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Biodegradable Polymers:

Chemistry, Degradation and Applications

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Definition A “biodegradable” product has the ability

to break down, safely, reliably, and relatively quickly, by biological means, into raw materials of nature and disappear into nature.

Nature’s way: every resource made by

nature returns to nature.

How long does it take?

Cotton rags 1-5 months Paper 2-5 months Rope 3-14 months Orange peels 6 months Wool socks 1 to 5 years Cigarette butts 1 to 12 years Plastic coated paper milk cartons 5 years Plastic bags 10 to 20 years Nylon fabric 30 to 40 years Aluminum cans 80 to 100 years Plastic 6-pack holder rings 450 years Glass bottles 1 million years Plastic bottles May be never

What is Polymer Degradation?

polymers were synthesized from glycolic acid in 1920s At that time, polymer degradation was viewed negatively as a process where properties and performance deteriorated with time.

Medical Applications of Biodegradable Polymers

Wound management Sutures Staples Clips Adhesives Surgical meshes

Orthopedic devices Pins Rods Screws Tacks Ligaments

Dental applications Guided tissue regeneration

Membrane Void filler following tooth

extraction Cardiovascular applications Stents

Intestinal applications Anastomosis rings

Drug delivery system Tissue engineering

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Why We Use Biodegradable Materials?

Eliminates additional surgery to remove an implant after it serves its function Ideal when the “temporary presence” of the implant is desired replaced by regenerated tissue as the implant degrades

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Biodegradable Materials

Degradation Short term applications sutures drug delivery orthopaedic fixation devices (requires

exceptionally strong polymers) adhesion prevention (requires polymers that

can form soft membranes or films) temporary vascular grafts (development

stage, blood compatibility is a problem)

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Biodegradable Materials

Four main types of degradable implants: the temporary scaffold the temporary barrier the drug delivery device multifunctional devices

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Biodegradable: Scaffold provides support until the tissue heals weakened by disease, injury or surgery healing wound, broken bone, damaged blood vessel sutures, bone fixation devices, vascular grafts

Rate of degradation: implant should degrade at the rate the tissue heals

Sutures are most widely used polyglycolic acid (PGA) - Dexon®

copolymers of PGA and PLA (polylactic acid), Vicryl® polydioxanone (PDS)

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Biodegradable: Barrier

Prevent adhesion caused by clotting of blood in the extravascular tissue space

• clotting inflammation fibrosis adhesions are common problems after cardiac,

spinal and tendon surgery • barrier in the form of thin membrane or film

Another barrier use is artificial skin for treatment of burns

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Biodegradable: Drug Delivery

Most widely investigated application PLA, PGA used frequently Polyanhydrides for administering chemotherapeutic agents to patients suffering from brain cancer

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Biodegradable: Multifunctional Devices

Combination of several functions mechanical support +

drug delivery: biodegradable stents to prevent collapse and restenosis (reblocking) of arteries opened by balloon angioplasty and treated with anti-inflammatory or anti-thrombogenic agents

Biodegradable intravascular stent molded from a blend of polylactide and trimethylene

carbonate. Photo: Cordis Corp. Prototype Molded by Tesco Associates, Inc.

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Biodegradable: Terminology Confusion between biodegradation, bioerosion,

bioabsorption and bioresorption! Consensus Conference of the European Society for

Biomaterials: Biodegradation: A biological agent (an enzyme, microbe or cell) responsible for degradation Bioerosion: Bioerosion contains both physical (such as dissolution) and chemical processes (such as backbone cleavage). A water-insoluble polymer that turns water-soluble under physiological conditions. Bioresorption, Bioabsorption: Polymer or its degradation products removed by cellular activity (e.g. phagocytosis)

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Biodegradable Polymers: Bioerosion

Bioerosion cause: changes in the appearance of the device changes in the physicomechanical properties swelling deformation structural disintegration weight loss loss of function

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Biodegradable Polymers: Bioerosion

Bioerosion is due to chemical degradation

cleavage of backbone cleavage of crosslinks side chains

physical processes (e.g. changes in pH) Two types of erosion bulk erosion surface erosion

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Biodegradable Polymers: Bioerosion

bulk erosion (homogeneous) uniform degradation throughout polymer

water enters polymer causes hydrolytic degradation component hollowed out finally crumbles (like sugar cube in water) releases acid groups (possible inflammation) characteristic of hydrophilic polymers

H2O H2O

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Biodegradable Polymers: Bioerosion

water penetration limited degradation occurs on the surface thinning of the component over time integrity is maintained over longer

time when compared to bulk erosion hydrophobic polymers experience

surface erosion since water intake limited

acidic byproducts are released gradually acid burst less likely, lower chance of inflammation

surface erosion can also occur via enzymatic degradation

H2O H2O

surface erosion (heterogeneous) polymer degrades only at polymer-water interface

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Polymer Degradation by Erosion

Erodible Matrices or Micro/Nanospheres

(a) Bulk-eroding system

(b) Surface-eroding system

Degradation Schemes

Surface erosion (poly(ortho)esters and polyanhydrides) Sample is eroded from the surface Mass loss is faster than the ingress of water into the

bulk

Bulk degradation (PLA,PGA,PLGA, PCL) Degradation takes place throughout the whole of the

sample Ingress of water is faster than the rate of degradation

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Biodegradable Polymers: Bioerosion

Factors that determine rate of erosion: 1. chemical stability of the polymer backbone (erosion rate: anhydride > ester > amide parallel to the activity of functional group!!)

