Hydrogels

and Their Biomedical Uses

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M. R. Naimi-Jamal

2013

Overview

Hydrogels – Structure – Swelling properties – Biomedical Uses

Common Hydrogels?

Can you think of hydrogels in your everyday life?

- Contact Lenses - Jello (a collagen gel ~ 97% water) - Extracellular matrix components - Polysaccharides - DNA/RNA - Blood clot

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Applications of Hydrogels Soft contact lenses Pills/capsules Bioadhesive carriers Implant coatings Transdermal drug delivery Electrophoresis gels Wound healing Chromatographic packaging material

Hydrogels

“Hydrogels are water swollen, cross-linked polymeric structures produced by the simple reaction of one or more monomers or by association of bonds such as hydrogen bonds and strong van der Waals interactions between chains.”

-N. A. Peppas in Biomaterials Science (1996)

Other definitions

Water insoluble, three dimensional network of polymeric chains that are crosslinked by chemical or physical bonding

Polymers capable of swelling substantially in aqueous conditions (eg hydrophilic)

Polymeric network in which water is dispersed throughout the structure

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Behavior of Hydrogels

No flow when in the steady-state By weight, gels are mostly liquid, yet they

behave like solids

They can absorb large quantities of water – May absorb up to 1000 times their dry

weight Cross linkers within the fluid give a gel its

structure (hardness) and contribute to stickiness (tack).

Volume degree of swelling (Q)

Q = actual sample volume in the swollen state volume in the dry state

Weight degree of swelling

= actual sample weight in the swollen state weight in the dry state

Based on structural features, hydrogels can be classified as...

Amorphous hydrogels – Randomly arranged macromolecular chains

Semicrystalline hydrogels – Dense regions of ordered macromolecular

chains (crystallites)

Hydrogen bonded hydrogels – 3-D network held together by hydrogen

bonds – Strong hydrophobic/hydrophillic interactions

Chemical Physical

Based on crosslinkers features, hydrogels can be classified as...

Chemical – Covalently crosslinked – Absorb water until they reach equilibrium

swelling (crosslink density dependent) – High stability in harsh environments (high

temp, acidic/basic and high stress)

Physical Non-covalently crosslinked Disordered networks are held together by

associative forces capable of forming non-covalent crosslinks (molecular entanglements, electrostatic interactions, hydrogen bonding, and hydrophobic interactions)

– Weaker and more reversible forms of chain-chain interaction

– Respond to physical changes (temperature, pH, ionic strength and stress)

Hydrogel Fabrication Chemical hydrogels Physical hydrogels

▪ Hydrogen bonding

▪ hydrophobic interaction

▪ crystallinity

▪ stereocomplex formation

▪ ionic complexation

Covalently crosslinked Noncovalently crosslinked

Thermoset hydrogels Thermoplastic hydrogels

Reliable shape stability and memory

Limited shape stability and memory

Physical crosslinking

• Ionic hydrogel

• Cross-linking without chemical reaction • ionic interaction, hydrogen bonding, antigen-antibody

interaction, supramolecular association

Chemical Hydrogels Methods

Co-polymerization of monomer and crosslinker – HEMA and EGDMA (Ethylene glycol dimethacrylate)

Crosslinking water soluble polymers

Conversion of hydrophobic polymers to hydrophilic

polymers plus crosslinking

Hydrogel Fabrication

+

Monomer Crosslinker

Vinyl group-containing water-soluble polymers

Copolymerization

Polymerization

Hydrogel network

Chemical crosslinking

• Polymerization of water soluble monomers in the presence of bi- or multifunctional cross-linking agent

EGDMA HEMA

An example as Wound Dressing

Ref.:

Based on ionic charges, hydrogels can be classified as...

