Download Polymers and biomaterials in medicine

Polymerization
Synthetic polymers used in
medicine
Department of General Chemistry
UMS Poznan
• History of polymers
• Chemistry of polymers
– definition
– structure
– properties
– polymerization
• Polymers used in medicine
• Biomaterials and composites
History of polymers
• Prior to the early 1920's, chemists doubted the existence of molecules
having molecular weights greater than a few thousand.
• Hermann Staudinger, a German chemist with experience in studying
natural compounds such as rubber and cellulose proposed they were
made up of macromolecules composed of 10,000 or more atoms.
• He formulated a polymeric structure for rubber, based on a repeating
isoprene unit (referred to as a monomer).
•
For his contributions to chemistry, Staudinger received the 1953 Nobel
Prize. The terms polymer and monomer were derived from the Greek
roots poly (many), mono (one) and meros (part)
A brief timeline of polymers in
medicine
1860’s
Aseptic
surgery
introduced
1900’s
Metal
bone
plates
used for
breaks
and
fractures
1940’s
PMMA
used in
cornea
replacement
surgery
1950’1960’s
Artificial
heart and
dialysis
machines
introduced
polymers
eventually
make units
better
1970’1980’s
Eye glass
lens are
made of
PMMA,
contact
lenses
revolutioni
-ze
industry
made of
PHEMA
1990-2000
More than
half of
biomaterial
aplications
are made
of or
contain
some
polymer
Beyond 2000
Artificial skin
derived from
skin in
labolatory,
Internal kidney
dialysis
machine
developed due
to mambrane
advancements
Polymers in medicine
Until recently, most medical devices are still made from
homogenous and isotropic materials such as
polymers, metals, and ceramics. A large number of
polymers is used in many medical applications. This
is mainly becouse they are available in a wide variety
of compositions, properties and forms (solid, fibres,
fabrics, films and gels) and can be fabricated readily
into complex shapes and structures.
Definition
Polymer – a chemical compound consisting
of giant molecules „MACROMOLECULES“
formed by union of many „POLY“ small
repeating units „mers“
MONO“MER“ molecules POLY“MER“ chain,
macromolecule
What controls polymer properties?
1. Chemical composition of polymers, type of monomer,
its structure
CH2=CH
Vinyl polymers
R
Examples:
R = H : polyethylene hydrophobic,
semicrystalline polymers
R = OH : poly(vinyl alcohol), hydrophilic water
soluble polymer with gelling properties
What controls polymer properties?
Writing Formulas for Polymeric Macromolecules
The repeating structural unit of most simple polymers not only reflects
the monomer(s) from which the polymers are constructed, but also
provides a concise means for drawing structures to represent these
macromolecules.
What controls polymer properties?
2. Topology of polymer chains
Linear polymers
A-A-A-A-A-A-ANonlinear (branched) polymers
What controls polymer properties?
Cross-linked polymer (polymer networks)
Cross-links (permanent
connections between
chains restricting motion
of chains rigidity)
Temporary cross-links
entanglements
What controls polymer properties?
3. Monomer distribution in copolymer chains
• Homopolymers (one type of monomer - A)
A-A-A-A-A-A-A- linear/branched
• Copolymers (2-3 comonomers)
A-B-A-B-B-B-A- statistical (random)
A-A-A-B-B-B-B-A-A- block
A-B-A-B-A-B-A- alternating
-A-A-A-A-A- graft/branched
-B-B-B-B-B
What controls polymer properties?
4. Polymer molecular weight
Two experimentally determined values are common:
– Mn , the number average molecular weight, is calculated from
the mole fraction distribution of different sized molecules in a
sample, and
– Mw , the weight average molecular weight, is calculated from
the weight fraction distribution of different sized molecules.
Definitions of molecular weight
averages
Since larger molecules in a sample weigh more than smaller molecules, the
weight average Mw is necessarily skewed to higher values, and is always greater
than Mn. As the weight dispersion of molecules in a sample narrows, Mw
approaches Mn, and in the unlikely case that all the polymer molecules have
identical weights (a pure monodisperse sample), the ratio Mw / Mn becomes
unity.
What controls polymer properties?
