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Page 1
Smart Polymers & Hydrogels
Smart = Intelligent
Intelligent Materials
Intelligent Gels Polymers: Hydrophilic (Water-soluble)Hydrophobic (Water-insoluble)
Hydrogels: Network of hydrophilic polymersOrganogels: Network of hydrophobic polymers
Types of hydrogels
Chemical gel.Covalent crosslinking
Physical gel.Non-covalent crosslinking
Interpenetrating networkCovalent and/orNon-covalent crosslinking
Ca+ +
Ch e la t in ga g e n t
Calcium ion
Sodium alginate
Polymers: Hydrophilic (Water-soluble)Hydrophobic (Water-insoluble)
Hydrogels: Network of hydrophilic polymersOrganogels: Network of hydrophobic polymers
Ordinary Polymers & Hydrogels
Drug
Shrunken state- Squeezing- Trapping
Swollen state- Opening- Absorbing
CrosslinkPrecipitation Dilution
Page 2
Smart Polymers & Hydrogels
Dissolution-PrecipitationSwelling-Deswelling
Respond to small changes in environmental signals by large changes in physicochemical properties
ξ
DegradationDegradation
Sol-gel phase transition Coil-Globule transitionShape transformation
Physical Environmental Stimuli
Chemical
BiologicalStimuli
Hydrogels: Publications
Smart HydrogelsIntelligent Hydrogels
Wichterle O, Lim, D. Hydrophilic gels for biological use. Nature. 1960;185:117-118.
Soluble InsolubleSIGNAL
(pH,T,
Solution Injection
Embolic Material
Pulsatile Drug Release
Membrane SeparationProtein Drug Loading
and Release
Hydrophobic Chromatography
Tumor Targeting
Prof. You Han Bae
Collapsed GelSwollen Gel
Solution Physical Gel
I,Biomol)
BasicResearch
ECM for 3-D Cell Culture
.
Cell culture & Harvest
...
Enzyme activity
Applied Research
Soft Actuator
Immunoassay
Bioreactor
E E
Sensor, Biosensor
Soluble InsolubleSIGNAL
(pH,T,
Solution Injection
Embolic Material
Pulsatile Drug Release
Membrane SeparationProtein Drug Loading
and Release
Hydrophobic Chromatography
Tumor TargetingDrug delivery Bioseparation
Collapsed GelSwollen Gel
Solution Physical Gel
I,Biomol)
BasicResearch
ECM for 3-D Cell Culture
.
Cell culture & Harvest
...
Enzyme activity
Applied Research
Soft Actuator
Immunoassay
Bioreactor
E E
Sensor, BiosensorBiosensor Tissue Engineering
Chronobiology (Biological rhythm):Physiological functions that exhibit prominent rhythmic change.
Ex: Circadian rhythmBody temperature
Blood pressure
Heart rate
Renal function
Plasma hormone concentration
The onset of certain diseases exhibits strong circadian temporal dependency
Self-Regulated Delivery SystemsDrug delivery patterns can be further optimized by pulsatile or self-regulated delivery, adjusted to the staging of biological rhythms.
Signal input
Outpu Eff
Pulsatile or externally regulated system
Self-regulated system(Closed-loop system)
SYSTEMOutput Effect
Signal input
SYSTEMOutput
Effect
Feed-back
system(Open-loop system)
Open-loop system Closed-loop system
Self-Regulated Systems
Changes in Environmental Factors
Sensor
Information Processor
Glucose sensor
Feedback
Glucose level changes in blood
Determine theamount of insulinto be released
Specificity, sensitivitySpeed
Accurate dose
Actuator Insulin release
Feedback: Stop insulin release
to be released
Accurate timing
ReversibilityRepeatabilityMagnitude
SafetyBiodegradability
Page 3
Ph-Sensitive Polymers (Polyelectrolytes)
Monomer pH-sensitive group
Acidic (Meth)acrylic acid -COOH
(Anionic) Sodium styrene sulfonate -SO3- Na+
Sulfoxyethyl methacrylate -SO3H Aminoethyl (meth)acrylate -NH2 N,N-dimethylaminoethyl -N(CH3) 2
(meth)acrylate Basic (Cationic)
N,N-diethylaminoethyl (meth)acrylate
-N(CH2CH3) 2
Vinylpyridine
Vinylbenzyl triethylammonium chloride
-N+(CH3)3Cl-
Brondsted and Kopecek, ACS Symp. Ser. 480, pp. 285-304 (1992)
N
Crosslinked poly(MMA-co-DEAEAm) (70/30 mole ratio)
ing
Rat
io
0.6
0.8
1.0
CH2 C CH2C O mn
CH3
O
CH3
CH
C OOCH2CH2
NC2H5C2H5 H
+
Ionized
Rel
ativ
e Sw
elli
pH
1 2 3 4 5 6 7 8 90.0
0.2
0.4CH2 C CH2
C O mn
CH3
O
CH3
CH
C OOCH2CH2
NC2H5C2H5
Neutral
Polymer-peptide Hybrid Hydrogels
Kopeček J Biomaterials 2Wang C et al Nature 1999
No charge.Poor water solubility.The ability to formintermolecular hydrogen bonding.
