Degradation

Question 1

Polyanhydride

Answer 1

Surface eroding polymer

One of the main synthetic biodegradable polymers

Have one of the fastest rates of degradation because anhydride bond is highly labile

Typically composed of hydrophobic diacid monomer units connected by anhydride bonds

hydrophobic diacid monomers + rapid hydrolysis rate of the anhydride bond results = reactive surface erosion profile ideal for drug delivery applications.

Question 2

PCL

Answer 2

• This family of polyesters also includes poly (e-caprolactone) (PCL).
• PCL is semicrystalline and has a slow degradation rate due to the high ratio of hydrophobic methylene groups to methyl groups in the main chain.
• PCL has a degradation rate of 2–5 years, which has allowed it to be used in long-term implants and controlled drug release applications.
• It is commonly used as a copolymer with PLA or PGA for applications where a shorter degradation time is required.
• Due to its mechanical behaviour PCL has been used for tissue engineering of bone and cartilage

Question 3

Copolymers

Answer 3

• PGA is commonly copolymerized with PLA to form poly(l-co-glycolic) acid (PLGA) to tailor degradation and improve material properties
• The improved degradation properties of PLGA allow it to be widely used for drug delivery devices, sutures, and longer-term tissue engineering scaffolds

Question 4

PGA

Answer 4

• PGA is the simplest linear aliphatic polyester and has a higher degree of crystallinity than PLLA (30%–55%).
• By itself, PGA is more hydrophilic than PLA due to the lack of methyl group and has a rapid degradation rate of 6–12 months.
• Due to its rapid degradation rate, pure PGA is used as in particle or fiber form as a filler material blended with other biomaterials or as shorter-term tissue engineering scaffolds

Question 5

PLA

Answer 5

• PLA is an aliphatic polymer that exists in two stereo isomeric forms, * poly(l-lactic) acid (PLLA) and poly(d-lactic) acid (PDLA),
• dictated by the orientation of the methyl group to the main chain.
• PLLA is semicrystalline (∼30%) and has a degradation time ranging from 12 months to 2–3 years.
• It is used for applications where mechanical properties are important. PDLLA is amorphous and is used in devices not subjected to high loads and in drug delivery applications

Question 6

Bulk eroding polymers

Answer 6

• The most widely researched synthetic biodegradable polymers for scaffold applications are poly (a-hydroxy) esters such as PLA, PGA, and their copolymers.
• This category of biodegradable polymers undergoes bulk hydrolytic degradation at the ester bond in the polymer backbone.
• Products metabolized in Kreb’s cycle

Question 7

Material composition and degradation rates

Answer 7

• At the molecular level, degradation rate is dependent on the accessibility of water to the hydrolytically susceptible bonds.
• This is directly related to the type of bond charge, the presence of conjugate structures, and any steric effects of chemical side groups

Question 8

Polymer factors that influence degradation

Answer 8

• These can be grouped into the main categories of polymer composition, molecular weight, morphology, processing, and implantation conditions in vivo.

Chemical structure
Chemical composition
Distribution of repeat units
Presence of ionic groups
Presence of unexpected units or chain defects
Configurational structure
Molecular weight
Polydispersity
Presence of low molecular weight compounds (monomers, oligomers, solvents, initiators, drugs, etc.)
Morphology
Crystallinity (amorphous vs. semicrystalline)
Processing
Processing technique
Annealing
Sterilization technique
Storage history
Implantation site
Adsorbed and absorbed compounds (water, lipids, ions, etc.)
pH
Size and shape
Applied stress
Mechanism of hydrolysis

Question 9

Poly (ortho esters) POE

Answer 9

Surface eroding polymer

POEs are more hydrophobic than polyanhydrides and have a slower and more stable surface erosion profile.

Question 10

Degradation rate vs molecular weight

Answer 10

• Degradation rate is also dependent on molecular weight and molecular weight distribution.
• As polymer chain length increases, accessibility of functional groups to water or other degrading species decreases.
• High-molecular-weight polymers degrade more slowly than low-molecular- weight polymers.

Question 11

Molecular weight and mechanical properties

Answer 11

• A high starting molecular weight is often required to obtain required mechanical properties in many medical device applications.
• Medical-grade varieties of polymers such as PLA, PGA, and PCL are synthesized using ring-opening polymerization (ROP or ROMP) to achieve the necessary starting high molecular weight and a uniform molecular weight distribution.

Question 12

Crystallinity def

Answer 12

??* Degree of crystallinity(extent to which the polymer chains are tightly packed in a regular, ordered structure) is determined by polymer chain ability to pack (determined by chain flexibility and size of functional groups) and the magnitude of intermolecular forces (determined by polarity of functional groups) between the polymer chains.

Question 13

Degradation and Crystallinity

Answer 13

Water, which often initiates the degradation process of biodegradable polymers, diffuses more easily into the amorphous regions of a polymer. These regions are less ordered and less densely packed, making them more permeable to water and other small molecules. Once water has entered, the degradation process can begin, breaking the polymer chains into smaller oligomers and monomers. These smaller molecules can then be more easily transported out of the polymer, especially from the more accessible amorphous regions.