5. Supramolecular structure
(molecular organization)
• Amorphous polymers –
coiled irregular
(random) shape of
polyme rchains
• Semicrystalline polymers
– domains with regular
(crystalline) structures
acting as
special type of cross-links
What controls polymer properties?
Properties of Macromolecules
• On heating or cooling most polymers undergo thermal
transitions that provide insight into their morphology.
These are defined as the melt transition, Tm , and the
glass transition, Tg .
• Tm is the temperature at which crystalline domains lose
their structure, or melt. As crystallinity increases, so
does Tm.
• Tg is the temperature below which amorphous domains
lose the structural mobility of the polymer chains and
become rigid glasses.
Tg
• Tg often depends on the history of the sample, particularly previous
heat treatment, mechanical manipulation and annealing. It is
sometimes interpreted as the temperature above which significant
portions of polymer chains are able to slide past each other in
response to an applied force.
• The introduction of relatively large and stiff substituents (such as
benzene rings) will interfere with this chain movement, thus
increasing Tg (note polystyrene below).
• The introduction of small molecular compounds called plasticisers
into the polymer matrix increases the interchain spacing, allowing
chain movement at lower temperatures. with a resulting decrease
in Tg.
Rubber is a elastomer
Elastomers are amorphous polymers that have the ability to
stretch and then return to their original shape at
temperatures above Tg.
At temperatures below Tg elastomers become rigid glassy solids and lose all
elasticity. A tragic example of this caused the space shuttle Challenger
disaster. The heat and chemical resistant O-rings used to seal sections of
the solid booster rockets had an unfortunately high Tg near 0 ºC. The
unexpectedly low temperatures on the morning of the launch were below
this Tg, allowing hot rocket gases to escape the seals.
Glass transition (softening temperature)
Temperature Tg
Temperature at which rigidity of polymer
decreases
Influence of cross-links on physical
properties of polymers
Linear or branched polymers - flow when
heated, can be easily reshaped upon heating –
thermoplastic polymers (usually soluble in
organic solvents)
Cross-linked polymers - they cannot be reshaped
on heating, do not melt, but decompose on
heating, insoluble in organic
liquids(thermosetting polymers).
Thermosetting vs. Thermoplastic
Polymers
• Most of the polymers are classified as thermoplastic. This reflects the fact
that above Tg they may be shaped or pressed into molds, spun or cast from
melts or dissolved in suitable solvents for later fashioning. Because of their
high melting point and poor solubility in most solvents, Kevlar and Nomex
proved to be a challenge, but this was eventually solved.
• Another group of polymers, characterized by a high degree of cross-linking
(Bakelite), resist deformation and solution once their final morphology is
achieved. Such polymers are usually prepared in molds that yield the
desired object. Because these polymers, once formed, cannot be reshaped
by heating, they are called thermosets.
Bakelite, one of the first completely synthetic plastics to
see commercial use (circa 1910).
Synthesis of Polymers used in medicine
Prepared via polymerization reactions:
• Addition (chain-growth) polymerization of
monomers with a double bond
• Condensation (step-growth)
polymerization of bifunctional monomers,
frequently with release of low molecular
compounds (analogous reaction to low
molecular weight compounds)
Addition polymerization
Characteristics
– Starts from an active center (only these
molecules are capable to react)
– π-bond of monomer is converted to σ-bond
in the polymer
– Monomers add sequentially to the end of a
growing chain
– Is very fast and exothermic
– Produces high molecular weight polymers
Types of addition polymerization
• Free-radical polymerization – active center
is a radical (contains unpaired electron) and
the propagating site of reactivity is a carbon
radical.
• Cationic polymerization - the active center is
an acid, and the propagating site of reactivity
is positively charged
• Anionic polymerization - the active center is
a nucleophile, and the propagating site of
reactivity is negatively charged
Synthesis of Addition Polymers
All the monomers from which addition polymers are made are alkenes or
functionally substituted alkenes.
Since a pi-bond in the monomer is converted to a sigma-bond in the polymer, the
polymerization reaction is usually exothermic by 8 to 20 kcal/mol. Indeed, cases
of explosively uncontrolled polymerizations have been reported.