Neutral hydrogels – No charge

Anionic hydrogels – Negatively charged

Cationic hydrogels – Positively charged

Ampholytic hydrogels – Capable of behaving either positively or negatively

Classes of Hydrogels

Hydrogel Forming Polymers

O H O

O H

H O 2 C

O O H O

N H

H O

O

O

O H O

O H

N a O 2 C

O

n p o l y ( h y a l u r o n i c a c i d ) p o l y ( s o d i u m a l g i n a t e )

n

O O

O

N H O n

poly ( e t h y l e n e g l y c o l )

n

p o l y ( l a c t i c a c i d )

n

p o l y ( N - i s o p r o p y l a c r y l a m i d e )

Natural

Synthetic

Hydrogel Swelling

One or more highly electronegative atoms which results in charge asymmetry favoring hydrogen bonding with water

Because of their hydrophilic nature dry materials absorb water

By definition, water must constitute at least 10% of the total weight (or volume) for a materials to be a hydrogel

When the content of water exceeds 95% of the total weight (or volume), the hydrogel is said to be superabsorbant

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Important features of hydrogels

– Usually comprised of highly polyionic polymers

– Often exhibit large volumetric changes eg. highly compressed in secretory vesicle and expand rapidly and dramatically on release

– Can undergo volumetric phase transitions in response to ionic concentrations (Ca++, H+), temperature, ...

– Volume is determined by combination of attractive and repulsive forces:

repulsive electrostatic, hydrophobic

attractive, hydrogen binding, cross-linking

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Swelling...Thermodynamically Speaking

Network starts to swell due to the thermodynamic compatibility of the polymer chains and water

– Swelling in chemical (crosslinked) polymers is dependent on the solvent

Swelling force is counterbalanced by the retractive force induced by the crosslinks of the network

Swelling equilibrium is reached when these two forces are equal

Degree of swelling can be quantified by:

• ratio of sample volume in the swollen state to volume in the dry state

• weight degree of swelling: ratio of the weight of swollen sample to that of the dry sample

Swelling Properties

Gibbs Free Energy � ∆G=∆Gelastic+∆Gmix

Chemical Potential

� µ1-µ1,0=∆µelastic+∆µmix

� ∆µmix=RT(ln(1-2v2,s)+v2,s+χ1v^22,s)

G=Gibbs Free Energy

– work exchanged by the system with its surroundings minus the work of the pressure forces during a reversible transformation of the system from the same initial state to the same final state

∆G<0 Spontaneous ∆G=0 Equilibrium ∆G>0 Non-spontaneous

Swelling Properties

Gibbs Free Energy � ∆G=∆Gelastic+∆Gmix

Chemical Potential

� µ1-µ1,0=∆µelastic+∆µmix

� ∆µmix=RT(ln(1-2v2,s)+v2,s+χ1v^22,s)

G=Gibbs Free Energy

– work exchanged by the system with its surroundings minus the work of the pressure forces during a reversible transformation of the system from the same initial state to the same final state

∆G<0 Spontaneous ∆G=0 Equilibrium ∆G>0 Non-spontaneous

µ= Chemical Potential ―the chemical potential is the change in a characteristic thermodynamic state function per change in the number of molecules ―Particles will tend to move from regions of high chemical potential to regions of low chemical potential

Swelling Properties

Gibbs Free Energy � ∆G=∆Gelastic+∆Gmix

Chemical Potential

� µ1-µ1,0=∆µelastic+∆µmix � ∆µmix=RT(ln(1-

2v2,s)+v2,s+χ1v^22,s)

v2,s=polymer volume fraction of the gel

v2,s= Volume of polymer = vp = 1 __________________ __ __ Volume of swollen gel vgel Q

Q= volume degree of swelling

χ1= polymer-water interaction

parameter (look up in a table)

R= Universal Gas Constant= 8.314 472(15) J K−1 mol−1

Some swollen Hydrogels Highly swollen hydrogels:

cellulose derivatives poly(vinyl alcohol) poly(ethylene glycol)

What do these all have in common? Lots of OH (or =O) groups to interact with acidic environments hydrophillic swelling Moderately or poorly swollen hydrogels:

poly(hydroxyethyl methacrylate), PHEMA and derivatives

One may copolymerize a highly hydrophilic monomer with other less hydrophilic monomers to achieve desired swelling properties

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Contact Angle (wetability)

Hydrophobic – “water hating”

Hydrophilic – “water loving”

Why is this important to materials selection? – Do you want your eyes

to be dried out by your contact lenses? Probably not…

* Cool fact, fluorinated surfaces have the most hydrophobic properties and are deemed super-hydrophobic.

Electrowetting of the surface Top: charge neutral (grounded)

surface with high contact angle Bottom: Allowing voltage

between the drop and the electrode changes the distribution of electric charge within the drop and significantly decreases the contact angle. – The polarity of voltage in

the drawing is arbitrary, and in both directions electrowetting will occur.

