WO2003020316A1 - Matieres a liberation lente de medicament in vivo - Google Patents

Matieres a liberation lente de medicament in vivo Download PDF

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Publication number
WO2003020316A1
WO2003020316A1 PCT/JP2002/008282 JP0208282W WO03020316A1 WO 2003020316 A1 WO2003020316 A1 WO 2003020316A1 JP 0208282 W JP0208282 W JP 0208282W WO 03020316 A1 WO03020316 A1 WO 03020316A1
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Prior art keywords
drug
vivo
hap
sustained
collagen
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PCT/JP2002/008282
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English (en)
French (fr)
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Shinichi Sotome
Toshimasa Uemura
Masanori Kikuchi
Kenichi Shinomiya
Junzo Tanaka
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Japan Science And Technology Agency
National Institute For Materials Science
National Institute Of Advanced Industrial Science And Technology
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Priority to US10/487,706 priority Critical patent/US20050031698A1/en
Priority to EP02760639A priority patent/EP1421954A4/en
Publication of WO2003020316A1 publication Critical patent/WO2003020316A1/ja

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6435—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a connective tissue peptide, e.g. collagen, fibronectin or gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle

Definitions

  • the present invention relates to an in vivo drug sustained release material comprising a hydroxyapatite and collagen (HApZCol) nanocomposite.
  • HpZCol hydroxyapatite and collagen
  • general drug sustained-release carriers include, for example, 1) a drug that is retained in a material that has a high water retention capacity, such as collagen, and diffused by being implanted into a living body. 2) In general, a drug is mixed with a biodegradable biomaterial such as polylactic acid in a manufacturing process, and is released when the biomaterial is decomposed.
  • JP-A-6-304242 Also known is a collagen phosphate composite material used as a tissue biomembrane (GTR membrane) in periodontal tissue, a hemostatic agent, a bone filler, a cartilage filler, and a three-dimensional culture substrate for hard tissue cells.
  • This composite material is obtained by drying a composite obtained by reacting collagen and a calcium phosphate compound in a calcium phosphate solution. Also. Calcium Phosphate and Coller A method for producing a composite material to be used as an artificial bone or the like having excellent orientation by subjecting the obtained precipitate to pressure molding after co-precipitation of gen (Japanese Patent Application Laid-Open No. 11-1999209) Is also known. Disclosure of the invention
  • Collagen has a high water retention capacity, can be transplanted into a living body while retaining a large amount of drug solution, and has been used as a carrier for various site-in, growth factors, and the like in experiments.
  • carriers of growth factors using a hydrogel material such as collagen or gelatin have a high drug release rate after transplantation and can exert their effects only for a relatively short period of time. Factors must be used.
  • Hydroxyapatite is widely used as a biomaterial having a high osteoinductive property, and many attempts have been made to use a bone filler as a carrier for a growth factor.
  • hydroxyapatite has a very polar crystal structure, and protein and
  • microcrystalline hydroxyapatite has been used as a material for chromatography.
  • microcrystals such as those used in chromatography are powdery for use as biomaterials and are not practical. For this reason, sintered bodies and the like are used as biomaterials, but this significantly reduces the area where the drug is adsorbed, and is not practical as a drug carrier.
  • Hydroxyapatite which has a high specific surface area, and growth factors bind strongly.
  • any substance having an electrical polarity such as a drug or DNA can be used as a sustained-release carrier having a high surface adsorption ability.
  • the present invention provides a hydroxyapatite (HAp) which is synthesized as a coprecipitate by reacting a phosphoric acid solution, a calcium hydroxide solution, and a collagen solution under certain conditions, and has a specific surface area of 50 to 30 Om 2 ng.
  • In vivo drug sustained-release material characterized by holding a physiologically active substance such as DNA enzyme and a drug.
  • the present invention provides a bioabsorbable capsule in which a growth factor is encapsulated by complexing highly water-containing glycosaminodalican (hyaluronic acid, chondroitin sulfate, keratan sulfate, etc.) or hydrogel.
  • highly water-containing glycosaminodalican hyaluronic acid, chondroitin sulfate, keratan sulfate, etc.
  • hydrogel hydrogel.
  • the present invention is the above-mentioned in vivo drug sustained-release material, which can be injected into a living body and gelates after injection.
  • the HAp ZC ⁇ 1 complex according to the present invention is composed of hydroxyapatite and collagen. Is a biomaterial obtained by compounding the above.
  • This HAp / Co1 complex is prepared by simultaneously dropping a suspension of calcium hydroxide and an aqueous solution of phosphoric acid containing collagen into distilled water to co-precipitate them, and forming the co-precipitates by dehydration under pressure. Synthesized.
  • the HAp / Co1 complex synthesized by this method is a nanocomposite in which HAp crystals are oriented around the Co1 fiber in the C-axis direction and complexed.
  • the specific surface area of hydroxyapatite by the BET method is very large, about 50-30 Om 2 Zg.
  • the hydroxyapatite contained in the HAp / Co1 complex has a small crystal (equivalent to or smaller than that used in mouth chromatography), so it can adsorb a large amount of drug on its surface.
  • the drug contained in collagen can be attracted and kept there.
  • the sustained-release drug material of the present invention compensates for problems as a drug carrier by combining two types of materials, and draws out advantages.
  • FGF 2 fibroblast growth factor
  • a disc-shaped hydroxyapatite / collagen complex (hereinafter referred to as “HApZCo1”) plate having a diameter of 12 mm ⁇ 0.5 mm was used.
  • the HApZCo1 plate was allowed to stand in a phosphate buffer solution at 37 ° C for 24 hours. Subsequently, they were divided into two groups, an FGF 2 (-) group and an FGF 2 (+) group, and immersed in the following buffer solutions at 4 ° C for 72 hours.
  • FGF 2 (+) group ' ⁇ ⁇ Immerse in 5 ml of Tyrode + b FGF (20 ng / m 1) mixed solution.
  • the HA pZCo1 plate was removed from each solution and washed three times with pure Tyrode solution to remove FGF2 present on the surface (the third time was 45 minutes).
  • the cell suspension (cells: 5 X 1 0 3 or 1) were sown. Twenty-four hours later, the cells were transferred to a culture vessel having a diameter of 10 cm (one per one), and cultivation was performed using a medium volume of 2 Om1. Thereafter, the medium was replaced every two days. Five days after the cell seeding, the cells were stained with propyl acetate and observed with a confocal microscope. As a result, cells hardly grew in the FGF 2 (-) group containing no growth factor.
  • the sustained-release drug material of the present invention can be used in tissue engineering as a growth factor for controlling cell proliferation / differentiation and a tissue regeneration scaffold for providing a place for cell proliferation. In regenerative medicine, it is also used as a bone filling material containing growth factors and drugs that promote bone regeneration.

