JP6104806B2 - 材料に基づく細胞治療のための注射可能孔形成性ハイドロゲル - Google Patents
材料に基づく細胞治療のための注射可能孔形成性ハイドロゲル Download PDFInfo
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Description
本願は、参照によりその全体が本明細書に組み入れられる、2010年10月6日に出願された米国仮出願第61/390,594号に基づく、35U.S.C.§119(e)による優先権の恩典を主張する。
本発明は、国立衛生研究所により授与されたNIH R37DE013033および全米科学財団により授与されたMRSEC DMR-0820484の下で、政府の援助を受けて作成された。政府は、本発明における一定の権利を有する。
本発明は、生体適合性ハイドロゲル組成物に関する。
最近の数十年にわたり、生体適合性重合体は、細胞移植のための担体として機能する足場を形成するため、またはデバイスへ宿主細胞集団を動員するため、使用されてきた。
第1のハイドロゲルと第2のハイドロゲルとを含む組成物であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ第1のハイドロゲルまたは第2のハイドロゲルが、単離された細胞を含む、組成物。
[本発明1002]
第2のハイドロゲルが第1のハイドロゲルの周りに架橋されているか、または第1のハイドロゲルが第2のハイドロゲルの中に物理的に捕捉されている、本発明1001の組成物。
[本発明1003]
血管内皮増殖因子(VEGF)、酸性繊維芽細胞増殖因子(aFGF)、塩基性繊維芽細胞増殖因子(bFGF)、胎盤増殖因子(PIGF)、血小板由来増殖因子(PDGF)、レプチン、造血増殖因子(HGF)、VEGF受容体-1(VEGFR-1)、VEGFR-2、骨形成タンパク質(BMP)ファミリーのメンバー、顆粒球マクロファージコロニー刺激因子(GM-CSF)、FMS様チロシンキナーゼ3リガンド(Flt3リガンド)、肝細胞増殖因子、ストロマ由来因子1(SDF-1)、インスリン様増殖因子(IGF)、抗VEGF抗体、抗aFGF抗体、抗bFGF抗体、抗PIGF抗体、抗レプチン抗体、抗HGF抗体、抗VEGFR-1抗体、抗VEGFR-2抗体、抗PDGF抗体、抗BMP抗体、抗Flt3リガンド、抗IGF抗体からなる群より選択される生理活性因子をさらに含む、本発明1001の組成物。
[本発明1004]
前記細胞が、間葉系幹細胞、筋芽細胞、血管前駆細胞、胚性幹細胞もしくは誘導多能性幹細胞に由来する分化細胞、誘導多能性細胞、または繊維芽細胞から分化状態へ直接再プログラムされた細胞である、本発明1001の組成物。
[本発明1005]
第1のハイドロゲルがポロゲンを含む、本発明1001の組成物。
[本発明1006]
第1のハイドロゲルが20kPa〜60kPaの弾性率を含む、本発明1001の組成物。
[本発明1007]
第2のハイドロゲルが、PHSRN、DGEA、またはRGDであるアミノ酸配列を含むペプチドを含む、本発明1001の組成物。
[本発明1008]
第2のハイドロゲルが、アルギン酸重合体鎖1本当たり2〜10ペプチドの密度のRGDペプチドを含む、本発明1001の組成物。
[本発明1009]
第2のハイドロゲルが少なくとも40kPaの初期弾性率を含む、本発明1001の組成物。
[本発明1010]
第1のハイドロゲルと第2のハイドロゲルとを含む組成物を対象へ投与する工程を含む、足場から哺乳動物対象の組織へ細胞を配備する方法であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ該組成物が、投与の時点では孔を欠いており、対象への滞留後に孔を含むようになり、かつ第1のハイドロゲルまたは第2のハイドロゲルが、単離された細胞を含む、方法。
[本発明1011]
第1のハイドロゲルと第2のハイドロゲルとを含む組成物を対象へ投与する工程を含む、インビボで足場へ細胞を動員する方法であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ該組成物が、投与の時点では孔を欠いており、対象への滞留後に孔を含むようになる、方法。
[本発明1012]
第1のハイドロゲルと第2のハイドロゲルとを含む組成物であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ第1のハイドロゲルまたは第2のハイドロゲルが、骨または軟骨の修復、再生、または形成の促進において使用するための生理活性因子を含む、組成物。
[本発明1013]
生理活性因子が、BMP-2、BMP-4、またはRunXを含む、本発明1012の組成物。
[本発明1014]
第1のハイドロゲルまたは第2のハイドロゲルが、骨芽細胞、骨細胞、破骨細胞、および骨前駆細胞からなる群より選択される単離された骨細胞を含む、本発明1012の組成物。
[本発明1015]
第1のハイドロゲルまたは第2のハイドロゲルが、単離された軟骨細胞を含み、単離された軟骨細胞が、軟骨芽細胞を含む、本発明1012の組成物。
[本発明1016]
単離された骨細胞が、自己または同種の細胞である、本発明1014の組成物。
[本発明1017]
第1のハイドロゲルと第2のハイドロゲルとを含む組成物であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ第1のハイドロゲルまたは第2のハイドロゲルが、筋肉の修復、再生、または形成において使用するための生理活性因子を含む、組成物。
[本発明1018]
生理活性因子がMyoDを含む、本発明1017の組成物。
[本発明1019]
第1のハイドロゲルまたは第2のハイドロゲルが、骨格筋細胞、心筋細胞、平滑筋細胞、および筋前駆細胞からなる群より選択される単離された筋細胞を含む、本発明1017の組成物。
[本発明1020]
単離された筋細胞が、自己または同種の細胞である、本発明1019の組成物。
[本発明1021]
第1のハイドロゲルと第2のハイドロゲルとを含む組成物であって、第1のハイドロゲルが第2のハイドロゲルより少なくとも10%速く分解し、かつ第1のハイドロゲルまたは第2のハイドロゲルが、皮膚の修復、再生、または形成において使用するための生理活性因子を含む、組成物。
[本発明1022]
生理活性因子がFGFを含む、本発明1021の組成物。
[本発明1023]
第1のハイドロゲルまたは第2のハイドロゲルが、繊維芽細胞、皮膚細胞、上皮細胞、または皮膚前駆細胞からなる群より選択される単離された皮膚細胞を含む、本発明1021の組成物。
[本発明1024]
単離された皮膚細胞が、自己細胞または同種細胞である、本発明1023の組成物。
[本発明1025]
ポロゲンの密度が、前記組成物の全体積の少なくとも50%である、本発明1005の組成物。
本発明のその他の特色および利点は、以下の好ましい態様の説明、および特許請求の範囲より明らかになるであろう。他に定義されない限り、本明細書において使用される技術用語および科学用語は、全て、本発明が属する技術分野の当業者により一般的に理解されるのと同一の意味を有する。本明細書に記載されたものに類似しているかまたは等価である方法および材料が、本発明の実施または試行において使用され得るが、適切な方法および材料が以下に記載される。本明細書に引用された公開された外国特許および特許出願は、全て、参照により本明細書に組み入れられる。本明細書に引用されたアクセッション番号により示されるGenbankおよびNCBIの寄託は、参照により本明細書に組み入れられる。本明細書に引用されたその他の公開された参照、文書、原稿、および科学文献は、全て、参照により本明細書に組み入れられる。矛盾する場合には、定義を含む本明細書が優先されるであろう。さらに、材料、方法、および例は、例示的なものに過ぎず、限定的なものではない。
最近の数十年にわたり、生体適合性重合体は、細胞移植のための担体として機能する足場を形成するため、またはデバイスへ宿主細胞集団を動員するため、使用されてきた。一般に、乳酸グリコール酸共重合体(PLGA)などのスポンジ、またはアルギン酸などの合成ハイドロゲルが、使用されている。しかしながら、いずれの材料のセットも、短所を有する。例えば、スポンジは、典型的には、血清タンパク質を吸収するため、材料からの接着タンパク質または接着ペプチド(例えば、RGD)の提示を制御することが困難である。また、スポンジ材料は、典型的には、注射に適用できず、埋め込みのために侵襲性の手術を必要とし、また、移植された細胞または宿主細胞を、初期には対立的である可能性のある(例えば、炎症時に存在する好中球は幹細胞を攻撃する可能性がある)宿主環境へ曝す。他方、合成ハイドロゲルは、典型的には、注射可能であり、最小限に侵襲性の送達を可能にし、タンパク質と相互作用しない。しかしながら、本明細書に記載された本発明以前には、ハイドロゲル中の孔サイズが、典型的には、真核細胞の直径よりはるかに小さかったため、移植された細胞集団を拡張させ、傷害組織を修復させるために移植された細胞を放出すること、またはデバイスへ宿主細胞を動員することは困難であった。
ハイドロゲルは、親水性である重合体鎖のネットワークを含む。(アクアゲルとも呼ばれる)ハイドロゲルは、時には、水が分散媒であるコロイドゲルとして見出される。ハイドロゲルは、高度に吸収性の(99.9%超の水を含有し得る)天然または合成の重合体である。ハイドロゲルはまた、その高い含水量ゆえに、天然組織に極めて類似した柔軟性の程度を有する。ハイドロゲルは、架橋された重合体から構成される。例示的なハイドロゲルは、アルギン酸、ポリエチレングリコール(PEG)、PEGアクリレート、アガロース、および合成タンパク質、例えば、コラーゲンまたは改変タンパク質(即ち、自己集合ペプチドに基づくハイドロゲル)などの、細胞封入と適合性の材料から構成される。例えば、市販のハイドロゲルには、細胞培養のための規定された三次元(3D)微小環境を作出するために使用される合成マトリックスである、BD(商標)PuraMatrix(商標)Peptide Hydrogelが含まれる。
ハイドロゲルミクロビーズ(「ポロゲン」)が形成される。次に、ポロゲンは、非分解性であるかまたはポロゲンと比較して遅い速度で分解する「バルク」ハイドロゲルへ封入される。細胞は、ポロゲンまたはバルクコンパートメントのいずれかへ任意で封入される。ハイドロゲル形成またはインビボの所望の部位への注射の直後には、複合材料は、孔を欠き、外科的充填剤として機能する。その後、ポロゲン分解により、インサイチューで孔が形成され、封入された細胞が、複合材料から離れて、周囲の組織または体内の遠隔の組織、例えば、リンパ節へ配備される。孔のサイズおよび分布は、ポロゲン形成、およびバルクハイドロゲルを形成する重合体との混合の間、制御される。
組成物および方法において利用される重合体は、天然に存在するものであってもよいし、または合成により作成されたものであってもよい。一例において、ポロゲンおよびバルクハイドロゲルの両方が、アルギン酸から形成される。「アルギン酸」という用語は、本明細書において使用されるように、アルギン酸の多数の誘導体(例えば、カルシウム塩、ナトリウム塩、カリウム塩、またはアルギン酸プロピレングリコール)をさす。例えば、参照により本明細書に組み入れられるPCT/US97/16890を参照のこと。
画像化および機械的特性試験を介して証明される、ハイドロゲル内のインサイチュー孔形成が、図1に示される。図1Aに示されるように、急速分解性ハイドロゲル(赤色の球)から構成されたミクロビーズを、第2のハイドロゲル形成性重合体材料と混合し、それをビーズの周りに架橋させた。インサイチューのミクロビーズの分解の後、完全なハイドロゲルネットワーク(桃色)が、孔のネットワークと共に残った。標準ハイドロゲル(左バー)または孔形成性ハイドロゲル(右バー)の弾性率測定を決定した(図1D)。0日目には、孔が形成されていなかったため、孔形成性複合物と標準ハイドロゲルとの間に全体的な硬度の統計的有意差は存在しなかった;しかしながら、4日後、複合物の率は、孔形成のゆえに、実質的に下落する。
分解性アルギン酸ポロゲンを、骨髄間質幹細胞(D1)と共に、高分子量バルクアルギン酸ゲルへ封入することにより、孔形成性ハイドロゲルを形成した。ポロゲンは、20mg/mLアルギン酸ジアルデヒド(高Mw高グルロン酸含量アルギン酸内のアルギン酸糖残基の7.5%の理論上の酸化)と、7.5mg/mL高Mw高グルロン酸(GA)含量アルギン酸との二成分混合物により形成された。この重合体混合物を、重合体を架橋するため、0.1M CaCl2および0.1M HEPESの槽へ同軸窒素気流によりガラス噴霧器を通して押し出した。ポロゲンを、無血清細胞培養培地により徹底的に洗浄した。バルクハイドロゲルは、アルギン酸重合体1本当たり2個のRGDペプチドにより修飾された、20mg/mL高Mw高GA含量アルギン酸で形成された。D1細胞およびポロゲンを、注射器を使用して、バルクハイドロゲル材料へ混合し、次いで、複合物を硫酸カルシウムで架橋した。インビトロでの時間経過とともにこの系から放出されたD1細胞の数が、図2に示される。(1)ポロゲンを形成するために使用されるCaCl2の濃度を制御することにより、(2)ポロゲンの組成(酸化度)を変動させることにより、そして(3)細胞の区画化(ポロゲン内かバルクゲル内か)を変動させることにより、放出の動力学を修飾することができた。
最後に、インビボのMSCの放出動力学を操作するために、孔形成性ハイドロゲルを使用し得るか否かを決定するためのインビボ研究を実施した。そのため、mCherryを発現するマウスMSCを、ヌードマウスへ皮下移植した。細胞の生着、増殖、および配備を、非侵襲性の蛍光画像化により観察した。これは、孔形成性ゲルが、生理食塩水で送達された細胞と比較して、生着を遅延させることのみならず、これらの材料が、最終的により大きな増殖をもたらすことを示した。ハイドロゲルは、孔が形成された後、増殖に適した微小環境を提供する。最後に、これらの材料が、インビボのMSCの放出および拡張を促進するのに有用であったため、ヒトMSCを、ヌードラットの頭蓋欠損を再生するために投与した。これは、初期の時点ですら、石灰化された骨の再生の改善をもたらした。