In a natural environment, this may be electric charge change due to pH changes

Other Important Properties

Solute diffusion coefficient through the hydrogel

Optical properties

Mechanical properties – Hydrophilic hydrogel surfaces are poor

substrates for Protein adsorption Cell adsorption

How biological hydrogels grow

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• Polymerization/deposition

(blood clots)

Environmentally Responsive Hydrogels

– Hydrogels that exhibit swelling changes due to the external

pH Temperature Ionic Concentration

Environmentally Responsive Hydrogels

pH

Location in Body pH

Gastric Contents 1.0

Urine 4.5-6.0

Intracellular 6.8

Interstitial (also called extravascular

compartment or tissue space) 7.0

Blood 7.15-7.35

Environmentally Responsive Hydrogels

Temperature

Location in Body Temperature °C

Normal Core 37

Deviations During Disease 20-42.5

Normal Skin 28

Skin at Extremeties 0-45

Environmentally Responsive Hydrogels

Ionic concentration

Cations Concentration in Blood (mEq/L)

Sodium 142

Pottasium 4

Calcium 5

Magnesium 2

Anions Concentration in Blood (mEq/L)

Chlorine 101

Bicarbonate 27

Phosphate 2

Sulfate 1

Proteins 22

Notice they both add up to the same…equillibrium

Hydrogel Advantages

– Non-thrombogenic

Non-ionic hydrogels used for blood contacting applications

Heparinized hydrogels show promise

– Biocompatible

– Good transport of nutrients to cells and products from cells

– May be easily modified with cell adhesion ligands

– Can be injected in vivo as a liquid that gels at body temperature

Advantages of Hydrogels Environment can protect cells and other substances (i.e.

drugs, proteins, and peptides) Timed release of growth factors and other nutrients to ensure

proper tissue growth Good transport properties Easy to modify

Disadvantages of Hydrogels

Low mechanical strength

Hard to handle

Difficult to load

difficult to be sterilized

Types of Hydrogels

Natural Polymers – Dextran, Chitosan, Collagen, Dextran Sulfate – Advantages Generally have high biocompatibility Intrinsic cellular interactions Biodegradable Cell controlled degradability Low toxicity byproducts

– Disadvantages Mechanical Strength Batch variation Animal derived materials may pass on viruses

Types of Hydrogels

Synthetic Polymers – PEG-PLA-PEG, Poly (vinyl alcohol) – Advantages Precise control and mass produced Can be tailored to give a wide range of properties (can be

designed to meet specific needs) Low immunogenecity Minimize risk of biological pathogens or contaminants

– Disadvantages Low biodegradability Can include toxic substances

Combination of natural and synthetic – Collagen-acrylate, P (PEG-co-peptides)

Properties of Hydrogels

Pore Size

Fabrication techniques

Shape and surface/volume ratio

H2O content

Strength

Swelling activation

Why Hydrogels?

Tissue Engineering – Scaffolds for tissue engineering

Cell Culture Systems

Drug Delivery – Time released delivery

Contact Lenses

Biomedical Uses for Hydrogels Common

– Scaffolds in tissue engineering. – Sustained-release delivery systems – Hydrogels that are responsive to specific molecules, such as

glucose or antigens can be used as biosensors. – Disposable diapers where they "capture" urine, or in sanitary

napkins – Contact lenses (silicone hydrogels, polyacrylamides) – Medical electrodes using hydrogels composed of cross linked

polymers (PEO, polyAMPS and polyvinylpyrrolidone) — Lubricating surface coating used with catheters, drainage tubes

and gloves

Biomedical Uses for Hydrogels Less common uses include

– Breast implants – Dressings for healing of burn or other hard-to-heal wounds.

Wound gels are excellent for helping to create or maintain a moist environment.

– Reservoirs in topical drug delivery; particularly ionic drugs – Artificial tendon and cartilage – Wound healing dressings (Vigilon®, Hydron®, Gelperm®)

non-antigenic, flexible wound cover permeable to water and metabolites

– Artificial kidney membranes – Artificial skin – Maxillofacial and sexual organ reconstruction materials – Vocal cord replacement – Butt injections

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Headlines

Smart Polymers: Hydrogels and Shape

Memory Polymers Dr. Jenny Amos

February 19, 2009

Ref.: