抗血栓性 (antithrombogenicity)nagasaki_lab/nagasaki/download/10...モルホロジー (Morphology...
Transcript of 抗血栓性 (antithrombogenicity)nagasaki_lab/nagasaki/download/10...モルホロジー (Morphology...
抗血栓性 (antithrombogenicity)
Structure of Biomembrane
Glycoprotein
Protein
Glycolipid
Cholesterol
Phospholiipid
Heterogenicity
Feature of inner wall of blood vessel
Structure Chemical structure Phydical Structure Morphology Water
Multi-components(protein,lipid,sugar, etc.) Highly ordered, orientation, Multi-phase separated, Hydrogel, hydration
Physical property
Hydrophilic/hydrophobic Charge Surface energy Mobility Mechanical property
Amphiphilic Negative charge Large surface energy High mobility Fluidity, soft
Physiological function
Permiability Diagnostics Secretion phagocytosis
Highly selective, passive and active transport Short life-time of endotherial cells Production of very small amount of active compounds low
Antithrombogenic materials
Inert
Hybrid
Neoinitimal
•Low interfacial energy surface •High water content, •Microphase separation
•Anti-coagulation agent immobilized surface •thrombolytic drug
•Neoinitimal surface formation •Organization of lipids on a surface
Phisicochemical design
Biochemical design
Biological design
血小板の粘着 Adsorption of platelet C3補体価 Activation of Complement Ca++イオン濃度 Concentration of Calc ium ion リンホカイン産生能 Lymphokine production
coagulation system
Activation of complement
Adsorption of platelet
Resp
onse
fro
m liv
ing b
ody
hydropho- polarity ionic
bicity acceptor donor OH anionic
cationic dispersion hydrogen bond coulomb force
生体適合性材料の設計 (Design of Biocompatible Materials)
1.ハイドロゲル
2.モルホロジー制御
3.生理活性物質固定
4.血管新生内膜形成
5.新しい材料
1. Hydrogel
2. Morphology
3. Immobilization of bioactive compounds
4. Neoinitimal surface formation
5. New polymers
ハイドロゲル(hydrogel)
血漿タンパクの吸着を抑制さ
せる
↓
ポリマー/水コンポジット
血中の血小板の減尐
↓
血中に微尐血栓の可能性
ハイドロゲル→水が多ければ血
中と同じで良い?(水の構造)
運動性が高い→柔らかくて細胞
つきにくい?
hydrogel→water content
improve biocompatibility?
High mobility→Soft surface
prevent cell adsorption ?
Suppression of serum proteins
↓
Polymer/water
Decrease in platelets in blood
stream
↓
Polymer/water
hydrogel
血漿タンパクの吸着を抑制さ
せる
↓
ポリマー/水コンポジット
血中の血小板の減尐
↓
血中に微尐血栓の可能性
ハイドロゲル→水が多ければ血
中と同じで良い?(水の構造)
運動性が高い→柔らかくて細胞
つきにくい?
hydrogel→water content
improve biocompatibility?
High mobility→Soft surface
prevent cell adsorption ?
Suppression of serum proteins
↓
Polymer/water
Decrease in platelets in blood
stream
↓
Polymer/water
Relation between surface graft content of hydrophilic polymers
and platelet concentration in blood stream
HEMA: 2-hydroxyethyl methacrylate
EMA: ethyl methacrylate
AAm: acrylamide
MAAC: methacrylic acid
surface graft content
Pla
tele
t co
nte
nt
in b
lood
Surface
modification
TEM of hollow fiber
surface 10 min after
blood contact
A: atelocollagen,
B:methylation,
C:succinylation
表面ブラシモデルの提案
(Mechanism of surface
brush)
1.動的構造(mobility)
2.エントロピー弾性(entropic elasticity)
3.No binding site
PEGブラシ(PEG tethered chain surface)
Protein
Material
surface
ポリエチレングリコール表面
(PEG tethered chain surface)
A: n=4
B: n=23
C: n=100
-(CH2 CH2 O)n-
モルホロジー
(Morphology control)
„73今井ら、ポリマーブレンドやブロックコポリマー表面の相分離と抗血栓性
Imai, Microphase separation of polymer blend and block copolymer surface plays an important role for anti-thrombogenicity
„75Lymanら、セグメント化ポリウレタン(SPU)のポリエーテルセグメント(ソフトセグメント)鎖長と血小板粘着の関係→ミクロ相分離の予測
Lyman, Segmented poly(urethane) (SPU) shows high blood compatibility. He proposed microphase separation of this material.