A. Stages of free radical polymerization
1. Initiation/induction – process starts
- Primary radical formation
– When radical polymerization is desired, it must be started by using a radical
initiator, such as a peroxide or certain azo compounds
2. Propagation –
the addition of monomer to an active center (free radical) to
generate a new active center
3. Termination –
the growing chain is stopped
- Radical coupling/recombination (most common)
In principle, once started a radical polymerization might be expected to continue unchecked,
producing a few extremely long chain polymers. In practice, larger numbers of moderately sized
chains are formed, indicating that chain-terminating reactions must be taking place. The most
common termination processes are Radical Combination and Disproportionation.
B. Anionic polymerization
Initiated with e.g. n-butyllithium, alkaline metals. Used
in superglues for methyl 2 cyanoacrylate
polymerization.
C. Cationic polymerization
Polymers used in medicine and
dentistry
Natural polymers
- polysaccharides (agar and alginates)
- poly(isoprene)
SOME COMMON ADDITION POLYMERS
NAME(S)
FORMULA
MONOMER
PROPERTIES
USES
Polyethylene
low density (LDPE)
–(CH2-CH2)n–
ethylene
CH2=CH2
soft, waxy solid
film wrap, plastic bags
Polyethylene
high density (HDPE)
–(CH2-CH2)n–
ethylene
CH2=CH2
rigid, translucent solid
electrical insulation
bottles, toys
Polypropylene
(PP) different grades
–[CH2-CH(CH3)]n–
propylene
CH2=CHCH3
atactic: soft, elastic solid
isotactic: hard, strong solid
similar to LDPE
carpet, upholstery
Poly(vinyl chloride)
(PVC)
–(CH2-CHCl)n–
vinyl chloride
CH2=CHCl
strong rigid solid
pipes, siding, flooring
Poly(vinylidene chloride)
(Saran A)
–(CH2-CCl2)n–
vinylidene chloride
CH2=CCl2
dense, high-melting solid
seat covers, films
Polystyrene
(PS)
–[CH2-CH(C6H5)]n–
styrene
CH2=CHC6H5
hard, rigid, clear solid
soluble in organic solvents
toys, cabinets
packaging (foamed)
Polyacrylonitrile
(PAN, Orlon, Acrilan)
–(CH2-CHCN)n–
acrylonitrile
CH2=CHCN
high-melting solid
soluble in organic solvents
rugs, blankets
clothing
Polytetrafluoroethylene
(PTFE, Teflon)
–(CF2-CF2)n–
tetrafluoroethylene
CF2=CF2
resistant, smooth solid
non-stick surfaces
electrical insulation
Poly(methyl methacrylate)
–[CH2-C(CH3)CO2CH3]n–
(PMMA, Lucite, Plexiglas)
methyl methacrylate
CH2=C(CH3)CO2CH3
hard, transparent solid
lighting covers, signs
skylights
Poly(vinyl acetate)
(PVAc)
–(CH2-CHOCOCH3)n–
vinyl acetate
CH2=CHOCOCH3
soft, sticky solid
latex paints, adhesives
cis-Polyisoprene
natural rubber
–[CH2-CH=C(CH3)-CH2]n–
isoprene
CH2=CH-C(CH3)=CH2
soft, sticky solid
requires vulcanization
for practical use
Polychloroprene (cis +
trans)
(Neoprene)
–[CH2-CH=CCl-CH2]n–
chloroprene
CH2=CH-CCl=CH2
tough, rubbery solid
synthetic rubber
oil resistant
Step-growth polymerization
Characteristics
• Proceeds by conventional functional group
reactions (condensation, addition)
• Needs at least 2 functional groups per reactant
• Any monomer molecule has the „same“ probability
to react
• After an elementary reaction – ability to grow
remains
• Combines two different reactants in an
alternating structure
Synthesis of Step-growth Polymers
• Polymers are formed more slowly than by
addition polymerization
• Polymers are generally of lower molecular
weight
• Types of step-growth polymerization
– Polycondensation
– Polyaddition
The polyester Dacron and the polyamide Nylon 66, shown here, are two examples of synthetic
condensation polymers, also known as step-growth polymers. In contrast to chain-growth polymers,
most of which grow by carbon-carbon bond formation, step-growth polymers generally grow by carbonheteroatom bond formation (C-O & C-N in Dacron & Nylon respectively). Although polymers of this kind
might be considered to be alternating copolymers, the repeating monomeric unit is usually defined as a
combined moiety.
