Biopolymer Phu 2

CC KHI NIM
POLYMER SINH HC
C ngun gc t cc qu trnh bin
n sinh hc: nm mc, vi khun,
C kh nng phn hy sinh hc.
C kh nng ng dng trong nhiu
lnh vc.

Chng 1
CC KHI NIM
POLYMER Y SINH
Tiu chun i mt polymer l polymer y sinh?

Polymer conc ( microgram/mL)
0 20 40 60 80 100 120
R
e
l
a
t
i
v
e

c
e
l
l

v
i
a
b
i
l
i
t
y

(
%
)
0
20
40
60
80
100
120
PEI
PEG 1.50K; PCL/PEG 1.5/1; PAE 1.3K
PEG 1.75K; PCL/PEG 1.5/1; PAE 1.25K
*Cell line: NIH 3T3 (fibroblast)
*Growth medium: DMEM
(90% Dulbeccos modified
Eagles medium, 10% fetal
calf serum, penicillin 100
units/mL, streptomycin
100 g/mL).
* XTT assay
(XTT :2,3-bis(2-methoxy-
4-nitro-5-susfophenyl)-
2H-tetrazolium-5-carbox
anilide)
* 96-well plates, incubator.
Microplate reader.

Cytotoxicity of PAE-PCL-PEG-PCL-PAE
CC KHI NIM
POLYMER Y SINH
Tiu chun i mt polymer l polymer y sinh?

Sol state
(pH 8.0, Room temperature)
Injection to Rat
Gel formation after minutes
Injected sites
Cytotoxicity of PAE-PCL-PEG-PCL-PAE
POLYMER Y SINH
Ngun gc ca polymer y sinh: Poly mer
tng hp.

CC KHI NIM
POLYMER Y SINH
Ngun gc ca polymer y sinh: polymer
thin nhin
CC KHI NIM
POLYMER Y SINH
nhn to,
CC KHI NIM
POLYMER Y SINH
sinh hc,

CC KHI NIM
POLYMER Y SINH
C kh nng phn hy sinh hc hoc khng.

CC KHI NIM
POLYMER Y SINH
ng dng ch yu trong ngnh y sinh.

Cht mang dc phm.

Cc loi c quan thay th.
Cc loi KIST phn tch, nh gi nh lng

CC KHI NIM
Tumor tissue
(pH <> 7.4)
POLYMER Y SINH
Cc loi c quan thay th.

CC KHI NIM
POLYMER Y SINH
Cc loi KIST phn tch, nh gi nh lng

CC KHI NIM
12
Polymer phn hy
Chng 2
13
S pht trin ca vt liu polymer
14
Qu trnh phn hy polymer
polymer nguyn sinh
Phn r
Ha mn
Phn hy
Cc vi sinh ch c th tiu ho cc
hidrocarbon khi khi lng phn t nh
hn 500
15
16
(a)
Bulk-eroding system

(b)
Surface-eroding
system
17
Thi gian phn hy

Si Cotton 1-5 thng
Giy 2-5 thng
Dy thng 3-14 thng
V tri cam 6 thng
Mt hng len 1 n 5 nm
u thuc l 1 n12 nm
Hp ng sa trng nha 5 nm
Bao nha 10 n 20 nm
Vi nylon 30 to 40 years
Lon nhm 80 to 100 years
Chai thy tinh 1 triu nm
Chai nha > 1 triu nm
18
19
Phn loi polymer phn hy
polymer thin nhin:
Polysaccharides (Td., tinh bt, cellulose, lignin, chitin)
Proteins (Td., gelatine, casein, wheat gluten, silk and
wool)
Lipids (Td., du castor v m ng vt)
polyesters produced by micro-organism or by plants
(e.g., polyhydroxy-alcanoates, poly-3-hydroxybutyrate)
polyesters synthesised from bio-derived monomers
(polylactic acid)
Cc loi khc (natural rubbers, composites).
20
polymer nhn to:
PHA: Poly-hydroxy-alkanoate
PHB: Poly-hydroxy-butyrate
PHB-PHV: Poly (hydroxybutyrate-
hydroxyvalerate)

21
polymer tng hp
Aliphatic polyesters (Td., polyglucolic acid,
polybutylene succinate, polycaprolactone)
Aromatic polyesters or blends of the two types
(Td., polybutylene succinate terephthalate)
Polyvinylalcohols
Polyolefins bin tnh (polyethylene or
polypropylene bin tnh vi cc cht nhy
nhit, nhy nh sng)
22
polymer IM E E-
Blow
E-
Casting
Blow TM Fiber
spining
Tinh bt X X X X
Celluloz X X X
PHB X X X X X X
PHB-PHV X X X X X X X
PLA X X X X X
PBS X
PCL X X X X X X
PBST X X X X
PBAT X X X
PTMAT X X X X
PVA X X X X X
PP, PE + X X X X X X X
Tinh bt + PVA X X X X X
Tinh bt + CA X X X X X
2005, Woodhead Publishing Limited
23
PHA: Poly-hydroxy-alkanoate
PHB: Poly-hydroxy-butyrate
PHB-PHV: Poly (hydroxybutyrate-hydroxyvalerate)
PCL: Poly -caprolactone
PLA: Poly Lactic Acid (Polylactide)
PGA: Poly glucolic Acid
PBST: Poly Butylene Succinate Terephthalate
PBAT: Poly Butylene Adipate terepthalate
PTMAT: Poly TetraMethylene Adipate Terephthalate

24
Tg ( C) Tm ( C) TS (MPa)
Modulus
(MPa)
E (%)
LDPE -100 98 115 8 20 300 500 100 1000
PCL -60 59 64 4 28 390 470 700 1000
Tinh bt - 110 115 35 80 600 850 580 820
PBAT -30 110 115 34 40 500 800
PTMAT -30 108 110 22 100 700
PS 70 115 100 34 50 2300 3300 1.2 2.5
Cellulose - - 55 120 3000 5000 18 55
PLA 40 70 130 180 48 53 3500 30 240
PHB 0 140 180 25 40 3500 5 8
PHA -30 10 70 170 18 24 700 1800 3 25
PHB-PHV 0 30 100 190 25 30 600 1000 7 15
PVA 58 85 180 230 28 46 380 530 -
CA - 115 10 460 13 15
PET 73 80 245 265 48 72 2800 4100 30 300
PGA 35 40 225 230 890 7000 8400 30
PEA -20 125 190 25 180 220 400
25
Cc tc nhn gy phn hy
C hc.
Nhit
nh sng
Ha hc
Tc nhn khc
Vi sinh
26
Cc yu t nh hng n tc
phn hy
bn ca ni ha hc
Tnh a nc ca vt liu polime
Hiu ng lp th ca phn t
Cc sn phm ph c tc dng t xc tc
Vi cu trc phn t: kt tinh, v nh hnh,
xp
27
Phng php v tiu
chun kim nghim
Chng 3
28
Mt s tiu chun
Tiu chun ISO 472
Nha phn hy sinh hc: L loi nha c s
thay i ng k cu trc ha hc trong iu
kin mi trng c trng a n gim mt
s tnh cht c th o lng c theo cc
phng php kim nghim chun dnh cho
nha v sn phm nha trong khong thi
gian xc nh ca loi ny. S thay i cu
trc l kt qu ca tc ng ca cc vi sinh vt
c trong thin nhin
29
Tiu chun DIN FNK102.3
Nha phn hy sinh hc: Vt liu nha c
gi l phn hy sinh hc nu tt c cc hp
cht hu c ca n u tri qu qu trnh
phn hy phn hy sinh hc hon ton. iu
kin mi trng v tc phn hy sinh hc
c xc nh bi cc phng php kim
nghim chun
S phn hy sinh hc: Phn hy sinhh hc l
qu trnh gy ra bi hot ng sinh hc lm
thay i cu trc ha hc cho ra cc sn phm
bin dng t nhin
Mt s tiu chun
30
Tiu chun ASTM D 20-96
Nha phn hy sinh hc: Nha trong s
phn hy l kt qu ca tc ng ca cc vi
sinh nh vi khu, nm, mc, to
Tiu chun Japanese Biodegradable
Plastics Society
Nha phn hy sinh hc: vt liu nha m qu
trnh bin i thnh cc hp cht thp phn t
t nht c mt giai on trong s gim cp
thng qua qu trnh bin dng bi s hin
din ca cc sinh vt c trong t nhin
Mt s tiu chun
31
Tiu chun CEN
Nha phn hy sinh hc: L vt liu phn hy
trong qu trnh phn hy l kt qu ca tc
ng ca vi sinh, cui cng vt liu chuyn
thnh nc, CO
2
v/hoc metan v sinh khi
mi
S phn hy sinh hc: L s phn hy gy ra
bi hot ng vi sinh, c bit bi tc ng
enzym a n s thay i ng k cu trc
ha hc ca vt liu

Mt s tiu chun
32
Trong cc cc nh ngha ny
thng khng cp n mi
trng v khung thi gian m cc
yu t ny c xc nh bi tiu
chun phng php

33
34
Cc phng php nh gi chun da
phi trn nh ngha v s phn hy sinh
hc no c xem xt.
Tiu chun ISO da trn s thay i ha hc
ca vt liu do vi sinh (t.d. s oxi ha)
Tiu chun CEN v DIN th nh ngha da
trn s bin i nha thnh cc sn phm do
bin dng vi sinh
Mt s nh ngha khc da trn tnh bn cht
phn hy sinh hc hay s suy gim khi lng
phn t n gia tr no
35
Cc phng php th nghim
Nguyn tc th nghim
Th nghim polime phn hy c chia lm 3
nhm
36
Th nghim ti hin trng: th d chn trong
t, b xung sng hoc th nghim trong cc
nh my phn hy rc.
Khng kim sot c iu kin mi trng th
nghim nh nhit , m, pH
Kh nng theo di s phn hy b gii hn. Thng
ch nh gi s thay i c thy c trn vt liu
hoc s phn r ca vt liu hay s thay i khi
lng
Kh khn khi phn tch cc sn phm trung gian hay
phn cn cn li v mi turng phc tp khng xc
nh c
S phn r thun vt l khng c xem l phn
hy sinh hc
37
Th nghim m phng:
c tin hnh ti PTN thc hin trong cc bnh
phn ng, mc d mi trng gn ging vi hin
trng nhng c th kim sot v iu chnh c
cc thng s bn ngoi (nhit , m, pH .)
C th s dng cc cng c kim nghim tt hn
ngoi hin trng (t.d. phn tch cn, sn phm
trung gian, CO
2
gii phng hay O
2
tiu th)
i khi c th gia tc qu trnh phn hy rt ngn
thi gian th nghim
38
Th nghim ti PTN
Mi trng th nghim l mi trng nhn to
S dng dng vi sinh xc nh hoc hn hp dng
vi sinh ty theo vt liu s dng
Tc phn hy nhanh hn iu kin t nhin
Thch hp khi mun kho st c ch phn hy
Kh ngoi suy tc phn hy trong mi trng t
nhin
Tnh lp li cao.
C th ch dng enzym tng thch vi polime kim
nghim tng tnh lp li v kim sot d dng th
nghim phn hy. Tuy nhin khng xc nh
cs phn hy do bin dng

39
Mi trng th nghim
40
iu kin th nghim
41
Th nghim enzym
Polime c cho vo bnh phn ng c kim sot
pH cha mt hay vi loi enzym. Th nghim thch
hp kho st qu trnh gim cp polime hoc cc
oligome hay monomer tch loi khi mch polime
trong iu kin th nghim.
Qu trnh xy ra nhanh (vi pht n vi gi)
Khng xc nh c tc v c ha.
Khng th dng sng chn polime v enzym ch
c th kt hp vi vi loi polime
Lu hot tnh ca enzym khi khng tinh khit hoc
iu kin tn tr, iu kin mi trng khng ph
hp.
42
Th nghim b mt.
Tm vt liu c t trn b mr ca mi trng
agar cha mui khong khng co ngun carbon.
Sau c phun mt chng loi nm hay mc xc
nh. Trong tng khong thi gian nht nh xc
nh lng nm mc pht trin trn b mt vt liu
Th nghim ch cc nh c nm mc c th pht
trin trn b mt vt liu nhng khng ni ln vt
liu c phi b phn hy vi sinh hay khng v nm
mc c th s dng cc ngun hu c khc trong
vt liu m khng phi l polime.
43
Th nghim h hp
Hot ng vi sinh hiu kh th hin s tiu th oxy.
Lng oxy tiu th trong qu trnh nhn ging c
gi l nhu cu oxy sinh ha (BOD: Biochemical
Oxygen Demand) c s dng nh gi qu
trnh phn hy vi sinh
Ngoi ra cn c cc phng php da trn vic xc
nh nhu cu oxy l thuyt (TOD: Theoretical
Oxygen Demand) hoc nhu cu oxy ha hc (COD:
Chemical Oxygen Demand)
Th nghim BOD d xc nh nhng rt nhy
thng dng lm th nghim sng chn. Khng s
dng c trong iu kin ym kh
44
Th nghim gii phng kh (CO
2
hay CH
4
)
S gii phng CO
2
hay CH
4
l thng s biu th qu
trnh v c ha. Do thng dng xc nh kh
nng phn hy ca polime.
C nhiu phng php xc nh nh th nghim
Sturm, th nghim ha mn, th nghim bn hot
tnh yn kh
45
46
47
48
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44
% C conversion to CO2
time (d)
lag-phase plateau phase
level of biodegradation = 65%
degradation phase
O2
Sea
water &
Test
Materials
CO
2

Measuring Biodegradation
% Carbon dioxide evolution = % Biodegradation
49
50
Phng php th nghim trong mi trng
lng
51
52
Phng php th nghim trong t
53
Phng php nh gi
nh gi b mt.
S thay i b mt
S thay i tnh cht b mt
54
nh gi s gim khi lng.
Tc gim khi lng
T l gim khi lng
55
56
57
58
nh gi c tnh:
bn chu lc
bin dng.
Phng php o c tnh khng th hin thc
qu trnh phn hy sinh hc v phng php
o c tnh th hin tnh cht tng th cn phn
hy sinh hoc l s bo mn b mt

59
nh gi khi lng phn t
S gim khi lng phn t
S thay i a phn tn.
Ch s MI
GPC l mt phng php nh gi khi lng
phn t chnh xc hn ch s MI
60
Phng php cn bng carbon
Phng php s dng carbon nh du C
14

tnh lng carbon trong vt liu v carbon trong
cc thnh phn phn hy. Carbon trong CO
2
c
xc nh bng u d IR. Carbon ha tan c
xc nh bng COD. Phn carbon trong sinh khi
v cn c tch khi dung dch v c phn
lp bng Natri hiposulphit.
Phng php o t tn thi gian. Hiu qu trong
kho st tnh phn hy ca polime.
Tuy nhin phng php phc tp v tnh khng
an ton ca ng v phng x
61
7.4. Phng hng pht trin
phng php kim nghim
Polime phn hy sinh hc c s dng
nhm gim nhim mi trng. Do cn
c cc nh gi tc ng ca cc loi vt
liu ny n mi trng.
Nhiu tiu chun quc t bo v mi
trng c ra DIN 54900, ASTM
D6002:1996 v EN 13432
62
Cc tiu chun ny tuy khc nhau v chi
tit nhng cng c s th nghim 4 bc
nh gi kh nng phn hy ca polime trn
c s thnh phn ha hc v khng c cc
ph gia c cho l c hoc c hi cho mi
trng (t.d. kim loai nng)
Xc nh kh nng phn hy bi tc ng vi
sinh v inh lng nhu cu oxy hoc lng
CO2 (hoc CH4) thi ra trong thi gian
qu trnh v c ha hon ton
63
Xc nh phn r trong iu kin thc hay
iu kin m phng hoc iu kin phn hy
ym kh bng phng php nh lng.
Nghin cu cht lng ca mn t qu trnh
phn r bng cch phn tch cc thng s ha,
l v xc inh tc ng n mi trng trn c
s cy trng.
64
65
66
67
C ch phn hy Polymer
Chng 4
68
Phn hy do tc dng c hc
Cc lc tc dng: ko, nn, x, trt, Ct trn mch C