Description

明 細 書 生体内薬物徐放材料 技術分野
本発明は、 ハイドロキシアパタイトとコラーゲン （HApZC o l) ナノ複合 体からなる生体内薬物徐放材料に関する。 背景技術
現在までの一般的な薬剤徐放担体というものは、 例えば、 1) コラーゲンのよ うに水分を保持する能力の高い材質に、 薬剤を保持させ、 それが生体内に移植さ れることにより、 拡散し放出されるといったもの、 2) ポリ乳酸等の生体分解性 の生体材料に製造過程において薬剤を混合し、 その生体材料の分解とともに放出 されるといったもの等、 が一般的である。
上記の 1) のコラーゲンを基剤とする注射的な投与が可能な長期徐放性製剤が 知られている （特公平 5—12328号公報、 特公平 5— 71566号公報、 特 公平 6— 94418号公報、 特開平 8— 34747号公報） 。
また、 歯周組織における組織 ¾^生膜 （GTR膜） 、 止血剤、 骨補填剤、 軟骨補 填剤、 硬組織細胞の三次元培養基材として用いられるコラーゲンリン酸カルシゥ ム複合材料も知られている （特開平 6— 304242号公報） 。
この複合材料はコラーゲンとリン酸カルシウム化合物をリン酸カルシウム溶液 中で反応させた複合物を乾燥させて得られる。 また、. リン酸カルシウムとコラー ゲンの共沈を行った後、 得られた沈殿物を加圧成形することによって配向性の優 れた人工骨等として用いられる複合材料の製造方法 （特開平 1 1— 1 9 9 2 0 9 号公報） も知られている。 発明の開示
コラーゲンは水分保持能力が高く、 多量の薬剤溶液を保持したまま、 生体内に 移植でき、 さまざまなサイ ト力イン、 増殖因子等の担体として実験等に使用され てきた。 しかし、 コラーゲンやゼラチン等の含水性ゲル状物質を用いた増殖因子 の担体は、 移植後の薬剤放出速度が早く比較的短期間しかその効果を発揮できな いため、 それら単独の担体では多量の増殖因子を使用しなければならない。 また、 ハイ ドロキシァパタイ トは、 骨誘導性が高い生体材料として広く利用さ れ、 骨充填材を増殖因子の担体として使用する試みが数多くなされている。 また 、 ハイ ドロキシァパタイ トは非常に極性の強い結晶構造をとつておりタンパクや
D N Aと電気的に親和性が高く、 その結晶の表面に吸着することが知られており 、 生化学の分野では微結晶のハイ ドロキシアパタイ トがクロマトグラフィーの材 料として使用されてきた。
しかし、 クロマトグラフィ一に使用されるような微結晶では生体材料として使 用するには粉末状であり、 実用的ではない。 そのため、 焼結体等が生体材料とし て使用されているが、 これでは薬剤が吸着する面積が極端に減少してしまうため 、 薬剤の担体としては実用的ではない。 発明を実施するための最良の形態 HAp/C o 1複合体は、 ハイ ドロキシァパタイ トの微結晶とコラーゲンから なる複合体であり、 増殖因子の吸着に有効なハイ ドロキシァパタイ トの比表面積 が約 50〜30 Om2/g程度と非常に大きく、 かつ水分保持能力の高いコラー ゲンを含んでいるため、 多量の増殖因子を保持し得る。
そして、 高比表面積のハイ ドロキシアパタイ トと増殖因子は強く結合するため
、 増殖因子の放出速度が遅く、 生体内で長期的かつ局所的に増殖効果を持続でき る。 增殖因子以外に薬剤、 DN A等の電気的に極性を持つ物質であれば表面吸着 能が高くその徐放性担体としても利用できる。
すなわち、 本発明は、 リン酸溶液、 水酸化カルシウム溶液及びコラーゲン溶液 を一定の条件で反応させることにより共沈物として合成され、 比表面積 50〜 3 0 Om2ノ gのハイ ドロキシアパタイ ト （HAp) 結晶がコラーゲン （C o l ) 線維の周りに C軸方向に配向して複合化した HA p/C o 1ナノ複合体のハイ ド 口キシァパタイ ト表面、 コラーゲン表面および両者の水和水中に增殖因子、 DN A酵素等の生理活性物質、 薬剤を保持したことを特徴とする生体内薬物徐放材料 である。