Question 14

Factors Affecting Crystallinity

Answer 14

Polymer Chain Packing: How well the polymer chains can pack into an orderly structure depends on the flexibility of the chains and the size of any functional groups attached to them. More flexible chains and smaller functional groups can pack more tightly, leading to higher crystallinity.

Intermolecular Forces: The strength of the forces between polymer chains also affects crystallinity. These forces are influenced by the polarity of the functional groups on the chains. Stronger intermolecular forces lead to a more stable and tightly packed structure, increasing crystallinity.

Question 15

Glass transition temperature def

Answer 15

• Tg is the temperature at which increased polymer chain mobility results in significant changes in thermal and mechanical properties and represents a transition of the polymer from a “glassy” to a “rubbery” state upon heating

Question 16

Tg and degradation

Answer 16

• When polymers are used at temperatures above their Tg, the mobile chains enable more rapid diffusion of degrading species into the bulk polymer, resulting in increased degradation rates.

Question 16

What does Tg depend on/ alterx

Answer 16

• Tg is dependent on polymer chain mobility.
• Polymer chain mobility is a function of molecular weight, chain flexibility, and presence of functional groups.
• Less mobile polymer chains will require a higher activation energy before they are able to achieve cooperative movement and as a result have a higher Tg.

Question 17

How can we alter polymer architecture

Answer 17

We can change compostion (homopolymer, statistical/random, alternating, block), topology (linear, branched, star) and structure (hydrogel, vesicle, micelle)

Question 18

How does architecture affect degradation

Answer 18

• By selecting the frequency, order, and composition of the polymer structure, a material with strategically designed hydrophilicity or crystallinity can be created.
• For example, a block copolymer with a high ratio of hydrophilic monomers would have an accelerated degradation rate.
• Copolymers can also be designed to assemble into structures such as micelles, vesicles, or hydrogels through self-assembly or using external stimuli such as pH or temperature.

Question 19

How can processing change degradation

Answer 19

• Synthetic biodegradable polymers are often fabricated into a useable form with melt-processing techniques such as extrusion, molding, or fiber spinning
• Heat and mechanical shear
• Thermal degradation causes depolymerization or polymer-chain fragmentation, which results in a reduction in mass and molecular weight.
• Mechanical degradation can cause physical changes such as crystallization, flow, or molecular orientation, or chemical changes such as scission or cross-linking
• Sterilization (radiation, deionized gas)

Question 20

In vivo degradation

Answer 20

In general, in vivo degradation is faster than in vitro due to this added biological response

• Primary degradation = Hydrolytic degradation
  but the rate of hydrolysis influenced by pH, salts, and enzymes.
• Device size and topography influence degradation rate, and the location of the implantation site itself determines what the polymer will be exposed to.

Question 21

Conditions at implantation site that affect degradation

Answer 21

Salt

pH

Mechanical loading

Question 22

How does pH affect polymers at implantation

Answer 22

• Biodegradable polymers degrade faster at basic pH due to rate of water absorption over osmotic pressure gradients.
• At neutral or basic pH, water absorption is increased due to the osmotic gradient created by acidic degradation groups
• Another pH-related degradation effect is autocatalysis.
• If the implantation site does not have enough flow to clear degradation products from the polymer matrix, a localized acidic environment will be created at the center of the polymer, resulting in accelerated degradation in this region.

Question 23

How does salt affect polymers at implantation

Answer 23

• Anions and cations produced by salts present in body fluids such as plasma, interstitial fluid, and cellular fluid can act as catalysts to hydrolytic degradation of polymer bonds.
• Salt solubility in polymers is related to polymer hydration rate.
• Hydrophobic polymers do not absorb salts as readily as hydrophilic polymers.
• The more hydrophilic a polymer is, the greater catalytic effect salts can have on degradation rate. Common ions include sodium, potassium, chloride, and phosphate.

Question 24

How does size and shape alter degradation

Answer 24

• Implant shape has a strong impact on phagocyte behavior at the tissue– implant interface, and that smooth, well-contoured shapes with no acute angles are more biocompatible.
• Higher surface area due to fragmentation or porosity can also affect tissue response.
• The size of the implant also plays a role in immune response.
• Larger implants produce a proportionally higher magnitude of foreign body reaction and fibrosis.
• For polymers that are susceptible to autocatalysis, in addition to being dependent on flow conditions at the implantation site, there is a critical thickness at which hydrolytic degradation will be accelerated due to accumulation of acidic degradation products in the implant

Question 25

In vitro testing of degradation methods

Answer 25

• varied media pH
• introduction of an applied strain
• addition of enzymes to the media
• elevated media temperature.