孔形成性ハイドロゲルを、実施例1および2に記載されたようにして形成した。等しい数(複合孔形成性ハイドロゲル1mL当たりおよそ106細胞)のGFP発現筋芽細胞および成長内皮細胞(OEC、血管前駆細胞)を、この材料の別々のコンパートメントへ封入した。5日間のインビトロ培養の後、放出された細胞および組織培養プラスチックへ接着した細胞を、エチジウムホモダイマー(EtD-1;赤色)により染色した。図4に示されるように、バルクゲルへ封入された細胞型は、より急速に配備された。配備のこのパターンは、GFP-筋芽細胞より緩徐に遊走し、GFP-筋芽細胞ほど広範に増殖しないOECですら起こった(等しい数の両方の細胞型が添加された基質の分析に基づく;図4d)。
孔形成性ハイドロゲルを、実施例1および2に記載されるようにして形成した。ポロゲン相を形成するため、7.5mg/mLの高Mw GAリッチアルギン酸重合体を、20mg/mLのアルギン酸ジアルデヒド(7.5%の理論上の酸化度)、またはアルデヒド基がアルコール基に還元されたアルギン酸ジアルデヒドのいずれかと組み合わせた。細胞が封入されていない孔形成性ハイドロゲルを、次に、C57/BL6マウスまたはBalb/cマウスの背部に注射した。14日後、宿主樹状細胞の動員を組織学的検査により観察した。
このアプローチの目的は、不溶性の合図を使用して、細胞の拡張および放出を操作することである。従って、接着リガンドの密度、およびポロゲン周囲の非分解性ハイドロゲルの機械的特性が、細胞に対する効果を有するか否かを決定した。図6に示されるように、リガンドの密度は、DNA合成を有意に改変し、弾性率の改変は、1週間にわたりDNA合成および細胞放出の両方を改変した。図6Dに組織像により示されるように、接着リガンド密度などの不溶性の合図は、長い時間枠で、細胞に対する効果を有した。
孔形成性ハイドロゲルを、実施例1に記載されるようにして形成した。バルクハイドロゲルの組成(インテグリン結合RGDペプチドの密度および弾性率)を操作することにより、インビトロの間葉系幹細胞(MSC)の増殖および放出を制御することが可能であった。インビボで、RGDペプチドの密度をアルギン酸重合体鎖1本当たり2ペプチドから10ペプチドへ増加させることにより、皮下空間へ配備されたmCherry標識マウスMSCの全体密度を増加させることができた(図6E)。治療的研究のため、ヒトMSCをヌードラットの頭蓋欠損部へ配備した。4週間後、ラットを安楽死させ、(新たな骨形成による)治癒の程度を、ヘマトキシリン/エオシン染色により査定した。簡単に説明すると、「治癒パーセント」計量を生成するため、欠損部内の新たに形成された骨の面積を、欠損部の全面積で割った。この定量的計量を使用して、孔形成性ハイドロゲルでのMSC送達が、新たな骨形成を誘導する能力に関して、標準ハイドロゲルまたは生理食塩水を介した送達より実質的に優れていることが見出された(図6F)。さらに、60kPa、10 RGD/アルギン酸重合体バルク相を含む孔形成性ハイドロゲルからの配備は、8kPa、10 RGD/アルギン酸重合体バルク相を含む孔形成性ハイドロゲルからの配備より、有意に多い骨形成をもたらしたように(p<0.05、両側t検定)、バルクハイドロゲル成分の弾性率は、4週間目の新たな骨形成に対する実質的な効果を有していた。
20mg/mLの一定の密度の酸化型アルギン酸(5%の理論上の酸化度)と未修飾高MWアルギン酸との二成分組み合わせを架橋することにより形成されたバルクハイドロゲルの弾性率および分解が、図7Aおよび図7Bに示される。インビトロでの4日後の乾燥質量を、初期乾燥質量と比較することにより、分解を査定した。20mg/mL酸化型アルギン酸と7.5mg/mL未修飾アルギン酸との二成分混合物から形成されたポロゲンの直径は、図7Cに示される。ポロゲン直径は、アミノフルオレセイン標識アルギン酸から調製されたポロゲンの蛍光顕微鏡写真の処理により測定された。
本発明を、その詳細な説明と共に記載したが、上記の説明は、本発明を例示するためのものであって、添付の特許請求の範囲の範囲により定義される本発明の範囲を制限するためのものではない。他の局面、利点、および改変は、以下の特許請求の範囲の範囲内にある。
Claims (41)
- 第1のハイドロゲルと第2のハイドロゲルとを含み、初期にはマクロ多孔性でないが、レシピエントの体内に滞留するときに時間経過とともにマクロ多孔性になる、組成物であって、該第1のハイドロゲルが、その場所にマクロ孔を残して、該第2のハイドロゲルより少なくとも10%速く加水分解的に分解し、かつ
(a)該第1のハイドロゲルが、酸化型アルギン酸を含むか、または
(b)該第1のハイドロゲルが、該第2のハイドロゲルよりも短い重合体を含む、
組成物。 - 第1のハイドロゲル、第2のハイドロゲル、または両ハイドロゲルが、単離された細胞、生理活性因子、および/または抗原を含む、請求項1記載の組成物。
- 第1のハイドロゲル、第2のハイドロゲル、または両ハイドロゲルが、組成物へ細胞を動員する、請求項1記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルまたは両ハイドロゲルが、樹状細胞、腫瘍抗原、またはケモカインを含む、請求項2記載の組成物。
- 第1のハイドロゲル、第2のハイドロゲルまたは両ハイドロゲルが、腫瘍抗原を含む、請求項2記載の組成物。
- 第2のハイドロゲルが第1のハイドロゲルの周りに架橋されているか、または第1のハイドロゲルが第2のハイドロゲルの中に物理的に捕捉されている、請求項1または2記載の組成物。
- 血管内皮増殖因子(VEGF)、酸性繊維芽細胞増殖因子(aFGF)、塩基性繊維芽細胞増殖因子(bFGF)、胎盤増殖因子(PIGF)、血小板由来増殖因子(PDGF)、レプチン、造血増殖因子(HGF)、VEGF受容体-1(VEGFR-1)、VEGFR-2、骨形成タンパク質(BMP)ファミリーのメンバー、顆粒球マクロファージコロニー刺激因子(GM-CSF)、FMS様チロシンキナーゼ3リガンド(Flt3リガンド)、肝細胞増殖因子、ストロマ由来因子1(SDF-1)、インスリン様増殖因子(IGF)、抗VEGF抗体、抗aFGF抗体、抗bFGF抗体、抗PIGF抗体、抗レプチン抗体、抗HGF抗体、抗VEGFR-1抗体、抗VEGFR-2抗体、抗PDGF抗体、抗BMP抗体、抗Flt3リガンド、抗IGF抗体からなる群より選択される生理活性因子をさらに含む、請求項1または2記載の組成物。
- 前記細胞が、間葉系幹細胞、筋芽細胞、血管前駆細胞、胚性幹細胞もしくは誘導多能性幹細胞に由来する分化細胞、誘導多能性細胞、または繊維芽細胞から分化状態へ直接再プログラムされた細胞である、請求項2記載の組成物。
- 第1のハイドロゲルがポロゲンを含む、請求項1または2記載の組成物。
- 第1のハイドロゲルが20kPa〜60kPaの弾性率を含む、請求項1または2記載の組成物。
- 第2のハイドロゲルが、PHSRN、DGEA、またはRGDであるアミノ酸配列を含むペプチドを含む、請求項1または2記載の組成物。
- 第2のハイドロゲルが、アルギン酸重合体鎖1本当たり2〜10ペプチドの密度のRGDペプチドを含む、請求項1または2記載の組成物。
- 第2のハイドロゲルが少なくとも40kPaの初期弾性率を含む、請求項1または2記載の組成物。
- 足場から哺乳動物対象の組織へ細胞を配備する方法において使用するための、請求項1または2記載の組成物であって、第1のハイドロゲルまたは第2のハイドロゲルが、単離された細胞を含み、該組成物が、投与の時点ではマクロ孔を欠いており、対象における滞留後にマクロ孔を含む、組成物。
- インビボで足場へ細胞を動員する方法において使用するための、請求項1または2記載の組成物であって、該組成物が、投与の時点ではマクロ孔を欠いており、対象における滞留後にマクロ孔を含む、組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、骨または軟骨の修復、再生、または形成の促進において使用するための生理活性因子を含む、請求項1または2記載の組成物。
- 生理活性因子が、BMP-2、BMP-4、またはRunXを含む、請求項16記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、骨芽細胞、骨細胞、破骨細胞、および骨前駆細胞からなる群より選択される単離された骨細胞を含む、請求項16記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、単離された軟骨細胞を含み、単離された軟骨細胞が、軟骨芽細胞を含む、請求項16記載の組成物。
- 単離された骨細胞が、自己または同種の細胞である、請求項18記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、筋肉の修復、再生、または形成において使用するための生理活性因子を含む、請求項1または2記載の組成物。
- 生理活性因子がMyoDを含む、請求項21記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、骨格筋細胞、心筋細胞、平滑筋細胞、および筋前駆細胞からなる群より選択される単離された筋細胞を含む、請求項21記載の組成物。
- 単離された筋細胞が、自己または同種の細胞である、請求項23記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、皮膚の修復、再生、または形成において使用するための生理活性因子を含む、請求項1または2記載の組成物。
- 生理活性因子がFGFを含む、請求項25記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、繊維芽細胞、皮膚細胞、上皮細胞、または皮膚前駆細胞からなる群より選択される単離された皮膚細胞を含む、請求項25記載の組成物。
- 単離された皮膚細胞が、自己細胞または同種細胞である、請求項27記載の組成物。
- ポロゲンの密度が、前記組成物の全体積の少なくとも50%である、請求項9記載の組成物。
- 第1のハイドロゲルまたは第2のハイドロゲルが、架橋された重合体を含む、請求項1記載の組成物。
- 架橋された重合体が、Ca+2、Mg+2、およびBa+2からなる群から選択される二価カチオンを含む、請求項30記載の組成物。
- 第1のハイドロゲルが、酸化型アルギン酸を含む、請求項1または2記載の組成物。
- 前記アルギン酸の少なくとも5%が酸化型である、請求項32記載の組成物。
- 第2のハイドロゲルが、未修飾アルギン酸を含む、請求項32記載の組成物。
- 第1のハイドロゲルが、第2のハイドロゲルよりも短い重合体を含む、請求項1または2記載の組成物。
- 第1のハイドロゲルが、5,000〜500,000ダルトン(Da)の分子量を有する酸化型アルギン酸重合体を含む、請求項35記載の組成物。
- 第2のハイドロゲルが、5,000〜500,000ダルトン(Da)の分子量を有するアルギン酸多糖を含む、請求項35記載の組成物。
- 第1のハイドロゲルが、およそ50kDaの分子量を有する重合体を含む、請求項35記載の組成物。
- 第2のハイドロゲルが、およそ250kDaの分子量を有する重合体を含む、請求項35記載の組成物。
- 樹状細胞が孔に動員され、かつ抗腫瘍応答を誘導するために活性化された抗原提示樹状細胞にプログラムされる、請求項15記載の組成物。
- 第1のハイドロゲルおよび第2のハイドロゲルが生分解性である、請求項1または2記載の組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007070660A2 (en) | 2005-12-13 | 2007-06-21 | President And Fellows Of Harvard College | Scaffolds for cell transplantation |
US9770535B2 (en) * | 2007-06-21 | 2017-09-26 | President And Fellows Of Harvard College | Scaffolds for cell collection or elimination |
CN102006891B (zh) | 2008-02-13 | 2017-04-26 | 哈佛学院董事会 | 连续的细胞程序化装置 |
US9370558B2 (en) | 2008-02-13 | 2016-06-21 | President And Fellows Of Harvard College | Controlled delivery of TLR agonists in structural polymeric devices |
US9012399B2 (en) | 2008-05-30 | 2015-04-21 | President And Fellows Of Harvard College | Controlled release of growth factors and signaling molecules for promoting angiogenesis |
WO2010120749A2 (en) | 2009-04-13 | 2010-10-21 | President And Fellow Of Harvard College | Harnessing cell dynamics to engineer materials |
JP5926180B2 (ja) | 2009-07-31 | 2016-05-25 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | 寛容原性療法のための細胞のプログラミングの方法 |
EP2542230A4 (en) * | 2010-03-05 | 2013-08-28 | Harvard College | ENHANCEMENT OF SKELETAL MUSCLE STRAIN CELL GRAFT WITH DUAL DELIVERY OF VEGF AND IGF-1 |
EP2585053A4 (en) | 2010-06-25 | 2014-02-26 | Harvard College | COMMON RELEASE OF STIMULATING AND HEMMING FACTORS FOR THE PRODUCTION OF TEMPORARY STABILIZED AND SPATULARLY LIMITED ZONES |
PT2624873T (pt) | 2010-10-06 | 2020-03-04 | Harvard College | Hidrogéis injectáveis formadores de poros para terapias celulares à base de materiais |
WO2012064697A2 (en) | 2010-11-08 | 2012-05-18 | President And Fellows Of Harvard College | Materials presenting notch signaling molecules to control cell behavior |
WO2012148684A1 (en) * | 2011-04-27 | 2012-11-01 | President And Fellows Of Harvard College | Cell-friendly inverse opal hydrogels for cell encapsulation, drug and protein delivery, and functional nanoparticle encapsulation |
US9675561B2 (en) | 2011-04-28 | 2017-06-13 | President And Fellows Of Harvard College | Injectable cryogel vaccine devices and methods of use thereof |
ES2878089T3 (es) | 2011-04-28 | 2021-11-18 | Harvard College | Armazones tridimensionales macroscópicos preformados inyectables para administración mínimamente invasiva |
EP2714073B1 (en) | 2011-06-03 | 2021-03-10 | President and Fellows of Harvard College | In situ antigen-generating cancer vaccine |
US8753309B2 (en) | 2011-06-24 | 2014-06-17 | The Invention Science Fund I, Llc | Device, system, and method including micro-patterned cell treatment array |
ES2773895T3 (es) | 2012-04-16 | 2020-07-15 | Harvard College | Composiciones de sílice mesoporosa para modular las respuestas inmunitarias |
ITTO20121159A1 (it) * | 2012-12-28 | 2014-06-29 | Fond Istituto Italiano Di Tecnologia | Procedimento per la produzione di spugne polimeriche |
WO2014133027A1 (ja) * | 2013-02-26 | 2014-09-04 | 株式会社スリー・ディー・マトリックス | ハイドロゲル |
KR101495281B1 (ko) * | 2014-01-10 | 2015-02-24 | (주)안트로젠 | 피부 재생 또는 상처 치유를 위한 중간엽 줄기세포-하이드로겔-생분해성 또는 중간엽 줄기세포-하이드로겔-비분해성 지지체 조성물 |
EP3137105A4 (en) | 2014-04-30 | 2017-12-27 | President and Fellows of Harvard College | Combination vaccine devices and methods of killing cancer cells |
US11065362B2 (en) | 2014-06-12 | 2021-07-20 | President And Fellows Of Harvard College | Viscoelastic hydrogels with fast stress relaxation |
WO2015192017A1 (en) * | 2014-06-12 | 2015-12-17 | President And Fellows Of Harvard College | Interpenetrating network hydrogels with independently tunable stiffness |
CA2955357A1 (en) * | 2014-07-17 | 2016-01-21 | The Regents Of The University Of California | Self-annealing microgel particles for biomedical applications |
MA41044A (fr) | 2014-10-08 | 2017-08-15 | Novartis Ag | Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer |
CU20170052A7 (es) | 2014-10-14 | 2017-11-07 | Dana Farber Cancer Inst Inc | Moléculas de anticuerpo que se unen a pd-l1 |
EP3250250A4 (en) | 2015-01-30 | 2019-05-22 | President and Fellows of Harvard College | PERITUMORAL AND INTRATUMORAL MATERIALS FOR CANCER THERAPY |
US10232345B2 (en) | 2015-02-12 | 2019-03-19 | Arizona Board Of Regents On Behalf Of Arizona State University | Aminoglycoside hydrogel microbeads and macroporous gels with chemical crosslink, method of preparation and use thereof |
US9856332B2 (en) * | 2015-03-23 | 2018-01-02 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods for high-throughput in-situ manufacture of user desired 3D polymeric scaffolds |
KR102311639B1 (ko) * | 2015-03-26 | 2021-10-12 | 주식회사 티앤알바이오팹 | 심근조직 재생용 3차원 구조체의 제조방법 |
CN107708756A (zh) | 2015-04-10 | 2018-02-16 | 哈佛学院院长等 | 免疫细胞捕获装置及其制备和使用方法 |
CN104984403B (zh) * | 2015-06-16 | 2017-08-25 | 南方医科大学珠江医院 | 一种荷载药物及脂肪来源间充质干细胞的多肽水凝胶支架及其制备方法 |
WO2016209987A1 (en) * | 2015-06-22 | 2016-12-29 | Cedars-Sinai Medical Center | A method for regenerating the interverterbral disc with notochordal cells |
SI3317301T1 (sl) | 2015-07-29 | 2021-10-29 | Novartis Ag | Kombinirane terapije, ki obsegajo molekule protitelesa na LAG-3 |
EP3316902A1 (en) | 2015-07-29 | 2018-05-09 | Novartis AG | Combination therapies comprising antibody molecules to tim-3 |
WO2017042301A1 (en) * | 2015-09-09 | 2017-03-16 | ETH Zürich | Injectable macroporous hydrogels |
JP7025021B2 (ja) | 2015-10-26 | 2022-02-24 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 還元多糖および酸化多糖ならびにそれらの使用の方法 |
CN105250994A (zh) * | 2015-10-29 | 2016-01-20 | 广州赛莱拉干细胞科技股份有限公司 | 一种促进皮肤伤口愈合的制剂及其制备方法和应用 |
CA3007671A1 (en) | 2015-12-17 | 2017-06-22 | Novartis Ag | Antibody molecules to pd-1 and uses thereof |
EP3411475A4 (en) | 2016-02-06 | 2019-09-11 | President and Fellows of Harvard College | REGENERATION OF THE HEMATOPOIETIC NICHE TO RECONSTITUTE IMMUNITY |
AU2017295704B2 (en) | 2016-07-13 | 2023-07-13 | President And Fellows Of Harvard College | Antigen-presenting cell-mimetic scaffolds and methods for making and using the same |
KR102204668B1 (ko) * | 2017-09-27 | 2021-01-19 | 한양대학교 산학협력단 | 3d 바이오프린팅 기반 조직공학을 위한 세포-봉입한 하이드로젤 블록 제작 및 이의 거대구조체 조립화 기술 |
CN107899074A (zh) * | 2017-12-29 | 2018-04-13 | 深圳清华大学研究院 | 皮肤细胞喷雾及其制备方法 |
KR20210035776A (ko) * | 2018-03-06 | 2021-04-01 | 에피본, 인크. | 주사가능한 기성품 연골, 힘줄 및 인대 복구 조성물 및 사용 방법 |
CN110478532B (zh) | 2019-08-22 | 2021-12-28 | 上海交通大学医学院附属第九人民医院 | 一种可注射原位生孔水凝胶体系及其制备方法和用途 |
GB2593203A (en) * | 2020-03-19 | 2021-09-22 | Griffin Paste Res Limited | Combinations, kits and methods |
CN111888524A (zh) * | 2020-08-04 | 2020-11-06 | 宁波迪创医疗科技有限公司 | 一种组织填充材料及其制备方法、组织工程支架和应用 |
CA3188208A1 (en) * | 2020-08-10 | 2022-02-17 | Yewoo LEE | Delivery of cells and tissues with self-assembling peptide hydrogel materials |
CN113813448B (zh) * | 2021-10-08 | 2022-12-06 | 大连大学附属中山医院 | 一种含有类软骨陷窝结构的硬度可调水凝胶支架 |
Family Cites Families (251)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5132405A (en) | 1987-05-21 | 1992-07-21 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US5073627A (en) | 1989-08-22 | 1991-12-17 | Immunex Corporation | Fusion proteins comprising GM-CSF and IL-3 |
GB9206504D0 (en) | 1992-03-25 | 1992-05-06 | Jevco Ltd | Heteromorphic sponges as wound implants |
EP0741580A4 (en) | 1993-12-14 | 2001-07-11 | Univ Johns Hopkins Med | CONTROLLED RELEASE OF PHARMACEUTICALLY ACTIVE SUBSTANCES FOR IMMUNOTHERAPY |
US5538733A (en) | 1994-07-07 | 1996-07-23 | Willmar Poultry Company, Inc. | Method of priming an immune response in a one-day old animal |
CA2194761C (en) | 1994-07-15 | 2006-12-19 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US5625048A (en) | 1994-11-10 | 1997-04-29 | The Regents Of The University Of California | Modified green fluorescent proteins |
