Journal

Medicine

8.2K ビュー.  University of North Carolina at Chapel Hill. 腫瘍を求めて治療間葉系幹細胞 (MSCs) 侵襲神経膠芽腫のための処置として約束を示します。最適な移植には、足場に腫瘍切除キャビティへの MSCs の配信が含まれます。ここでは、神経膠芽腫の MSC 治療を研究する臨床技術を含んで提供される: 画像ガイド下腫瘍切除;MSC シード足場; の注入術後療法を追跡します。

ビデオ: Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds

Intracranial Implantation with Subsequent 3D In Vivo Bioluminescent Imaging of Murine Gliomas

The mouse glioma 261 (GL261) is recognized as an in vivo model system that recapitulates many of the features of human glioblastoma multiforme (GBM). The cell line was originally induced by intracranial injection of 3-methyl-cholantrene into a C57BL/6 syngeneic mouse strain 1; therefore, immunologically competent C57BL/6 mice can be used. While we use GL261, the following protocol can be used for the implantation and monitoring of any intracranial mouse tumor model. GL261 cells were engineered to stably express firefly luciferase (GL261-luc). We also created the brighter GL261-luc2 cell line by stable transfection of the luc2 gene expressed from the CMV promoter. C57BL/6-cBrd/cBrd/Cr mice (albino variant of C57BL/6) from the National Cancer Institute, Frederick, MD were used to eliminate the light attenuation caused by black skin and fur. With the use of albino C57BL/6 mice; in vivo imaging using the IVIS Spectrum in vivo imaging system is possible from the day of implantation (Caliper Life Sciences, Hopkinton, MA). The GL261-luc and GL261-luc2 cell lines showed the same in vivo behavior as the parental GL261 cells. Some of the shared histological features present in human GBMs and this mouse model include: tumor necrosis, pseudopalisades, neovascularization, invasion, hypercellularity, and inflammation 1.
Prior to implantation animals were anesthetized by an intraperitoneal injection of ketamine (50 mg/kg), xylazine (5 mg/kg) and buprenorphine (0.05 mg/kg), placed in a stereotactic apparatus and an incision was made with a scalpel over the cranial midline. A burrhole was made 0.1mm posterior to the bregma and 2.3mm to the right of the midline. A needle was inserted to a depth of 3mm and withdrawn 0.4mm to a depth of 2.6mm. Two &mu;l of GL261-luc or GL261-luc2 cells (107 cells/ml) were infused over the course of 3 minutes. The burrhole was closed with bonewax and the incision was sutured.
Following stereotactic implantation the bioluminescent cells are detectable from the day of implantation and the tumor can be analyzed using the 3D image reconstruction feature of the IVIS Spectrum instrument. Animals receive a subcutaneous injection of 150&mu;g luciferin /kg body weight 20 min prior to imaging. Tumor burden is quantified using mean tumor bioluminescence over time. Tumor-bearing mice were observed daily to assess morbidity and were euthanized when one or more of the following symptoms are present: lethargy, failure to ambulate, hunched posture, failure to groom, anorexia resulting in &gt;10% loss of weight. Tumors were evident in all of the animals on necropsy.

Intracranial Implantation with Subsequent 3D In Vivo Bioluminescent Imaging of Murine Gliomas

Intracranial implantation of GL261 cells into C57BL/6 mice produces malignant gliomas that recapitulate many of the hallmarks of human glioblastoma multiforme. We used GL261 cells stably expressing luciferase to allow us to use in vivo imaging to follow tumor progression. The surgery and 3D in vivo imaging are demonstrated.

その後の3Dと頭蓋内注入インビボでの</emマウス神経膠腫の>生物発光イメージング

The mouse glioma 261 (GL261) is recognized as an in vivo model system that recapitulates many of the features of human glioblastoma multiforme (GBM). The ...

医学

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy 1. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM 2. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments 3-5. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

We describe an integrated method for the precise, stereotactic implantation of human glioblastoma multiforme cells into the brains of nude mice and subsequent serial in vivo imaging to monitor growth and response to treatment of the resultant xenografts.

定位頭蓋内注入と<emインビボ&gt;</em多形性膠芽腫のマウスモデル系における腫瘍異種移植片の&gt;生物発光イメージング

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality ...

