Lecture 5: Polymer Degradation & Design of Degradable Biomaterials

degradation

chemical process resulting in the cleavage of covalent bonds in the backbone or crosslinks

types of degradation

oxidative, enzymatic, hydrolytic

oxidative degradation

oxidative agents attack covalent bonds and breaks bond and polymer

enzymatic degradation

enzymes target bonds that are cleavable by enzymatic reaction in biological macromolecules

hydrolytic degradation

cleavage is caused by hydrolytic reactions (hydrolysis)

erosion

physical change in size, shape, or mass as a result of either degradation or simply dissolution

bioerosion

water-insoluble being converted into water-soluble under physiological condition; including both physical (dissolution) and chemical (cleavage of backbone) process

erosion driving by chemical process I

cleavage of crosslinks between water soluble polymer chains

erosion driving by chemical process II

transformation or cleavage of side chains (X) leading to the formation of polar or charged groups (Y)

erosion driving by chemical process III

cleavage of backbone linkages between polymer repeat units

bulk erosion

the rate of water penetration into the solid device (fast) > the rate at which the polymer is transformed into water soluble materials

surface erosion

• the rate of water penetration into the solid device (slow) < the rate at which the polymer is transformed into water soluble materials

• this happens when polymers are hydrophobic and the degradation reaction is at a high rate; polyanhydrides and poly(orthoesters) undergo surface erosion

oxidative: polymer degradation

polymer chain attacked by reactive species (free radicals or oxidative ions produce by the inflammatory process or metal implant corrosion)

oxidative: polymer degradation - initiation steps for homolysis

R-R → 2R. (ultimately end up with two free radicals and these can continue to attack other polymers with covalent bond, continued degradation)

oxidative: polymer degradation - initiation steps for heterolysis

R-R → R⁺+R^- (electron goes to one to make a - charged ions and one a + charged ions, these ions can be reactive and therefore cause more degradation)

readily oxidizable groups

branched aliphatic hydrocarbon, aromatic ring containing polymer, allylic hydrocarbon, ether, amine, aldehyde, alcohol, phenol

polymer degradation-oxidative design choice as a degradable polymer

• not common choice because their reaction is complex and not really predictable

• exception: ROS (reactive oxygen species) responsive materials

enzymatic: polymer degradation

• major degradation mechanism for natural polymers

• not predictable as the levels of enzymes varies from time to time, location to location, and subject to subject (usually not a choice)

• surface erosion can be realized by enzyme mediated degradation

• polymer may be designed to degrade by a specific cell type or specific bio condition

enzymatic: polymer degradation selective processes

protease, esterase, lipases, glycosidase, nucleosidase

hydrolytic: polymer degradation

the chemical breakdown of a large polymer chain into smaller pieces when water splits its internal bonds

rate of degradation

polyanhydrides > polyesters > polyamides

the erosion rate is strongly dependent on…

on the ability of water to penetrate into the polymer matrix

hydrolyzable vs. hydrolysis-resistant groups

hydrolyzable groups: carbonyl bonded to heterochain elements (O,S,N)

host-induced hydrolysis

• neutral water

• ion-catalyzed

• pH-catalyzed, low pH occurs at acute inflammation or infection site

• enzyme catalyzed

factors influencing hydrolytic erosion: erosion rate

erosion rate is strongly dependent on the ability of water to penetrate into polymer matrix

factors influencing hydrolytic erosion: hydrophobicity

1) more polar groups, more hydrophilic

2) more nonpolar groups, more hydrophobic

factors influencing hydrolytic erosion: microstructure, crystalline vs. amorphous

• crystalline structure is resistant to water penetration

• amorphous materials degrade faster when they are above Tg (rubbery state) than below Tg (glassy state)

factors influencing hydrolytic erosion: molecular weight distribution

lower initial molecular weight, quicker to break down

factors influencing hydrolytic erosion: geometry & morphology

more surface area, faster erosion

factors influencing hydrolytic erosion: additives, etc

additives, catalysts, plasticizers, may inhibit or aid water penetration

factors influencing hydrolytic erosion: mechanical stress

points of residue stress concentration degrade more rapidly

factors influencing hydrolytic erosion: processing & fabrication

morphology, microstructure, and residual stress

advantages of degradable biomaterials

• permanent implants may cause chronic inflammation, stress shielding, etc

• gradually absorbed by the body and do not permanently leave traces

• rate can be adjustable according to the application needs

biocompatibility considerations of degradable biomaterials

neither the polymer nor its degradation products nor the subsequent metabolites should provoke excessive inflammation or toxicity

storage, packaging, and sterilization stability

• avoid moisture

• packed in air-tight aluminum backed plastic foil, low temp

• sterilization (no autoclaving, ethylene oxide OK)

applications

• drug delivery

• temporary support: sutures, bone fixation devices

• tissue engineering scaffold

• multifunctional

hydrolytic ester bond

very straight forward reaction, easy to pivot and commonly used in degradation

after hydrolysis of hydrolytic ester bond, you are left with…

carboxylic acid and alcohol

poly(glycolic acid) and PGA

• simplest linear aliphatic polyester

• highly crystalline

• hight Tm and low solubility

• rapid mech. deterioration upon degradation

• first synthetic absorbance sutures

• ex: bone pines, bone screws

adding a methyl group to PGA gives you…

PLA, poly(lactic acid)

PLA, poly(lactic acid)

• chiral molecule

• able to make multiple poly lactic acid (4 possible configs)

• more complex than PGA

• highly variable (semi crystalline vs amorphous)

• low Tm, higher solubility

copolymer of LA and GA (PLGA)

• PLLA more hydrophobic than PGA, limits the water uptake and reduce backbone hydrolysis

• addition of PLA component to PGA helps reduce hydrolysis rate (lower deg)

• no simple linear relationship between ration of GA:LA

poly (ε-caprolactone)

• sutures and drug release

• slower degradation than PLA

• semi-crystalline

• copolymers have been made with PGA

polyanhydrides

• among most reactive unstable polymers used as biomaterials

• fast degradation, excellent in vivo

• reacts with drugs having free amino groups or other nucleophilic functionalities → limits types of drugs that can be successfully incorporated