US6251396B1 (en) | 1994-11-18 | 2001-06-26 | Neurocrine Biosciences, Inc. | Methods for treatment of multiple sclerosis using peptide analogs of human myelin basic protein |
US6329499B1 (en) | 1994-11-18 | 2001-12-11 | Neurocrine Biosciences, Inc. | Methods for treatment of multiple sclerosis using peptide analogues of human myelin basic protein |
US5951976A (en) | 1996-03-28 | 1999-09-14 | Whitenead Institute For Biomedical Research | Opsonin-enhanced cells, and methods of modulating an immune response to an antigen |
IL118376A0 (en) | 1996-05-22 | 1996-09-12 | Univ Ben Gurion | Polysaccharide sponges for cell culture and transplantation |
EP0915967A1 (en) | 1996-05-28 | 1999-05-19 | The Board Of Regents Of The University Of Michigan | Engineering oral tissues |
US6124128A (en) | 1996-08-16 | 2000-09-26 | The Regents Of The University Of California | Long wavelength engineered fluorescent proteins |
JP4335316B2 (ja) | 1996-09-19 | 2009-09-30 | ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・ミシガン | アルギネートまたは修飾アルギネートのようなポリサッカライドを含むポリマー |
US5863551A (en) | 1996-10-16 | 1999-01-26 | Organogel Canada Ltee | Implantable polymer hydrogel for therapeutic uses |
GB2318577B (en) | 1996-10-28 | 2000-02-02 | Johnson & Johnson Medical | Solvent dried polysaccharide sponges |
GB2323282B (en) | 1997-03-17 | 2001-03-07 | Bristol Myers Squibb Co | Improvements relating to hygiene and medical products |
DK0991705T3 (da) | 1997-03-31 | 2004-01-12 | Univ Michigan Technology Man W | Åbenporede, bionedbrydelige matricer |
EP1014897B1 (en) | 1997-05-30 | 2008-10-29 | Osteobiologics, Inc. | Fiber-reinforced, porous, biodegradable implant device |
AU8748198A (en) | 1997-08-21 | 1999-03-16 | Takara Shuzo Co., Ltd. | Carcinostatic agents |
HU222543B1 (hu) | 1998-02-23 | 2003-08-28 | Massachusetts Institute Of Technology | Biológiai úton lebomlani képes emlékező polimerek |
WO1999044583A2 (en) | 1998-03-02 | 1999-09-10 | Applied Vaccine Technologies Corp. | Methods and devices for modulating the immune response |
ES2284247T3 (es) | 1998-04-03 | 2007-11-01 | University Of Iowa Research Foundation | Metodos y productos para estimular el sistema inmunitario usando oligonucleotidos y citoquinas inmunoterapeuticos. |
US7427602B1 (en) | 1998-05-13 | 2008-09-23 | The Regents Of The University Of Michigan | Sustained DNA delivery from structural matrices |
US7244714B1 (en) | 1998-06-12 | 2007-07-17 | Aradigm Corporation | Methods of delivering aerosolized polynucleotides to the respiratory tract |
FR2780730B1 (fr) | 1998-07-01 | 2000-10-13 | Corneal Ind | Compositions biphasiques injectables, notamment utiles en chirurgies reparatrice et esthetique |
CA2338928A1 (en) | 1998-07-30 | 2000-02-10 | Hynda K. Kleinman | Thymosin .beta.4 promotes wound repair |
EP1117444A2 (en) | 1998-10-09 | 2001-07-25 | The University Of Michigan | Hydrogels and water soluble polymeric carriers for drug delivery |
US7109003B2 (en) | 1998-12-23 | 2006-09-19 | Abgenix, Inc. | Methods for expressing and recovering human monoclonal antibodies to CTLA-4 |
US6974698B1 (en) | 1999-01-15 | 2005-12-13 | The United States Of America As Represented By The Department Of Health And Human Services | Methods for delivering biologically active molecules into cells |
CA2363141C (en) | 1999-02-26 | 2010-04-06 | Chiron Corporation | Microemulsions with adsorbed macromolecules and microparticles |
AU4173000A (en) | 1999-03-19 | 2000-10-09 | Regents Of The University Of Michigan, The | Mineralization and cellular patterning on biomaterial surfaces |
US6767928B1 (en) | 1999-03-19 | 2004-07-27 | The Regents Of The University Of Michigan | Mineralization and biological modification of biomaterial surfaces |
US6548569B1 (en) | 1999-03-25 | 2003-04-15 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
US6511650B1 (en) | 1999-04-09 | 2003-01-28 | The Regents Of The University Of Michigan | Preparing porous hydrogel products |
AU782297B2 (en) | 1999-06-30 | 2005-07-14 | Ethicon Inc. | Porous tissue scaffoldings for the repair or regeneration of tissue |
US8084258B2 (en) | 1999-07-12 | 2011-12-27 | University Of Basel | Manipulation of tissue of organ type using the notch pathway |
EP1206254A1 (en) | 1999-08-06 | 2002-05-22 | The Board Of Regents, The University Of Texas System | Drug releasing biodegradable fiber implant |
US7015205B1 (en) | 1999-10-18 | 2006-03-21 | St. Vincent's Hospital And Medical Center Of New York | Melanoma vaccine and methods of making and using same |
WO2001035932A2 (en) | 1999-11-18 | 2001-05-25 | The Regents Of The University Of Michigan | Sustained drug delivery from structural matrices |
US6682754B2 (en) | 1999-11-24 | 2004-01-27 | Willmar Poultry Company, Inc. | Ovo delivery of an immunogen containing implant |
US6790840B1 (en) | 1999-11-26 | 2004-09-14 | The Regents Of The University Of Michigan | Reversibly cross-linked hydrogels |
AU2001284695A1 (en) | 2000-07-31 | 2002-02-13 | New York Medical College | Methods and compositions for the repair and/or regeneration of damaged myocardium |
US7635592B2 (en) | 2000-08-21 | 2009-12-22 | Rice University | Tissue engineering scaffolds promoting matrix protein production |
JP5433840B2 (ja) | 2000-09-09 | 2014-03-05 | ザ・リサーチ・ファウンデーション・フォー・ザ・ステイト・ユニヴァーシティ・オブ・ニューヨーク | 転移癌細胞を単離するための方法および組成物、ならびに癌の転移能の測定におけるその使用 |
US6748954B2 (en) | 2000-10-27 | 2004-06-15 | The Regents Of The University Of Michigan | Drug release from polymer matrices through mechanical stimulation |
WO2002040071A1 (fr) | 2000-11-14 | 2002-05-23 | Osteogenesis Co., Ltd. | Compositions stimulant la formation d'un os ou d'un parodonte et injections pour la formation d'un os ou d'un parodonte |
AU2002218154A1 (en) | 2000-11-27 | 2002-06-03 | Jens Christian Jensenius | Collectins as adjuvants |
US9674575B2 (en) | 2001-01-19 | 2017-06-06 | SITO Mobile R&D IP, LLC | System and method for routing media |
MXPA03006587A (es) | 2001-01-24 | 2003-09-22 | Schering Corp | Quimiocinas como adyuvantes de respuesta inmune. |
US7029697B2 (en) | 2001-02-14 | 2006-04-18 | Northwestern University | Controlled surface-associated delivery of genes and oligonucleotides |