Poly(acrylic acid) in acid form
CH2HC
COO
H
CH CH2
CO N
CH3
CH3
CH2HC
COO
H
CH CH2
CO N
H
H
INTER- AND INTRAMOLECULAR HYDROGEN BONDING POLYMERS
n
nn
n
(A)
Intermolecular Hydrogen Bonding
CH2HC
CO O
CH2
N
N
O
H
H
O NN
O
O
H2C O
CO
CH
CH2
n
(B)
n
Strong Adhesive
Poly(acrylic acid) in ionized form
C C
H
H
H
COOH-
SAP: crosslinked hydrophilic polymers having the swelling ratio of 20 or larger.Swelling ratio = wet wt/dry wt
Temperature-Sensitive Polymers & Hydrogels
Positive Thermosensitivity
as T ↑ Solubility/Swelling ↑
Negative Thermosensitivity
as T ↑ Solubility/Swelling ↓
Covalent bond: ~ 5 eV (≈ 0.8 x 10-18 J)
Secondary interaction forces: ~ 0.1 eV
Thermal fluctuation energy: ~ 0.03 eV (≈ 1 kT)
Competition between the two forces(H-bonding & Hydrophobic interaction)
Temperature dependent interactions
as T ↑ Hydrogen-bonding ↓
as T ↑ Hydrophobic interaction ↑
Hydrophobic interactions
Poly(N-isopropylacrylamide Poly(N-cyclopropylmethacrylamide
C
H
CH2 C
C
H
H3C CH3
O
N
H
( )C
H
CH2 C
C
CH3
H2C CH2
O
N
H
( )
Competition between hydrogen bonding &hydrophobic interactions.
Water-soluble at low temperatureWater-insoluble at high temperature.
Lower critical solution temperature: Temperature that induces polymer precipitation, i.e., phase separation. Textbook Of Biochemistry With Clinical
Correlations, Thomas M. Delvin, Ed., 5th Edn., 2002
Temp
UCST
2 Phases
Soluble
(Hydrophobic Interaction)
Polymer Volume Fraction0 1
1 Phase
LCST
Soluble
Insoluble
)
Soluble Insoluble Soluble
Page 4
C C
H
H
H
C O
NR1 R2
HN
HN CH
CH2
CH2
HN CH
CH2
CH2
HN C
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH C H
n
Cloud Temp. (oC)
(45.5)
C2H5
(72.0)
(5.5)(56.0)
C C
H
H
R1
C O
NH R2
CH2 O CH2 O CH3
CH2 O CH3
CH2 O C2H5
n
Cloud Temp. (oC)
R2 R1= CH3 R1= H
3 3
3
2
84.0
63.5
45.5
79.0
44.5
35.0
HN CH
CH3
CH3
NH
CHC2H5
C2H5
NC2H5
CH3
NCH
CH3
CH3
HN CH2CH2CH3 N
CH3
CH2CH2CH3
(30.9) (32.0)
(56.0) (22.3)
(21.5) (19.8)
adopted from S. Ito, Kobunshi Ronbunshu, 46 (1989) 437
H3C
CHCH3
CH2 O CH3
CH2 O C2H5
CH2O
CHC2H5
CH2 O CH3
CH2 O CH
2
CH3
CH3
3
3
42.6
38.5
33.0
14.0
13.0
33.5
24.3
27.7
11.0
8.7
adopted from S. Ito, Kobunshi Ronbunshu, 47 (1990) 467
CH2 CCH3
CO
O
H2CH2C
CH2 CCH3
CCH
OO
CH2
C ON
NCH3
CH3
CH2 CCH3
CCH
OO
CH2
C ON
AAm
EAAm
LCST
50oC
X content (mole %)60
OCH2
NH H
H2C NCH3
CH3
CH2
NH CH2CH3
H2C NCH3
CH3
Poly(DMAEMA-co-EAAm)
LCST80oC
CH2 CCH3
CCH
OO
CH2
CH2
C ON
H CH2CH3
H2C NCH3
CH3
EAAm content (mole%)
80 C
50
50oC
pH 7.4
pH 4.0
37oC
insoluble
soluble
Polymers for Cosmetics and Personal Care
Homo polymer gel
Faster Shrinking to temperature changes
Comb-type graft polymer gel
: Hydrophobic cluster
Faster Swelling to temperature changes?
