polymers in biomedicine introduction of polymers polymeric ... · • introduction of polymers •...

Polymers in Biomedicine • Introduction of Polymers

• Polymeric Biomaterials

• Smart Biomaterials

• Polymer Drug Transporter

Prof. Dr. Tanja Weil, OCIII@UniUlm

1. Definition Polymer

2

• Macromolecule consisting of repetition units

• Properties often more complex compared with small molecules (2 monomers are miscible, polymer consisting of these monomers not!)

1. Polymers are Nanosized Objects

• Polyesters Polylactic acid Polyhydroxyalkanoates • Proteins Silk Soy protein Corn protein (zein) • Polysaccharides Xanthan Gellan Cellulose Starch Chitin • Polyphenols Lignin Tannin • Lipids Waxes • Specialty polymers Shellac Natural rubber Nylon (from castor oil)

2. Overview over Nature’s Polymers

1. How to Synthesize Polymers?

20000 2000 4000 6000 m/z

6

Polymer: Polydisperse

Very long chains Short chains

Most abundand chain lengths

1. Polymers: Mixtures of Macromolecules

Polymer in solution: Statistical coil

Copolymer: Consists of two different monomers

7

1. Molecular Weight of Polymers

• Synthetic polymers: Molecular weight distribution

(more than one molecular weight)

• Statistical distribution of molecular weight

• Average values

• Important features such as biodegradability depend

on the molecular weight

PDI: Polydispersity indey Commercial polymers Often very high (PDI: 3-10) MW of linear polymers In biomedicine: 104-106 g/mol

Number average molar mass

Weight average molar mass

8

Solid State Properties

• Amorpous

Glas state, hard material, no order of the chains, chains are physically cross-

linked

• Semi-crystalline

Domains of high order are connected with domains of no order

• Crystallin

High degree of order (near and far-order)

1. Composition of Polymers

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Homopolymer

Copolymer

1. Structures/ Topologies of Polymers

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Linear

Branched

Star-shaped

Cross-linked

1. “Perfect Polymers” = Dendrimers

1. Overview over different Dendrimer Scaffolds

1. Polymer versus Dendrimer

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B B

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B B B B

B B

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F F F

F F F

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F F

F F

F F

F F

F F

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1. Polymer versus Dendrimer

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2. Polymers as Biomaterials - Applications

• Dental Applications (Implants, Fillers,…)

• Cardiovascular and general surgery: Implants (bladder, skin, heart)

• Contact lenses

• Sensors, biochips, implants, microoptic devices

• Drugs

• Drug Transporter

16

2. Very Brief: Biodegradation of Polymeric Materials

Material is not toxic and is resorbed/ degraded

Material releases toxic substances upon degradation

Material is not toxic and is not degraded

Encapsulation

Necrosis

Degradation and Resorption

Characteristics of an Interaction

e.g. Tissue Engineering

e.g. Metal implants, non-degradable polymers

polymer-coated sensors

2. Biodegradable and Non-degradable Polymers

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• Functional groups that can be cleaved

• Chemical Degradation

• Tissue Engineering / Drug Delivery

Biodegradable Non-Degradable

• Long term application in the body

(Carboxylic acid, alcohol)

Biodegradation of Polymers

18

Hydrolysis is increased by

• High numbers of functional groups

• Low crystallization

• Low or no crosslinks

• High surface / volume ratio

• Mechanic stress

Hydrolysis is reduced by

• High molecular weight

• Low numbers of hydrophilic

groups

• Lipophilic polymers

• High crosslinking

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2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water

• Polymer is not degraded after implantation

• Low degree of structural changes

• Breakage due to (low degree of ) water adsorption

• Teflon

• Polyolefines (PE, PP)

• Acrylic polymers (PMMA, PDMAA)

• Inorganic polymers (PDMS)

( )n ( )n ( )n

PMMA

Polyethylene (PE)

• Hydrophobic

• Semi-crystalline, can be soft or hard

• Transparent Catheters,

• Mechanically stable Implants, Plastics


Polyethylen (PE)

• Soft, low density LDPE is used for tubings, packing material

• Highly branched polymer chains result in lower densities 0,915 g/cm3 und 0,935 g/cm3

(„LD“ means „low density“).

• Hard HDPE is used for producing more stable flasks etc.


• Implants: „Ultra High Molecular Weight Polyethylen (UHMWPE)“.