Treatment of Osteochondral Defects in the Rabbit's Knee Joint by Implantation of Allogeneic Mesenchymal Stem Cells in Fibrin Clots

The treatment of osteochondral articular defects has been challenging physicians for many years. The better understanding of interactions of articular cartilage and subchondral bone in recent years led to increased attention to restoration of the entire osteochondral unit. In comparison to chondral lesions the regeneration of osteochondral defects is much more complex and a far greater surgical and therapeutic challenge. The damaged tissue does not only include the superficial cartilage layer but also the subchondral bone. For deep, osteochondral damage, as it occurs for example with osteochondrosis dissecans, the full thickness of the defect needs to be replaced to restore the joint surface 1. Eligible therapeutic procedures have to consider these two different tissues with their different intrinsic healing potential 2. In the last decades, several surgical treatment options have emerged and have already been clinically established 3-6.
Autologous or allogeneic osteochondral transplants consist of articular cartilage and subchondral bone and allow the replacement of the entire osteochondral unit. The defects are filled with cylindrical osteochondral grafts that aim to provide a congruent hyaline cartilage covered surface 3,7,8. Disadvantages are the limited amount of available grafts, donor site morbidity (for autologous transplants) and the incongruence of the surface; thereby the application of this method is especially limited for large defects.
New approaches in the field of tissue engineering opened up promising possibilities for regenerative osteochondral therapy. The implantation of autologous chondrocytes marked the first cell based biological approach for the treatment of full-thickness cartilage lesions and is now worldwide established with good clinical results even 10 to 20 years after implantation 9,10. However, to date, this technique is not suitable for the treatment of all types of lesions such as deep defects involving the subchondral bone 11.
The sandwich-technique combines bone grafting with current approaches in Tissue Engineering 5,6. This combination seems to be able to overcome the limitations seen in osteochondral grafts alone. After autologous bone grafting to the subchondral defect area, a membrane seeded with autologous chondrocytes is sutured above and facilitates to match the topology of the graft with the injured site. Of course, the previous bone reconstruction needs additional surgical time and often even an additional surgery. Moreover, to date, long-term data is missing 12.
Tissue Engineering without additional bone grafting aims to restore the complex structure and properties of native articular cartilage by chondrogenic and osteogenic potential of the transplanted cells. However, again, it is usually only the cartilage tissue that is more or less regenerated. Additional osteochondral damage needs a specific further treatment. In order to achieve a regeneration of the multilayered structure of osteochondral defects, three-dimensional tissue engineered products seeded with autologous/allogeneic cells might provide a good regeneration capacity 11.
Beside autologous chondrocytes, mesenchymal stem cells (MSC) seem to be an attractive alternative for the development of a full-thickness cartilage tissue. In numerous preclinical in vitro and in vivo studies, mesenchymal stem cells have displayed excellent tissue regeneration potential 13,14. The important advantage of mesenchymal stem cells especially for the treatment of osteochondral defects is that they have the capacity to differentiate in osteocytes as well as chondrocytes. Therefore, they potentially allow a multilayered regeneration of the defect.
In recent years, several scaffolds with osteochondral regenerative potential have therefore been developed and evaluated with promising preliminary results 1,15-18. Furthermore, fibrin glue as a cell carrier became one of the preferred techniques in experimental cartilage repair and has already successfully been used in several animal studies 19-21 and even first human trials 22.
The following protocol will demonstrate an experimental technique for isolating mesenchymal stem cells from a rabbit's bone marrow, for subsequent proliferation in cell culture and for preparing a standardized in vitro-model for fibrin-cell-clots. Finally, a technique for the implantation of pre-established fibrin-cell-clots into artificial osteochondral defects of the rabbit's knee joint will be described.

An experimental technique for the treatment of osteochondral defects in the rabbit's knee joint is described. The implantation of allogeneic mesenchymal stem cells into osteochondral defects provides a promising development in the field of tissue engineering. The preparation of fibrin-cell-clots in vitro offers a standardized method for implantation.

フィブリン塊における同種間葉系幹細胞の注入によってウサギの膝関節における骨軟骨欠損の治療

The treatment of osteochondral articular defects has been challenging physicians for many years. The better understanding of interactions of articular ...

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows for positive pressure bulk flow to deliver greater quantities of therapeutics to an intracranial target than traditional drug delivery methods. The clinical utility of real time MRI guided CED (rCED) lies in the ability to accurately target, monitor therapy, and identify complications. With training, rCED is efficient and complications may be minimized. The agarose gel model of the brain provides an accessible tool for CED testing, research, and training. Simulated brain rCED allows practice of the mock surgery while also providing visual feedback of the infusion. Analysis of infusion allows for calculation of the distribution fraction (Vd/Vi) allowing the trainee to verify the similarity of the model as compared to human brain tissue. This article describes our agarose gel brain phantom and outlines important metrics during a CED infusion and analysis protocols while addressing common pitfalls faced during CED infusion for the treatment of neurological disease.

