Structure of Biomembranenagasaki_lab/nagasaki/download/09...Feature of inner wall of blood vessel Structure Chemical structure Multi-components(protein,lipid,sugar, t) Phydical Structure

Heterogenicity

Glycoprotein

Protein

Glycolipid

Cholesterol

Phospholiipid

Structure of Biomembrane

Feature of inner wall of blood vessel

Structure Chemical structure Multi-components(protein,lipid,sugar, t )

Phydical StructureMorphologyWater

etc.)Highly ordered, orientation,Multi-phase separated,Hydrogel hydrationWater Hydrogel, hydration

Physical property

Hydrophilic/hydrophobicCharge

AmphiphilicNegative charge

Surface energyMobilityMechanical property

Large surface energyHigh mobilityFluidity, soft

Physiological function

PermiabilityDiagnosticsSecretion

Highly selective, passive and active transportShort life-time of endotherial cellsProduction of very small amount of active

phagocytosiscompoundslow

Antithrombogenic materialsAntithrombogenic materials

Inert•Low interfacial energy surface•High water content, Microphase separation

Phisicochemical design•Microphase separation

•Anti-coagulation agent i h i l d iHybrid

g gimmobilized surface•thrombolytic drug

Biochemical design

Neoinitimal•Neoinitimal surface formation•Organization of lipids on a surface

Biological design

coagulation tg

body

血小板の粘着Adsorption of platelet

補体価

system

from

livi

ng

C3補体価Activation of ComplementCa++イオン濃度 Activation of

l tResp

onse

f

Concentration of Calcium ionリンホカイン産生能

complementR

リンホカイン産生能Lymphokine production Adsorption

of platelet

hydropho- polarity ionicbicity acceptor donor OHanionic cationicdispersion hydrogen bond coulomb force

生体適合性材料の設計生体適合性材料の設計（Design of Biocompatible Materials)g p )

1.ハイドロゲル 1. Hydrogel

2 M h l2.モルホロジー制御

2. Morphology

3. Immobilization of

3.生理活性物質固定

3. Immobilization of bioactive compounds

4 N i iti l f4.血管新生内膜形成

4. Neoinitimal surface formation

5.新しい材料 5. New polymers

ハイドロゲル(hydrogel)

ハイドロゲル→水が多ければ血

中と同じで良い？（水の構造）

hydrogel→water content

improve biocompatibility?

Hi h bilit S ft f運動性が高い→柔らかくて細胞

つきにくい？

High mobility→Soft surface

prevent cell adsorption ?

血漿タンパクの吸着を抑制さSuppression of serum proteins血漿タンパクの吸着を抑制さ

せる

↓

Suppression of serum proteins

↓

ポリマー／水コンポジットPolymer/water

血中の血小板の減少

↓

Decrease in platelets in blood

stream

血中に微少血栓の可能性↓

Polymer/water

hydrogel

od

ハイドロゲル→水が多ければ血

中と同じで良い？（水の構造）

hydrogel→water content

improve biocompatibility?

Hi h bilit S ft f

in b

loo

運動性が高い→柔らかくて細胞

つきにくい？

High mobility→Soft surface

prevent cell adsorption ?

con

ten

t

血漿タンパクの吸着を抑制さSuppression of serum proteins atel

et c

血漿タンパクの吸着を抑制さ

せる

↓

Suppression of serum proteins

↓P

la

ポリマー／水コンポジットPolymer/water

Relation between surface graft content of hydrophilic polymers

d l l i i bl d

surface graft content

血中の血小板の減少

↓

Decrease in platelets in blood

stream

and platelet concentration in blood stream

HEMA: 2-hydroxyethyl methacrylate

EMA: ethyl methacrylate血中に微少血栓の可能性↓

Polymer/waterAAm: acrylamide

MAAC: methacrylic acid

Surface modification

TEM of hollow fiber f 10 i ftsurface 10 min after blood contact

A: atelocollagenA: atelocollagen,

B:methylation,

C:succinylation

PEGブラシ(PEG tethered chain surface)

表面ブラシモデルの提案

(Mechanism of surface brush)