CA2439400A1 (en) | 2001-02-26 | 2002-09-06 | The Regents Of The University Of California | Non-oligomerizing tandem fluorescent proteins |
US20020131953A1 (en) | 2001-03-14 | 2002-09-19 | Ut Southwestern Medical Center | In situ langerhans cell vaccine |
JP2002263981A (ja) | 2001-03-14 | 2002-09-17 | Murata Mach Ltd | 板材吸着持ち上げ装置の吸着制御装置 |
US6656488B2 (en) * | 2001-04-11 | 2003-12-02 | Ethicon Endo-Surgery, Inc. | Bioabsorbable bag containing bioabsorbable materials of different bioabsorption rates for tissue engineering |
US20030082806A1 (en) | 2001-04-27 | 2003-05-01 | Xcyte Therapies, Inc. | Maturation of antigen-presenting cells using activated T cells |
US20030118630A1 (en) | 2001-12-07 | 2003-06-26 | Anthony Cerami | Immune modulation device for use in animals |
EP1387670B1 (en) | 2001-05-11 | 2008-10-15 | Ortho-McNeil-Janssen Pharmaceuticals, Inc. | Immune modulation device for use in animals |
AU2002345691C1 (en) | 2001-06-13 | 2008-07-24 | Massachusetts Institute Of Technology | In vivo bioreactors |
US7297343B2 (en) | 2001-07-31 | 2007-11-20 | Biosurface Engineering Technologies, Inc. | Bioactive medical films |
AU2002361468A1 (en) | 2001-08-14 | 2003-03-18 | The Government Of The United States Of America As Represented By The Secretary Of Health And Human S | Method for rapid generation of mature dendritic cells |
CA2412012C (en) | 2001-11-20 | 2011-08-02 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage |
MXPA04006438A (es) | 2001-12-31 | 2005-06-08 | Ares Lab Llc | Composiciones hemostaticas y metodos para el control de sangrado. |
US7575759B2 (en) | 2002-01-02 | 2009-08-18 | The Regents Of The University Of Michigan | Tissue engineering scaffolds |
US20070026518A1 (en) | 2005-03-29 | 2007-02-01 | The Regents Of The University Of California | Controlling stem cell destiny with tunable matrices |
US20080233181A1 (en) | 2002-04-12 | 2008-09-25 | Nagy Jon O | Nanoparticle adjuvants for sub-unit vaccines |
US6811777B2 (en) | 2002-04-13 | 2004-11-02 | Allan Mishra | Compositions and minimally invasive methods for treating incomplete connective tissue repair |
KR20050009697A (ko) | 2002-04-22 | 2005-01-25 | 바이오니취 라이프 사이언시즈 인코포레이티드 | 올리고뉴클레오티드 조성물 및 면역 반응 조절시 이의 용도 |
AU2003234159A1 (en) | 2002-04-22 | 2003-11-03 | Purdue Research Foundation | Hydrogels having enhanced elasticity and mechanical strength properties |
US20040242469A1 (en) | 2002-05-13 | 2004-12-02 | Lee Richard T. | Angiogenesis and cardiac tissue engineering with peptide hydrogels and related compositions and methods of use thereof |
AUPS312602A0 (en) | 2002-06-21 | 2002-07-18 | James Cook University | Organ arrest, protection, preservation and recovery |
US7332160B2 (en) | 2002-07-12 | 2008-02-19 | Boston Scientific Scimed, Inc. | Medical device and method for tissue removal and repair |
ES2327040T3 (es) | 2002-09-12 | 2009-10-23 | Oncotherapy Science, Inc. | Peptidos kdr y vacunas que los contienen. |
US20040136968A1 (en) | 2002-09-27 | 2004-07-15 | Verigen Ag | Autologous cells on a support matrix for tissue repair |
US20040063206A1 (en) | 2002-09-30 | 2004-04-01 | Rowley Jon A. | Programmable scaffold and method for making and using the same |
WO2004030706A2 (en) | 2002-10-01 | 2004-04-15 | Law Peter K | Bioactive implants |
JP2004159849A (ja) * | 2002-11-12 | 2004-06-10 | National Institute Of Advanced Industrial & Technology | 細胞接着性生体吸収材料、人工血管およびそれらの製造方法 |
JP4511943B2 (ja) | 2002-12-23 | 2010-07-28 | ワイス エルエルシー | Pd−1に対する抗体およびその使用 |
US8940292B2 (en) | 2003-01-28 | 2015-01-27 | Wake Forest University Health Sciences | Enhancement of angiogenesis to grafts using cells engineered to produce growth factors |
SE0301109D0 (sv) | 2003-04-14 | 2003-04-14 | Mallen Huang | Nucleotide vaccine composition |
JP2006525405A (ja) * | 2003-05-05 | 2006-11-09 | ベン‐グリオン ユニバーシティ オブ ザ ネゲヴ リサーチ アンド デベロップメント オーソリティ | 注入可能な架橋されたポリマー調製物およびその使用 |
EP1475434A1 (en) | 2003-05-09 | 2004-11-10 | Oncoscience AG | Method for storing tumor cells |
US20050053667A1 (en) | 2003-07-09 | 2005-03-10 | Darrell Irvine | Programmed immune responses using a vaccination node |
US20060264380A1 (en) | 2003-07-21 | 2006-11-23 | Mats Hellstrom | Compounds and Methods for Promoting Angiogenesis |
GB0317999D0 (en) | 2003-07-31 | 2003-09-03 | Univ Liege | Improvements in or relating to drug delivery systems |
EP1651259A4 (en) | 2003-07-31 | 2008-05-28 | Endacea Inc | METHOD AND COMPOSITIONS FOR PRODUCING ANTIGENIC ANSWERS |
DE602004018163D1 (de) * | 2003-08-29 | 2009-01-15 | Mayo Foundation | Hydrogel-porenbildner zur herstellung von biologisch abbaubaren gerüsten |
WO2005037190A2 (en) | 2003-09-03 | 2005-04-28 | Dendritherapeutics, Inc. | Multiplex vaccines |
GB0321615D0 (en) | 2003-09-15 | 2003-10-15 | Glaxo Group Ltd | Improvements in vaccination |
EP2591786B1 (en) | 2003-10-16 | 2017-04-12 | Cancure Limited | Immunomodulating compositions and uses therefor |
US8162925B2 (en) | 2003-11-07 | 2012-04-24 | Carnegie Mellon University | Robot for minimally invasive interventions |
CA2448995A1 (en) | 2003-11-12 | 2005-05-12 | James Keenan | Device and method for attracting diseased cells and foreign substances |
JP2005160669A (ja) | 2003-12-02 | 2005-06-23 | Olympus Corp | 生体組織補填体の製造方法 |
JP2005170816A (ja) | 2003-12-09 | 2005-06-30 | Naoki Ishiguro | 軟骨修復用材料、およびその製造方法 |
CA2548992A1 (en) | 2003-12-11 | 2005-08-11 | Vaxdesign Corporation | Immunotherapy compositions, method of making and method of use thereof |
US11395865B2 (en) | 2004-02-09 | 2022-07-26 | DePuy Synthes Products, Inc. | Scaffolds with viable tissue |
US7192693B2 (en) | 2004-02-24 | 2007-03-20 | University Of Washington | Methods for photopatterning hydrogels |
WO2005087238A2 (en) | 2004-03-15 | 2005-09-22 | Karaolis David K R | Method for stimulating the immune, inflammatory or neuroprotective response |
US7592326B2 (en) | 2004-03-15 | 2009-09-22 | Karaolis David K R | Method for stimulating the immune, inflammatory or neuroprotective response |
WO2005104755A2 (en) | 2004-04-28 | 2005-11-10 | Vaxdesign Corporation | Artificial immune system: methods for making and use |
CA2567789A1 (en) | 2004-06-08 | 2006-08-03 | Coley Pharmaceutical Gmbh | Abasic oligonucleotide as carrier platform for antigen and immunostimulatory agonist and antagonist |