+
+
69
+
*
*
Ct trn mch C:Tch loi nhnh. Td. PVC;
Ct ngu nhin. Td. PE
70
+
*
*
Ct ngu nhin. Td. PE
71
+
*
*
*
Ct ngu nhin. Td. PE
72

S phn hy ty theo tnh khng iu ha
ca cu trc phn t polime.
Tc phn hy c gia tng khi c hin
din ca nhng cht gi l cht tng hot.
Hai loi thng dng l: nhm carbonyl v
phc kim loi
Phn hy do tc dng Quang, T, siu m,
nhit
73
Nhm carbonyl
Ceton carbonyl copolime: Td. Thm vinyl ceton
comonomer vo cc polime nh PE, PS.
Copolime s phn hy khi phi sng do cc nhm
carbonyl hp thu nh sng.
Cc polime ny ch phn hy khi c nh sng nn p
dng thch hp trong cc mng nng nghip
Carbon monoxid copolime: thm nhm CO vo
polime. Copolime cung c kh nng phn hy khi
phi sng
nhit
74
nhit
Ct ngu nhin. Td. PE
+
*
*
75
+
+
Phn hy do tc dng Quang, T, siu m
Ct ngu nhin. Td. PE
76
Phn hy do tc dng Quang, T, siu m
+
*
*
Ct ngu nhin. Td. PE
77
nhit
+
*
*
*
Ct ngu nhin. Td. PE
78
Gii trng hp (depolymerization): Td. PMMA, PS (phn hy nhit)
nhit
O
O
O
O
79
Ct d mch ti v tr yu
nhit
X
R
2
X = N, S, P..
XHx
XHx
R2
*x
*
80
Phn hy do tc nhn oxy ha
Qu trnh ct mch xy ra gia mch
phn t
Qu trnh khi u vi s oxi ha v tr
hot tnh cao ca mch phn t polime,
hnh thnh cc hidroperoxid.
Cc hidroperoxid b phn hy to thnh
cc gc t do v din bin ct mch phn
t polime.
Qu trnh t oxy ha ct mch
81
Phc kim loi
Phc kim loi s khi mo qu trnh oxi ha
ct mch.
Loi polime ny c kh nng phn hy ngay
c khi khng c nh sng sau khi nhn
nh sng trc khi chn t.
Nhc im ca loi ny l khi pht tn kim
loi c vo mi trng khi polime phn hy.
82
83
84
85
C ch oxi ha ct mch ca PP
86
Thy phn ha hc
Cc yu t nh hng n tc phn
hy
bn ca ni ha hc
Tnh a nc ca vt liu polime
Hiu ng lp th ca phn t
Cc sn phm ph c tc dng t xc tc
Vi cu trc phn t: kt tinh, v nh hnh,
xp
87
Thy phn ha hc
88

Sebacic Acid
Hydrophobicity
Thy phn ha hc
89
Thy phn ha hc
90
Carbonyl bond to
O
N
S
R
1
C X
O
R
2
O H
2
R
1
C OH
O
+
HX R
2
X= O, N, S
R
1
C O
O
R
2
Ester
R
1
C NH
O
R
2
Amide
R
1
C S
O
R
2
A.
Thioester
Thy phn ha hc
91
X C X'
O
R
2
R
1
O H
2
+
HX' R
2
X C OH
O
R
1
X v X= O, N, S
B.
O C O
O
R
2
R
1
NH C O
O
R
2
R
1
NH C NH
O
R
2
R
1
Carbonate
Urethane
Urea
C.
R
1
C X
O
C
O
R
2
O H
2
+
R
1
C OH
O
HX C
O
R
2
R
1
C NH
O
C
O
R
2
R
1
C O
O
C
O
R
2
Imide Anhydride
X v X= O, N, S
Thy phn ha hc
92
Acetal:

Hemiacetal:

Ether

Nitrile

Phosphonate

Polycyanocrylate
O H
2
+
C
O
H H
R' OH O C O
H
H
R R' R OH
+
O C
C
C C
C
OH
OH
OH
OH
OH
OH C
C
C C
OH
OH
OH
OH
H
2
O
+
C==O
H
H
2
O
R C O C R'
H H
H H
O H
2
R C OH
H
H
R' C OH
H
H
+
R C R
C
N
H
R C R
C
O
H
N H
2
R C R
C
O
H
O H
O H
2
O H
2
RO P OR'
O
OR''
O H P OH
O
OR''
O H
2
+ +
R OH O H R'
R C C C C R'
CN
C
OR''
CN
H
H
O C
OR'''
O
H
H
O H
2
R C C C
CN
C
OR''
H
H
O
H
H
OH C R'
CN
C
OR'''
O
+
Thy phn ha hc
93
Thy phn ha hc
94
A. Hp thu phn t lipas
B. Lipas thy gii lipid tao
thnh cc mnh trn b
mt
C. Qu trnh solvat ha
tch cc mnh lipid khi
mng
95
Qu trnh phn hy sinh hc ca polme
lin quan n tc ng ca vi sinh vt: vi
khun, nm mc.

Phn hy sinh hc
96
Phn hy sinh hc
97
Phn hy sinh hc
Qu trnh phn hy sinh hoc lin quan n hot
ng ca vi sinh hay cc sinh vt cp thp thng
qua c ch xc tc enzym
Cc vi sinh vt s dng polime nh l thc n
tng trng v chuyn ha chng thnh CO2,
nc v sinh khi.
Cc loi polymer thin nhin,Polymer c trng
lng phn t thp;Cc aliphatic poliester d
gim cp sinh hc nht, td. gim cp poliglucolic
acid.

98
PE, PP, PVC v PS khng th gim cp
sinh hc v l mch sn carbon, khng c
nhm c kh nng thy phn.
Cc polimer nay ch c kh nng tiu ha
bi vi sinh khi khi lng phn t di
500.
Cc mch nhnh s lm gim kh nng
phn hy ca polime
Phn hy sinh hc
99
Trong mt s trng hp phn hy oxi ha
vn din bin ngay c khi chn di t,
hoc vng ng nc thiu oxy
Td. PE nu c phi sng s gim cp
nhanh hn trng hp khng phi sng nu
b chn di t.

Phn hy sinh hc
100

Trong iu kin thiu oxy, st hoc
mangan b phn cc trong nc hay t
m v to thnh hidro bm ln b mt kim
loi, bo v kim loi khi b oxi ha

Phn hy sinh hc
101
Mt s vi sinh vt c th s dng oxy cc dng nitrat,
sulfat, carbonat, fumarat v ngay c Fe(III) ion.
Khi ion sulfat v vi khun sulfat hin din ng thi trong
t, st s b tc dng do hin tng kh cc catod
thnh sulfur st v st (II) hidroxid
Chu trnh oxi ha kh xy ra do tc ng ca vi sinh
vt dn ti c mt lng nh oxi hnh thnh trn b mt
polimer.
Oxi ny tc kch to ra cc gc peroxid, carbonyl gip
cho cc vi sinh s dng alcan tn cng vo b mt
polimer.
Phn hy sinh hc
102
Enzym
Enzym l mt loi protein hot tnh. Chng c kh nng
xc tc cho nhng phn ng chuyn bit v c th trn
nhng c cht chuyn bit.
Tn ca enzym da trn
Tc dng vi ci g?
Tc dng nh th no?
V tn cng l tip v ng -ase
Td. Lactase l enzym phn ng vi lactoz. Lipase l enzym phn
ng vi lipid

Phn hy sinh hc
103
Mt s enzym cn s hin din ca mt
cht th hai mi hot ng c.
i vi Cofactor enzym th gm 2 phn:
Apoenzym: l phn protein chnh ca enzym
Cofactor: l phn th hai dng kch hot
apoenzym
i vi Coenzym th phn th hai ny gn
tm thi vo apoenzym n hot ng
Enzym
Phn hy sinh hc
104
Oxidoreductases
catalyze oxidation-reduction reactions
dehydrogenases, reductases
lactate dehydrogenase (NAD+), acyl CoA dehydrogenase
(FAD), ketoacyl-ACP reductase (NADPH/H+)
Transferases
catalyze functional group transfers
kinases, aminotransferases, thiolases
glucokinase (ATP), aspartate aminotransferase (PLP),
b-ketothiolase

Enzym
Phn hy sinh hc
105
Hydrolases
catalyze hydrolysis reactions
peptidases, glycosidases, lipases, phosphatases
trypsin, amylase, triacylglycerol lipase, fructose-1,6-
bisphosphatase
Lyases
catalyze elimination (or addition) of groups to form (or
break) double bonds
synthases, decarboxylases, dehydratases
citrate synthase, pyruvate decarboxylase (TPP), fumarase

Enzym
Phn hy sinh hc
106
Isomerases
catalyze reactions that alter structure, not composition
(optical, geometric, or structural isomers)
isomerases, mutases
glucose-6-phosphate isomerase, phosphoglycerate mutase
Ligases
catalyze coupling of two compounds along with
hydrolysis of a phosphoanhydride bond
synthetases, carboxylases, polymerases
glutamine synthetase (ATP), pyruvate carboxylase
(biotin), DNA polymerase

Enzym
Phn hy sinh hc
107
Phn t enzym c cu trc 3D
Khi lng phn t 10 100 Kda
ng knh 5 10 nm
V tr hot tnh (rt nh) xc nh chc nng
ca enzym

Enzym
Phn hy sinh hc
108
Mi enzym c khong nhit v pH ti
u hot tnh
Khong ti u c th thy i theo iu kin
Enzym
Phn hy sinh hc
109
Enzym
Phn hy sinh hc
110
Enzym
Phn hy sinh hc
111
Enzym
Phn hy sinh hc
112
Enzym
Phn hy sinh hc
113
Enzym
Phn hy sinh hc
114
Mt s enzym cn s hin din ca mt cht th hai mi
hot ng c.
i vi Cofactor enzym th gm 2 phn:
Apoenzym: l phn protein chnh ca enzym
Cofactor: l phn th hai dng kch hot
apoenzym
i vi Coenzym th phn th hai ny gn tm thi vo
apoenzym n hot ng
Co- Enzym
Phn hy sinh hc
115
116
Co- Enzym
Phn hy sinh hc
117
Co- Enzym
Phn hy sinh hc
118
Vitamin Coenzym Tc dng
B1
Thiamine
Pyrophosphate
Decarboxylation
B2
Flavin
mononucleotide
Ti hidro
Folic acid
Tetra hydrofolic
acid
Bin dng amino
acid
Biotin Biocytin C nh CO2
Pento
thenic acid
Coenzym A Mang nhm acyl
Co- Enzym
Phn hy sinh hc
119
120
121
122
Phn hy kt hp
123
Phn hy kt hp
124
Phn hy kt hp
125
Phn hy kt hp
126
C ch phn hy oxi-bio
Qu trnh phn hy oxi ha ca cc olefin
gm 5 giai on:
Khi mo
Pht trin gc t do
Pht trin mch
Phn nhnh
Kt thc

127
128 C ch oxi ha ct mch ca PP
129
130
Polymer phn hy ha sinh (kt
hp)
Poliolefin c kh nng phn hy c sn
xut theo 2 hng:
Ceton polime: Bng phng php ng trng hp vinil
ceton v etilen hoc propilen. Mt sn phm thng
mi c tn Ecolyte
TM
.
Ceton polime da trn nguyn tc cc polime c gn
nhm carbonil c bit khi nm v tr trn mch
phn t polime c kh nng hp thu bc x vng gn
t ngoi trong vng nh sng thy c. Cc polime
ny t phn hy trong nh, nhng khi phi sng s
phn hy nhanh. Phn t polime cng c nhiu nhm
carbonil cng phn hy nhanh di tc dng ca nh
sng
131
132
133
134

S dng ph gia tr phn hy.
Qui trnh Scott/Gilead: da trn c ch xc tc oxi
ha ca cc ion kim loi. Cc ion kim loi dng ha
tan c a vo polime xc tc cho qu trnh oxi
ha trn b mt polime.
Qui trnh EPI: theo cng ngh ny ph gia di
dng masterbacth c trn vo polime kim
sot qu trnh phn hy.
Qui trnh s dng ph gia tr phn hy c
s rng ri v thng mi ha vi nhiu thng
phm khc nhau.

135
STT Tn sn phm Nc sn
xut
Ghi ch
1 Ecoplaz
TM
Thi lan Resin
2 R
3
plas
TM
USA Ph gia
3 Reverte
TM
USA Ph gia
4 TDPA

Canada Ph gia
5 Natur-Tec
TM
USA Resin
6 Addiflex

Canada Ph gia
7 D
2
W
TM
Trung Quc Resin
8 ECO-3 Nht Ph gia
9 Mater-Bi
TM
Resin
136
5.4. Tnh cht v ng dng
Thay i MW ca LDPE cha Mn
137
dn di ca HDPE lo ha 80 C
138
nh hng ca R-Plas n bn ko ca PE
139
nh hng R-Plas n dn t ca BOPP
140
141
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Without Omyalene and 3% Addiflex with 20%-30% Omyalene and 3%
Addiflex
I
n
c
r
e
a
s
e

o
f

p
h
o
t
o
-
o
x
i
d
a
t
i
o
n

b
a
s
e
d

o
n

I
n
d
e
x

1

This is an essential property in case the application is littered.
+ 66% of
photooxydation
with Omyalene
(CaCO3)
142
Trade Name Product Application Supplier-location
Production
Capacity
Cost per
unit
Biomax Plates, bowls, containers
Dupont/ Metabolix
Inc
TBD
Biopol PHA Film, sheet, cups, trays, containers. Metabolix Inc-
100 million pounds
per year
[]

EASTAR Bio
Bags, films, liners, fiber and
nonwovens applications,
Novamont NA-
33 million pounds
per year
[]

Ecovio plastic
PLA-Ecoflex
Bags, sheets, film TBD
Cereplast resins
Nat-UR cold drink cups, foodservice
containers and cutlery
Cereplast
Corporation-
40 million pounds
per year
[]

EcoFlex Bags, liners, film BASF- Denmark
60 million pounds
per year
[]

NatureWorks
PLA
Cold drink cups, foodservice
containers and cutlery
Nature Works LLC,
Cargil-Dow-
300 million pounds
per year
[]

Stalk Market
Sugar Cane
Foodservice containers and cutlery Asean Corporation,
30 million pounds
per year

Mater-Bi Resins Bags, liners, and film products
Novamont
Corporation-
40 million pounds
per year
[]

EPI additives for
LDPE and HDPE
Bags, sheets, film, trays.
Additive is available for many plastic
products.
Biocorp, Inc.
20 million pounds
per year

Oxo- and UV-
degradable
additives for
LDPE and HDPE
Bags, sheets, film, trays.
Additive is available for many plastic
products.
EPI Environmental
Technologies, Inc.
,
20 million pounds
per year

Polystarch
master batch for
LDPE, HDPE,
and PP
Bags, sheets, film, trays. Containers.
Starch additive is available for many
plastic products.
Willow Ridge
Plastics, Inc.
10 million pounds
per year