„クラレ高倉ら、ポリ(2-ヒドロキシエチルメタクリレート)グラフトポリスチレン、PMMA/PHEMA
Takakura, poly(2-hydroxyethyl methacrylate)-g-polystyrene (PHEMA-g-PSt)
„82、片岡、岡野ら、ポリ(2-ヒドロキシエチルメタクリレート)-b-ポリスチレン
Kataoka, Okano, PHEMA-b-PSt
Microphase separation of block copolymer as a function of the composition
A Sphere A cylinder A,B lamellae B cylinder B sphere
Increase in A component
Decrease in B component
セグメント化ポリエーテルウレタンウレア Segmented poly(ether urethane urea)
SPUU
poly(ether) urethane urea
hard segment hard segment soft segment
Hard segment •strong hydrogen bond •Hard benzene ring
Soft segment •Soft polyether chain
Poly(HEMA-b-styrene)
-(CH2CH)m- (CH2C(CH3 ))n-
COOCH2 CH2OH
相分離構造
Bypass of the aorta- the coronary arteries
by
Polystyrene-b-PHEMA
Lymphocyte adhesion
A:polyamine graft
polystyrene copolymers B:polystyrene C:polyamine
Membrane protein
Homogeneous surface
Membrane protein
activation
cell cell
Heterogeneous surface
cell
Suppression of assembling of membrane proteins
Suppression of activation
Proposal of suppression of cell activation by “Capping Control Model” on micsophase separated surface (Kataoka, 1988)
Miceophase separation of PPO-
Nylon 610
ナイロン610:ヘキサメチレンジアミン(炭素数6)+ セバシン酸(炭素数10)
PPO:ポリプロピレンオキシド
Nylon 610:polycondensation of hexamethylenediamine (n=6) + sevacic acid (n=10)
PPO:poly(propylene oxide(¥)
Adsorption of platelets on miceophase separated PPO-Nylon 610 surface
A: TEM B: adsorption of platelets on Nylon 610 surface
C: adsorption of platelets on PPO-Nylon 610 surface
生理活性物質固定
(Immobilization of bioactive compounds)
•プロスタグランジン: 血小板活性化抑制
Prostaglandin: Suppressor of platelet activation
•ヘパリン: 血液凝固因子活性化抑制剤
Heparin: a highly-sulfated glycosaminoglycan, is widely used as an
injectable anticoagulant, and has the highest negative charge density of
any known biological molecule.
•ウロキナーゼ: 血栓溶解剤
Urokinase: Activation of plasmin triggers a proteolysis cascade which,
depending on the physiological environment participate in
thrombolysis or extracellular matrix degradation.
ヘパリン:
内因系凝固因子過程のみ有効→血小板の効果は明らかでない→アンチトロンビンIIIとの分子複合体→トロンビン酵素活性の阻害→フィブリンクロット構築阻害
Heparin binds to the enzyme inhibitor antithrombin (AT) causing a conformational change that results in its activation
through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other
proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can
increase by up to 1000-fold due to the binding of heparin.
Heparin
highly-sulfated glycosaminoglycan
Example: pentarmer
ヘパリンカテーテル (丹沢ら)
塩ビにPEG+AMAグラフト重合 ヘパリンをイオン結合によって担持
親水性ヘパリン化チューブ(hydrophilic heparinized tube:H-PSD)
Heparin catheter (Tanzawa, Toray)
Graft copolymerization of PEG
and AMA on
poly(chloroethylene)
Heparin is immobilized by
electrostatic interaction
blood
vein
Heparin release
blood Heparin release
Physiological saline
H-PSD(percutaneous stricture dilation) catheter
新生内膜形成
(Neoinitimal formation )
ポリエステル人工血管埋入試験
植え込み直後に抗血栓性がないため
に赤色血栓が生じる
1705日後には新生
内膜に覆われ、乳白色をしている。
Implantation tests of polyester artificial blood
vessel
The surface was covered by red
thrombus just after the implantation due to the no antithrombogenicity
of polyester surface.
The surface was covered by neointimal with milk-white color
after 1705 d.
新しい高分子材料 (New Polymers)
ポリ[2-(メタクリロイルオキシ)エチルホスホリルコリン] (Poly[2-(methacryloyloxy)ethyl phosphorylcholine)
-(CH2C(CH3))n- COOCH2CH2OPOCH2CH2N+(CH3) 3
O
O-
ポリ(アクリル酸2-メトキシエチル) Poly(2-methoxyethyl acrylate)
-(CH2CH)n- COOCH2CH2OCH3
-(CH2C(CH3))n- COOCH2CH2OH
Poly(HEMA)
-(CH2CH)n- OH
PVA
-(CF2CF2)n-
PTFE
-(CH2CF2)n-
PVDF CH3
-(SiO)n- CH3
Silicone
Mole fraction Mole fraction
Tissue engineering
Defect part
Scaffold
Materials in addition to scaffold 1.Cells 2.Growth factor 3.Gene Biodegradable polymers are usually employed as scaffold
Repaired tissue
Culture media
Immune isolation
film
Art. pancreas Art. liver
バイオマテリアルの一例 (Example of Biomaterials)
人工透析のQOL
Quality of life in Hemodialysis
腎臓の働き(Kidney)
1. 老廃物の排泄(Excretion of body wastes)
2. 水分の調節(Control of water content)
3. 電解質の調節(Control of an electrolyte)
4. ホルモンの分泌、ビタミンDの活性化(secretion of hormone, activation of vitamin D)
老廃物の排泄
主に蛋白質の代謝産物が腎臓より排泄される。
腎機能を知るために、通常、血液生化学検査を施行するが、特に次に述べるBUN,Crが腎機能を知るための代表的な物質である。
• BUN(血液尿素窒素):食事由来の蛋白質の最終代謝産物(外因性蛋白質)
• Cr(クレアチニン):筋肉由来の蛋白質の最終代謝産物(内因性蛋白質)
通常、腎機能が低下すると、血中のBUN,Crが、共に上昇する。通常、その比は、10:1前後であるが、蛋白制限が守られていると、外因性蛋白質の代謝産物であるBUNは低下し、両者の比は5:1前後に低下する。また、比が10:1以上を示す場合は脱水、消化管出血、飢餓状態等を考えなくてはならない。