2. Smart Polymers & Hydrogels

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


(pH,T,

Solution Injection

Embolic Material



and Release


Tumor TargetingDrug delivery Bioseparation



I,Biomol)

BasicResearch


.


...

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


(pH,T,

Solution Injection

Embolic Material



and Release


Tumor Targeting

Why do we do

Drug delivery Bioseparation



I,Biomol)

BasicResearch


.


...

Enzyme activity

Applied Research

Soft Actuator

Immunoassay

Bioreactor

E E

Sensor, Biosensor

ywhat we do?

Biosensor Tissue Engineering

Page 6


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

2. Smart Polymers & Hydrogels

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