Step-growth polymerization
Step-growth polymerization
2. Setting reaction of epoxies
Step-growth polymerization
• Polyaddition
Step-growth polymerization
polyaddition cont.
2. Setting reaction of A-silicone impression
materials
Some Condensation Polymers
Formula
Type
Components
Tg ºC
Tm ºC
~[CO(CH2)4COOCH2CH2O]n~
polyester
HO2C-(CH2)4-CO2H
HO-CH2CH2-OH
<0
50
polyester
Dacron
Mylar
para HO2C-C6H4-CO2H
HO-CH2CH2-OH
70
265
polyester
meta HO2C-C6H4-CO2H
HO-CH2CH2-OH
50
240
polycarbonate
Lexan
(HO-C6H4-)2C(CH3)2
(Bisphenol A)
X2C=O
(X = OCH3 or Cl)
150
267
polyamide
Nylon 66
HO2C-(CH2)4-CO2H
H2N-(CH2)6-NH2
45
265
53
223
~[CO(CH2)4CONH(CH2)6NH]n~
~[CO(CH2)5NH]n~
polyamide
Nylon 6
Perlon
polyamide
Kevlar
para HO2C-C6H4-CO2H
para H2N-C6H4-NH2
---
500
polyamide
Nomex
meta HO2C-C6H4-CO2H
meta H2N-C6H4-NH2
273
390
polyurethane
Spandex
HOCH2CH2OH
52
---
Biocompatibility
Biocompatibility - describes how well a material
(regardless of source) works with a living system. In any
living system only the host's own tissues are truly inert
- all other materials (synthetic or natural) will illicit
some level of response. Successful integration of a
health product with a patient's own tissues is therefore
absolutely critical. Biocompatibility and the risk of
rejection due to the hosts' immunological response is a
significant challenge.
This is becoming a growing challenge since those awaiting
replacement / transplantation of organs greatly
outnumber the number of available donors.
Polymers in Medicine
Transdermal Patch
Biodegradable Polymer
Drug: Fentanyl (pain killer)
Nicotine
Name: Duragesic, Nicoderm,
Habitrol, Prostep, Nicotrol
Dosis: 72 hours (fentanyl)
Implantable medical devices
• Permanent implants that saves livespacemakers,vascular grafts, central nervous system
shunts for hydrocephalus
• Permanent implants that enhance livesreplacement eye lenses for cataracts, hip prosthesis,
incontinence implants
• Temporary implants that save livesemergency airways, catheters, balloon angioplasty
devices
• Temporary implants that enhance livesbone growth stymulators, wound healing patches,
fracture fixation devices
TYPICAL USES OF POLYMERS AS
BIOMATERIALS
PMMA-bone cement, contact lenses
PTFE-artificial vasculature
PU-facial protheses, blood/device interfaces
PVC-blood vessels, gastrointestinal grafts,
heart components
PDMS-ear and ear parts,heart components,
bones and joints
POLYESTERS-lungs, kidneys, livers, blood vessels
NYLONS-joints, blood vessels, kidneydialysis
Cellophane
• Cellophane is regenerated cellulose. It is in the form of a film; as opposed
to rayon, which has the same properties yet is a fiber.
• In the 1960’s Brandenberger’s original cellophane was put to use as the
membrane that filters and separates the dialysis fluid from the blood. The
precursor to the saran wrap that we use today had properties that are so
desirable because of its ultra small permeability.
• The production of cellophane as stated earlier is simply the regeneration
of cellulose. Obtained naturally from wood and cotton fiber. Cellulose is
reacted with NaOH and carbon disulfide to produce cellulose xanthate.
Cellulose xanthate is then treated with sulfuric acid. The result of the
reaction is extruded to a sheet and after a small “aging” period, a thin
clear film of cellophane can be peeled. The process by which cellophane is
known is viscose .