• Knee and finger joint implants

• If PE is used alone as acetabulum (Hüftgelenkpfanne), bone substance is

degraded after few years only (e.g. by attrition) nowadays mainly used in titane

inlets.

Polyvinylchloride (PVC)

• Bags for blood, urine, nutrition media, gloves, tubings, catheters, blister packing

material as well as medical disposables.

• Advantages: good thermoformability, stiffness, flexibility, chemical resistance and

low allergic potential

• Disadvantage: Softeners such as phthalate, e.g. di-2-(ethylhexyl)-phthalate (DEHP)

and Di-n-octylphthalate (DnOP).


• Di-2-(ethylhexyl)-phthalat (DEHP) and di-n-octylphthalat (DnOP) potentially teratogenic,

cancerogenic

• Medical usage: Ultrapure PVC with very low quantities of additives and impurities

• Flasks, medical devices (hard trays) can be sterilized

• Not suitable for long-term usage in the body


24

Polytetrafluorethylene (PTFE, “Teflon”)

• Hydrophobic

• Chemically inert

• Thermally very stable

• Mechanically stable

“Gore-Tex”

Artificial blood vessels (low degree of protein adsorption)


Polypropylene (PP)

• Nahtmaterial

• als Netze zur Überbrückung von Gewebedefekten

• zur Abdeckung von Leistenbrüchen etc..

• Membranen für Blutoxygenatoren und Nierendialyse,

• Fingergelenkprothesen, Herzklappen

• Einweg-Spritzen, Verpackungsmaterial


Polystyrene (PS)

• Important packing material for medical articles, can be sterilized via γ-radiation

• Not so useful for reusable articles, which require sterilization by steam

• Transparent

• Cuvettes, petri dishes, blood tubings


27

Biodegradable Polymers

Polymethylmetacrylate (PMMA, “Plexiglas”)

• Hydrophobic

• Glass state, amorphous (Tg > 100°C)


• Transparent

Artificial Lenses (Eye)

MST-Devices (Copolymer)

• Bone cement and for dental prostheses or dental fillings

• Polymerization mixture together with monomer is hardened by light in the mounth

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Polyhydroxyethylmethacrylate (PHEMA)

• Hydrophilic

• Soft, gel-like (Tg < 25°C)

• Transparent


Contact Lenses

(cross-linked copolymer)

Bladder catheter and coating for suture materials (“Nähmaterialien”)

2a. Non-Hydrolysable Smart Polymers & Hydrogels

Poly-N-isopropylamide (PNIPAM)

• Hydrophilic/hydrophobic

• LCST – lower critical solution temperature (homopolymer: 32°C)

Hydrogel (cross-linked)

Cell cultivation, cell monolayers, tissue engineering

Drug Delivery

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Responsive Polymer will be discussed in chapter 3 “Smart Polymers” in greater

details

2a. Non-Hydrolysable Smart Polymers & Hydrogels

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Polydimethylsiloxane (PDMS)

• Inorganic polymer

• Hydrophobic

• Soft, gel-like (Tg < -50°C)

Catheters, implants

Devices: Soft Lithography


Polysiloxane

• Breast implants

• Long-term resistance against hydrolytic and enzymatic degradation

• No softeners, aging inhibitors or other materials that maintain elasticity required

• Drainage tubing, blood vessels, urethral tubes, catheters, tubing probes, dialysis and blood

transfusion tubes

• Artificial joints for fingers, wrists, toes, elbows, imprinting material for dental medicine,

artificial tendons, heart valves, respiratory bellows, artificial skin and bladder prostheses


2b. Biodegradable Polymers with Low Tendency to Adsorb Water

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• Polymer is degraded slowly after implantation

• Degradation starts at the surface of the material

• Morphology, crystalinity of the material has great impact on degradation

• Aromatic polyesters

• Polyamides

• Polyurethanes

Polyurethane

• Construction of artificial blood vessels and blood vessel coatings

• Skin transplants, heart valves, dialysis membranes, tubings

• Polyethylene(oxide) chains with terminal amino groups are often grafted as side

chains to reduce the adsorption of the blood components.