1 動的構造( bilit )1.動的構造(mobility)

2.エントロピー弾性(entropic elasticity)

Protein

(entropic elasticity)

3.No binding site

Material surface

ポリエチレングリコール表面ポリエチレングリコ ル表面(PEG tethered chain surface)

-(CH2 CH2 O)n-

A: n=4A: n 4B: n=23C 100C: n=100

モルホロジー(M h l t l)(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-thrombogenicitysurface 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

L S t d l ( th ) (SPU) h hi h bl dLyman, 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

Mi h ti f bl k lMicrophase separation of block copolymer as a function of the composition

A Sphere A cylinder A,B lamellae B cylinder B spherecylinder 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)Segmented poly(ether urethane urea)

SPUUpoly(ether) urethane urea

hard segment hard segmentsoft segment

Hard segment•strong hydrogen bond•Hard benzene ring

Soft segment•Soft polyether chain

Poly(HEMA-b-styrene)

(CH CH) (CH C(CH ))-(CH2CH)m- (CH2C(CH3 ))n-COOCH2 CH2OHCOOCH2 CH2OH

相分離構造

Bypass of the aorta- the coronary arteriescoronary arteries

by

Polystyrene-b-PHEMA

LymphocyteLymphocyte adhesion

A:polyamine graftA:polyamine graft polystyrene copolymers

B:polystyreneB:polystyreneC:polyamine

Homogeneous surfaceMembrane protein Membrane protein

cell cell

activation

Heterogeneous surfaceHeterogeneous surface

cell

Suppression of activation

cell

Suppression of assemblingSuppression of assembling of membrane proteins

Proposal of suppression of cell activation by “Capping Control Model” on micsophaseseparated surface (Kataoka, 1988)

Miceophaseseparation of PPOseparation of PPO-

Nylon 610y

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

O l 6 0 fPPO-Nylon 610 surface

A: TEMB: adsorption of platelets onB: adsorption of platelets on Nylon 610 surface

C: adsorption of platelets onC: adsorption of platelets on PPO-Nylon 610 surface

生理活性物質固定( bili i f bi i d )(Immobilization of bioactive compounds)

•プロスタグランジン： 血小板活性化抑制•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

k bi l i l l lany known biological molecule.

•ウロキナーゼ： 血栓溶解剤

Urokinase: Acti ation of plasmin triggers a proteol sis cascade hichUrokinase: 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.

HeparinHeparinhighly-sulfated glycosaminoglycang y g y g y

E l tExample: pentarmer

ヘパリンカテーテル(丹沢ら)

塩ビにPEG AMAグラフト重合塩ビに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)親水性ヘパリン化チューブ(hydrophilic heparinized tube:H-PSD)

Heparin catheterp(Tanzawa, Toray)

G f l i i f PEGGraft copolymerization of PEG and AMA on poly(chloroethylene)

Heparin is immobilized by electrostatic interaction

bl d

vein

H i lblood Heparin release

Physiological saline

blood Heparin release

H PSD(percutaneous stricture dilation) catheterH-PSD(percutaneous stricture dilation) catheter

新生内膜形成新生内膜形成(Neoinitimal formation )(Neoinitimal formation )

ポリエステル人工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 乳白内膜に覆われ、乳白色をしている。

Implantation tests of polyester artificial blood po yeste a t c a b ood

vessel

The surface wasThe surface was covered by red

thrombus just after the i l t ti d t thimplantation due to the no antithrombogenicity

of polyester surface.

The surface was covered by neointimalwith 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

Poly(HEMA) PVA PTFE PVDFCH

Silicone

-(CH2C(CH3))n-COOCH2CH2OH

-(CH2CH)n-OH

-(CF2CF2)n- -(CH2CF2)n-CH3

-(SiO)n-CH3

Mole fraction Mole fraction

Tissue engineeringDefect part

Culture media

Scaffold

Materials in addition to scaffold1.Cells2 G h f2.Growth factor3.GeneBiodegradable polymers are usually employed as scaffold

Immune isolation

film

Repaired tissue Art. pancreas Art. liver