lecture 14: - resorbable polymers · effect of ph on degradation • the concentration of h+ has...
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Martin Luther University Halle-Wittenberg
Lecture 14:- Resorbable Polymers -
Prof. Dr. Thomas Groth
Biomedical Materials
Martin Luther University Halle-Wittenberg
Content
• Characterization of polymer properties
• Medical applied degradable polymers• poly(-glycolide), poly(-lactide)
• co-polyesters based on dilactides/diglycolides
• poly(-p-dioxanone)
• poly(-caprolactone)
• poly(-anhydride)
• poly(-alkanoate)
• Degradation behavior• hydrolysable chemical bonds
• degradation behavior in general
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Classification of Polymers
Comparison of polymer types
Type General structure Scheme
Flexible, linear chains
Stiff,3-D network
Linear chains with cross-links
Cross-links
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Structure of Polymer Chains
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Structure of Polymers
• Linear, branched or cross-linked chains
• Isochains, if only carbon makes the main chain
• Heterochains, if other atoms like O or N are part of main chain
• Stereoisomerie of chains like cis/trans with double bonds and tacticity (next overhead)
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Stereo Isomeria of Side Chains
Isotactic– all side groups or chains on one side
Syndiotactic – alternating change of position of side groups/chains
Atactic – no ordering of side groups
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Molecular Weight of Polymers
• Polymerisation degree = molar mass polymer/molar mass monomer
• Number related mean molar mass
Mn = S NiMi/S Ni
• Weight related mean
Mw – SNiMi²/SNiMi
• Ni as number of moles of species i and Mi as their molecular weight.
Typical molecular weight distribution of polymers
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Mechanical Properties
Stress = s = F/Ao
Strain = e = (l – lo)/lo
Force F
Length l
Sample area A
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Stress-Strain-Diagram
Stress
Strain
Tensile strength
E (Youngs) modulus
Elongation at break
Elastic deformation
Plastic Deformation
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Note: Natural isotactic PHB (PHB) blends with synthetic atactic PHB(at-PHB)
Configuration Effects on Mechanical Properties and Glass Transition Temperature
http://dx.doi.org/10.1590/S1517-70762008000100002, http://doi:10.1016/j.biomaterials.2005.05.095
The elastic modulus and the tensile strength of the blends decreased with increasing content of amorphous synthetic atactic at-PHB, while the elongation at break increased
Tg decreased with the increase of atactic at-PHB, which indicated the miscibility of the amorphous phases of blends
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Thermal Properties of Polymers
Mechanical properties thermoplastics in dependence on T
Stiff/Glassy
Leather-like
Rubber-like
Viscous
Liquid state – chains are mobile
Melting temperature
Glass transition temperature
Glass-like state: only local movement of chain segments brittle material
Amorphous polymer: Chain move under stress (reversible) deformation
Cristallin polymer:
movement of chains
diffcult
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Configuration Effects on Tg
Poly(D-Lactide) Poly(L-Lactide) Isotactic PLA
David E. Henton, Patrick Gruber et al, Polylactic Acid Technology, P541
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Poly(-glycolide) (PGA)
„monomer“ polymer
O
O
O
O
O
O
n
Tm = 225°C, Tg = 35 – 40°C, hydrolytic cleavable, „bulk degradation“, 40 – 55%
crystallinity, thermoplastic behavior, stiff and brittle, insoluble in most organic
solvents
FDA approved !
(Food and Drug Adminstration – US licensing authority for biomedical materials)
Ring opening polymerization
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Dependence of PGA Crystallinity on Cooling Rate
influence of the cooling rate on the degree of crystallinity of poly(-glycolic acid) after heating above Tm
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Poly(-lactide) (PLA)
„monomer“ polymer
Tm = 172 - 180°C, Tg = 35-55°C,
hydrolytic cleavable, „bulk degradation“,
stereo-isomeric structures: L- and D-shape, DL- racemic mixture
poly-L-lactides and poly-D-lactides are semicrystalline (Cr~37%), poly-DL-lactide is amorphous
lactic acid = 2-hydroxy-propane-acid; -hydroxy-propane-acid
PLA´s are more hydrophobic than PGA, FDA approved
O
O
O
O
O
Oring opening polymerisation
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Poly(-glycolides)
substituentR
Name Tg
[°C]/1/general specific
- H glycolide glycolide 35 - 40
- CH3
substitutedglycolides
methylglycolide= lactide
35 – 55
- CH2CH3 ethylglycolide 15
- (CH2)5CH3 hexylglycolide -37
- CH(CH3)2 isobutylglycolide 22
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Poly(-lactide)
Poly(-lactide) - steric hindrance due to their methyl group
slower degradation rate than
poly(-glycolide)
Thumb rule:
The bigger the substituent the slower the degradation rate.
Poly(-lactide)
autocatalytic, acidic hydrolysis in bulk due to the enrichment of the monomeric degradation products (lactide-"monomer" = lactic acid) [consider: mass transport].
Inflammations can be caused by pH-lowering in the surrounding of the
implant, due to resorption of the poly(-lactide) degradation products
Gutwald R: Biomedizinische Technik, Bd. 40, Erg.-band 1, 1995, S. 49
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Poly(-lactide-co-glycolide)
• copolymer of lactic acid and glycolic acid
• cristallinity as well as melting temperature dependend on ratio of monomers
• FDA approved
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Crystallinity as a Function of Composition
de
gre
e o
f cr
ysta
llin
ity
(%)
poly(-L-lactide-co-glycolide)
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Tg / Tm at Different Compositions
Tm ()
Tg (o) in dependence
on the composition
of
poly(-L-lactide-co-glycolide)T g
and
Tm
(°C
)
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Poly(-lactides)
Lactide is a general group name of double esters of -hydroxy-carbonic acids
Lactide the dimer of lactic acid (also called di-lactide, sometimes)that does mean: an intermolecular ester of two molecules of lactide acid
Lactate salts or esters of lactic acid, esters of lactic acid in their monomeric style
Lactone internal ester of lactic acid, that does mean ester formed by the reaction between –OH and –COOH of one and the same molecule („intramolecular“)(consider: stability of cyclic molecular systems in dependence on the numbers of atoms belonging to the cyclic structure of the molecule)
cross reference: lactame → e-caprolactames → poly(-e-caprolactame)
(DeDeRon / Nylon)
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Poly(-hydroxyalkanoates) (e.g. PHB´s)
Idea: economical preparation of stereo regular polyesters by fermentation
O
OH R
nSynthesis
A) Bacteria by:
Alcaligenes eutrophus – Poly-D-(-)-3-hydroxybutane-acid and poly(D-(-)-3-hydroxybutan-acid-co-D-(-)-3-hydroxypentane-acid) from glucose und propane acid (PHB)
B) Technical Synthesis
O
OH CH3
O
OH
H3C
;
0 – 16 mol%
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Thermal and Mechanical Properties of PLA, PGA and PHB
Polymer Mw Tg [°C] Tm [°C]tensile
strength[N/mm²]
E-Modul [N/mm²]
elongation at break [%]
P(L-LA) 50.000 54 170 28 1.200 6.0
P(L-LA) 300.000 59 178 48 3.000 2.0
P(D,L-LA) 107.000 51 29 1.900 5.0
PGA 50.000 35 210
PHB > 100.000 9 177 40 3.500 2.0
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Applications of PLA, PGA and P(LA-co-GA) and PHB
• Barrier-membranes to avoid adhesion
of tissues, temporary skin substitute
• Guiding membranes for the
regeneration of tissue in dental
applications (to treat paradontose)
• Orthopedic applications (nails, screws)
• Resorbable stents
• Clamps and suture materials for
surgery
• Scaffolds for tissue engineering
• Drug release products
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Poly(p-dioxanone) (PPDO)
monomer polymer
O
O
O
O
O
O
n
Tm appr. 115°C, Tg = -10 - 0°C
hydrolytic cleavable, „bulk degradation“
semicrystalline polymer of appr. 55% crystallinity
FDA approved
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Poly(e-caprolactone) (PCL)
monomer polymer
Tm = 59 - 64°C, Tg = -60°C,
hydrolytic cleavable
„bulk degradation“
crystallinity rises the lower the mol mass , 40% at Mn = 100.000 g/mol, 80% at Mn = 5.000 g/mol
FDA approved
O
O
O
O
n
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Application of PPDO and PCL
• Reservoirs for drug release systems
• Scaffolds for tissue engineering
• Surgical clamps
• Suture materials
21 days p.I. 90 days p.I. 180 days p.I. 210 days p.I.1 day p.I.
Process of resorption of PPDO (source Ethicon)
E-Modul gegenüber Lagerzeit
0
200
400
600
800
1000
0 5 10 15 20 25
Lagerzeit [d]
E-M
od
ul [N
/mm
²]
E-Modul [N/mm²]
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Poly(-anhydrides)
- Poly(-anhydrides) are crystalline (normally) and in comparison to poly(-orthoesters) they have lower mechanical strength
- Hydrophobic polymers due to long fatty-di-acids as monomer
- Applications exclusively as drug release systems
- FDA approved for medical application
- Important are poly(-carboxyphenoxypropane-co-decane-diacid) and polymersbased fatty di-acids copolymerised with decane-di-acid
HOOCR
1
COOH+
Cl Cl
O
Et3N
0°CR
1O
O O
+ Et3N+H Cl
-+ CO2
"Phosgen"
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Poly(-orthoester)
Tg: 25 – 110°C (related to the composition)
Hydrophobic polymers
Hydrolytic degradation via the surface
Degradation periods from several to some hundreds days
Application as „drug release systems“
general structural feature of orthoesters:
the related acids do not exist
H
an example:(Ratner et al. Biomaterials Science 2004)
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insolubility in water
Solubility in water is achieved
mechanism III
Chemical Mechanisms of Degradation
cleavage of intramolecular bonds- depolymerisation ( forming oligo or monomers)
Most frequent mechanism of degradation (e.g. all polyesters, polyanhydrids, polyorthoesterns)
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Degradation of Polymers in Aqueous Media
• Hydrolysis and/or enzymatic degradation in biological surroundings (mostly esterases, lipases)
• Degradation rate depends on type of covalent linkage in polymer (e.g. ester bond)
• Degradation rate depends on hydrophilicity
( penetration of water into the polymeric matrix: hydrophobic polymers < hydrophilic)
• Degradation rate depends on phase morphology: semi-crystalline < amorphous-glassy < amorphous-elastomeric
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Degradation of Polymers
• Macroscopical changes visible (e.g. colour changes)
• Changes of physical-chemical properties
- swelling
- shape changes
- weight loss
- lowering of the molecular weight
- loss of physical / mechanical properties
- loss of functionality
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Effect of Chemical Bonds on Degradation
• Type of chemical bond between monomers important for degradation rate
• Anhydrides and poly(-orthoester) short degradation times (t50%= 0.1 h ... 4 h)
• Poly(-esters) t50%= 3.3 years
• Poly(-amides) t50%= 83.000 years
• Strong influence of chemical surrounding (functional groups in neighbourhood) due to their steric and or electronic effects
- for example:
slower degradation of PLA in comparison to PGA due to the steric hindrance of the water attack on ester bond by the methyl side group
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Effect of pH on Degradation
• The concentration of H+ has catalytic activity.
esp. hydrolysis of esters is enhanced at acidic or basic pH accompagnied by different degradation rates!
• PLA degrades faster at lower pH-values
• Autokatalytic effect during the degradation of poly(a-hydroxy-acids) (PLA, PGA, etc.)
The degradation of these polymers generates
monomers containing carboxylic groups releasing
protons
decreases pH-value!
The presence of proton increases the degradation
rate.
The effect of pH on the change in molecular weight (Mw) of PLGA microspheres (formulation 25 K) incubated at 37 °C. Mw was plotted against time in days. Samples were incubated in PBS buffer: (□) pH 7.4, and (▪) pH 2.4. The polymer molecular weight was measured using gel permeation chromatography (GPC). (Mean ± std dev; n = 3).
http://dx.doi.org/10.1016/j.jconrel.2007.05.034
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Mechanisms of Degradation
Bulk degradation
Surface degradation
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Bulk Degradation
Fu K, Pack DW, Klibanov AM, Langer R: Pharm. Res. 2000, 1, 100Hooper KA; Macon ND, Kohn J: J. Biomed. Mat. Res. 1998, 32, 443
m
t t
M
kdiffusion >> khydrolysis
The rate of water penetration is higher than the rate of hydrolysis.
Abrupt decline of molecular weight whereas successive decrease of total mass of polymer happens.
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Bulk Degradation
• The penetration rate of water is higher than the conversion /
degradation rate into water soluble fragments
• Degradation / erosion takes place in the whole volume of the
polymeric implant
• Polyesters possess some polar atoms (oxygen) – penetration of water
is facilitated „bulk degradation/ ~ erosion“)
• Formation of smaller loose, disconnected particles due to yielded
cracks and fragments
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Surface Degradation
m
t
Degradation rate (loss of mass) depends on the relationship of surface to volume. The higher it is the faster can be the degradation rate.
kdiffusion << khydrolysis
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Surface Degradation
• True for hydrophobic polymers, mainly resistant against penetration of
water
• The inner structure persists.