Polyamide / Nylon

• Molecular weights between 10.000 bis 15.000

• Application as textile fibers and implants

n


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Carboxylic acid + alcohol

2c. Water-Resorbing & Biodegradable Polymers

• Functional groups of the polymer backbone could be cleaved

• Degradation of the polymer chain into smaller chain segments

• Application: Tissue enmgineering, drug transport

• Carbonyl bond to O

N

S

R1 C X

O

R2

OH2

R1 C OH

O

+ HX R2

Where X= O, N, S

R1 C O

O

R2

Ester

R1 C NH

O

R2

Amide

R1 C S

O

R2

Thioester

2c. Biodegradable Polymers - Examples

X C X'

O

R2R1

OH2

+ HX' R2X C OH

O

R1

Where X and X’= O, N, S

O C O

O

R2R1 NH C O

O

R2R1 NH C NH

O

R2R1

Carbonate Urethane Urea

R1 C X

O

C

O

R2

OH2

+R1 C OH

O

HX C

O

R2

R1 C NH

O

C

O

R2 R1 C O

O

C

O

R2

Imide Anhydride

Where X and X’= O, N, S

2c. Biodegradable Polymers - Examples

• Enzymatic degradation

• Hydrolysis (depend on main chain structure: anhydride > ester > carbonate)

– Homogenous degradation

– Heterogeneous degradation

Degradation proceeds in four steps:

• water sorption

• reduction of mechanical properties (modulus & strength)

• reduction of molar mass

• weight loss



Polyglycolide (PGA) and Polylactide (PLA)

Self-degrading fibers

• Examples

– Polyglycolide (PGA)

– Polylactide (PLA)

– Copolymers thereof

O Cn

O

O Cn

O

CH3

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Poly-Glycolid-co-lactide (PGL)

• Degradable copolymer

• Hydrophilic

• Often cross-linked

Tissue Engineering, self-degrading

fibers


Summary: Not only the Polymer Structure is Important!

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Hydrolysis is increased by

• High numbers of functional groups

• Low crystallization

• Low or no crosslinks

• High surface / volume ratio

• Mechanic stress

Hydrolysis is reduced by

• High molecular weight

• Low numbers of hydrophilic

groups

• Lipophilic polymers

• High crosslinking

• Materials that have one or more properties that can be significantly changed in a

controlled fashion by external stimuli,

• Such as stress

• Temperature

• Moisture

• pH

• electric or magnetic fields

• Akustik sounds

• Example:

• pH-sensitive polymers are materials that change in volume when the pH of the

surrounding medium changes

3. “Smart” Biomaterials

• Hydrogels are crosslinked network polymeric materials that are not soluble but

can absorb large quantities of water.

• These materials are soft and rubbery in nature, resembling living tissues in their

physical properties.

Hydrogels

http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84 http://www.youtube.com/watch?v=pxIJdjizQes&feature=related

Many hydrogels are smart and respond to external stimuli

https://www.youtube.com/watch?v=iBZAwhxwHX0 https://www.youtube.com/watch?v=by53LP0Yu4c

http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84










http://www.youtube.com/watch?v=pxIJdjizQes&feature=related







https://www.youtube.com/watch?v=iBZAwhxwHX0

https://www.youtube.com/watch?v=by53LP0Yu4c

12/2/2016 44

Definition of a Hydrogel

• Water insoluble, three dimensional network of

polymeric chains that are cross-linked 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

12/2/2016 45

Hydrogel Forming Polymers – Hydrophilc 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

O

O

O

N H 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

n

p o l y ( 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

Characteristics of Hydrogels

• No flow when in the steady-state

• By weight, gels are mostly liquid but behave like solids

• Absorption of large quantities of water

– 1-20% up to 1000 times their dry weight

• Cross linkers within the fluid give a gel its structure

(hardness) and contribute to stickiness (tack).

Hydrogels

Highly swollen hydrogels

• Cellulose derivatives

• Poly(vinyl alcohol)

• Poly(ethylene glycol)

Common structural features

• Many OH (or =O) groups to interact with

• Acidic environments hydrophillic swelling

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O

n

Poly(ethylene glycol)

• The polymer chains usually exist in the

shape of randomly coiled molecules.

• In the absence of Na+ ions the negative

charges on the carboxylate ions along

the polymer chains repel each other and

the chains tend to uncoil.

Polyacrylate Hydrogel

• Water molecules are attracted to the

negative charges by hydrogen bonding

• The hydrogel can absorb over five

hundred times its own weight of pure

water but less salty water


• When salt is added to the hydrogel, the chains start to change their shape and water

is lost from the gel


Hydrogel Swelling

• Swelling due to 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

12/2/2016 52

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