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. In order to prepare health care professionals for adoption of CED, accessible training models are needed. We describe the use of agarose gel as such a model of the human brain for testing, research, and training.

脳のアガロースゲルモデルに画像誘導対流増加送達

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows ...

Creating Anatomically Accurate and Reproducible Intracranial Xenografts of Human Brain Tumors

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live animal &#8211;&#160;particularly in sites with unique physiological and architectural qualities such as the brain. In vitro and ectopic models cannot account for features such as vasculature, blood brain barrier, metabolism, drug delivery and toxicity, and a host of other relevant factors. Orthotopic models have their limitations too, but with proper technique tumor cells of interest can be accurately engrafted into tissue that most closely mimics conditions in the human brain. By employing methods that deliver precisely measured volumes to accurately defined locations at a consistent rate and pressure, mouse models of human brain tumors with predictable growth rates can be reproducibly created and are suitable for reliable analysis of various interventions. The protocol described here focuses on the technical details of designing and preparing for an intracranial injection, performing the surgery, and ensuring successful and reproducible tumor growth and provides starting points for a variety of conditions that can be customized for a range of different brain tumor models.

The brain is a unique site with qualities that are not well represented by in vitro or ectopic analyses. Orthotopic mouse models with reproducible location and growth characteristics can be reliably created with intracranial injections using a stereotaxic fixation instrument and a low pressure syringe pump.

解剖学的に正確な作成と人間の脳の腫瘍の再現性頭蓋内異種移植片

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live ...

High Throughput Characterization of Adult Stem Cells Engineered for Delivery of Therapeutic Factors for Neuroprotective Strategies

Mesenchymal stem cells (MSCs) derived from bone marrow are a powerful cellular resource and have been used in numerous studies as potential candidates to develop strategies for treating a variety of diseases. The purpose of this study was to develop and characterize MSCs as cellular vehicles engineered for delivery of therapeutic factors as part of a neuroprotective strategy for rescuing the damaged or diseased nervous system. In this study we used mouse MSCs that were genetically modified using lentiviral vectors, which encoded brain-derived neurotrophic factor (BDNF) or glial cell-derived neurotrophic factor (GDNF), together with green fluorescent protein (GFP). 
Before proceeding with in vivo transplant studies it was important to characterize the engineered cells to determine whether or not the genetic modification altered aspects of normal cell behavior. Different culture substrates were examined for their ability to support cell adhesion, proliferation, survival, and cell migration of the four subpopulations of engineered MSCs. High content screening (HCS) was conducted and image analysis performed. 
Substrates examined included: poly-L-lysine, fibronectin, collagen type I, laminin, entactin-collagen IV-laminin (ECL). Ki67 immunolabeling was used to investigate cell proliferation and Propidium Iodide staining was used to investigate cell viability. Time-lapse imaging was conducted using a transmitted light/environmental chamber system on the high content screening system.
Our results demonstrated that the different subpopulations of the genetically modified MSCs displayed similar behaviors that were in general comparable to that of the original, non-modified MSCs. The influence of different culture substrates on cell growth and cell migration was not dramatically different between groups comparing the different MSC subtypes, as well as culture substrates. 
This study provides an experimental strategy to rapidly characterize engineered stem cells and their behaviors before their application in long-term in vivo transplant studies for nervous system rescue and repair.

This study describes an experimental platform to rapidly characterize engineered stem cells and their behaviors before their application in long-term in vivo transplant studies for nervous system rescue and repair.

神経保護戦略のための治療因子の送達のために設計成体幹細胞の高スループット特性評価

Mesenchymal stem cells (MSCs) derived from bone marrow are a powerful cellular resource and have been used in numerous studies as potential candidates to ...

Bioluminescence Imaging of an Immunocompetent Animal Model for Glioblastoma

In contrast to commonly reported human glioma xenograft animal models, GL261 murine glioma xenografts recapitulate nearly all relevant clinical and histopathologic features of the human disease. When GL261 cells are implanted intracranially in syngeneic C57BL/6 mice, the model has the added advantage of maintaining an intact immune microenvironment. Stable expression of luciferase in GL261 cells allows non-invasive cost effective bioluminescence monitoring of intracranial tumor growth. We have recently demonstrated that luciferase expression in GL261 cells does not affect the tumor growth properties, tumor cell immunomodulatory cytokine expression, infiltration of immune cells into the tumor, or overall survival of animals bearing the intracranial tumor. Therefore, it appears that the GL261 luciferase glioma model can be useful in the study of novel chemotherapeutic and immunotherapeutic modalities. Here we report the technique for generating stable luciferase expression in GL261 cells and how to study the in vitro and in vivo growth of the tumor cells by bioluminescence imaging.

