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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
9
Homopolymer
Copolymer
1. Structures/ Topologies of Polymers
10
Linear
Branched
Star-shaped
Cross-linked
1. “Perfect Polymers” = Dendrimers
1. Overview over different Dendrimer Scaffolds
1. Polymer versus Dendrimer
B
B
B
B B
A
A A
B B
B
B B
B
A A
A
A A
A
B B B
B
B
B
B B B
B
B
B
A
A
A
A
A
A A
A
A
A
A
A B B
B B B B
B B
B B
B B
B B
B B B B
B B
B B
A
A
A
A
A
A
A
A
A A A A
A
A
A
A
A
A
A
A
A A A
F F F
F F F
F
F
F
F
F F
F F F
F
F F
F
F
F F
F
F
F
F
F
F
F
F
F F
F F
F F
F F
F F
F
F
F F
F
F
A
F F
1. Polymer versus Dendrimer
15
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
17
• 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
19
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
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
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.
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
• 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).
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
• 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
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
24
Polytetrafluorethylene (PTFE, “Teflon”)
• Hydrophobic
• Chemically inert
• Thermally very stable
• Mechanically stable
“Gore-Tex”
Artificial blood vessels (low degree of protein adsorption)
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
Polypropylene (PP)
• Nahtmaterial
• als Netze zur Überbrückung von Gewebedefekten
• zur Abdeckung von Leistenbrüchen etc..
• Membranen für Blutoxygenatoren und Nierendialyse,
• Fingergelenkprothesen, Herzklappen
• Einweg-Spritzen, Verpackungsmaterial
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
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
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
27
Biodegradable Polymers
Polymethylmetacrylate (PMMA, “Plexiglas”)
• Hydrophobic
• Glass state, amorphous (Tg > 100°C)
• Mechanically stable
• 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
28
Polyhydroxyethylmethacrylate (PHEMA)
• Hydrophilic
• Soft, gel-like (Tg < 25°C)
• Transparent
• Mechanically stable
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
29
Responsive Polymer will be discussed in chapter 3 “Smart Polymers” in greater
details
2a. Non-Hydrolysable Smart Polymers & Hydrogels
30
Polydimethylsiloxane (PDMS)
• Inorganic polymer
• Hydrophobic
• Soft, gel-like (Tg < -50°C)
Catheters, implants
Devices: Soft Lithography
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
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
2a. Non-Hydrolysable Polymers with low Tendency to Adsorb Water
2b. Biodegradable Polymers with Low Tendency to Adsorb Water
32
• 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.
2b. Biodegradable Polymers with Low Tendency to Adsorb Water
Polyamide / Nylon
• Molecular weights between 10.000 bis 15.000
• Application as textile fibers and implants
n
2b. Biodegradable Polymers with Low Tendency to Adsorb Water
35
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
2c. Water-Resorbing & Biodegradable Polymers
2c. Water-Resorbing & Biodegradable Polymers
Polyglycolide (PGA) and Polylactide (PLA)
Self-degrading fibers
• Examples
– Polyglycolide (PGA)
– Polylactide (PLA)
– Copolymers thereof
O Cn
O
O Cn
O
CH3
40
Poly-Glycolid-co-lactide (PGL)
• Degradable copolymer
• Hydrophilic
• Often cross-linked
Tissue Engineering, self-degrading
fibers
2c. Water-Resorbing & Biodegradable Polymers
Summary: Not only the Polymer Structure is Important!
41
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
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
48
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
Polyacrylate Hydrogel
• When salt is added to the hydrogel, the chains start to change their shape and water
is lost from the gel
Polyacrylate Hydrogel
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