また、 本発明は、 含水性の高いグリコサミノダリカン （ヒアルロン酸 · コンド ロイチン硫酸 ·ケラタン硫酸等） またはハイ ドロゲルなどを複合化することによ り増殖因子を封入した生体吸収性のカプセルとなることを特徴とする上記の生体 内薬物徐放材料である。
また、 本発明は、 生体内に注射的な投与が可能で注入後ゲル化することを特徴 とする上記の生体内薬物徐放材料である。
本発明に係わる HAp ZC ο 1複合体はハイ ドロキシァパタイ トとコラーゲン を複合することにより得られた生体材料である。 この HAp/C o 1複合体は、 水酸化カルシウムの懸濁液とコラーゲンを含んだリン酸水溶液を蒸留水に同時滴 下し共沈させ、 共沈物を加圧脱水して成形することにより合成される。
この方法で合成した HAp/C o 1複合体は、 HAp結晶が C o 1線維の周り に C軸方向に配向し複合化したナノ複合体である。 ハイ ドロキシアパタイ トの B ET法による比表面積が非常に大きく、 約 50〜30 Om2Zgである。 また、 HAp/C o 1複合体れに含まれるハイ ドロキシァパタイ トは結晶が小さい （ク 口マトグラフィ一に使用されるものと同等、 もしくはそれ以下） ため多量の薬剤 をその表面に吸着することができ、 かつコラーゲンに含まれた薬剤をも引き寄せ 、 その場にとどめる効果をもたらすことができる。
水分保持能力の高い材料と薬剤に親和性の高い材料を組み合わせることにより 、 薬剤の放出速度を遅くすることができ、 増殖因子を生体内で長期的にかつ局所 的に徐放できる。 本発明の薬物徐放材料は 2種類の材料を複合させることにより 薬剤担体としての問題点を補い合い、 長所を引き出し合っているといえる。
(実施例）
実施例 1
FGF 2 (繊維芽細胞増殖因子） 担体としての利用
直径 1 2mmX 0. 5 mmの円盤状のハイ ドロキシァパタイ ト/コラーゲン複 合体 （以下： 「HApZC o 1」 と記載） プレートを用いた。 HApZC o 1プ レートをリン酸バッファー溶液中で 37 °C、 24時間静置した。 続いて、 FGF 2 (―) 群と FGF 2 ( + ) 群の 2群に分け、 それぞれ下記のバッファー溶液に 4°C、 72時間浸潰した。 FGF 2 (― ) 群 · · · 5m lの Tyrode溶液 （血小板系免疫グロブリン検査用 緩衝溶液） に浸漬。 FGF 2 ( + ) 群 ' · · 5 m 1の Tyrode+ b FGF (20 n g/m 1 ) 混合溶液に浸漬。 各溶液から HA pZC o 1プレートを取り出し、 純粋な Tyrode溶液で 3回洗浄して表面に存在する FGF 2を除去した （3回目は 45分間） 。
その後、 6穴の培養プレートに HAp/C o 1プレートを置き、 その細胞浮遊 液 （細胞： 5 X 1 03個 1 ) を播種した。 24時間後、 1 0 c m径の培養容 器 （1個につき 1枚） に移し培地の量を 2 Om 1として培養を行った。 以降 2日 ごとに培地交換を行った。 細胞播種後 5日目に、 細胞をプロピルョードで染色し 、 共焦点顕微鏡で観察した。 その結果、 増殖因子を含まない FGF 2 (-) 群で は、 細胞がほとんど増殖しなかった。
一方、 増殖因子を保持した FGF 2 ( + ) 群では、 細胞の旺盛な増殖が認めら れた。 本複合体は FGF 2の徐放担体として優れた特性を示すことが明らかにな つた。 産業上の利用可能性
本発明の薬物徐放材料は、 組織工学において、 細胞の増殖 ·分化を制御する増 殖因子と細胞の増殖の場を提供する組織再生足場材料として利用できる。 また、 再生医学において、 骨再生を促進する増殖因子 ·薬剤等を含んだ骨充填材料とし ての用途も有する。