GL261 glioma cells provide a useful immunocompetent animal model of glioblastoma. The goals of this protocol are to demonstrate proper techniques for monitoring intracranial tumor growth using in vivo bioluminescence imaging, and to verify the utility of luciferase-modified GL261 cells for studying tumor immunology and immunotherapeutic approaches for treating glioblastoma.

神経膠芽腫のための免疫担当動物モデルの生物発光イメージング

In contrast to commonly reported human glioma xenograft animal models, GL261 murine glioma xenografts recapitulate nearly all relevant clinical and ...

Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model

The intrinsic tropism towards brain malignancies renders stem cells as promising carriers of therapeutic agents against malignant tumors. The delivery of therapeutic stem cells via the intranasal route is a recently discovered alternative strategy, with strong potential for clinical translation, due to its non-invasive nature compared to intracranial implantation or delivery via systemic routes. The lack of blood brain barrier further strengthens the therapeutic potential of stem cells undergoing intranasal brain entry. This article summarizes the essential techniques utilized in our studies and outlines the basic principles of intranasal strategy for stem cell delivery using a mouse model of intracranial glioma xenografts. We demonstrate the optimized procedures that generate consistent and reproducible results with specific predetermined experimental parameters and offer guidelines for streamlined work flow that ensure efficient execution and reliable experimental outcome. The article is designed to serve as a baseline for further experimental customization based on hypothesis, stem cell types, or tumor specifics.

Stem cells are promising therapeutic carriers to treat brain tumors due to their intrinsic tumor tropism. Non-invasive intranasal stem cell delivery bypasses the blood brain barrier and demonstrates strong potential for clinical translation. This article summarizes the basic principles of intranasal stem cell delivery in a mouse model of glioma.

マウスモデルにおける膠芽細胞腫に対する治療用幹細胞の鼻腔内送達

The intrinsic tropism towards brain malignancies renders stem cells as promising carriers of therapeutic agents against malignant tumors. The delivery of ...

Predicting Treatment Response to Image-Guided Therapies Using Machine Learning: An Example for Trans-Arterial Treatment of Hepatocellular Carcinoma

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this study was to develop a method to predict response to intra-arterial treatment prior to intervention.
The method provides a general framework for predicting outcomes prior to intra-arterial therapy. It involves pooling clinical, demographic and imaging data across a cohort of patients and using these data to train a machine learning model. The trained model is applied to new patients in order to predict their likelihood of response to intra-arterial therapy.
The method entails the acquisition and parsing of clinical, demographic and imaging data from N patients who have already undergone trans-arterial therapies. These data are parsed into discrete features (age, sex, cirrhosis, degree of tumor enhancement, etc.) and binarized into true/false values (e.g., age over 60, male gender, tumor enhancement beyond a set threshold, etc.). Low-variance features and features with low univariate associations with the outcome are removed. Each treated patient is labeled according to whether they responded or did not respond to treatment. Each training patient is thus represented by a set of binary features and an outcome label. Machine learning models are trained using N - 1 patients with testing on the left-out patient. This process is repeated for each of the N patients. The N models are averaged to arrive at a final model.
The technique is extensible and enables inclusion of additional features in the future. It is also a generalizable process that may be applied to clinical research questions outside of interventional radiology. The main limitation is the need to derive features manually from each patient. A popular modern form of machine learning called deep learning does not suffer from this limitation, but requires larger datasets.

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. A method for predicting response to these therapies is proposed. The technique uses pre-procedural clinical, demographic, and imaging information to train machine learning models capable of predicting response prior to treatment.

機械学習を用いた画像誘導治療治療に対する反応を予測: 肝細胞癌における経動脈的治療の例

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this ...

Transaxillary First Rib Resection for Treatment of the Thoracic Outlet Syndrome

Thoracic outlet syndrome (TOS) is a common disorder that causes a significant loss of productivity. The transaxillary first rib resection (TFRR) protocol has been used for the decompression of trapped neurovascular structures in the TOS. Among the other surgical procedures, the advantage of the TFRR is that it has the smallest rate of recurrence and better cosmetic outcomes. The disadvantage of TFRR is that it provides a narrow, and deep working corridor that makes obtaining vascular control challenging.

Here, we present a protocol of the transaxillary resection of the first rib for treatment of thoracic outlet syndrome caused by compression of the brachial plexus, subclavian vein and artery.

胸郭出口症候群の治療のための経腋窩第一肋骨切除術

Thoracic outlet syndrome (TOS) is a common disorder that causes a significant loss of productivity. The transaxillary first rib resection (TFRR) protocol ...