Cellophane
Today dialysis machines save thousands
of lives daily. The only true alternative to
dialysis is kidney transplant. Even in the
very unlikely case of a successful
transplant (over 50% rejection rate)
dialysis is continued for many month or
years, to ensure stability. The future of
cellulose membranes in the treatment of
renal failure has no limits.
How dialysis membranes work. A dialysis
membrane is a semi-permeable film
(usually a sheet of regenerated cellulose)
containing various sized pores. Molecules
larger than the pores cannot pass through
the membrane but small molecules can do
so freely.
The main inconvenience with dialysis is
the actual administration of the lengthy
procedure. With improvements in the
engineering of the membrane in dialysis,
the result has been healthier patients and
longer lives for the unfortunate victims.
The polymer polyglycolic acid (PGA),
and polylactic acid (PLA,PLGA)
• The polymer polyglycolic acid, PGA, initially started out as an absorbable
suture named Dexon. Dupont, under the direction of Norton Higgins, first
synthesized PGA by a three-step process from glycolic acid by
manipulating temperature and pressure.
• These polymers are then used for drug-delivery systems, to construct
synthetic scaffolding, etc.
• The amorphous form of PLA is used for drug delivery applications. The
latest treatment in treating brain tumors involves attaching dimesized
wafers directly into the skull. The wafers are made out of PLA or PLGA and
slowly distribute cancer-killing reagents directly into the location where
it’s needed.
Polymers delivery systems
EPR Effect
Tumors have “leaky” blood
vessels, which allow relatively
large nano-sized “pills” to enter.
This is called Enhanced
Permeability and Retention (EPR)
Effect. Normal blood vessels are
not “leaky” and nano-particles are
prevented from entering. This
allows one to selectively target
tumors.
Duncan, R. Nature Reviews Cancer 2006, 6, 688-701
Tumors Grow Blood Vessels
Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760
Polydimethyl siloxane (PDMS)
•The polymer polydimethyl siloxane (PDMS) is used in
pacemakers, the delivery of vaccines, and the
construction cerebrospinal fluid shunts. PDMS is an
amorphous structure with low cross-linked elasticity.
•For the delivery of the vaccine, biodegradable pellets
made of PDMS are used. The pellets are very small in
diameter and generally contain soluble antigens to be
released within the body. The pellets consist of
vulcanized rubber and have a mean diameter of 188
um which allows for the particles to
stay in the localized region.
Pacemaker
•One method for the production of dimethyl siloxane
starts with the monomer, dichlorodimethylsilane.
Hydroxyl groups, through hydrolysis, replace the two
chlorines in the monomer. To achieve a higher
molecular weight, however, a different approach is
used. This new method is done by a base catalyzed
ring-opening polymerization of the siloxanes.
CSF shunts
Polyethylene and
Polymethylmethacrylate (PMMA)
Many common thermoplastics, such as
polyethylene and polyester, are used as
biomaterials.
Hip-joint replacements are principally used for
structural support. Consequently, materials that
possess high strength, such as metals, tough
plastics, and reinforced polymer-matrix
composites dominate them. In addition,
biomaterials used for orthopedic applications
must have high modulus, long-term dimensional
stability, high fatigue resistance, and
biocompatibility
A typical modern artificial hip consists of a nitrided
and highly polished cobaltchromium ball
connected to a titanium alloy stem that is inserted
into the femur and cemented into place by in situ
polymerization of polymethyl-methacrylate.
Modern artificial hip
Methyl methacrylate (MMA) polymers
Most frequently used group of polymers in
medicine
Why? Because these materials can be easily
adopted to individual purposes (fillings, prostheses)
and can be in contact human body
• Suitable manipulation/processing properties
(easy to mix, shapable, simple to process and cure)
• Good mechanical properties (rigidity, strength, wear
resistance)
• Biocompatible (tasteless, odourless, non-toxic or nonirritating, resistance to microbial colonization)
Methyl methacrylate (MMA) polymers
Most frequently used group of polymers in
medicine
• Aesthetic properties translucency and transparency
(colour and optical properties of tooth tissues)
• Chemical resistance in oral environment, to
disinfectants etc.