143
Trade Name Polymer Source/Type
Rate and Extent of
Degradation
(Environment)
Shelf Life
BPI
Certified
ISO
Certified

Biomax
Mixed aliphatic and
aromatic polyester
Compostable in 6
months (compost)
12 to 18 months Yes Yes
Biopol PHA
poly-hydroxyalkanate via
bacteria
Compostable in 6
months (compost)
12 to 18 months No No
EASTAR Bio Modified PET polyester
Compostable in 6
months (compost)
Ecovio plastic PLA-Ecoflex TBD TBD No No
Cereplast resins Plant organic sources
Compostable in 6
months (compost)
EcoFlex
Mixed aliphatic and
aromatic polyester
Compostable in 6
months (compost)
NatureWorks
PLA
polyester
Compostable in 6
months (compost)
Stalk Market
Sugar Cane
Sugar cane
Biodegradable
(compost)
12 to 18
months
No No
Mater-Bi Resins Corn starch
Compostable in 6
months (compost)
EPI additives for
LDPE and HDPE
Oxodegradable additive for
HDPE and LDPE
Disintegrates but not
compostable
2 to 3 years No No
Polystarch
master batch
Starch and LDPE or
HDPE, and PP
Disintegrates but not
compostable
2 to 3 years No No
144
145
Use Storage Degradation
Situation 1
Controlled Service Life and tailored Degradation
or Situation 2
or Situation 3
(e.g. Littering)
Why is the AddiFlex
system unique?
It allows to controll the time for...
146
AddiFlex
- applied in a carrier bag

HDPE
+ 3% AddiFlex
HES
+ up to 40 % CaCO
3
e.g. 54% CaCO
3

masterbatch at 18

= Biodegradable
Carrier bag

Storage Degradation
612 3 12-48 [months]
Storage Use Degradation
Depending on the disposal system
147
AddiFlex
- applied in another carrier

bag
HDPE
+ 5% AddiFlex

HE
+ 20% CaCO
3
e.g. 27% CaCO
3
masterbatch

= Biodegradable
Carrier Bag
612 3 9-24 [months]
Storage Storage Use Degradation
148
AddiFlex
- applied in a bread pack

LDPE
+ 3 % AddiFlex

HE

= Biodegradable
Bread pack

3-6 3 12-48 [months]
149
AddiFlex
- applied in refuse sacks

Recycled PE
+ 5% AddiFlex

HE
+ up to 20% CaCO
3
e.g. 27% CaCO
3
masterbatch

= Biodegradable
Refuse sacks

6-12 3 9-48 [months]
150
AddiFlex
applied in food trays

PP
+ 5% AddiFlex

HE
+ up to 20% CaCO
3
e.g. 27% CaCO
3

masterbatch

= Biodegradable
Food trays
3-12 1-3 9-36 [months]
Use Degradation
151
AddiFlex
applied in a
mushroom punnet
PP
+ 5% AddiFlex

HE
+ up to 20% CaCO
3
e.g. 27% CaCO
3

masterbatch

= Biodegradable
mushroom punnet
after ca. 8 -10 weeks outdoor weathering

3-6 1 9-36 [months]
Use Degradation
Storage Stor. Use Degradation

152
153
154
155
156
157
Polimer sinh hc
Chng 5
158
159
Renewable
Resource-based
Microbial
synthesized

Aliphatic polyester
Aliphatic-aromatic
polyesters
Polyesteramides
Polyvinyl alcohols

Polyhydroxy
alkanoates (PHAs)
Polyhydoxybutyrate co-
valerate (PHBV)

PLA Polymer
(From Corn)
Cellulosic plastics
Soy-based plastics
Starch plastics
Petro-Bio
(Mixed) Sources
Sorona

Biobased
Polyurethane

Biobased
epoxy

Blends etc.
BIOPOLYMERS: CLASSIFICATION
Petro-based
synthetic
160
161
Biodegradation
Plastic Products
Carbon Cycle of Bioplastics
CO
2

H
2
O
Plants
Fermentation PHA Polymer
Recycle
Photosynthesis
162
S pht trin ca polimer t
sinh khi vi sinh
1927 poli(3-hydroxy butirat) c tng hp u
tin t vi khun Bacillus megaterium.
Nm 1958 vai tr ca P(3HB) c pht hin bi
Macrae and Wikinson khi cc ng thy vi khun
sn sinh polime khi ti l glucoz/nitrogen trong
mi trng cao. iu ny cho thy P(3HB) l
sn phm d tr nng lng v carbon ca vi
khun.
1973 khi d on ngun du d tr s cn kit
th cc nh khoa hc ch n vic thng mi
ha P(3HB)

163
Cc PHA c th l homopolime hoc
copolime ca 2 hay 3 loi HA.
1972 cc nh hoa hc khm ph copolime
P(3HB-co-HV).
S chng loi PHA cng ngy cng gia
tng. Theo thng k th c trn 91
chng loi PHA.
Trong cc copolime th poli (3HB-co- 3HV)
l thng dng nht.
164
Trong thin nhiu PHA l mt polime
khng ha tan nm trong t bo cht ca
vi khun.
Ty theo s carbon trong mch, PHA c
chia thnh 2 nhm:
Nhm mch ngn: cha t 3- 5 carbon
Nhm mch trung bnh: cha t 6 -14 carbon
165
166
167
168
169
Tng hp v gia cng
PHA c th tng hp bng 3 phng php:
Sinh tng hp t cc vi sinh.
Quang tng hp t cc thc vt chuyn i gen.
Sinh tng hp trong ng nghim vi cc enzym thch
hp.
Trong hu ht cc vi khun, t bo s tng hp
PHA trong iu kin pht trin khng thun li v
nitrogen, phosphor v oxygen. Khi PHA s l
ngun d tr carbon v nng lng. PHA cn l
cht iu ha oxi ha-kh trong t bo.

170
Cu trc ha hc ca PHA ty thuc vo
cht nn do chng loi vi khun xc nh
v ngun carbon s dng tng hp
PHA.
Ngun carbon l yu t quyt nh chnh
i vi gi thnh ca PHA. Ngi ta tm
kim nhiu ngun carbon r tin trong
c bn nc thi.
171
172
Qu trnh tch t PHA trong t bo, khi lng phn t
cng nh kch thc phn t chu nh hng bi nhiu
yu t cng ngh.
Khi lng phn t PHA chu nh hng nhiu bi pH
v nng ngun cung cp carbon.
S ht polime trong t bo cht thay i t 8 12
S tch t polime trong t bo cht lm thay i hnh
dng t bo t hnh tr sang hnh cu. T bo s ngng
pht trin khi polime chim khong 80%. Do cc iu
kin gii han vt l s quyt nh qu trnh tch ly PHA
trong t bo cht.
173
Vi khun tng hp PHA c chia thnh 2 nhm
da trn iu kin nui cy
Nhm 1: iu kin nui cy thiu cc cht dinh dng
nh nitrogen, phosphor, magnesium, lu hunh
tng hp PHA t ngun carbon d. Cc vi kun nhm
ny bao gm: R. eutropha, Protomonas extorquens, v
Protomonas oleovorans
Nhm 2: khng cn hn ch cc cht dinh dng,
polime sinh ra trong qu trnh tng trng. Cc vi
khun nhm ny bao gm: Alcaligenes latus, mt
chng bin i ca Azotobacter vinelandii v chng ti
kt hp ca E. coli.
174
Cc enzym tng hp PHA c th chia
thnh 2 nhm:
Nhm Ralstonia eutropha synthases s kt
hp cc HA mch ngn (HA
SCL
) gm t 3 n
5 carbon thnh PHA. Cc cht nn thuc
nhm ny bao gm:
3-hydroxypropionate (1); 3HB (2); 4HB (3); 3HV (4);
4-hydroxyvalerate (4HV, 5); v
5-hydroxyvalerate (5HV, 6).
175
Nhm Pseudomonas oleovorans synthases
thch hp kt hp cc HA no, mch thng
chiu di mch trung bnh c t 6 14 carbon
(HA
MCL
).
3HA
MCL
(7).
Ngoi ra n cng c th kt hp:
Unsaturated MCL-3-hydroxy- -alkenoate (8)
Non-linear MCL-3-hydroxy- -methylalkanoate (9)
3HA
MCL
vi cc nhm chc v tr (10,11)

176
177
178
Lee et al., 1996
179
Cc ht PHB tch t trong dng Ralstonia eutropha
trong iu kin thiu dinh dng
(A) wild-type ; (B) phaP ; (C) PhaP
180
181
Cht nn
Gi ca PHA cao hn cc polime thng
thng khong 5 ln l do qui trnh ln
men chi ph cao.
Chi ph nh hng nhiu n gi thnh
ca PHA l gi ca cht nn.
gim gi thnh ngoi vic tm cc
ngun carbon gi r cn phi tm kin cc
chng vi khun thch hp.
182
Glycerol l ngun carbon c ch . y
l sn phm ph ca mt s cng ngh.
Qui trnh s dng chng P. oleovorans.
Bn thi hot tnh, glutamic acid trong
nc thi, cc du d trong nc thi ca
cc nh my ch bin du n, ph liu
nng nghip cng l nhng ngun dinh
dng cho vi khun c ch
183
KT ln men
iu kin ln men phi lm cho vi khun
tch carbon trong t bo di dng PHA
ch khng dng nhn ging.
Qu trnh ln men c th chia thnh 2 giai
on:
Nhn ging: giai on ny cc cht dinh
dng phi c cung cp y tng s
lng vi khun.
Tng hp PHA: giai on ny iu kin dinh
dng b gii hn vi khun tch ly PHA.
184
Qui trnh gin on.
Hai giai on ca qui trnh c tin hnh tun t
trn 1 thit b.
Kim sot qui trnh theo ch open-loop. H thng
theo di v kim sot s dng nng oxygen lm
ch bo cho lng carbon tiu th. C th s dng
h thng n nh pH. H thng kim sot ny thch
hp cho qui trnh s dng 1 ngun cht nn.
Khi s dng 2 ngun cht nn th s dng ch
kim sot closed-loop.
vi khun tng hp PHA th t l C/N cao (40
mol/mol). Khi t l ny thp vi khun s ngng tng
hp polime.
185
Qui trnh lin tc.
Qui trnh tin hnh lin tc qua 2 giai on trn 2
thit b phn ng lin tc.
Giai on 1: s dng glucoz v lng d nitrogen.
Giai on 2: s dng cc cht dinh dng khng phi l
carbon.
Qui trnh nhiu giai on s s dng hiu qu ngun
cht nn, cho hiu sut tng hp cao hn.
186
Tch loi sn phm
Sau khi tng hp sinh khi c tch loi
bng phng php li tm, lc hoc li tm
lng.
Vic tch polime khi t bo vi sinh c
tin hnh theo 2 phng php:
Li trch PHA khi t bo: PHA khng tan trong
nc. Dng cc dung mi ho tan PHA li
trong dung dch.
Tch cc phn t t bo khi polime: ph v
vch t bo v ra sch PHA.
187
Li trch bng dung mi.
Cc dung mi thng dng l chloroform, methylene
chloride, propylene chloride, v dichlororethane.
Lng dung mi s dng ln do nht dung dch
cao. T l tiu hao l dung mi/PHA l 20/1.
C th s dung dung dch mui hipoclorit. Phng
php thng s dung ph v t bo. Tuy nhin
vic s dng hipoclorit l gim cp PHA (c th ti
50% khi lng phn t)
C th s dng hn hp hipoclorit v cloroform
trnh gim cp PHA.
T l thu hi ln n 95%.

188
Tch loi t bo vi khun.
Cc enzym lysozyme, proteinases, DNAses
c th s dng ha tan t bo tch loi
PHA.
Sau khi tch loi, PHA c ra vi dung
dch cht hot ng b mt anionic.
i vi t bo c hm lng polime cao, v t
bo dn nn c th s dng NaOH hoc
NH
4
OH x l, td. s dng vi khun A.
vinelandii hoc E. coli.

189
190
191
4.3. Bin tnh polime t sinh
khi vi sinh
C cng nhit ha thu tinh nh PP,
nhng nh cu trc iu ha lp th nn
kt tinh ca PHB cao. iu ny a
n PHB cng v dn.
PHB gim cp nhanh khi nhit cao hn
nhit nng chy a n tnh cht sn
phm gim.
PHB c th gia cng bng phng php
c p. Tuy nhin khng th gia cng to
mng mm do.
gim dn ca PHB phi gim kt
tinh.
192
Trn hp PHA
MCL
vi cc polime khc ci
thin c tnh v tnh thy gii. Thng cc
PHA c trn hp vi PLA, PEG hoc
PLGA.
Khu mch bng cc ha cht nh benzoil
peroxid, benzophenon, etilen glicol
dimetacrilat kt hp vi nhit hoc bc x.
Vic khu mch gia tng c tnh ca
polime.
Khu mch bng ha cht c th xut hin
nhng cht c hi trong polime.
Khu mch bng bc x cho polime sch hn.
193
Thc hin phn ng th ha hc i vi
poliester khng no c th t c nhng
tnh cht bt ng. Th d
Epoxy ha PHA
MCL
tng bn ko v modun.
P(HO-co- HU) cha 25% nhm COOH cha
kt ni v 40 60% nhm hydroxyl s tan rt
tt trong dung mi c cc nh metanol, DMS,
hn hp aceton/nc.
Clo ha PHA
MCL
bin i t chy dnh sang
cng, dn ty theo mc clo ha.
194
Copolime ghp PHA
MCL
: ghp cc nhm
vinil vo PHA
MCL
lm thay i tnh cht vt
l v ha hc ca vt liu. Phn ng ghp
c th c thc hin bi ha cht, bc
x hoc pht x plasma.
X l plasma l phng php hiu qu
thay i tnh cht b mt ca polime m
khng thay i tnh cht ca khi polime
cn li.
PHO ghp acrylamid bng plasma s tng tnh
a nc ph hp vi cc ng dng y sinh.
195
PHO-g-PEG v PHU-g-PEG bng phng
php bc x cng ci thin tnh a nc
ca polime, ng dng trong cc b phn
thit b tip xc vi mu
Mt s polime ghp khc lm tng tnh
cht nhit v tnh cht c.
Ngoi ra cn c cc sn phm PHN-g-PS
hoc PHN-g-PMMA