2. hydrophobicity of the monomer (addition of

hydrophobic comonomers reduce erosion rate)

3. morphology of polymer crystalline vs. amorphous: crystallinity ↑ packing density ↑ water penetration ↓ erosion rate ↓

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Biodegradable Polymers: Bioerosion

Factors that determine rate of erosion (cont.): 4. initial molecular weight of the polymer 5. fabrication process 6. presence of catalysts, additives or plasticizers 7. geometry of the implanted device (surface/volume

ratio) 8. Annealing: Polymer less permeable to water in

glassy state: Tg of the polymer should be greater than 37 °C to maintain resistance to hydrolysis under physiological conditions

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Biodegradable Polymers: Bioerosion

Factors that determine rate of erosion (cont.): 9. Method of Sterilization 10. Storage History 11. Site of Implantation 12. Absorbed Compounds 13. Mechanism of Hydrolysis (enzymes vs water)

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Biodegradable Polymers: Chemical Degradation

Chemical degradation mediated by water, enzymes, microorganisms Mechanisms of chemical degradation cleavage of crosslinks between chains cleavage of side chains cleavage of polymer backbone combination of above

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Biodegradable Polymers: Chemical Degradation

CLEAVAGE OF CROSSLINKS

TRANSFORMATION OF SIDE CHAINS

CLEAVAGE OF BACKBONE

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Biodegradable Polymers: Storage, Sterilization and Packaging

minimize premature polymer degradation during fabrication and storage moisture can seriously degrade, controlled atmosphere facilities sterilization γ-irradiation or ethylene oxide both methods degrade physical properties choose lesser of two evils for a given polymer γ-irradiation dose at 2-3 Mrad (standard level to

reduce HIV) can induce significant backbone damage ethylene oxide highly toxic

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Biodegradable Polymers: Storage, Sterilization and Packaging

Packed in airtight, aluminum-backed, plastic foil pouches. Refrigeration may be necessary

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Enzymatic Degradation Natural polymers degrade primarily via enzyme action collagen by collagenases, lysozyme glycosaminoglycans by hyaluronidase, lysozyme

There is also evidence that degradation of synthetic polymers is due to or enhanced by enzymes. poly(ε-caprolactone) elastomers

-20.0

0.0

20.0

40.0

60.0

80.0

-5 0 5 10 15 20 25

in vitro

in vivo

% w

eigh

t los

s

time (weeks)

C.G. Pitt et al., J. Control. Rel. 1(1984) 3-14

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Methods of Studying Polymer Degradation

Morphological changes (swelling, deformation, bubbling, disappearance…)

Weight lose Thermal behavior changes Differential Scanning Calorimetry (DSC)

Molecular weight changes Dilute solution viscosity Size exclusion chromatograpgy(SEC) Gel permeation chromatography(GPC)

Change in chemistry Infared spectroscopy (IR) Nuclear Magnetic Resonance Spectroscopy (NMR)

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Biodegradable Polymers

Variety of available degradable polymers is limited due to stringent requirements biocompatibility free from degradation related toxic products

(e.g. monomers, stabilizers, polymerization initiators, emulsifiers)

Few approved by FDA PLA, PGA, PDS used routinely

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Biodegradable Polymers

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Biodegradable Polymers

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Biodegradable Polymers

Effect of molecular weight on the mechanical

strength????

Biodegradable Polymers

Carbonyl bond to

O N S

R1 C X

O

R2 R1 C OH

O

+ HX R2

OH2

Where X= O, N, S

R1 C O

O

R2

Ester

R1 C NH

O

R2

Amide

R1 C S

O

R2

A.

Thioester

X C X'

O

R2R1 + HX' R2X C OH

O

R1

OH2

Where X and X’= O, N

B.

O C O

O

R2R1 NH C O

O

R2R1 NH C NH

O

R2R1

Carbonate Urethane Urea

C. R1 C X

O

C

O

R2 +R1 C OH

O

HX C

O

R2

OH2

R1 C NH

O

C

O

R2 R1 C O

O

C

O

R2

Imide Anhydride

Where X and X’= O, N

Biodegradable Polymers

Biodegradable Polymers

Acetal:

Hemiacetal:

Ether

OH2 +C

O

H H

R' OHO C O

H

H

R R' R OH +

O C

C

C C

C

OH

OH

OH

OH

OH OH C

C

C C

OH

OH

OH

OH

H2O +

C==O

H

H2O

R C O C R'