US8080245B2 (en) | 2004-08-04 | 2011-12-20 | University Of Massachusetts | Anti-pathogen immunoadhesins |
WO2006039045A2 (en) | 2004-09-01 | 2006-04-13 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Adenoviral vectors able to transduce apcs, potential use in immune response generation |
US7235592B2 (en) | 2004-10-12 | 2007-06-26 | Zimmer Gmbh | PVA hydrogel |
AU2005295927B2 (en) | 2004-10-12 | 2012-02-02 | Fmc Biopolymer As | Self-gelling alginate systems and uses thereof |
JP4487734B2 (ja) * | 2004-11-10 | 2010-06-23 | 株式会社デンソー | フィン製造装置 |
US7999161B2 (en) | 2005-01-22 | 2011-08-16 | Alexander Oraevsky | Laser-activated nanothermolysis of cells |
US7569850B2 (en) | 2005-01-24 | 2009-08-04 | Lawrence Livermore National Security, Llc | Lipid bilayers on nano-templates |
WO2006102530A1 (en) | 2005-03-23 | 2006-09-28 | Mayo Foundation For Medical Education And Research | Photocrosslinkable oligo(poly (ethylene glycol) fumarate) hydrogels for cell and drug delivery |
EP1712238A1 (en) | 2005-04-11 | 2006-10-18 | Institut Gustave Roussy | Anthracyclin induced immunogenic dead or dying cells composition |
US20070003595A1 (en) | 2005-04-19 | 2007-01-04 | Shaopeng Wang | Three dimensional micro-environments and methods of making and using same |
US8828433B2 (en) | 2005-04-19 | 2014-09-09 | Advanced Cardiovascular Systems, Inc. | Hydrogel bioscaffoldings and biomedical device coatings |
CN101355928B (zh) | 2005-04-26 | 2013-05-22 | 卫材R&D管理株式会社 | 用于癌症免疫疗法的组合物和方法 |
WO2006119619A1 (en) | 2005-05-06 | 2006-11-16 | Replicor Inc. | Oligonucleotides inhibiting cell proliferation |
ITPI20050071A1 (it) * | 2005-06-20 | 2006-12-21 | Giuseppe Calvosa | Composizione biocompatibile per la sostituzione/rigenerazione di tessuti |
US7645742B2 (en) | 2005-06-22 | 2010-01-12 | Advocare International, L.P. | Composition for enhancing cellular energy |
CN1302050C (zh) | 2005-07-07 | 2007-02-28 | 复旦大学 | 一种互穿网络聚合物超多孔水凝胶及其制备方法和应用 |
US20090017096A1 (en) * | 2005-08-15 | 2009-01-15 | Anthony Lowman | Porous non-biodegradable hydrogel admixed with a chemoattractant for tissue replacement |
US20090214614A1 (en) * | 2005-09-02 | 2009-08-27 | Interface Biotech A/S | Method for Cell Implantation |
BRPI0503817A (pt) | 2005-09-12 | 2007-05-15 | Cristalia Prod Quimicos Farm | complexo imunogênico formado por antìgenos vacinais encapsulados por sìlica mesoporosa nanoestruturada |
JP5925408B2 (ja) | 2005-09-23 | 2016-05-25 | タイジェニックス、ソシエダッド、アノニマ、ウニペルソナルTigenix S.A.U. | 免疫調節活性を有する細胞集団、単離方法および使用 |
US20070081972A1 (en) | 2005-09-30 | 2007-04-12 | The University Of Iowa Research Foundation | Polymer-based delivery system for immunotherapy of cancer |
EA200801045A1 (ru) | 2005-10-12 | 2008-10-30 | Кэнсер Рисерч Текнолоджи Лтд. | Способы и композиции для лечения иммунных нарушений |
US8029575B2 (en) * | 2005-10-25 | 2011-10-04 | Globus Medical, Inc. | Porous and nonporous materials for tissue grafting and repair |
US20070116680A1 (en) | 2005-11-18 | 2007-05-24 | Rensselaer Polytechnic Institute | Stem cells within gel microenvironments |
CA2631598C (en) | 2005-11-29 | 2017-06-27 | Actogenix Nv | Induction of mucosal tolerance to antigens |
KR100687281B1 (ko) | 2005-11-30 | 2007-02-27 | 한국과학기술연구원 | 생리 활성 물질이 결합된 조직 재생용 주입형 온도 감응성플루로닉 유도체 하이드로겔 및 이의 제조 방법 |
JP5122474B2 (ja) | 2005-12-01 | 2013-01-16 | プロネイ・セラピューティクス・インコーポレイテッド | 両性リポソーム製剤 |
WO2007070660A2 (en) | 2005-12-13 | 2007-06-21 | President And Fellows Of Harvard College | Scaffolds for cell transplantation |
AU2015264807A1 (en) | 2005-12-13 | 2015-12-17 | President And Fellows Of Harvard College | Scaffolds for Cell Transplantation |
US20090148487A1 (en) * | 2005-12-14 | 2009-06-11 | Scil Technology Gmbh | Moldable biomaterial for bone regeneration |
EP1806395A1 (en) | 2006-01-06 | 2007-07-11 | Stichting Sanquin Bloedvoorziening | Maturation of dendritic cells |
US7615556B2 (en) | 2006-01-27 | 2009-11-10 | Bristol-Myers Squibb Company | Piperazinyl derivatives as modulators of chemokine receptor activity |
US20070178159A1 (en) | 2006-01-30 | 2007-08-02 | Alza Corporation | In-Situ Forming Porous Scaffold |
CA2676601A1 (en) | 2006-01-31 | 2007-08-09 | Medivas, Llc | Vaccine delivery compositions and methods of use |
US20070190646A1 (en) | 2006-02-10 | 2007-08-16 | The Trustees Of The University Of Pennsylvania | Regulating stem cell differentiation by controlling matrix elasticity |
US20100015709A1 (en) | 2006-02-10 | 2010-01-21 | Trustees Of The University Of Pennsylvania | Regulating Stem Cell Differentiation By Controlling 2D and 3D Matrix Elasticity |
JP2009528080A (ja) | 2006-02-27 | 2009-08-06 | エイジェンシー・フォー・サイエンス,テクノロジー・アンド・リサーチ | 硬化性骨セメント |
US9456860B2 (en) | 2006-03-14 | 2016-10-04 | Kci Licensing, Inc. | Bioresorbable foaming tissue dressing |
GB0605521D0 (en) | 2006-03-18 | 2006-04-26 | Isis Innovation | Adjuvant |
WO2008127256A1 (en) | 2006-06-01 | 2008-10-23 | Massachusetts Institute Of Technology | Control of cells and cell multipotentiality in three dimensional matrices |
US20080069801A1 (en) * | 2006-06-13 | 2008-03-20 | Lee Randall J | Methods and apparatus for using polymer-based beads and hydrogels for cardiac applications |
EP2029727B1 (en) * | 2006-06-16 | 2012-04-11 | FMC Biopolymer AS | Alginate coated, collagen matrix cellular device, preparative methods, and uses thereof. |
US20070298067A1 (en) | 2006-06-22 | 2007-12-27 | Boston Scientific Scimed, Inc. | Control release drug coating for medical devices |
CA2690973A1 (en) | 2006-06-23 | 2007-12-27 | Paul M. Simon | Targeted immune conjugates |
WO2008008266A2 (en) | 2006-07-07 | 2008-01-17 | University Of Pittsburgh- Of The Commonwealth System Of Higher Education | Biohybrid elastomeric scaffolds and methods of use thereof |
US7993918B2 (en) | 2006-08-04 | 2011-08-09 | Anthrogenesis Corporation | Tumor suppression using placental stem cells |
KR100802139B1 (ko) | 2006-08-08 | 2008-02-11 | 한국생명공학연구원 | 자성 나노입자를 함유하는 골드 나노케이지 |
KR100818708B1 (ko) | 2006-08-18 | 2008-04-01 | 주식회사 하이닉스반도체 | 표면 세정을 포함하는 반도체소자 제조방법 |
ITMI20061726A1 (it) | 2006-09-11 | 2008-03-12 | Fidia Farmaceutici | Derivati crosslinkati a base di acido ialuronico reticolato via click chemistry |
US8084055B2 (en) | 2006-09-21 | 2011-12-27 | Purdue Research Foundation | Collagen preparation and method of isolation |