196
197
4.4. Tnh cht v ng dng
PHA c ch do c kh nng phn hy
sinh hc, trc ht c s dng lm bao
b mng trong hp dng v trng ln giy.
C th s dng nh trong cc ng dng
thng thng nh dng c nh bp, giy
t, bng v sinh, hp cha m phm.
Cht mang thuc dung trong dc cng
nh cc ng dng trong y sinh: bng sinh
hc, implant
198
199
200
201
Cng ngh ti sinh polimer v
s phn hy
Chng 6
202
Cc phng php ti sinh
Ti sinh l qu trnh ti gia cng cc sn
phm qua s dng nu khng thi b
Ti sinh nha nhm:
To thm ngun nguyn liu
Tit kim nng lng
Gim thiu nhim mi trng
Vic s dng nha ti sinh gip gim gi
thnh sn phm
203
Khi t vn ti sinh nha cn quan tm
Nha c thu hi trong qu trnh gia cng
dng thch hp ho vic ti sinh hay khng?
Nha c chu nh hng nhiu i vi cc
iu kin gia cng hay khng?
C l tnh ca nha c gim nhiu khi ti sinh
hay khng?
Nha ti sinh s c s dng ton phn hay
trn vi nha nguyn sinh sn xut sn
phm?
Ti sinh nha c kinh t khng?
204
205
Phn bit 2 loi ph liu c th ti sinh
Nha ph liu trn dy chuyn
Nha ph liu sau khi s dng
Vic ti sinh nha ph liu sau khi s
dng phc tp hn v:
Ln vi cc loi nha khc v nhiu cht bn
Vic phn loi v lm sch tn nhiu cng hn
206
Mt s tr ngi i vi vic ti sinh
Gi nguyn liu nguyn sinh thp so vi tng
chi ph ca cc cng on ti sinh: thu gom,
phn loi, lm sch, ti gia cng
Khng s dng sn phm ti sinh trong bao b
tip xc vi thc phm
S khng tng hp ca hn hp polime i
hi khu phn loi phi chn c mt chng
loi polime
T trng cc sn phm ti sinh qu b so vi
tng sn lng sn phm nha
207
i vi polime phn hy vn ti sinh sn
phm sau khi s dng thng khng c t
ra v:
Bn thn vt liu ny mang tnh t phn hy tc
tnh cht gim nhanh sau khi s dng.
Polime phn hy c thi b sau khi s dng thng
xy ra qu trnh cm ng khi mo cho s phn hy.
Do s b phn hy nhanh hn trong qu trnh ti
sinh
Trong qu trnh ti sinh di tc dng ca c v nhit
polime s b gim cp nhanh v sn phm s khng
tnh cht s dng
208
i vi a s polime phn hy vn ti sinh
t ra ch i vi ph liu trn dy chuyn.
Mt s polime phn hy trn c s bin tnh tinh
bt, do bn thn polime khng b gim cp nhiu
sau khi s dng nn thng c ti sinh
Tuy nhin trong qu trnh ti sinh c c
cht lng sn phm tt cn ch gii quyt
mt s vn trong gia cng
209
PLLA
210
211
212
213
214
215
216
Poliester Mater-Bi
217
218
Tinh bt Mater-Bi
219
Gia cng ph liu PE/tinh bt
Cc vn phi gii quyt khi ti sinh PE/tinh
bt
Do PE sn xut nhiu cp khc nhau ty theo cng
dng. Gi c khc nhau v i khi nu trn chung th
lm gim cht lng sn phm.
i vi bao b mng PE th vn mc in trn mng
s nh hng n tnh cht v mu sc ca sn phm
ti sinh
i vi ph liu trn dy chuyn th d kim sot hn
220
Cc cng on gia cng
Xay: mng PE phn hy c xay qua li 10 mm
n to ht: S dng my n c b phn ht kh qua
u to hnh dng si
Ct nng v lm ngui bng khng kh
Do tinh bt d ht m nn mng t nha ti sinh
100% thng c bt. gim bt c th dng
thm CaO. CaO ng vai tr cht ht m. Hm
lng CaO t 0.5 2%. d trn c th dng
master batch 50% ca CaO trong PE (MI=20)
221
Nhit my n to ht cn gi thp trnh
lm chy tinh bt cng nh trnh phn hy PE.
My n cn c li lc loi b cc cht bn
v nha cha chy. Li lc phi thay thng
xuyn
i vi nha c cht tr oxi ha th qu trnh
gim cp xy ra nhanh khi nhit ln trn
220
0
C v s gim cp nhit cn xy ra khi gia
cng to sn phm, nn thng khng ti sinh
nha ny.
Khi trn vi nha nguyn sinh th hiu ng gim
cp s gim
222
iu kin gia cng
Thng s gia cng PE nguyn sinh PE/tinh bt (6%)
p sut (psig) 1600 3200 1600 3200
Vng xi lanh Nhit
# 1 nhp liu
# 2
# 3
# 4 u to hnh
# 5 u to hnh
135
140
152
130
120
135
140
152
125
115
CaO MB (%)
Tc n (kg/gi)
0
75
0.5 4.0
80
223
S dng PE/tinh bt ti sinh
Sau khi gia cng khng nha tip xc lu
khng kh m do m s b ht tr vo nha
Tuy nhin nu y kn nha sm qu nhit tn
ti c th lm nha b phn hy
Nha PE/tinh bt ti sinh c trn vi nha
nguyn sinh vi t l 10 50%, hoc c th gia
cng 100% nha ti sinh. Gi thnh nha ti
sinh thp hn gi thnh nha ban u t 30
50%
224
Bng phn tch kinh t
Hn hp nha Gi nguyn liu
$/kg
Gi hn hp $/kg
88% PE nguyn
sinh
12% MB tinh bt
0.75
2.20
Gi thnh
0.66
0.26
0.92
50% gi nha ban
u
Nha ti sinh
2% MB CaO
Li lc

0.46
2.20
0.02
Gi thnh

0.46
0.04
0.02
0.52
70% gi nha ban
u
Nha ti sinh
2% MB CaO
Li lc

0.64
2.20
0.02
Gi thnh

0.64
0.04
0.02
0.70
225
Gii php n
Qu trnh gim cp nha khi n bao gm
gim cp bi nhit v gim cp bi oxi
ha.
Vic phn tch ph IR trong cc iu kin
khc nhau cho thy qu trnh gim cp ch
yu l do qu trnh gim cp oxi ha

226
227
CN ngn chn qu trnh gim cp
Gim nng oxi trong nha bng cch
thay 9i cu trc trc vt
228
Gim qu trnh sinh nhit.
Khe h gia nh rng vt v thnh xi lanh
cng nh th nhit ma st nht cng ln
Thay i chuyn ng ca dng chy trong
rnh vt thi gian lu ngn li
Thay i profile ca rng vt tng vn tc
trt trnh nha b ng li ti chn vt.

229
230
231
232
Hydrogel
Chng 7
233

5/8/2014 233
234
Cu to v tnh cht
Ch to
ng dng
235
Cu to v tnh cht
Polimer khng tan trong nc. Cu trc
mng ca hydrogel c th do ni ngang
ha hc hay ni ngang vt l
Polimer c kh nng trng phng ng
k trong nc
Polimer cu trc mng trong nc phn
tn u khp cu trc ca polimer
236
Khi c nhng thay i do tc nhn bn ngoi
hydrogel c s thay i thun nghch tnh cht
a nc v s trng phng hay co rt
Hydrogel vt l lin kt bi cc lin kt vt l, c
nhng vng a nc (hydrophilic) v k nc
(hydrophobic)
Hydrogel ha hc to bi cc ni ngang ha
hc, c nhng vng mt lin kt cao v vng
mt lin kt thp. Vng mt lin kt thp
s trng phng nhiu
237
238
Phn loi
Theo bn cht ni ngang
Hydrogel ha hc
Ni ngang l ni cng ha tr.
Hp thu nc n t trng thi cn bng (ph thuc mt
ni ngang). Tnh n nh cao trong iu kin nhit cao, mi
trng acid/baz mnh, ng sut cao
Hydogel vt l
Ni ngang vt l
Tng tc ni yu v thun nghch
Chu nh hng ca mi trng (nhit , pH, lc ion, ng
sut)

239
Theo in tch ca phn t polimer
Hydrogel trung tnh: khng mang in tch
Hydrogel anion: mang in tch m
Hydrogel cation: mang in tch dng
Hydogel lng tnh: c kh nng thay i in
tch theo mi trng
240
241
Theo cu trc polimer
Hydrogel v nh hnh
Hydrogel bn kt tinh
Hydrogel c ni hydro
Mng 3D c to bi ni hydro
Tng tc hydrophilic/hydrophobic mnh
242
Trn c s in tch ca mch phn t
Hydrogel trung tnh
Hydrogel anion
Hydrogel cation
Hydrogel lng tnh
243
Trn c s cu trc vt l
Hydrogel v nh hnh
Hydrogel bn kt tinh
Hydrogel cu trc khc
244
245
Tnh cht ca hydrogel
trng thi tnh hydrogel khng chy
Hydrogel l cht lng nhng c tnh cht
ca cht rn
Hydogel c kh nng hp thu mt lng
nc. Lng nc hp thu t 20% n
hn 1000% khi lng gel kh
Ni ngang trong cu trc gel nh hng
n cng v dnh ca hydrogel
246
Hydrogel trng nhiu:
cellulose derivatives
poly(vinyl alcohol)
poly(ethylene glycol)
Do c nhiu nhm OH (hay =O) tng tc vi mi
trng acid a nc trng
Hydrogel trng trung bnh hoc thp:
Poly(hydroxyethyl methacrylate), PHEMA v cc dn xut
c c mt tnh cht trng thch hp c th ng
trng hp mt monome c a nc cao vi mt
monome c k nc thp
247
Tnh cht trng
Lc trng nhit ng hc cn bng vi
lc co rt ca cu trc mng
Khi t cn bng hai lc tng tc ny
bng nhau
trng th tch Q
Q = 1/V = Th tch trng/th tch kh
248
Cu trc v s trng ca hydrogel ha hc
Cu trc mng c hnh thnh do cc monome kt
mng bi cc cht to ni ngang a chc
Mng t cc monomer vinyl a nc
Hydroxy Ethyl Methacrylate
Poly(ethylene glycol) methacrylate
Acrylic acid
Acrylamide, N-isopropylacrylamide
Cht to ni ngang thng dng
PEGDMA, EGDMA
Bis-Acrylamide
249
Qu trnh trng ca hydrogel tng t qu
trnh pha long dung dch polimer nhng b
gii hn bi cu trc mng ca gel
Hydrogel poly(2-hydroxyethyl methacrylate)
PHEMA l hydrogel y sinh u tin c s
dng trong knh st trng (contact lens)
250
Cu trc v s trng ca hydrogel vt l
Cu trc mng c to thnh bi s kt hp
cc nhm a nc/k nc
(hydrophilic/hydrophobic)
PEO-PPO-PEO; PPO-PEO-PPO
PLGA-PEG-PLGA; PEG-PLGA-PEG
251
Hydrogel thng minh (Stimulus
responsive)
S trng thay i theo pH, nhit , lc
ion, cht gy trng, enzym, in trng,
t trng

Kch thch vt l: nhit , in trng, t
trng, UV
PNIPAAm trng nhit thp v co rt nhit
cao
252
253
Kch thch ha hc: pH, lc ion
C ch hot ng ca hydrogel nhy pH
Qu trnh ion ha nhm carboxyl gii phng H
+
H
+
kt hp vi OH
-
to nc
in tch c cn bng bi s khuch tn cation (Na+ v
OH
-
) vo trong gel
S khuch tan ny to p sut thm thu lm gel b trng

254
Ni hydro
Polyvinyl alcohol
Gelatin
255
Ni ion
Sodium alginate
256
Kch thnh sinh hc: enzym, cht sinh hc
Hydrogel nhy vi glucoz
257
u im ca hydrogel
Khng gy ng mu: s dng non-ion
hydrogel
Tng thch sinh hc
Vn chuyn tt cc cht b dng n t bo
v cht thi khi t bo
D dng bin tnh vi cc ligan kt dnh t bo
C th chch trc tip vo ngi dng lng.
Sau d s gel nhit thn th
258
Nhc im ca hydrogel
C th kh s dng
C tnh yu
Khi to mng in vitro th kh a thuc hoc t
bo v dng lng v khu mch
C khkh kh trng
259
9.2. Ch to
260
ng trng hp monome v cht to ni ngang
HEMA v EGDMA (Ethylene glycol dimethacrylate)
To ni ngang i vi cc polime tan trong nc
Bin i polime khng cc thnh polime c cc kt hp
vi to ni ngang
261
ng dng
Cc tnh cht quan trng ca hydrogel s
dng trong y sinh
C kh nng hnh thnh in situ
C kh nng phn hy
L mt hydrogel thng minh
C cu trc v tnh cht ging m sinh hc
262
C kh nng hnh thnh in situ
Qu trnh gel ha c kch thch bi
Bc x, nh sng
Thay i nhit , th d 4 C n 37 C
To ni ngang bi enzym
C s hin din ca mui ha tr 2
263
C kh nng phn hy

Trng phng thng minh
Tc nhn kch thch: pH, nhit , nng
264
265
Cc ng dng trong KT sinh hc
Mi trng sinh hc
pH
Location in
Body
pH
Gastric Contents 1.0
Urine 4.5-6.0
Intracellular 6.8
Interstitial 7.0
Blood 7.15-7.35
266
Nhit
Location in
Body
Temperature C
Normal Core 37
Deviations During
Disease
20-42.5
Normal Skin 28
Skin at
Extremeties
0-45
267
Nng ion
Cations Concentratio
n in Blood
(mEq/L)
Sodium 142
Pottasium 4
Calcium 5
Magnesium 2
Anions Concentratio
n in Blood
(mEq/L)

Chlorine 101
Bicarbonate 27
Phosphate 2
Sulfate 1
Proteins 22
268
Cc ng dng trong y sinh
Lm khung cy m
Hp thu, tch bc cc t bo cht hay s ha
Cc hydrogel nhy vi cc phn t nh
glucoz, antigen c dng trong cc bio-
sensor
Knh st trng
T v sinh
Ph bi trn cc ng dn dch, gng tay
269
Cc ng dng khc
n ngc
Dng trong cc gt gi m iu tr phng
Thuc iu tr cc b
Gn sn nhn to
Mng thn nhn to
Da nhn to
.
270
Thuc tan chm
C ch tan chm
271
Bnh i ng c iu tr vi hydrogel
nhy vi glucoz.
Chuyn i sol-gel ca hydrogel vi Con-A

272
273
ng dng hydrogel nhy pH iu tr bnh tiu
ng
274
275
ng dng hydrogel nhy nhit iu tr
bnh thoi ha m ct sng
276
277
Cht cch li m
Ngn chn cc ng mu, hp mch mu
Ngn chn dnh m sau phu thut
278
TE scaffold, cell encapsulation,
immunoisolation
279
A Study on the Functionalized Biodegradable
Injectable Hydrogels for Controlled Protein and
Drug Delivery
280
1. Why use protein & drugs in devices ?
i) Diabetes (Insulin, Symlin, Exendin, Somatokine)
ii) Cancer (Interferon, Monoclonal Antibodies, Vaccines)
iii) Cardiovascular Drugs (Natrecor, GPIIB receptor, Protein G receptor)
iv) HIV/AIDS (Somatostatin, T20, T1249, IL-2, Interferon)
Introduction
2. Why use biodegradable polymer hydrogels for implant
protein drugs delivery ?
i) Poor oral bioavailability
- Protein denaturation
- Acid hydrolysis
- Enzymatic degradation
ii) Poor adsorption due to size and polar/charge distribution
281
Background
Maximum desired level
Minimum effective level
Dose Dose
Dose
Time
D
r
u
g

l
e
v
e
l

Maximum desired level
Minimum effective level
Dose
Time
D
r
u
g

l
e
v
e
l

traditional drug
dosing
(oral, singular inject, vain
transfer, nasal, ..)

controlled delivery
dosing.
(hydrogel systems)
Therapeutic concentration range
282
Background
web.indstate.edu/mary/N645/mod8.htm
Profiles of human insulins and analogues