• The rate of penetration of water is lower than the rate of degradation.
• esp. poly(-anhydride) and poly(-orthoester)
• Material resp. implant becomes smaller (onion-like degradation layer-
by-layer)
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Surface - versus – Volume Degradation
via the surface due to hydrophobic properties
e.g. poly(-anhydride)
bulk degradation due to hydrophilic properties
e.g. PCL/PLA/PHB/PPDO
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Dependence of Degradation on the (co)polymer Composition
• Co-monomer proerties & fractions influence polymer properties
(hydrophilicity, hydrophobicity, cristallinity)
• Amorphous polymers low ordering of polymer chains easier
penetration of water
• Cristalline domains tight packing of chains water molecules cannot
diffuse in
• E.g. hydrophobic (e.g. aromatic or apolar side groups) comonomers decrease the
degradation rate higher fractions of glycolic acid in PLA-PGA-copolymers
accelerate the degradation because of lack of methyl side group
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Influence of Water Absorption on Degradation
• Hydrolysis the most important process
• Degradation rate depends on polymer bulk composition:
Hydrophobic (lipophilic) polymers absorb only small amounts of water
lowered hydrolytic degradation rate
Hydrophilic (lipophobic) polymers absorb more water higher
hydrolytic degradation rates
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Degradation Times of Lactic Acid and Glycolic Acid (co)polymers
polymer completely degraded after … (months)
poly(-L-lactic acid) 18 - 24
poly(-D,L-lactic acid) 12 – 16
poly(-D,L-lactic-co-glycolic acid) 85:15 5
poly(-L-lactic-co-glycolic acid) 50:50 2
poly(-D,L-lactic-co-caprolactone) 90:10 2
poly(-glycolic acid) 2 - 4
poly(-e-caprolactone) 24 - 36
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Degradation and Loss of Function
Ethicon Produktinformation Nahtmaterial, S. 25
important for the application is t=0,5t=0
not the time of resorption!
tensile strength resorption
days
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Degradation of Polyglycolid (PLG)/Poly-Anhydride (PCPH) Core/Shell Particles
Core shell particles from different polymers
International Journal of Pharmaceutics, Volume 301, 2005, 294–303
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Degradation of Polyglycolid (PLG)/Poly-Anhydride (PCPH) Core/Shell Particles
Optical micrographs at time zero (first column); 3 weeks (second column); 4 weeks (third column) and 25 weeks (fourth column) of in vitro degradation, and confocal fluorescent images of rhodamine B uptake at 5 weeks (fifth column) of in vitro degradation. Images are of (A–C, P) PLG; (D–G, Q) PLG(PCPH); (H–K, R) PCPH(PLG) and (L–O, S) PCPH. Scale bars are 50 μm. (Ref. see previous page)
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Degradation of Polyglycolid (PLG)/Poly-Anhydride (PCPH) Core/Shell Particles
Weight-averaged molecular weight during in vitro incubation (in PBS, 37 °C) of PLG microspheres (●), PLG(PCPH) (○) and PCPH(PLG) (□) DWMS, and PCPH microspheres (■). DWMS initially consisted of 1:1 mass ratio of PLG and PCPH.
Bulk degradation
Surface degradation
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Summary Degradation I
Dependent on polymer
• Chemical composition and bonds between monomers
•Presence of polar groups
•Molecular weight and its distribution (Mw/Mn)
• Low molecular additives (plastiziser)
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Summary Degradation II
Specimen / Implant
• Processing conditions
• Sterilisation procedure
• History of the polymer (e.g. storage)
• Mechanical stress
• Shape of the implant
• Roughness
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Surface Morphology and Degradation
A. Kochan, project work 2001
Monofil Polyfil
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Degradation conditions
• „location of implantation (e.g. blood, gastrointestinal, bone)
• adsorbed or absorbed substances (water, ions, etc.)
• ionic strength, pH-value, oxygen radicals
• changes of the diffusion coefficients (e.g. swelling of polymer network)
• mechanism of the hydrolysis (H2O, enzymatic)
micro-cracks caused by hydrolysis (mechanism-dependent!) or due to mechanical loading
Summary Degradation III
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Literature
• Wintermantel E, Ha S-W
Biokompatible Werkstoffe und Bauweisen, Springerverlag, 1998
• Buddy Ratner et al. (eds),
Biomaterials Science 2nd Edition, Elsevier
• Lendlein A,
Polymere als Implantatwerkstoffe. Chemie in unserer Zeit, Jahrg. 33 Nr. 5 (1999) 279-295