Lecture 14: - Resorbable Polymers · Effect of pH on Degradation • The concentration of H+ has...

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

Structure of Polymer Chains

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

Mechanical Properties

Stress = s = F/Ao

Strain = e = (l – lo)/lo

Force F

Length l

Sample area A

Martin Luther University Halle-Wittenberg

Stress-Strain-Diagram

Stress

Strain

Tensile strength

E (Youngs) modulus

Elongation at break

Elastic deformation

Plastic Deformation

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

Configuration Effects on Tg

Poly(D-Lactide) Poly(L-Lactide) Isotactic PLA

David E. Henton, Patrick Gruber et al, Polylactic Acid Technology, P541

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

Poly(-lactide-co-glycolide)

• copolymer of lactic acid and glycolic acid

• cristallinity as well as melting temperature dependend on ratio of monomers

• FDA approved

Martin Luther University Halle-Wittenberg

Crystallinity as a Function of Composition

de

gre

e o

f cr

ysta

llin

ity

(%)

poly(-L-lactide-co-glycolide)

Martin Luther University Halle-Wittenberg

Tg / Tm at Different Compositions

Tm ()

Tg (o) in dependence

on the composition

of

poly(-L-lactide-co-glycolide)T g

and

Tm

(°C

)

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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%

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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]

Martin Luther University Halle-Wittenberg

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"

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

Mechanisms of Degradation

Bulk degradation

Surface degradation

Martin Luther University Halle-Wittenberg

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.

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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)

Martin Luther University Halle-Wittenberg

Summary Degradation II

Specimen / Implant

• Processing conditions

• Sterilisation procedure

• History of the polymer (e.g. storage)

• Mechanical stress

• Shape of the implant

• Roughness

Martin Luther University Halle-Wittenberg

Surface Morphology and Degradation

A. Kochan, project work 2001

Monofil Polyfil

Martin Luther University Halle-Wittenberg

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

Martin Luther University Halle-Wittenberg

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