Claims

請 求 の 範 囲
1. 共沈物として合成され、 比表面積 50〜30
Figure imgf000008_0001
のハイド口キシァ パタイ ト （HAp) 結晶がコラーゲン （Co l) 線維の周りに C軸方向に配向し て複合化した HApZCo 1ナノ複合体のハイ ドロキシァパタイ ト表面、 コラー ゲン表面および両者の水和水中に増殖因子、 DN A酵素等の生理活性物質、 薬剤 を保持したことを特徴とする生体内薬物徐放材料。
2. 含水性の高いグリコサミノダリカンまたはハイ ドロゲルを複合化すること により増殖因子を封入した生体吸収性のカプセルとなることを特徴とする請求の 範囲第 1項記載の生体内薬物徐放材料。
3. 生体内に注射的な投与が可能で注入後ゲル化することを特徴とする請求の 範囲第 1項記載の生体内薬物徐放材料。
PCT/JP2002/008282 2001-08-30 2002-08-14 Matieres a liberation lente de medicament in vivo WO2003020316A1 (fr)

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US9724308B2 (en) 2010-09-10 2017-08-08 Fibralign Corporation Biodegradable multilayer constructs
US10065046B2 (en) 2010-07-15 2018-09-04 Fibralign Corporation Conductive biopolymer implant for enhancing tissue repair and regeneration using electromagnetic fields
US10086079B2 (en) 2008-08-11 2018-10-02 Fibralign Corporation Biocomposites and methods of making the same
US10238769B2 (en) 2011-10-11 2019-03-26 Fibralign Corporation Graft for directed vascular and lymphatic regeneration and methods to guide endothelial cell assembly
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