283
www.thecesolution.com/ce/lessons/TCES_NewDrug...
Other studies related to insulin release
Morimoto Group
Gelatin microsphere
Background
284
Other studies related to insulin release
<Disadvantages>
Difficult to load
Aggregation of insulin
+ +
+ +
+ +
+ +
_
_ _
_
_
_
_
_
_
Background
Prof. SW Kim Group
285
Disadvantages of non-biodegradable
polymer hydrogels:
Poor adsorption due to size
Easy denaturation of protein
Difficult to load
Difficult to sterilize and hard to handle.
Degradation
release
B-A-B triblock copolymer
temperature sensitive
micelles
PLGA-PEO-PLGA
Loops
Bridge
PLGA-PEO-PLGA
B-A-B triblock copolymer
temperature sensitive
hydrogel
Temp.
Change
Temperature-sensitive Hydrogel
Background
286
Gelation
inside the
needle
during
injection by
temperature
change
Disadvantages of temperature-sensitive hydrogels

Protein drug loading and release problem due to size of protein
Mechanically weak
Difficult to load drugs and cells
Poor controlling of drug concentration level during therapy
Difficult to sterilize and hard to handle.
Gelation occurs inside needle during injection
Clogging problem
287
Challenges
+
+
+
_ _ _
Anionic drug/protein loading
Cationic drug loading
_
_
+ +
_
_
_
_
+
+
+
+
+
+
+ +
+ +
_
_
_
_
_
_
Control of drug release rate by ionic complex
Resolve clogging problem
pH
Temp.
Sol
Gel
A --- --B----- C--- --B-- --- A
pH sensitive block
Temperature sensitive block
pH sensitive block
288
Anionic & cationic pH/temp.-sensitive hydrogels
Ref.) Shim, W. S.; Kim, S. W.; Lee, D. S. Biomacromolecules 2006, 7 (6), 1935
Type 2: Anionic hydrogel
pH
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)

7.4
37
Sol
Gel
Sol (Sedimentation)

Human body
condition

Type 1 : Cationic hydrogel
pH
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)

7.4
37
Sol
Gel
Sol (Sedimentation)

Human body
condition

A --- --B----- C--- --B-- --- A
pH-sensitive block
Temperature-sensitive block
pH-sensitive block
289
Contents
Control of degradation rate of cationic hydrogels
* Synthesis of new hydrogels with various biodegradable polymers
* Control of degradation in vitro and in vivo
* Effect of copolymer degradation on insulin delivery
Molecular design of new pH/temperature-sensitive hydrogels
* Synthesis of PAE-PCL-PEG-PCL-PAE
* Sol-gel transition
* Degradation in vitro drug/protein delivery test
* Insulin release in vivo on Female Sprague-Dawley rats.
Part I
Control of insulin release rate in vivo
* Controlled insulin release using Female Sprague-Dawley rats
* Controlled insulin release using diabetic fat rats
Control of degradation rate of anionic hydrogels
* Synthesis of new pH/Temperature sensitive hydrogels
Part II
Part III
Part IV
290
Acidic moiety : pKa(7.8-7.4)

- Acid group
(-COOH, -SH, - SONH-)
- Negative charge
-Complex with cationic drug

- Sulphamethazine
- Histidine

Basic moiety : pKb (6.2-7.5)

- Backbone amine group
- Pendent amine group
(Tertiary & secondary amine)
- Possitive charge
- Complex with anionic drug

- Screening work (also FDA list)
Poly(amino acid) derivatives
Poly(amido amine) derivatives

Screening works
Screening works of pH-sensitive moiety
A --- --B----- C--- --B-- --- A
pH-sensitive block
Temperature-sensitive block
pH-sensitive block
291
Candidate -Amino ester pH-sensitive moiety
Di-acrylate
Di-amine
NH HN O
O
O
O
4,4 trimethylene dipiperidine 1,4-Butane diol diacrylate
292
0.1N NaOH aqueous solution(ml)
0 2 4 6 8 10 12 14
p
H
1
2
3
4
5
6
7
8
9
10
11
12
-Amino ester
pK
b
= 6.50 - 6.75
H
2
C
C
H
2
H
2
C
N
H
2
C
C
H
2
H
2
C
C
H
2
C
C
H
2
H
2
C
O
O C
H
2
C
C
H
2
O
O
*
N
*
n
293
ionization deionization
As pH sensitive moiety is ionized, polymer solution will be a sol state.
pK
b

Ionization / deionization of pH-sensitive moiety
N O N O
O O
n
B-C-B
N O N O
O O
n
pH-sensitive block pH-sensitive block
Temperature
sensitive block
pH sensitive block (moiety)
294
Synthesis of PAE-PCL-PEG-PCL-PAE
PCL-PEG-PCL triblock polymer
Sn(Oct)
2
130
o
C
+ O
O
HO
H
2
C
H
2
C O H
n
H
2
C
H
2
C O
n
C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O H
x
O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O H
x
O PCL PEG PCL O C C
H
CH
2
O
C
O
C
H
H
2
C
PAE-PCL-PEG-PCL-PAE
NH HN
+

O
O
O
O
+

50
o
C
O PCL PEG PCL O C C
H
CH
2
O
C
H
C H
2
C
O
DCM
N N
O
O
O
O
O
O
N N
O
O
O
O
O
n
PCL PEG PCL O
n
Cl C
O
C
H
CH
2
HO-PCL-PEG-PCL-OH
HO-PCL-PEG-PCL-OH (yield 85%)
Pentablock copolymer product (powder form, yield 85%)
Acrylated PCL-PEG-PCL
295
Characterization of PAE-PCL-PEG-PCL-PAE
G3 G1
6.0 5.0
ppm
2 . 0 3 . 0 4 . 0 5 . 0 6 . 0
A, A
C
B,F
D E
G2
O
H
2
C
H
2
C O
H
2
C
H
2
C O
H
2
C
H
2
C O
n-2
C
H
2
C
O
H
2
C
H
2
C
H
2
C
H
2
C O C
O
C
H
C
H
H
y
A A A' A' B
B
C D G1 G2
G3
D' E F
PEG
CL
Acrylate
Acrylate
1
H-NMR spectrum of acrylated PCL-PEG-PCL
296
ppm
2 . 0 3 . 0 4 . 0 5 . 0 6 . 0
PEG
CL
A, E
B C
G
F
D
N N
O
O
O
O
O
O
n PCL PEG PCL PAE
G G E E D A A A D B C H H
Aminoester
1
H-NMR spectrum of PAE-PCL-PEG-PCL-PAE
297
GPC traces of tri- and pentablock copolymers
Elution time
R
I

r
e
s
p
o
n
s
e

s
i
g
n
a
l
Triblock (PEG 1650, PCl/PEG 1.8/1)
Pentablock (PEG 1650, PCL/PEG 1.8/, PAE 1.26k)
298
PCL-PEG-PCL
(Mn
a
)
PEG/PCL
(wt ratio)
PEG
(Mn)
PAE-PCL-PEG-PCL-PAE
b
PAE-PCL-PEG-PCL-PAE
c
PDI
984-1500-984 1/1.3 1500 2000-984-1500-984-2000 1285-984-1500-984-1285 1.43
1110-1500-1110 1/1.5 1500 2000-1110-1500-1110-2000 1301-1110-1500-1110-1301 1.46
1364-1500-1364 1/1.8 1500 1000-1364-1500-1364-1000 762-1364-1500-1364-762 1.35
1364-1500-1364 1/1.8 1500 2000-1364-1500-1364-2000 1225-1364-1500-1364-1225 1.45
1364-1500-1364 1/1.8 1500 3000-1364-1500-1364-3000 1925-1364-1500-1364-1925 1.52
1364-1500-1364 1/1.8 1500 4000-1364-1500-1364-4000 2345-1364-1500-1364-2345 1.58
1104-1650-1104 1/1.3 1650 2000-1104-1650-1104-2000 1249-1104-1650-1104-1249 1.42
1262-1650-1262 1/1.5

1650 2000-1262-1650-1262-2000 1287-1262-1650-1262-1287 1.43
1572-1650-1572 1/1.8

1650 2000-1572-1650-1572-2000 1267-1572-1650-1572-1267 1.41
1310-1750-1310 1/1.5

1750 2000-1310-1750-1310-2000 1254-1310-1750-1310-1254 1.43
a Number-average molecular weight calculated from
1
H-NMR
b Number-average molecular weight (feed ratio)
c Number-average molecular weight calculated from GPC
Molecular weight and PDI of block copolymers
299
Concentration (wt%) (pH 7.4)
5 10 15 20 25 30
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Control of phase diagram : PEG mol. wt. effect
PAE-PCL-PEG-PCL-PAE (PCL/PEG~1.5/1; PEA~1.25k)
pH (20wt%)
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Gel
Sol (Sedimentation)
Sol
Gel
Sol (Sedimentation)
PEG 1.5k
PEG 1.75k
PEG 1.65k
300
Concentration (wt%) (pH 7.4)
5 10 15 20 25 30
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Gel
Sol (Sedimentation)
PCL/PEG ~1.3/1
PCL/PEG ~1.5/1
PCL/PEG ~1.8/1
pH (20wt%)
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Gel
Sol (Sedimentation)
PAE-PCL-PEG-PCL-PAE (PEG 1.65k; PEA~1.25k)
Control of phase diagram: PCL/PEG ratios
301
pH (20wt%)
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Gel
Sol (Sedimentation)
PAE-PCL-PEG-PCL-PAE (PEG1.5k; PCL/PEG~1.8)
-amino ester 1.25k
-amino ester 0.76k
-amino ester 1.95k
-amino ester 2.35k
-amino ester 0k
Control of phase diagram: PAE mol.wt effect
302
PAE-PCL-PEG-PCL-PAE (PEG1.65k; PCL/PEG~1.8)
Sol state at
pH 6.4, 10 C
Gel state at
pH 7.4, 37 C
Tem. & pH
So-Gel phenomena
20 wt%
25 wt%
30 wt%
Control of phase diagram: Polymer conc. effect
pH
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Gel
Sol (Sedimentation)
S
G
G
S
303
pH (20wt% copolymer)
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
0 mg/ml insulin
5 mg/ml insulin
10 mg/ml insulin
Sol (Sedimentation)
Gel
sol
(PEG1.65k; PCL/PEG~1.8/1; PAE~1.25k)
copolymer solution (20%)

In vitro
Control of phase diagram: Loading insulin effect
304
*Cell line: NIH 3T3 (fibroblast).
*Growth medium: DMEM
(90% Dulbeccos modified
Eagles medium, 10% fetal
calf serum, penicillin 100
units/mL, streptomycin
100 g/mL).
* XTT assay
(XTT :2,3-bis(2-methoxy-
4-nitro-5-susfophenyl)-
2H-tetrazolium-5-carbox
anilide)
* 96-well plates, incubator.
Microplate reader.

Cytotoxicity of PAE-PCL-PEG-PCL-PAE in vivo test
PAE-PCL-PEG-PCL-PAE (PCL/PEG~1.5; PAE~1.25k)
0
20
40
60
80
100
120
0
20
40
60
80
100
120
PEI
PEG1500
PEG1650
PEG1750
R
e
l
a
t
i
v
e

c
e
l
l

v
i
a
b
i
l
i
t
y

(
%
)
P
o
l
y
m
e
r

C
o
n
c
.

(
g
/
m
l
)
305
Degradability evaluation
Time (days)
0 10 20 30 40 50
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
0
2000
4000
6000
8000
PCL-PEG-PCL
PAE-PCL-PEG-PCL-PAE
Complex Gel (5 mg/ml of Insulin in coplymer solution)
(PEG1.65k; PCL/PEG~1.8/1; PAE~1.25k)
copolymer solution (20%)

In vitro
37
o
C and pH 7.4
306
Insulin loading & release in vitro
Step 1
Step 2 Step 3
Sampling
method 1
Sampling
method 2
1. 0.5 ml of the complex mixture at pH 7.4 is placed in a 6 ml vial
2. The sample vials were incubate at 37
o
C for 30 min, at 37
o
C is added to the vial samples.
3. Sampling the insulin release to serum by two methods:
Method 1: The amount of beginning fresh serum was 3 ml. At a given time, 1.5 ml of the serum in vials (releasi
ng sample) was extracted from the vial samples, and 1.5 ml of fresh serum was supplemented.
Method 2: The amount of beginning fresh serum was 6 ml. At a given time, the releasing sample was 3 mle, and
fresh serum supplemented was 3 ml.

Mixture
307
Insulin release in vitro
Time (days)
0 10 20 30 40
C
u
m
u
l
a
t
i
v
e

r
e
l
e
a
s
e

o
f

i
n
s
u
l
i
n

(
%
)
0
20
40
60
80
100
PCL-PEG-PCL gel. Sampling method 1
Complex gel. Sampling method. 1
Triblock and pentablock (PEG 1.65k; PCL/PEG~1.8/1; PAE~1.25k)
5 mg/ml insulin in copolymer solution (20%)
Time (days)
0 10 20 30 40
I
n
s
u
l
i
n

c
o
n
c
e
n
t
r
a
t
i
o
n

i
n

s
e
r
u
m

(
m
g
.
m
l
-
1
)
0.0
0.2
0.4
0.6
0.8
1.0
PCL-PEG-PCL gel. Sampling method 1
308
Insulin loading & release in vivo ; SD rats
Tail cutting blood
Sampling
Mixture pH 7.0
and 10 oC
Subcutaneous
injection (200 l/rat)
Insulin solution
0.25mg/ml
Injection
200 l/rat
Tail cutting blood
Sampling
Centrifuging to
get Serum
Centrifuging to
get Serum
Insulin assay
Insulin assay
309
Insulin release in vivo ; SD rats
Time (days)
0 5 10 15 20 25
I
n
s
u
l
i
n

i
n

p
l
a
s
m
a

o
f

b
l
o
o
d

(
m
U
.
l
-
1
)
0
1000
2000
3000
4000
Insulin only
Insulin - PCL-PEG-PCL gel
Complex gel
Time (hours)
0 10 20 30 40 50
I
n
s
u
l
i
n

i
n

p
l
a
s
m
a

o
f

b
l
o
o
d

(
m
U
.
l
-
1
)
0
1000
2000
3000
4000
PAE-PCL-PEG-PCL-PAE (PEG 1.65k; PCL/PEG~1.8; PAE~1.25k)
5 mg/ml insulin in copolymer solution (25 wt%)
310
PEG hydrophilic
Amino ester ionized
Amino ester de-ionized
hydrophobic
PCL hydrophobic
Insulin
Negative charge on Insulin
B
C
A. Copolymer solution and insulin
at 10
o
C and pH 5.0
B. Complex gel of copolymer and
insulin at 37
o
C and pH 7.4
C. Insulin releasing depend on the
degradation of copolymer at 37
o
C
and pH 7.4
PAE-PCL-PEG-PCL-PAE at
low pH and low temperature
PAE-PCL-PEG-PCL-PAE at high
pH and high temperature
A
Expected mechanism of insulin release
311
Part I Conclusion
PAE-PCL-PEG-PCL-PAE pentablock copolymers were successfully
synthesized with a high purity and yield.
Gel phase diagram of PAE-PCL-PEG-PCL-PAE can be controlled by;
- PEG mol. wt.
- PCL/PEG ratio and the concentration
- PAE mol. wt.
PAE-PCL-PEG-PCL-PAE pentablock copolymer shows
- Gel stage at pH 7.4 & 37
- Sol stage at pH 6.4 & 10
PAE plays as a duo-functional group:
- pH-sensitive moiety.
- Encapsulation of insulin by forming ionic complex.
The dominant factor of insulin release mechanism is degradation of
PAE block copolymer.