CASE I. BULK SQUEEZING
T
T
PolyNIPAAm Poly(NIPAAm-co-BMA)
T
T
CASE II. SURFACE BLOCKING
Effect of Shrinking on Drug Release
Swollen state(low temperature)
Shrunken state(high temperature)
More drug release
Surface skin layer
Swollen state(low temperature)
Surface skin formation(high temperature)
Less drug release
CH3O(CH2CH2O)X CCH2OO
CCHOO
CH3
CNO
H(CH2)6 NC
H
OHCC
O
CH3
OOCH2C (OCH2CH2)XCH3
O
PEG-PLGA-OH HDI HO-PLGA-PEG
LLA/GA = 78/22
EG12-L31G9-EG12
PEG-PLGA-PEG triblock copolymer
gel
70oC
Temperature
sol30oC
70%Polymer conc. wt%
PLGAPEG
Biomolecule-sensitive Polymer and HydrogelsGlucose-sensitive Sol-Gel Phase-reversible hydrogels
NO
(CH2 CH)m (CH2 CH)n
CH2
O
O
OH
CH2OH
OH
OH
(CH2 CH)m (CH2 CH)n
O
C O
O
CH2
CH2
CH2
SO3 K
CH2
O
OH
CH2OH
OH
OH Lee & Park. J. Mol. Rec. 9: 549, 1996.Kim & Park. J. Control. Release. 77: 39, 2001
O
C O
NH2
CH2
(CH2 CH)m (CH2 CH)n
CH2
O
OH
CH2OH
OH
OH
Page 5
Glucose-sensitive hydrogelsBoronic acid-based system
HO
HOHO
B
OH
OO
B
OH
OO
OHO
Insulin
Microcapsule
Insulin
Polymer A Polymer B
HOPolymer A Polymer B
HO OHGlucose
Kazunori Kataoka
HO
HO
B
OH
OO
B
OH
OO
HO
HO RELEASE
Glucose sensitive polymers
Glucose Gluconic acid
1) Glucose/Glucose Oxidase Reaction
O
HO
CH2OH
OHOH
C
C
C
H OH
HO H
O OH
(Glucose Oxidase)
CH2 CH
CH2N
CH2 CH
CH2
N
H2O2
Use pH change or H2O2 for glucose sensitive hydrogels which contain GOD.
OH
α-D-glucose
C
C
CH2OH
H OH
H OH
gluconic acid
CO
H2N
N
C NH2
O
reduced form(hydrophobic)
oxidized form(hydrophilic)
Chamber
Chamber II
Diaphragm
MovablePartition
Chamber III
Orificewithvalve
Housing(a) Glucose Sensitive
Swellable Hydorgel
Screen
One WayValve
InsulinFormulation
(b)
BloodGlucose
Up
BloodGlucose
Down
(c)
KineticsReproducibility
Glucose-sensitive Microvalve
Safety
Baldi A et al. IEEE J Microelectromech Sys 12: 613, 2003
Drug loading & release
Biodegradability
Light-sensitive Polymer and Hydrogels
NN
hv
hv' or ΔN
N
trans cis
azobenzene
MeMehv
MeMe
CH2 CH CH
C O
NH
CH CH3CH3
C O
NH
CH CH3CH3
CH2N
NCH3
CH2
N
C
CH3
N
CH3
CH2CH3
ONa
O
CH CH2
CH3
CH2CH2CNaO
O CNaO
Cu
NMe
O NO2
hv
hv' or Δ NMe
O NO2
closed ring open ringspiropiran
COH
N NCH3
CH3
H3C
H3C
hv
ΔCN N
CH3
CH3
H3C
H3C
OH
triphenylmethane (malachite green leucohydroxide)
nonionic ionic
Photo-induced structural changes of photochromic compounds
O
Light
gelLight
Electric field-sensitive Polymer and Hydrogels
Hysterisis
Sol-gel phase transition.Swell-deswell phase transition.