H H

H HOH2

R C OH

H

H

R' C OH

H

H

+

R C R

C

H

N

R C R

C O

H

NH2

R C R

C O

H

OH

OH2 OH2

RO P OR'

O

OR''

OH P OH

O

OR''

+ +R OH OH R'OH2

R C C C C R'

CN

C

OR''

CNH

H O C

OR'''

O

H

H

OH2R C C C

CN

C

OR''

H

H O

H

H

OH C R'

CN

C

OR'''

O

+

Nitrile

Phosphonate

Polycyanocrylate

Biodegradable Polymers

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Biodegradable Polymers

Most degradable polymers are polyesters ester is a covalent bond with polar nature, more reactive can be broken down by hydrolysis the C-O bond breaks

ESTER BOND

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Biodegradable Polymers

contain a peptide (or amide) link can be broken down by hydrolysis the C-N bond breaks can be spun into fibres for strength

AMIDE BOND

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Biodegradable Polymers: Hydrolysis

Breakdown of a molecule in the presence of water Hydrolysis of the ester bond results in formation of an acid and an alcohol Inverse of reaction to condensation is hydrolysis (remember condensation polymerization)

Preparation of ester

Preparation of anhydride

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Biodegradable Polymers PGA and PLA most widely used biodegradable polymers PGA is the simplest aliphatic polyester

highly crystalline, high melting point, low solubility appeared with the trade name Dexon Dexon sutures lose strength within 2-4 weeks sooner than desired used as bone screws, Biofix®

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Biodegradable Polymers

PLA D,L-PLA amorphous polymer; thus, used for drug delivery L-PLA semicrystalline; thus, mechanical applications such as sutures or orthopaedic devices compare mechanical properties of D,L-PLA and L-PLA in the Table in slide # 33

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Biodegradable Polymers

PGA and PLA (cont.) PLA is more hydrophobic than PGA hydrophobicity of PLA limits water uptake of thin films to about 2% and reduces the rate of hydrolysis compared with PGA sutures with trade names Vicryl® and Polyglactin 910®

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Biodegradable Polymers

PGA and PLA (cont.) copolymers of PGA and PLA used to adapt

material properties suitable for wider range of applications

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Biodegradable Polymers

polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and copolymers polyesters synthesized and used by

microorganisms for intracellular energy storage

70% PHB-30% PHV copolymer commercially available as Biopol®

rate of degradation controlled by varying copolymer composition

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Biodegradable Polymers

polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and copolymers (cont) in vivo PHB degrades to hydroxybutyric acid which is a

normal constituent of human blood biocompatible, nontoxic

PHB homopolymer is highly crystalline and brittle copolymer of PHB with hydroxyvaleric acid is less

crystalline, more flexible and more processible used in controlled drug release, suturing, artificial skin,

and paramedical disposables

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Biodegradable Polymers

polycaprolactone semi-crystalline polymer slower degradation rate than PLA remains active as long as a year for drug delivery Capronor®, implantable biodegradable contraceptive

implanted under skin dissolve in the body and does not require removal degradation of the poly(epsilon-caprolactone) matrix occurs through bulk hydrolysis of ester linkages autocatalyzed by the carboxylic acid end groups of the polymer, eventually forming carbon dioxide and water

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Polyesters

Biodegradable Polymers

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Biodegradable Polymers Capronor®, implantable biodegradable

contraceptive (cont.) Capronor II consists of 2 rods of poly(e-caprolactone) each containing 18 mg of levonorgestrel Capronor III is a single capsule of copolymer (caprolactone and trimethylenecarbonate) filled with 32 mg of levonorgestrel the implant remains intact during the first year of use, thus could be removed if needed. Over the second year, it biodegrades to carbon dioxide and water, which are absorbed by the body

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Biodegradable Polymers

polyanhydrides highly reactive and hydrolytically unstable degrade by surface degradation without the

need for catalysts aliphatic (CH2 in backbone and side chains)

polyanhydrides degrade within days aromatic (benzene ring as the side chain)

polyanhydrides degrade over several years

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Biodegradable Polymers

ester bond

o

c o o

= anhydride

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Biodegradable Polymers

polyanhydrides (cont.) aliphatic-aromatic copolymers can be used to

tailor degradation rate excellent biocompatibility used in drug delivery drug loaded devices prepared by

compression molding or microencapsulation insulin, bovine growth factors, angiogenesis

inhibitors, enzymes

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Biodegradable Polymers

polyorthoesters formulated so that degradation occurs by

surface erosion drug release at a constant rate

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Polyesters

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Biodegradable Polymers

polyaminoacids poly-L-lysine, polyglutamic acid aminoacid side-chains offer sites for drug

attachment low-level systemic toxicity owing to their

similarity to naturally occurring amino acids investigated as suture materials artificial skin subtitutes

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Biodegradable Polymers

polycyanocrylates used as bioadhesives use as implantable material is limited due to

significant inflammatory response

polyphosphazenes inorganic polymer backbone consists of nitrogen-phosphorus bonds use for drug delivery under investigation