312
Contents
Part I
Part II
Part III
Part IV
313
Tail cutting blood
Sampling
Mixture pH 7.0
and 10
o
C
Subcutaneous
injection (200 l/rat)
Centrifuging to
get Serum
Insulin
assay
Materials
Pentablock copolymer (PEG 1.65k; PCL/PEG~1.8/1; PAE~1.25k)
Insulin formulations:
Controlled Insulin release in vivo on SD rats
0.75 mg/ml insulin in coplex gel (20wt%)
5 mg/ml insulin in coplex gel (20wt%)
314 Time (days)
0 5 10 15 20 25
I
n
s
u
l
i
n

i
n

p
l
a
s
m
a

o
f

b
l
o
o
d

(
m
U
.
l
-
1
)
0
200
400
600
800
1000
1200
1400
1600
1800
0.75 mg/ml insulin in coplex gel (20wt%)
Time (days)
-0.5 0.0 0.5 1.0 1.5 2.0
I
n
s
u
.

i
n

p
l
a
s
m
a

(
m
U
.
l
-
1
)
0
200
400
600
800
1000
1200
1400
1600
PAE-PCL-PEG-PCL-PAE (PEG 1.65k;PCL/PEG~1.8; PAE~1.25k)
Controlled Insulin release in vivo on SD rats
315
Treatment the Diabolical disease on DFR
SD rats DFR rats making
STZ
solution
Intraperitioneal
injection to SD rats
Tail cutting blood sampling
DFR, Glucose assay
Complex mixture
pH 7.0 and 10 oC
Subcutaneous
injection
DFR induced from SD rats
1. Streptozotocin (STZ) injected: 60
mg.kg
-1.
Treatment the Diabolical disease
1. PAE-PCL-PEG-PCL-PAE (PEG
1.65k; PCLA/PEG~1.8/1; PAE~
1,25k)
2. Copolymers solution
concentration: 30 wt%.
3. Insulin in the complex mixture 1-
10 mg.ml
-1
4. Complex mixture injected: 200l.
5. Blood sampling from the rat tail
vein.
Treatment the Diabetical disease on DFR
Centrifuging to
get Serum
Insulin assay
Tail cutting blood sampling
DFR, Glucose assay
316
Change of glucose conc. with time
Glucose concentration in blood of diabetic rat
with insulin-hydrogel complex
Time (days)
-5 0 5 10 15 20 G
l
u
c
o
s
e

c
o
n
c
e
n
t
r
a
t
i
o
n

i
n

b
l
o
o
d

(
m
g
/
d
L
)
0
100
200
300
400
500
600
700
Control
1 mg insulin/ml polymer solution (30 wt%)
Complex gel injected
STZ injected
317
Insulin concentration
in blood of Diabetic rat
Time (days)
0 5 10 15 20
I
n
s
u
l
i
n

i
n

p
l
a
s
m
a

o
f

b
l
o
o
d

(
m
U
/
l
)
0
50
100
150
200
250
Control
5 mg insulin/ml polymer solution (30wt%)
Complex gel Injected
Change of insulin conc. with time
318
Body weight of diabetic rat
with insulin-hydrogel complex
Time (days)
-5 0 5 10 15 20
B
o
d
y

w
e
i
g
h
t

(
g
)
100
150
200
250
300
350
Control
Complex gel Injected
STZ injected
Change of body weight with time
319

The steady level of insulin concentration in blood can be controlled by
- Insulin formulations
- Copolymer concentration

Diabetes rats can be treated by a single injected of the complex gel
with the therapeutic treatment: 10mg/ml of insulin in PAE-PCL-PEG-
PCL-PAE (PEG 1.65k; PCLA/PEG~1.8/1; PAE~ 1,25k); 200 l/rat of
complex mixture; repeat injection time: 10 days.

Insulin concentration in blood plasma is lower than upper limit of
Part II Conclusion
320
Contents
Part I
Part II
Part III
Part IV
321
Biodegradability of Triblock copolymer
PCLA-PEG-PCLA
H
2
C
H
2
C O C
n
O
H
C O C
H
2
C
H
2
C
CH
3
O
H
2
C
H
2
C
H
2
C O
x
H
y
C
O
C
H
O C
H
2
C
H
2
C
CH
3
O
H
2
C
H
2
C
H
2
C O
x
H O
y
PCL-PEG-PCL
H
2
C
H
2
C O
n
C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O H
x
O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O H
x
322
Acrylated PCLA-PEG-PCLA
Cl C
O
C
H
CH
2
+

Acrylation in
Chloroform
PAE-PCLA-PEG-PCLA-PAE
NH HN
+

O
O
O
O
+

50
o
C
10
o
C
4,4 trimethylene dipiperidine 1,4 Butane diol diacrylate
HO PCLA PEG PCLA OH
O PCLA PEG PCLA O C C
H
CH
2
O
C
H
C H
2
C
O
O PCLA PEG PCLA O C C
H
CH
2
O
C
H
C H
2
C
O
N N
O
O
O
O
O
O
N N
O
O
O
O
O
n PCLA PEG PCLA O
n
DCM
Acryloyl chloride Triblock copolymer
Synthesis of PAE-PCLA-PEG-PCLA-PAE
Pentablock copolymer (Yield 71 %)
323
PAE-PCLA-PEG-PCLA-PAE (PCLA/PEG~2.0/1; PEA~1.3k)
Concentration (wt% at pH 7.4)
5 10 15 20 25 30 35
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
PEG 1500
PEG 1750
PEG 2000
Sol
Gel
Sol (Sedimentation)
pH (20wt%)
6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
PEG 1500
PEG 1750
PEG 2000
Sol
Gel
Sol (Sedimentation)
PEG 1.75k
PEG 1.5k
PEG 2.00k
Control of phase diagram: PEG mol.wt. effect
324
Concentration (wt% at pH 7.4)
0 5 10 15 20 25 30 35
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
PCLA/PEG = 2.0/1
PCLA/PEG = 2.2/1
PCLA/PEG = 2.5/1
Sol
Gel
Sol (Sedimentation)
PAE-PCLA-PEG-PCLA-PAE (PEG1.5k; PEA~1.3k)
pH (20 wt%)
6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
PCLA/PEG = 2.0/1
PCLA/PEG = 2.2/1
PCLA/PEG = 2.5/1
Sol
Gel
Sol (Sedimentation)
Control of phase diagram: PCLA/PEG ratio effect
325 pH ( 20 wt%)
5.5 6.0 6.5 7.0 7.5
T
e
m
p
e
r
a
t
u
r
e

(
o
C
)
0
10
20
30
40
50
60
Sol
Sol (Sedimentation)
Gel
PAE-PCLA-PEG-PCLA-PAE (PEG1.5k; PCLA/PEG~2.5/1)
-amino ester 0.8k
-amino ester 1.3k
-amino ester 2.0k
-amino ester 2.55k
-amino ester 0k
Control of phase diagram: PAE mol.wt. effect
326

In vitro
Time (days)
0 10 20 30 40 50
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
0
2000
4000
6000
8000
PCLA-PEG-PCLA
PAE-PCLA-PEG-PCLA-PAE
Complex Gel (5 mg/ml of Insulin in coplymer solution)
Degradation of PAE-PCLA-PEG-PCLA-PAE
(PEG 1.5k; PCLA/PEG~2.5;PEA~1.3k) copolymer solution (20%)
37
o
C and pH 7.4
327
Time (days)
0 10 20 30 40 50
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
2000
3000
4000
5000
6000
7000
8000
Pentablock gel 1
Complex Gel 1
Pentablock gel 2
Pentablock gel 2
Time (days)
0 10 20 30 40 50
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
3000
3500
4000
4500
5000
5500
Triblock gel 1
Triblock gel 2
In vitro
Group 2: PAE-PCL-PEG-PCL-PAE
(PEG 1.65k; PCL/PEG~1.8;PEA~1.25k)
Triblock gel:PCL-PEG-PCL
pentablock gel: PAE-PCL-PEG-PCL-PAE
Complex gel: 5mg/ml insulin in pentablock
solution
Group 1: PAE-PCLA-PEG-PCLA-PAE
(PEG 1.5k; PCLA/PEG~2.5;PEA~1.3k)
Triblock gel:PCLA-PEG-PCLA
pentablock gel: PAE-PCLA-PEG-PCLA-PAE
Complex gel: 5mg/ml insulin in pentablock
solution
Degradability evaluation; PCLA vs. PCL system
37
o
C and pH 7.4
328
Change of gel integrity with time in vivo
PAE-PCL-PEG-PCL-PAE (PEG1.65k; PCL/PEG~1.8/1; PAE~1.25k)
1 day
1 week 2 week 4 week 7 week
1 day 1 week 2 week 3 week 4 week
PAE-PCLA-PEG-PCLA-PAE (PEG1.5k;PCLA/PEG~2.5/1; PEA~1.3k)
329
Comparisons of release rate; PCLA vs. PCL system
5 mg/ml Insulin in complex gel (20wt%)- sampling method 1
Time (days)
0 10 20 30 40
C
u
m
u
l
a
t
i
v
e

R
e
l
e
a
s
e

o
f

I
n
s
u
l
i
n

(
%
)
0
20
40
60
80
100
Complex gel 1
Complex gel 2
Group 2: PAE-PCL-PEG-PCL-PAE
(PEG 1.65k; PCL/PEG~1.8;PEA~1.25k)
Triblock gel:PCL-PEG-PCL
pentablock gel: PAE-PCL-PEG-PCL-PAE
Complex gel 2: 5mg/ml insulin in
pentablock solution
Group 1: PAE-PCLA-PEG-PCLA-PAE
(PEG 1.5k; PCLA/PEG~2.5;PEA~1.3k)
Triblock gel:PCLA-PEG-PCLA
pentablock gel: PAE-PCLA-PEG-PCLA-PAE
Complex gel 1: 5mg/ml insulin in
pentablock solution
330
Degradation rate of these hydrogel depends on the biodegradability
property of each block polymer.

Gel integrity of PAE-PCLA-PEG-PCLA-PAE was changed within 4
week after injected to rat, whereas it takes 7 week for PAE-PCL-PEG-
PCL-PAE system.

The dominant factor of insulin release is the degradation of hydro
gels. The secondary factor is diffusion release.

Insulin release can be also controlled by the degradation rate of
copolymer hydrogels.

Part III Conclusion
331
Contents
Part I
Controlled insulin delivery in vivo
Part II
Part III
Part IV
332
Conventional pH-sensitive moiety
pH
5 6 7 8 9 10
%
T

0
20
40
60
80
100
120
0.5 wt %
1
2
sulfamethazine 20%
turbidity of polymer solution
CH
2
C CH
2
C O
NH
CH
3
S O O
CH
C O
N
H
3
C CH
3
N N
H
3
C CH
3
x
y
NH
pKa=7.4
333
ionization
deionization
As pH sensitive moiety is ionized, polymer solution will be a sol state.
pK
a

A-B-A
pH-sensitive block pH-sensitive block
Temperature sensitive block
pH sensitive block (moiety)
CH
2
C
C O
NH
CH
3
S
O
O
N
N
H
3
C
H
3
C
x
H
N
S
H
2
C
H
2
C COO
H
2
C C
C O
HN
CH
3
S
O
O
N
N
CH
3
CH
3
x
H
N
S
H
2
C
H
2
C OOC
Ionization / deionization of pH-sensitive moiety
334
H
2
C
H
2
C O C
n
O
H
2
C O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O
x
H
y
C
O
H
2
C O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O
x
H O
y
PCGA-PEG-PCGA
H
2
C
H
2
C O C
n
O
H
C O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O
x
H
y
C
O
C
H
O C
H
2
C
H
2
C
O
H
2
C
H
2
C
H
2
C O
x
H O
y
CH
3
CH
3
PCLA-PEG-PCLA
Biodegradability of Triblock copolymer
335
DCC, 4-DMAP
Biodegradable & Temperature-sensitive
pH -sensitive
pH -sensitive
NH
S O O
NH
N N
CH
3
CH
3
C
CH
2
S CH
2
CH
2
COOH C
CH
3
H
O
n
PCGA-PEG-PCGA
OSM C
O
CH
2
CH
2
C
O
O PCGA PEG PCGA O C
O
CH
2
CH
2
C
O
OSM
Synthesis of OSM-PCGA-PEG-PCGA-OSM
OSM-PCGA-PEG-PCGA-OSM pentablock copolymer
336
Ionic complex mechanism of PTX loading and releasing
Mechanism of anionic drug loading and release.
Advantages
Good absorption.
Ease to control drug level in the blood
between the desired maximum and
minimum for an extended period of time
Drug and matrix are a complete gel:
good mechanical property.
Ease to apply by injection.
Useful for cationic protein drug
Protein loading at pH 8.0, 15
o
C Gel formation at pH 7.4, 37
o
C
Sustained Release
(Degradation & Diffusion)
+
+ +
+
+
+
+
+
+
+
337
Time (day)
0 10 20 30 40
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
0
2000
4000
6000
8000
10000
OSM-PCGA-PEG-PCGA-OSM (904-2118-1750-2118-904)
PCGA-PEG-PCGA (2118-1750-2118)
Time (day)
0 10 20 30 40
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

(
M
p
)
2000
4000
6000
8000
10000
OSM-PCGA-PEG-PCGA-OSM (904-2118-1750-2118-904)
OSM-PCLA-PEG-PCLA-OSM (1114-1820-1750-1820-1114)
37
o
C and pH 7.4
338
Time (day)
0 4 8 12 16 20 24 28 32 36
C
o
m
u
l
a
t
i
v
e

R
e
l
e
a
s
e

o
f

P
T
X

(
%
)
0
20
40
60
80
100
PTX loading and release in vitro
OSM-PCGA-PEG-PCGA-OSM
(PEG 1750; PCGA/PEG= 2.67; OSM 904)
Time(day)
0 4 8 12 16 20 24 28 32 36
C
u
m
u
l
a
t
i
v
e

R
e
l
e
a
s
e

o
f

P
T
X

(
)
0
20
40
60
80
100
2.5 mg PTX/ml of polymer solution (20wt%)
5 mg PTX/ml of polymer solution (20wt%)
10 mg PTX/ml of polymer solution (20wt%)
OSM-PCLA-PEG-PCLA-OSM
(PEG 1750; PCGA/PEG= 2.67; OSM 904)
(Reference from Dr. Shim)
339
OSM-PCGA-PEG-PCGA-OSM pentablock copolymer shows
- Gel stage at pH 7.4 & 37.
- Sol stage at pH 8.0 & 37

The degradation rate of Anionic pH/temperature sensitive hydrogels
can be controlled by replace LA with GA, which have the better
biodegradability

PTX release from anionic hydrogel was effected by copolymers
degradation. More than 90% of the PTX drug was released from
OSM-PCGA-PEG-PCGA-OSM after 21 days, while it taken 29 days in
the case of OSM-PCLA-PEG-PCLA-OSM

Part IV Conclusion
340
1. Doo Sung Lee, Dai Phu Huynh, Woo Sun Shim, Min Sang Kim, Bong Sup Kim. pH &
temperature-sensitive anionic hydrogel, Korea patent, 10-2004-0005586, 10-2006-
0049376(2006.6.1 Registered).

2. Doo Sung Lee, Je Sun Yoo, Dai Phu Huynh, Min Sang Kim, Minh Khanh Nguyen, Bong Sup Kim,
Woo Sun Shim, Korean Patent, 10-2005-0030834(2005.4.13).

3. Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Huynh Dai Phu, "pH
and Temperature Sensitive Hydrogels", Application No. PCT/KR2005/000207 (Jan. 26, 2005),
Publication No. WO 2005/073281 A1(Aug. 11, 2005).