Differences in energies:Energy required for gellingEnergy required for melting
Issues with hydrogels1. Mechanical strength
2. Swelling/deswelling kinetics
Polyacrylonitrile hydrogels
Jelly fish
Soluble InsolubleSIGNAL
(pH,T,
Solution Injection
Embolic Material
Pulsatile Drug Release
Membrane SeparationProtein Drug Loading
and Release
Hydrophobic Chromatography
Tumor Targeting
Why do we do
Drug delivery Bioseparation
Collapsed GelSwollen Gel
Solution Physical Gel
I,Biomol)
BasicResearch
ECM for 3-D Cell Culture
.
Cell culture & Harvest
...
Enzyme activity
Applied Research
Soft Actuator
Immunoassay
Bioreactor
E E
Sensor, Biosensor
ywhat we do?
Biosensor Tissue Engineering
Page 6
Pulsatile Drug Release
Protein Drug Loadingand Release
Tumor TargetingDrug delivery
Inherent limitations of hydrogel formulations
Translation into clinical formulations
Drug loading & releaseSafety Biodegradability
Enzyme-responsive Hydrogel Nanoparticles
Thornton. et al. Soft Matt 4: 821, 2008
Albumin release Albumin releaseAvidin release Avidin release
Magnetic Hydrogel for Controlled Release
Satarkar NS and Hilt JZ J Control Release 130: 246,
Drug-sensitive Hydrogel
Ehrbar, et al. Nat Mater 7:800, 2008
Hydrogels for Dual Protein Delivery
Lin & Metters, Biomacromolecules 9: 789. 2008
Cell-free Enzyme Synthesis
Nokyoung Park et al .Nat Mater 8: 432, 2009
DNA Hydrogels
Um et al ., Nat Mater 5:797, 2006
Insulin & camptothecin
Evolution of Smart Hydrogels
IQ 1: Swelling
IQ 2: Sensitive to 1 stimulus
Stimuli
IQ 3: Sensitive to 2 stimuli
IQ 4: Sensitive to 3 stimuli
IQ 5, ---
Really Smart Hydrogels
Allan Hoffman
Page 7
Extremely Smart Hydrogels
Tania BetancourtLisa Brannon-Peppas
Int J Nanomed 1(4): 483, 2006.
Getting Smaller
Cohen Stuart, et al. Nat Mater 9: 101, 2010
‘Galaxy’ of Stimuli-responsive Polymers
FasterStimuli-responsive Nanoparticles for Drug Delivery
Cohen Stuart, et al. Nat Mater 9: 101, 2010
pH-sensitive Protein Release from Nanogels
Shi et al., Macromolecules 41:
Instability of polymer micelles in Blood3 h15 min 1 h
Chen et al., PNAS 105: 6596, 2008Chen et al., Langmuir 24: 5213, 2008
Virus-Mimetic Nanogel
Lee, E. S., Kim, D., Youn, Y. S., Oh, K. T. & Bae, Y. H. A virus-mimetic nanogel vehicle. Angew. Chem. Int. Ed. 47, 2418–2421 (2008)
Migration to neighboring cells
Hydrogel biomaterials: A smart future? (Jindrich Kopecek)
Self-assembling hydrogelsKopecek. Biomaterials 28: 5185, 2007
FutureMaterial development: Smart hydrogels with
high IQ
Find applications:
Target application: Understand physiological
requirements
Clinical success:
Current
Find applications:Mismatch between material properties
and application
Clinical success:
Faster translation to clinical formulations
Natural Systems Synthetic Systems
Efficacy,Simplicity
DiffusionSelectivity
Mimicking Biosystems
Survival
Biological Need
Miniaturization
Clinical Efficacy
Simplicity(Bottom-up)
Selectivity(Top-down)
Page 8
Ultimate smart hydrogels
REWARD: Early Retirement
?IQ – based nomenclature?
Future of Smart Polymers & Hydrogels?
IQ 2IQ 1 IQ 3 IQ 4
Fancy polymers & hydrogels.
Make first and then find applications?Find applications first and then make?
Getting Smarter
• Smarter materials: – proteins, peptides, DNAs, hybrid materials
• Smarter response: – multiple stimuli-sensitivity, new stimuli
• Smarter function: cell free enzyme synthesis– cell-free enzyme synthesis, microfabrication, extracellular matrix, bioseparation, actucation, sensor
From Polaroid to Digital CameraGetting SmarterBioactive Polymers and Polymeric Drugs