EP2077821B1 (en) | 2006-10-12 | 2019-08-14 | The University Of Queensland | Compositions and methods for modulating immune responses |
CN103169571B (zh) | 2006-11-09 | 2015-04-15 | 凯希特许有限公司 | 包含微球的多孔生物可吸收连接敷料及其制备方法 |
US8709464B2 (en) | 2007-01-10 | 2014-04-29 | The Regents Of The University Of Michigan | Porous objects having immobilized encapsulated biomolecules |
WO2008109852A2 (en) | 2007-03-07 | 2008-09-12 | Uti Limited Partnership | Compositions and methods for the prevention and treatment of autoimmune conditions |
CA2684578A1 (en) | 2007-03-21 | 2008-09-25 | Id Biomedical Corporation Of Quebec | Chimeric antigens |
WO2008118392A2 (en) | 2007-03-22 | 2008-10-02 | The Regents Of The University Of California | Synthetic cell platforms and methods of use thereof |
EP1975230A1 (en) | 2007-03-30 | 2008-10-01 | Capsulution Nanoscience AG | Method for forming glucose sensing micro-particles, use of micro-particles, and kit |
WO2008131074A1 (en) | 2007-04-19 | 2008-10-30 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Use of toll-like receptor-9 agonists, toll-like receptor-4 antagonists, and/or nuclear oligomerization domain-2 agonists for the treatment or prevention of toll-like receptor-4-associated disorders |
KR20100035643A (ko) | 2007-06-05 | 2010-04-05 | 노파르티스 아게 | 성숙 수지상 세포에서의 허용유발 표현형의 유도 |
WO2008157280A1 (en) * | 2007-06-13 | 2008-12-24 | Fmc Corporation | Implantable degradable biopolymer fiber devices |
US20090136470A1 (en) | 2007-06-13 | 2009-05-28 | Hilde Cheroutre | Regulatory t cells and methods of making and using same |
US9770535B2 (en) | 2007-06-21 | 2017-09-26 | President And Fellows Of Harvard College | Scaffolds for cell collection or elimination |
JP5780759B2 (ja) | 2007-06-29 | 2015-09-16 | 真理 船木 | 幹細胞の進展の調節における柔らかいゲル系 |
CA2695385A1 (en) | 2007-07-31 | 2009-02-05 | Atul Bedi | Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders |
GB0716264D0 (en) | 2007-08-21 | 2007-09-26 | Isis Innovation | Bilayers |
WO2009032247A1 (en) | 2007-08-30 | 2009-03-12 | Northwestern University | Synthetic peptide and peptide conjugates and related tissue coupling methods via transglutaminase enzyme |
US20090192079A1 (en) | 2007-10-09 | 2009-07-30 | Genzyme Corporation | Prolonged delivery of heparin-binding growth factors from heparin-derivatized collagen |
CN101439206A (zh) * | 2007-11-22 | 2009-05-27 | 郭倩 | 酶催化快速固化水凝胶的制备及其应用 |
KR100900837B1 (ko) | 2007-12-07 | 2009-06-04 | (주)두비엘 | 리포펩타이드와 폴리(i:c)를 아쥬반트로 포함하는 강력한백신 조성물 |
EP2072617A1 (en) | 2007-12-12 | 2009-06-24 | Trimed Biotech GmbH | Method for producing dendritic cells |
DE102008008522A1 (de) | 2008-02-11 | 2009-08-13 | Magforce Nanotechnologies Ag | Implantierbare Nanopartikel-enthaltende Produkte |
CN102006891B (zh) | 2008-02-13 | 2017-04-26 | 哈佛学院董事会 | 连续的细胞程序化装置 |
WO2011063336A2 (en) | 2009-11-20 | 2011-05-26 | President And Fellows Of Harvard College | Secondary site of antigen stimulation for therapeutic vaccination |
US9370558B2 (en) | 2008-02-13 | 2016-06-21 | President And Fellows Of Harvard College | Controlled delivery of TLR agonists in structural polymeric devices |
US20090238853A1 (en) | 2008-03-21 | 2009-09-24 | 3D Biotek, Llc | Hybrid Biomedical Device Fabricated From Biomaterials and Coated With a Natural Extra Cellular Matrix (ECM) Coating |
US9012399B2 (en) | 2008-05-30 | 2015-04-21 | President And Fellows Of Harvard College | Controlled release of growth factors and signaling molecules for promoting angiogenesis |
US20110182957A1 (en) | 2008-06-19 | 2011-07-28 | Nicoll Steven B | Cellulosics for tissue replacement |
NZ591130A (en) | 2008-08-25 | 2012-09-28 | Amplimmune Inc | Compositions comprising a PD-1 antagonists and cyclophosphamide and methods of use thereof |
US8889124B2 (en) | 2008-09-25 | 2014-11-18 | The Board Of Trustees Of The Leland Stanford Junior University | Tolerogenic populations of dendritic cells |
US8940331B2 (en) | 2008-11-22 | 2015-01-27 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrogels, methods of making hydrogels, methods of using hydrogels, and methods of isolating, trapping, attracting, and/or killing cancer cells |
KR101132732B1 (ko) | 2008-11-26 | 2012-04-06 | 한국과학기술연구원 | 인 시튜 조직재생용 지능형 다공성 생분해 고분자 지지체 및 이의 제조방법 |
US8273373B2 (en) | 2008-12-30 | 2012-09-25 | Case Western Reserve University | Photocrosslinked biodegradable hydrogel |
US9139809B2 (en) | 2009-01-08 | 2015-09-22 | Albert Einstein College Of Medicine Of Yeshiva University | Bacterial vaccines with cell wall-associated ceramide-like glycolipids and uses thereof |
CN101612437B (zh) * | 2009-01-09 | 2011-09-14 | 清华大学 | 纳曲酮微球-水凝胶骨架原位埋植给药系统 |
JP2010227012A (ja) | 2009-03-27 | 2010-10-14 | Seiko Epson Corp | がん細胞捕捉デバイス |
WO2010120749A2 (en) | 2009-04-13 | 2010-10-21 | President And Fellow Of Harvard College | Harnessing cell dynamics to engineer materials |
US8551749B2 (en) | 2009-04-23 | 2013-10-08 | The Invention Science Fund I, Llc | Device including bone cage and method for treatment of disease in a subject |
JP5926180B2 (ja) | 2009-07-31 | 2016-05-25 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | 寛容原性療法のための細胞のプログラミングの方法 |
CN101655611B (zh) | 2009-09-11 | 2011-06-08 | 中国科学院长春应用化学研究所 | 一种具有双层杂化结构的反蛋白石水凝胶光子晶体的制备方法 |
CA2776954A1 (en) | 2009-10-09 | 2011-04-14 | Anaphore, Inc. | Combinatorial libraries based on c-type lectin domain |
WO2011043835A1 (en) | 2009-10-09 | 2011-04-14 | Anaphore, Inc. | Polypeptides that bind il-23r |
US20110207166A1 (en) | 2009-11-06 | 2011-08-25 | Sarah Rivkah Vaiselbuh | Human bone marrow microenvironments and uses thereof |
CN102656119B (zh) | 2009-12-18 | 2015-11-25 | 花王株式会社 | 介孔二氧化硅颗粒的制造方法 |
JP5603063B2 (ja) | 2009-12-21 | 2014-10-08 | 花王株式会社 | 複合シリカ粒子の製造方法 |
AU2011207626B2 (en) | 2010-01-19 | 2015-06-18 | President And Fellows Of Harvard College | Engineered opsonin for pathogen detection and treatment |
AU2011217780B2 (en) | 2010-02-22 | 2016-02-11 | Incredible Foods, Inc. | Enclosing materials in natural transport systems |
JP5972796B2 (ja) | 2010-03-02 | 2016-08-17 | キング アブドゥーラ ユニバーシティ オブ サイエンス アンド テクノロジー | 高表面積の繊維状シリカナノ粒子 |
JP5647669B2 (ja) | 2010-03-04 | 2015-01-07 | 地方独立行政法人東京都立産業技術研究センター | 多孔質シリカの製造方法 |