4. Doo Sung Lee, Je Sun Yoo, Huynh Dai Phu, Bong Sup Kim, Min Sang Kim, Nguyen Minh Khanh,
"pH and Temperature Sensitive Hydrogels" Application No. PCT/KR2006/001185 (Mar. 31, 2006),
Publication No. WO 2006/109945 A1(Oct. 19. 2006).

5. Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Huynh Dai Phu, "pH
and Temperature Sensitive Hydrogels", USA 2006/USP10/590959, Jan.26, 2005(Application).

6. Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Huynh Dai Phu, "pH and
Temperature Sensitive Hydrogels" China 2006-80010601.X, Sep.29, 2006(Application).

Temperature Sensitive Hydrogels" Japan 2007-58882, Mar.8, 2007(Application).

Patents
341

Temperature Sensitive Hydrogels" EU(31), EP 05 710 824.3, Jan.26,2005(), Aug. 29,
2006 (). (Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Huynh
Dai Phu, "pH and Temperature Sensitive Hydrogels" EU(31 countries), EP 05 710 824.3,
Jan.26,2005(Application)).

9. , , , , , , pH , 10-
2004-0005586(2004.1.29) 10-2006-0641270(2006.10.25). (Doo Sung Lee, Woo Sun Shim, You Han
Bae, Je Sun Yoo, Min Sang Kim, Huynh Dai Phu, Temperature and pH Sensitive Hydrogels, Korea
patent application 10-2004-0005586(2004.1.29) registered 10-2006-0641270(2006.10.25)).

10. , , , , , , pH
, 10-2005-0030834(2005.4.13), 10-2006-
0109269(2006.10.19), 10-2006-0665672(2006. 12. 29). (Doo Sung Lee, Woo Sun Shim, Huynh Dai
Phu, Min Sang Kim, Nguyen Minh Khanh, Bong Sup Kim, Novel Temperature and pH Sensitive
block copolymer and application of polymer-hydrogels, Korea patent application 10-2005-
0030834(2005.4.13), Open 10-2006-0109269(2006.10.19), Registered 10-2006-0665672(2006. 12. 29)).

11. , , , , , , pH
2007-0015586 (2007.2.14). (Doo Sung Lee,
Min Sang Kim, Huynh Dai Phu, Bong Su Pi, Nguyen Minh Khanh, Bong Sup Kim, Su Young Jae
Temperature and pH Sensitive block copolymer apply for injectable drug carrier and drug delivery
application Korea patent application 2007-0015586 (2007.2.14)).

Patents
342
<Papers published>

1. Dai Phu Huynh, Woo Sun Shim, Ji Heung Kim, Doo Sung Lee.
pH/temperature sensitive poly(ethylene glycol)-based biodegradable
polyester block copolymer hydrogels. Polymer (2006), 47(23), 7918-7926.

<Papers Submitted>

1. D. P. Huynh, M. K. Nguyen, B. S. Pi, M.S. Kim, S. Y. Chae, K. C. Lee, B. S. Kim,
S. W. Kim, D. S. Lee, A new functionalized injectable hydrogel for controlled
insulin delivery. (Submitted to Advanced Materials)

2. D. P. Huynh, B. S. Kim, D. S. Lee, Controlled release of insulin by a new
functionalized injectable hydrogel. (Submitted to J. Controlled Release)

3. D. P. Huynh, M. K. Nguyen, M.S. Kim, B. S. Kim, D. S. Lee, pH/temperature
sensitive Injectable-biodegradable hydrogel with duo-functional of pH moiety for
anionic drug/protein delivery (manuscript in preparation for Biomaterials).

Paper
343
Paper
<Papers Submitted>

4. D. P. Huynh, M. K. Nguyen, M.S. Kim, B. S. Kim, D. S. Lee, Controlled the
degradation of pH/temperature sensitive Injectable-biodegradable hydrogel for
anionic drug/protein delivery (manuscript in preparation for
Biombiomacromolecules)

5. M. K. Nguyen, D. P. Huynh, M.S. Kim, B. S. Kim, D. S. Lee, Modified pH
sensitive moiety block copolymer of pH/temperature Injectable-biodegradable
hydrogel for anionic drug/protein delivery (manuscript in preparation for Polymer)

6. M. K. Nguyen, D. P. Huynh, B. S. Pi, B. S. Kim, D. S. Lee, Controlled release of
Human growth homone based on pH/temperature Injectable-biodegradable
hydrogel for anionic drug/protein delivery (manuscript in preparation for
J.Controlled Release)

344
Vt liu v Polimer y sinh
Chng 8
345
S pht trin ca polimer y sinh
Vt liu y sinh l vt liu tng hp c s
dng ch to cc b phn thay th
trong c th sng hoc hot ng tip xc
vi t bo sng.
Vt liu y sinh l cc cht tr vi c th v
tr dc tnh c ch to lp ghp
hoc kt hp vi c th sng. Vt liu y
sinh khng phi l vt th sng dng trong
y hc nhm tng tc vi c th sng
346
Vt liu y sinh l vt liu tng hp hoc vt liu
c ngun gc thin nhin s dng trong vic
thay th, chun on, iu tr, hoc lu gi m
khng c hiu ng xu i vi cc t bo sng
hoc b phn ca n. (Black, 1992)
Vt liu y sinh l bt c cht no hay hn hp
ca chng c ngun gc tng hp hay thin
nhin c s dng bt c thi gian no, ton
phn hay mt phn dng iu tr, tng cng,
hay thay th m, c quan, hay b phn chc
nng ca c th (Bruck, 1980)
347
Vt liu y sinh c th l:
Kim loi: thp khng r, hp kim Co-Cr, hp
kim Ti
Ceramic: calcium phosphat, aluminum calcium
phosphat (ALCAP), zinc-calcium phosphorous
oxide (ZCAP) , zinc sulphat calcium phosphat
(ZSCAP)
Polime: PVC, PE, PP, PMMA, PS, Poliester,
poliamid, cao su, Policarbonat,polisulfon .
348
Tnh tng hp sinh hc v tnh bn sinh
hc
L kh nng vt liu thc hin trn mt ch
th thch hp cho mt ng dng chuyn bit
Tnh tng hp l mi quan tm u tin i
vi hin tng b mt
349
Polimer y sinh tng hp
u im
Tng thch sinh hc tt
Thnh phn v tnh cht vt l c th kim
sot d dng
H s ma st thp
D gia cng
Kh nng bin tnh b mt d dng
C kh nng c nh t bo hay cc phn t
sinh hc (drug eluting stent)
350
Nhc im:
C nhng cht c th a vo trong c th
[monome (c), xc tc, ph gia ) sau khi
phn hy
D hp thu nc v cc phn t sinh hc t
c th
Tnh cht c hc thp
i khi kh tit trng
351
Bioengineers
Material Scientists
Immunologists
Chemists
Biologists
Surgeons
...
Muhammad Wasim Akhtar
352
Organ/Tissue Examples
heart pacemaker, artificial valve, artificial heart
eye contact lens, intraocular lens
ear artificial stapes, cochlea implant
bone bone plate, intramedullary rod, joint
prosthesis, bone cement, bone defect
repair
kidney dialysis machine
bladder catheter and stent
muscle sutures, muscle stimulator
circulation artificial blood vessels
skin burn dressings, artificial skin
endocrine encapsulated pancreatic islet cells
353
Important dates
1860's: Lister develops aseptic surgical technique
early 1900's: Bone plates used to fix fractures
1930's: Introduction of stainless steel, cobalt chromium alloys
1938 : first total hip prosthesis (P. Wiles)
1940's: Polymers in medicine: PMMA bone repair; cellulose for
dialysis; nylon sutures
1952: Mechanical heart valve
1953: Dacron (polymer fiber) vascular grafts
1958: Cemented (PMMA) joint replacement
1960: first commercial heart valves
1970's: PEO (polyethyleneoxide) protein resistant thin film coating
1976: FDA ammendment governing testing & production of
biomaterials /devices
1976: Artificial heart (W. Kolff, Prof. Emeritus U of U)

354
355
356
357
358
359
360
361
362
363
Chn la vt liu sinh hc: Vic chn la
vt liu sinh hc da trn 2 yu t:
Tnh cht c l: bn v bin dng; tnh
cht mi v ro; s ma st v mi mn; tr lc
chy v gim p cng nh mt s tnh cht k
thut khc.
Tnh tng hp sinh hc: bao gm mt s v
vt liu v cc hn ch llin quan n tng
tc gia vt liu v m. Cc yu t ny c
th nghim in-vitro v in-vivo
364
Phn loi
Phn loi theo ngun gc:
Polime tng hp: Silicon, PE, PVC, PUR, PLA
..
Polime t nhin: collagen, gelatin, la,
polisaccarid
Phn loi theo tnh nng:
Polime khng phn hu sinh hc: Cc polime
nh PVC, PE, PP, PS, PMMA, PA, PC .
Polime phn hy sinh hc: PLA, PGA, PLGA,
polidioxanon .
365
Phn loi theo th h
Th h th nht: tr
Khng gy ra mt phn ng no i vi ch
th: khng chp nhn cng khng b thi loi
Khng c kt qu tt.
Th h th hai: hot tnh sinh hc
m bo n nh tnh nng trong thi gian
di
Th h th 3: phn hy sinh hc
C th phn hy bi ha cht hoc cc tc
nhn t nhin (thi tit, vi sinh, thc vt )
366
Vt liu cy ghp th h th nht:
Do cc nh vt l thc hin, s dung cc loi
vt liu thng dng hoc vay mn.
S thnh cng l do tnh c hn l do thit k
Th d:
Chnh rng bng nha PMMA
Cc khp bng thp khng r, vng, ng
Mt thy tinh
Mch mu bng dacron
367
Intraocular Lens
3 basic materials - PMMA, acrylic, silicone
368
Vascular Grafts
369
Vt liu cy ghp th h th hai:
c thit k k thut, s dung cc loi vt liu thng
dng hoc vay mn.
L kt qu ca s phi hp cu nh vt l v k s
Da trn kinh nghim ca th h th nht
S dng cc tin b ca khoa hc vt liu
Th d:
S dng hp kim titan trong chnh hnh rng
Dng UHMW PE bc khp
Ch to van tim v mch iu khin nhp tim
370
Artificial Hip Joints
http://www.totaljoints.info/Hip.jpg
371
Substitute Heart Valves
372
Vt liu cy ghp th h th ba:
S dng vt liu y sinh .
Mt s b phn bng polimer
Mt s vt liu ang nghin cu pht trin
Th d:
Cy ghp m
Cy da nhn to
Keo dn xng ti to
373
Synthetic polymer scaffolds

... in the shape of a nose (left) is "seeded" with cells called
chondrocytes that replace the polymer with cartilage over time
(right) to make a suitable implant.
374
SEM displaying the cross section of a composite disk,
which had been seeded with cultured bone marrow
stromal cells.

375
ng dng
376
377
Chnh hnh:
UHMW PE c ng bc khp gi bng ceramic
Nha khoa:
Lm khung hay rng gi
Tim mch: nhiu loi vt liu c s dng ty
theo thit k.
ng dn cho b iu khin nhp tim bng PUR
Gii phu thm m:
Silicon l loi polie thng dng trong lnh vc ny
378
VT LIU COMPOSITE CHO CC B
PHN GI CHO NGI
379
BIOMEDICAL APPLICATION OF POLYMER-COMPOSITE
COMPOSITE FOR HIP REPLACEMENT
COMPOSITE FOR PROSTHETIC LIMB
Vt liu y sinh dng trong nha khoa
NI DUNG
380
1. BIOMEDICAL APPLICATION OF POLYMER-COMPOSITE
The various materials used in biomedical applications :(a) metals, (b)
ceramics, (c) polymers, and (d) composites made from various
combinations
Metals:
High strength, ductility, and resistance to wear.
Low biocompatibility, corrosion, too high stiffness compared to tissues, high
density, and release of metal ions which may cause allergic tissue reactions.
Ceramics:
Good biocompatibility, corrosion resistance, and high compression resistance.
Brittleness, low fracture strength, difficult to fabricate, low mechanical
reliability, lack of resilience, and high density.
Polymer composite materials provide alternative choice to overcome many
shortcomings of homogenous materials mentioned above.
The special advantages of polymer composites are highlighted in the
following.
381
Reasons for the development of polymer composite biomaterials include:
absence of corrosion and fatigue failure of metal alloys and release of metal
ions such as Nickel or Chromium which may cause loosening of the implant,
patient discomfort, and allergic skin reactions; and low fracture toughness of
ceramic materials which make them a difficult choice forload bearing
applications.
Composite materials offer several other significant advantages over metal
alloys and ceramics in correcting the above mentioned
Metals alloys and ceramics are radio opaque and in some cases they result in
undesirable artifacts in X-ray radiography. In the case of polymer composite
materials the radio transparancy can be adjusted by adding contrast medium
to the polymer. Moreover the polymer composite materials are fully compatible
with the modern diagnostic methods such as computed tomography (CT) and
magnetic resonance imaging (MRI) as they are non-magnetic.
Considering their light weight and superior mechanical porperties, the polymer
composites are also used as structural components of these imaging devices.
Some times, the unreinforced polymers may not have properties sufficient for
intended application.
1. BIOMEDICAL APPLICATION OF POLYMER-COMPOSITE
382
Various applications of dierent
polymer composite biomaterials.
383
2. COMPOSITE FOR HIP REPLACEMENT
hip replacement
384
normal hip cartilage

arthritic hip cartilage

385
Total hip replacement (THR) is the most common
artificial joint in human beings.
For example, over 150,000 total hip replacements are
performed every year in USA alone.
Over the years the design of total hip replacement
evolved completely from a simple intuitive design to
biomechanics based functional design.
386
A typical THR consists of:
+ cup acetabular component
+ femoral component whose head is designed to
fit into the acetabular cup, thus enabling joint
articulations.
The shaft of the femoral component (also called
femoral stem) is tapered such that it can be fixed
into a reamed medullary canal of the femur
387
388
Materials:

389
390
The manufacturing of femoral stem
using polymeric matrix composites can
be done using various fabrication
methods based on reinforcement
phase geometry
The methods based on particulate
and short ber reinforcement
usually produce near isotropic
properties, and are hence ruled out
for the stem design
391
392
393
Mechanics of hip prosthesis
394
3. COMPOSITE FOR PROSTHETIC LIMB
These materials are limited by their weight, and poor durability due to
corrosion and moisture induced swelling. As a result the user is often
restricted to slow and non-strenuous activities.
So polymer composite materials made them ideal choice for modern
limbs systems
Material
Thermoset polymer
composites reinforced with
glass, carbon, or Kevlar fibers
are widely used in these
systems. A typical artificial leg
system consists of three parts
namely
Socket
Shaft
Foot
395
Sockets can be divided into two categories: direct and indirect sockets.
A widely used indirect socket is fabricated by wrapping several layers of
knitted or woven fabrics on a customized plastic mold, vacuuming the
fabrics enclosed in a plastic bag, and impregnating the vacuumed fabrics
with polyester resin. The socket is formed after the resin is cured under the
vacuum pressuring condition. It is reported that the performance of an
indirect socket depends mainly on the quality of the mold. Moreover, the
fabrication process is time-consuming and greatly influenced by the
prosthesist skills.
A direct socket, as the name suggests, is fabricated directly on the stump
of a patient, without using any kind of mold. Compared with indirect
sockets, the benefit of direct socket fabrication is that it can reduce the
amount of skill dependency in the creation of a socket and lead to
reduction of fitting errors between the stump and the socket. In addition,
the direct socket fabrication also reduces the number of patient visits and
improves service to the physically disabled people. The direct sockets
appeared in the market in recent years, are made using a combination of
knitted or braided carbon or glass fiber fabrics and water-curable (water-
activated) resins. As expected the braided fabric reinforced sockets are sti
and strong, whereas the knitted fabric reinforced sockets are flexible and
more conformable to the patient's stump
396
The shaft or stem is often made of lament wound or laminated
woven/braided fabric carbon fiber reinforced epoxy composites. It
provides structural support and force trasmittance to mimic the skeleton
397
The foot unit consists of heel and forefoot components, which are made of
laminated CF/epoxy composites and are designed to serve as flat spring-like
leaves so that the foot provides strong cushioning and energy storing effect .
They are designed to store energy during stance and release energy as
body weight progresses forward, thus helping to propel the body and to
achieve smooth ambulation. This gives the user a higher degree of mobility
with a more natural feel compared with conventional wood prosthetic feet .
Delamination of plies is a major concern and need to be addressed for
longer life of the foot.
398
Negative cast being poured with plaster
finished plaster cast
the inner bag is placed over the plaster mold
vacuum is applied
aluminum lock adaptor is
placed on the mold
399
5" carbon fiber is placed over the mold
Next layer is a nylon/fiberglass
add some 2" unidirectional
carbon fiber tape
apply the outer bag
400
Vacuum is applied to the outer bag
resin is poured into the bag
1 hour the resin is cured
401
402
Chn gi bng nha composite cacbon gm hai lp si cacbon bn cho kt
hp vi 4-6 lp cng mt loi nha tng hp.
C hai loi ng chn gi:
Loi dnh cho ngi ln c chiu di 30 cm, nng 190 gram
v loi dnh cho tr em, di 25 cm, nng 135 gram.
Chn gi lm bng nha composite cacbon c bn 3 nm, c chc nng
gn ging chn tht. Trong khi , thi gian dng chn g l 2 nm. c im
ca chn g l cu to lin, do vy nu hng mt b phn l thay c chn.
Ga chn g c ba loi: Loi ct t u gi xung gi 1 triu ng/chn
Ct di u gi l 600.000 ng/chn
Tho khp hng l 1,5 triu ng/chn.
Gi ca loi chn chn gi bng composite cacbon t hn so vi chn g
v ch c hai loi: Loi ct t trn u gi c gi khong 1,5 triu ng/chn.
Loi ct t di u gi gi khong 800.000 ng/chn.
POF t hng cho Trung tm Cng ngh Vt liu sn xut chn gi cung
cp cho T chc ny vi gi t hng 13-15 USD/chn. Mi nm, Trung tm
Cng ngh Vt liu sn xut v cung cp khong 500-600 sn phm chn gi
bng nha composite cacbon cho khch hng nc ngoi nh Bn tay Hy
vng (M), Hi Cu tr Ngi tn tt VN, T chc Chnh hnh Ngoi tuyn
Hoa K (POF).
Chn gi bng vt liu composite cacbon do Trung tm Cng ngh
Vt liu ch to
403
4. Vt liu y sinh dng trong nha khoa
Composite
dng trm rng

404
Mt s vt liu c in trm
rng
Kim loi hp kim : Amalgam l hp kim gm:
thy ngn, bc, ng, thic,... ; hp kim vng

u : bn cao , trm trc tip , thc hin nhanh
Nhc im : km thm m , c vn d , gi thnh
cao (trm vng ) , h b ming trm theo thi
gian gy su ti pht.
405
Mt s vt liu c in trm
rng
S
Tnh thm m cao
bn mu cao

Thng dng trm trc tip nhng v tr rng
t chu lc nhai mnh do d v
Gi thnh cao
C th b su ti pht ti cc khe h
S dng composite

406
u im ca composite ng dng
trong nha khoa
Mu sc gn ging mu rng,
Chu mi mn,
nn chu lc v c bit l khng c cho c th
Nh sn xut v bc s kim sot v lm ch
c mu sc ca Composite khi s dng
Thi gian thao tc nhanh, di nhit
thng
bng mang li v thm m cho rng
trn b mt lp composite duy tr c
khong 2 n 3 nm

407
Thnh phn

Nha nn : oligome ca Bisphenol A-glycidyl
methacrylate (BISMA) , Urethane
dimethacrylate (UDMA)
Cht n : Silica Si02
Thy tinh , gm thy tinh
Cht lin kt 2 thnh phn: silane
Cht khi mo bng nh
sng Camphorquinone (CQ), Phenylpropanedio
ne (PPD) or Lucirin (TPO)
408
Phn loi cch trm rng
Trm trc tip : ( s dng cho trm composite )
to xoang trm, t cht xoi mn nh men rng , bi
keo dn, nha Composite c t thnh tng
lp mng v lm cng bng n Halogen, cui
cng nh bng rng hon tt.

Trm gin tip ( inlay hay onlay - dng cho vt liu
trm c in ) : to xoang trm, ly du , gi labo
v trm tm l su. Ming trm vng (onlay, inlay)
c lm trong labo (gin tip) c hnh dng, kch
tc ging nh trn rng tht v gi li cho bc s
gn ln rng bng ciment.

409
Clip

410
Nhc im
- Thao tc phc tp , bc s tay ngh cao
- Mt ni mng c th khng ng u
dn n bn nh hng

411
412
NI DUNG
I. GII THIU VT LiU SILICON
II. CC PHNG PHP TNG HP
III. NG DNG
IV. NG DNG SILICON TRONG GiI PHU THM
M V CC C QUAN
1.KNH P TRNG SILICON (Contact lens silicon)
2. SILICON NNG NGC (Silicone Breast implant)
3. SILICON GEL CHA BNG

413
I. GiI THIU VT LiU SILICON
I.1. Khi nim
Silicon l loi polyme c kim m c mch chnh
c s lp li ca nhm -Si-O- lin kt mnh vi
nhm hu c v c gi l polyorganosiloxane
hoc polysiloxane c tn thng gi l silicon.

R, R
1
l nhng gc ankyl
414
CC PHNG PHP TNG HP SILICON

Nguyn liu
Ankylclosilanol hay Arylclosilanol:
RSiCl
3
, R
2
SiCl
2
, R
3
SiCl
Ete ca axit o-silicic: RSi(OR)
3
, R
2
Si(OR)
2
,
R
3
SiOR
Phng trnh tng hp
415
I.2. PHN LOI
Silicon thp phn t: n= 2-10
ng dng: lm du bi trn chu nhit, tm ln cc
vt liu tng tnh chu nc
Silicon cao phn t: n > 10
ng dng: lm nha chu nhit, sn, men, keo dn,
chip silicon, knh p trng,

416
Tnh cht ca silicon
Tng thch sinh hc
Tnh chu nhit cao
n hi tt
Bn trong nhiu mi trng

417
NG DNG

418
IV. NG DNG SILICON TRONG GiI PHU
THM M V CC C QUAN

1. KNH P TRNG SILICON
(Contact lens silicon)
419
KNH P TRNG SILICON (Contact lens silicon)

Yu cu k thut:
C cm gic thoi mi khi eo
Kh nng thm oxi cao
bn tt
Tng thch sinh hc
Thi gian s dng di
Trong sut
420
Vt liu trc y:
PMMA(Polymetylmetacrylate)
HEMA(2-hydroxy ethyl metharylate)
- thm oxi thp
- eo khng thoi mi, d nhim trng (thi
gian eo t 8-12h/ngy)

421
Silicon contact lens:
- thm kh cao gp 10 ln HEMA
- Tnh cht tt
- Tng thch sinh hc
- Cm gic thoi mi khi eo
- Thi gian s dng di

422
Qui trnh cng ngh
VT LiU Y SINH A NC
SILICON
t
0
, UV
423
Cc phng php ph ln b mt khun:
Spray printing
Ink-jet printing
Pad transfer printing
Ultrasonic printing,
424
Vt liu y sinh a nc(dy 0.1-10m):
GMMA(Glycerol metyl metacrylate), MMA(metyl
metacrylate), PU(Polyurethane), PVA(Polyvinylancol),
colagen,

Ph gia: Blue-19, Blue-15, cht khng UV, TiO
2
,
Cht ng rn:
EDGMA(ethylenglycoldimethylacrylate), AIBN(Azo
isobutylonitril)
425


426

427
SILICON BREAST IMPLANT
428
Gii thiu

Silicon bag
429
Lch s
1940s vt liu: cao su, teflon,.
tim cht lng: parafin, du,. silicon lng
Gy au n, bin mu da, nhim trng,
kh th, tc phi hn m v t vong
430
1963s silicon gel implant u tin c gii thiu
bi tp on Dow vi:
V: nha cao phn t + trong: silica v nh hnh
V: nha cao phn t ph PU + trong: silica v nh
hnh

1980s ci tin silicon gel implant v saline breast
implant vi lp v bn hn
T l ph n t ti tng t 3%(1983) 25%(1992)

Lch s

431
BREAST IMPLANT
Hin nay:
Saline Breast implant
Ti silicon(v: silicon + rut: dung dch mui

Silicone gel Breast implant
Ti silicon(v: silicon + rut: silicon gel)
432
u im
Lm p
Nhc im
Chi ph cao
Mt thi gian do kim tra nh k
Phi phu thut nhiu ln
S dng trong 1 khong thi gian nht nh
433
Yu cu:
- Tng thch sinh hc, khng gy bin chng
- Thi gian s dng di
- D a vo c th
- Khng b bin dng khi tc dng lc
BREAST IMPLANT
434
HNH THC T TI
t di c ti t b x cng hn t di tuyn sa

t di tuyn sa t di c ngc
435

436
Ti silicon
v: silicon
Rut: dung dch mui
437
2. t v vo ri bm dung dch nc mui vo
u im:
- Vt rch ngn
-D khng ch kch thc ti
- Gi thnh r
Nhc im:
-Cht lng ti khng tt nh ti silicon gel

Phng php phu thut

438
u im:
Thi gian s dng lu(10-14 nm)
R hn ln so vi dng silicone gel implant
D thc hin
Tng thch vi c th

Nhc im:
Thi gian s dng ngn hn silicone implant
D b bin dng do lc tc dng
Cm gic v dng v khng t nhin nh silicone gel implant
Cht lng khng cao nh silicon gel implant

439

Silicone gel implant
440
Silicone gel implant
Ti silicon
V: silicon
Rut: silicon gel
441
Phng php phu thut

1. t trc tip ti silicon vo
-> thng p dng cho ti silicon gel
u im
-Cht lng ti tt
Nhc im:
- Vt phu thut rch di
- Phi xc nh k kch thc ti trc khi t vo
- Gi thnh t

442
u im:
Cm gic tt hn, t b mo m do lc tc dng
Thi gian s dng lu (~18 nm)
Silicone gel c kh nng nh hnht b nhn,np
theo thi gian
an ton cao hn saline breast implant

Nhc im:
t tin
Qu trnh a vo kh hn(so di)
Tm n kh nng c th c th hp thu silicon

Silicone gel
443
Mt s th tch ti thng dng:120 cc - 850 cc
Thng thng: 350 cc

444
Nn chn hnh thc no?
Silicon gel implant
445
Silicone gel cha bng

Silicone gels c dng u tin ti
Australia bi nhm Perkins,1982, silicone
gel (Cica-Care , UK)
446
Mahnoush Momeni, Farhad Hafezi,
Hossein Rahbar v Hamid Karimi,
Effects of silicone gel on burn scars
Phng php th nghim: chia bnh
phm ra 2 phn, 1 phn th vi silicone
gel sheet, phn cn li vi thuc ch c tc
dng trn an self-adhesive propylene
glycol and hydroxyethyl cellulose
Th nghim trn 38 bnh nhn b bng
nng, vng bng ln hn 5 cm * 5 cm

447

-silicone gel (Cica-
Care)
-SPSS software version
14 dng phn tch
kt qu
-Chn 2 thi im test:
sau 1 thng v 4 thng
448
Kt qu
449
Tho lun
Lp gel bo v da vi mi trng bn
ngai, gim ph n, co mch
Vt bng tr nn xu i sau 3-4 thng khi
collagen lng ng v co cng
n nh in hc ca silicone c th nh
hng s lng ng collagen??

450
i lc sinh hc b mt Silicone

Hong Chen,Michael A. Brook, Heather D.
Sheardown, Yang Chen, Bettina Klenkler
Department of Chemical Engineering and
Department of Chemistry, McMaster
University, 1280 Main Street W., Hamilton
ON Canada, L8S 4M1. 2005
451
Silicone elastomer
Silicone elastomer: Dow Corning, Sylgard 184,
PDMS + Pt catalyst (2-3 wt % in xylene, [(Pt)2-
(H2CdCH-SiMe2OSiMe2CHdCH2)3]) -> cross-
linker t l 10:1 (w/w) Film ng rn nhit
phng 48 h.
Film c ct trong a 5 mm diameter v dy
0.5 mm.
Film c ra vi hexane v lm kh chn
khng.
452
Si-H Surface Functionalization
(Me-HSiO)n MeOH
453
Synthesis of -Allyl--N-succinimidyl Carbonate-
Poly(ethylene glycol), 2
poly(ethylene
glycol) monoallyl ether,
MW=500
N,N disuccinimidyl
carbonate
NSC-PEG,2
triethylamine
trong CH3CN
10h, N2
H.Sut 60%
454
Gn dn xut PEG ln b mt Si-H,3
Pt-catalyst
platinumdivinyltetramethyldisiloxane
NSC- Bin tnh/
Silicone
455

Lin kt cc phn t protein ln b mt
NSC- Bin tnh/Silicone

The cell adhesion peptides: -Tyr-Ile-Gly-
Ser-Arg (YIGSR), Arg-Gly-Asp-Ser
(RGDS)
Proteins: Epidermal growth factor(EGF),
lysozyme, albumin.
Glycosaminoglycan heparin: ng
chng ng mu

456
- YIGSR(4) , RGDS(5)
- EGF(6), albumin(7)
lysozyme(8),
- Glycosaminoglycan
heparin(9)

457
Xc nh tnh cht b mt:Ph IR
458
Hp th protein trn b mt
B mt Silicone
elastomer
B mt Silicone bin
tnh PEG-NCS
Trc
ra SDS
Sau ra
SDS
Trc
ra SDS
Sau ra
SDS

EGF 116 26 190 180
albumin 220 50 180 170
lysozyme 200 40 460 402
heparin ? ? ? 680
n v ng/cm2
459
Tnh cht b mt
460
T bo c nui dng trn
Peptide-Modified-Surfaces
-b mt 4,5:human corneal epithelial cells, EGF trong Keratinocyte Serum Free
Medium medium containing antibiotics (penicillin, streptomycin,and gentamycin)
- B mt 6: 4,5:human corneal epithelial cells trong Keratinocyte Serum Free
Medium, khng khng sinh v EGF,37 C
461
462
463
"Beauty Is in the Eye of the Beholder
"Ci Nt nh Cht Ci p

464
Ti liu tham kho
1. Mahnoush Momeni, Farhad Hafezi, Hossein
Rahbar v Hamid Karimi, Effects of silicone
gel on burn scars, Burn, volume 35, Issue 1,
February 2009, Pages 70-74
2. Hong Chen,Michael A. Brook, Heather D.
Sheardown, Yang Chen, Bettina Klenkler,
Generic Bioaffinity Silicone Surfaces,
Bioconjugate Chem. 2006, 17, 21-28

Biopolymer Phu 2

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CC KHI NIM

- applied in a carrier bag

- applied in another carrier

- applied in a bread pack

- applied in refuse sacks

applied in food trays

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