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。