EP2542230A4 (en) | 2010-03-05 | 2013-08-28 | Harvard College | ENHANCEMENT OF SKELETAL MUSCLE STRAIN CELL GRAFT WITH DUAL DELIVERY OF VEGF AND IGF-1 |
CN102905732A (zh) | 2010-03-15 | 2013-01-30 | 弗罗桑医疗设备公司 | 用于促进止血和/或伤口愈合的方法 |
US20110256184A1 (en) | 2010-04-14 | 2011-10-20 | Battelle Memorial Institute | Non-ordered Mesoporous Silica Structure for Biomolecule Loading and Release |
US20110300186A1 (en) | 2010-04-14 | 2011-12-08 | Battelle Memorial Institute | Functionalized Nano- and Micro-materials for Medical Therapies |
AU2011258156B2 (en) | 2010-05-26 | 2016-11-24 | Selecta Biosciences, Inc. | Multivalent synthetic nanocarrier vaccines |
GB201009273D0 (en) | 2010-06-03 | 2010-07-21 | Glaxosmithkline Biolog Sa | Novel vaccine |
EP2585053A4 (en) | 2010-06-25 | 2014-02-26 | Harvard College | COMMON RELEASE OF STIMULATING AND HEMMING FACTORS FOR THE PRODUCTION OF TEMPORARY STABILIZED AND SPATULARLY LIMITED ZONES |
CN103118678A (zh) | 2010-07-16 | 2013-05-22 | 约翰斯·霍普金斯大学 | 用于癌症免疫治疗的方法和组合物 |
AU2011285639B2 (en) | 2010-08-04 | 2014-12-18 | Georgia Tech Research Corporation | Devices, systems, and methods for excavating cancer cells |
PT2624873T (pt) | 2010-10-06 | 2020-03-04 | Harvard College | Hidrogéis injectáveis formadores de poros para terapias celulares à base de materiais |
WO2012064697A2 (en) | 2010-11-08 | 2012-05-18 | President And Fellows Of Harvard College | Materials presenting notch signaling molecules to control cell behavior |
WO2012148684A1 (en) | 2011-04-27 | 2012-11-01 | President And Fellows Of Harvard College | Cell-friendly inverse opal hydrogels for cell encapsulation, drug and protein delivery, and functional nanoparticle encapsulation |
US9675561B2 (en) | 2011-04-28 | 2017-06-13 | President And Fellows Of Harvard College | Injectable cryogel vaccine devices and methods of use thereof |
ES2878089T3 (es) | 2011-04-28 | 2021-11-18 | Harvard College | Armazones tridimensionales macroscópicos preformados inyectables para administración mínimamente invasiva |
WO2012149393A2 (en) | 2011-04-29 | 2012-11-01 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for antigen-specific deletion of t effector cells |
EP2714073B1 (en) | 2011-06-03 | 2021-03-10 | President and Fellows of Harvard College | In situ antigen-generating cancer vaccine |
JP6046710B2 (ja) | 2011-06-24 | 2016-12-21 | アーキュール,インコーポレイティド | 置換されたイミダゾピリジニル−アミノピリジン化合物 |
EP3081937B1 (en) | 2011-07-18 | 2019-11-13 | President and Fellows of Harvard College | Engineered microbe-targeting molecules and uses thereof |
EP4009640A1 (en) | 2011-11-08 | 2022-06-08 | Electronics and Telecommunications Research Institute | Method and device for sharing a candidate list |
US20130145488A1 (en) | 2011-12-06 | 2013-06-06 | Iowa State University Research Foundation, Inc. | Mesoporous silica nanoparticles suitable for co-delivery |
CN109125718A (zh) | 2012-01-13 | 2019-01-04 | 哈佛学院董事会 | 在结构聚合装置中tlr激动剂的控制传递 |
JP6527331B2 (ja) | 2012-03-16 | 2019-06-05 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 標的指向アミノ酸脂質 |
ES2773895T3 (es) | 2012-04-16 | 2020-07-15 | Harvard College | Composiciones de sílice mesoporosa para modular las respuestas inmunitarias |
KR102238317B1 (ko) | 2012-05-17 | 2021-04-12 | 익스텐드 바이오사이언시즈, 인크. | 개선된 약물 전달용 캐리어 |
WO2013190555A1 (en) | 2012-06-21 | 2013-12-27 | Compugen Ltd. | Lsr antibodies, and uses thereof for treatment of cancer |
US20140072510A1 (en) | 2012-09-13 | 2014-03-13 | Northwestern University | Synthetic Scaffolds for Metastasis Detection |
CN105209074A (zh) | 2012-10-20 | 2015-12-30 | 得克萨斯大学体系董事会 | 癌细胞陷阱 |
SG10201704611WA (en) | 2012-12-13 | 2017-07-28 | Aduro Biotech Inc | Compositions comprising cyclic purine dinucleotides having defined stereochemistries and methods for their preparation and use |
EP2972375A2 (en) | 2013-03-13 | 2016-01-20 | Creatics LLC | Methods and compositions for detecting pancreatic cancer |
AU2014268836B2 (en) | 2013-05-18 | 2018-08-02 | Aduro Biotech, Inc. | Compositions and methods for activating "stimulator of interferon gene"-dependent signalling |
AU2014268603B2 (en) | 2013-05-21 | 2018-03-22 | President And Fellows Of Harvard College | Engineered heme-binding compositions and uses thereof |
WO2014190229A1 (en) | 2013-05-24 | 2014-11-27 | President And Fellows Of Harvard College | Methods of isolating microorganisms and uses thereof |
CA2987519A1 (en) | 2013-11-01 | 2015-05-07 | Yale University | Delivery vehicles |
US20160287623A1 (en) | 2013-11-19 | 2016-10-06 | The University Of Chicago | Use of sting agonist as cancer treatment |
EP3125960B1 (en) | 2014-04-04 | 2020-06-03 | President and Fellows of Harvard College | Click-crosslinked hydrogels and methods of use |
EP3137105A4 (en) | 2014-04-30 | 2017-12-27 | President and Fellows of Harvard College | Combination vaccine devices and methods of killing cancer cells |
US11065362B2 (en) | 2014-06-12 | 2021-07-20 | President And Fellows Of Harvard College | Viscoelastic hydrogels with fast stress relaxation |
WO2016004068A1 (en) | 2014-06-30 | 2016-01-07 | Jae-Won Shin | Hydrogel compositions comprising encapsulated cells and methods of use thereof |
EP3250250A4 (en) | 2015-01-30 | 2019-05-22 | President and Fellows of Harvard College | PERITUMORAL AND INTRATUMORAL MATERIALS FOR CANCER THERAPY |
US20180117171A1 (en) | 2015-04-01 | 2018-05-03 | President And Fellows Of Harvard College | Immunoconjugates for programming or reprogramming of cells |
CN107708756A (zh) | 2015-04-10 | 2018-02-16 | 哈佛学院院长等 | 免疫细胞捕获装置及其制备和使用方法 |
US10435457B2 (en) | 2015-08-06 | 2019-10-08 | President And Fellows Of Harvard College | Microbe-binding molecules and uses thereof |
EP3411475A4 (en) | 2016-02-06 | 2019-09-11 | President and Fellows of Harvard College | REGENERATION OF THE HEMATOPOIETIC NICHE TO RECONSTITUTE IMMUNITY |
WO2017143024A2 (en) | 2016-02-16 | 2017-08-24 | President And Fellows Of Harvard College | Pathogen vaccines and methods of producing and using the same |
AU2017295704B2 (en) | 2016-07-13 | 2023-07-13 | President And Fellows Of Harvard College | Antigen-presenting cell-mimetic scaffolds and methods for making and using the same |
JP7274214B2 (ja) | 2016-08-02 | 2023-05-16 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 免疫応答を調節するための生体材料 |
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