• Acceptable cost of both material and processing
method
Polytetrafluoroethylene
PTFE is thermosetting polymer very limited
application in medicine, but its characteristic
properties, which combine high strength and
chemical resistance, are useful for some orthopedic
and dental devices. The polymer chains in this
material are highly cross-linked and therefore have
severely macromolecular mobility; this limits
extension of the polymer chains under an applied
load.
Biomaterials are used in many blood-contacting
devices. These include artificial heart valves,
synthetic vascular grafts, ventricular assist devices,
drug releases, and a wide range of invasive
treatment and diagnostic systems.
Artificial heart valves and vascular grafts, while not
ideal, have been used successful and have saved
many thousands of lives. However, the risk of
thrombosis has limited the success of existing
cardiovascular devices and has restricted potential
application of the biomaterials to other devices.
Bioprosthetic Heart Valves
Mechanical Prosthetic Heart Valves
Polyurethane
Polyurethane is a thermoset that is also a noncondensation step growth polymer.
Polyurethane has a very low molecular weight
compared to many other polymers with a
molecular weight average of only 47,000 g/mol.
The benefits of this material lie in the basics of
it visible physical properties. Polyurethane
today is one of the most important materials in
use for ventricular assist devices (VAD).
Most commonly seen in the operating room
during open-heart surgery, postoperatively, and
in the cases of extreme cardiac trauma. They
consist of tubing attached to the heart valves
leading to a pump that can be
centrifugal,electrical, or pneumatic.
Polyurethane (segmented) stabilized the VAD,
making not only the contact barrier of the blood
and machine the safest possible, but also using
the compressive properties that it exhibits
made it function more like the
actual heart itself.
Ventricular Assist Device
Composites materials
• Composite materials are formed by combining two or more
materials that have quite different properties.
• The different materials work together to give the composite unique
properties, but within the composite you can easily tell the
different materials apart – they do not dissolve or blend into each
other.
• Most composites are made up of just two materials. One material
(the matrix or binder) surrounds and binds together a cluster of
fibres or fragments of a much stronger material (the
reinforcement).
• The greatest advantage of composite materials is strength and
stiffness combined with lightness. By choosing an appropriate
combination of reinforcement and matrix material, manufacturers
can produce properties that exactly fit the requirements for a
particular structure for a particular purpose
Composites
COMMON NAMES OF BIOMATERIALS AND POLYMERS
ABBREVIATION
NAME
ABBREVIATION
NAME
BIS-GMA
BIS-PHENOL A GLYCIDYL
METHACRYLATE
CARBON FIBRES
GLASS FIBRES
HYDROXYAPATITE
HIGH DENSITY
POLYETHYLENE
LOW DENSITY
POLYETHYLENE
METHYL
METAHACRYLATE
POLYCARBONATE
POLIDIMETHYLSILOXANE
(SILICONE)
POLYETHYLENE
POLYETHYLENE GLYCOL
PELA
BLOCK COPOLYMER OF LACTIC
ACID AND POLYETHYLENE
GLYCOL
POLYETHYLENE TEREPHTALATE
POLYMETHACRYLATE
POLYMETHYLMETACRYLATE
POLYPROPYLENE
POLYTETRAFLUOROETHYLENE
CF
GF
HA
HDP
LDP
MMA
PC
PDMS
PE
PEG
PET
PMA
PMMA
PP
PTFE
PU
PVC
PVP
SR
UHMWPE
POLYURETHANE
POLYVINYLCHLORIDE
POLYVINYLPYRROLIDONE
SILICONE RUBBER
ULTRA HIGH MOLECULAR
WEIGHT POLYETHYLENE
Aplication of polymers
POLYMER
APLICATION
PDMS
Catheters, heart valves
Polyurethane
ventricular assist devices
PGA, PLA, PLGA
Drug delivery, devices
Polytetrafluoroe, thylene
Heart valves, vascular grafts,
nerve repair
Polyethylene
Catheters, hip prostheses
Polymethylmethacrylate
(PMMA)
Fracture fixation
Cellophane
Dialysis membranes
Conclusion
Biomaterials have already made a huge impact on
medical practices. But, the opportunities that lie ahead of
us are enormous. “Tissue engineering and related
subjects have the potential to change paradigms” for
treating diseases that today cannot be treated effectively
like certain forms of liver failure, paralysis, and certain
disorders.
Thank you