The most widely used approach to induce accelerated degradation is elevated temperature, as its relation to degradation rate is well characterized by the Arrhenius equation

Question 26

Biodegradation

Answer 26

• The degradation of a material is its breakdown due to the environmental factors that it is exposed to.
• Biodegradation can be triggered by biological/physical/chemical events * Passive environmental (presence of water and oxygen)
• Active biological (inflammatory responses such as phagocytosis)
• Biodegradable polymers needs to be designed to meet clinical prerequisites.
• Must have mechanical properties which supports the native tissue and and a degradation profile that accommodates the healing process
• During the degradation process, any by-products must be noncytotoxic and produce no adverse immune response.

Question 27

Synthetic biodegradable polymers

Answer 27

• Can be tailored to meet specific mechanical, biological, and degradation requirements of the tissue engineered scaffold.
• They have consistently reproducible properties, are inexpensive to produce in bulk, and are compatible with a wide range of processing techniques
• The processability of synthetic biodegradable polymers allows them to be fabricated into complex three-dimensional architectures for tissue engineering such as fiber networks and porous scaffolds

Question 28

Degradation

Answer 28

• Degradation occurs when the bonds between units are cleaved in a process known as chain scission
• Scission leads to irreversible change in material structure and is characterized by a loss of mechanical properties or polymer fragmentation.
• Degradation causes the molecular weight to decrease as the initial polymer chains are broken down into oligomers and monomers and is accompanied by an eventual loss in mechanical stability.

Question 29

What is the primary degradation mechanism of interest in vivo

Answer 29

Synthetic bioresorbable polymers, chemical degradation through hydrolysis is the primary degradation mechanism of interest in vivo.

Question 30

Hydrolysis

Answer 30

• Hydrolysis is the process by which labile chemical bonds in a polymer chain react with water molecules and are cleaved,
• Hydrolysis results in shorter polymer chains and eventual polymer degradation (kinetics control rate).

Question 31

Erosion

Answer 31

• As polymer degradation progresses erosion occurs
• The loss of mass as oligomers and monomers leaves the polymer, resulting in a change to the physical size or shape

Question 32

When surface vs bulk erosion occurs

Answer 32

Whether a polymer undergoes bulk or surface erosion is dependent on two processes:
1. The diffusion of water into the polymer bulk and the degradation rate of the polymer backbone. If the rate of water diffusion is faster than the rate of degradation of the polymer backbone, the polymer will undergo bulk erosion
2. If the rate of degradation of the polymer backbone is faster than the rate of water diffusion, hydrolysis of bonds at the polymer surface will prevent diffusion into the bulk and the polymer will undergo surface erosion.

Question 33

Bulk erosion

Answer 33

Mass loss occurs through out the material following polymer hydration; water penetrates the polymer at a faster rate than it is broken down

*Decreaseinmolecularweightandlossofmechanicalpropertiesbeginatthestartof degradation, while mass loss is delayed.
*Theexternaldimensionsofthepolymerremainessentiallyunchanged,untildisintegration occurs at a critical time point.
*Mostbiodegradablepolymerscurrentlyuseddegradebyabulkerosionprocessthat predominantly involves simple hydrolysis of main chain bonds, as surface erosion is difficult to achieve.

Question 34

First vs end stages of bulk erosion

Answer 34

• The polymer becomes hydrated and chemical bonds are broken.
• Cleavage of bonds present in the amorphous domains of the polymer causes a decrease in molecular weight and polymer chains are broken into smaller oligomers.
• Initially, this decrease in molecular weight will not affect the mechanical properties of the device as physical cross-linkages due to entanglements and regions of crystallinity maintain the structure of the material.

End: * As molecular weight continues to decrease, polymer chains have a greater degree of movement, which leads to a reduction in mechanical properties.
* Mass loss begins to occur when the degradation products become soluble in water.
* Low-molecular-weight chain fragments dissolve and are released into the surrounding medium.
* The polymer continues to lose mass and physical integrity, and this progresses until there is no remaining material

Question 35

Autocatalysis of bulk erosion

Answer 35

If degradation products are not rapidly cleared from the polymer matrix, autocatalysis will occur.

Toward the center of the material, degradation products are unable to diffuse away, often resulting in a localized acidic environment.

Increased acidity induces accelerated degradation at the center of the material.

The surface of the polymer continues to degrade at its original rate, resulting in a surface-to-center differentiation of mechanical properties and molecular weight.

Question 36

Surface erosion

Answer 36

Degradation reactions are limited to the surface of the polymer material or occur at a significantly higher rate relative to diffusion rate of water into the bulk.

Surface-eroding polymers have very hydrolytically labile (easily broken) bonds in their main chains, which react with water rapidly.

SE proceeds via an erosion front and the size and mass of surface eroding polymers decrease over time, while molecular weight and mechanical properties of the residual polymer remain unchanged.

degradation products are concentrated at the surface, they can quickly diffuse away and therefore have no autocatalytic effect on degradation.

Rate of mass loss is proportional to polymer surface area.

Question 37

Why is surface erosion good

Answer 37

• The predictability of this erosion process makes surface eroding polymers desirable for the release of growth factors or chemical molecules
• The release rate is directly related to the rate of polymer erosion and can easily be altered by changing model geometry

Question 38

What shows surface erosion vs bulk

Answer 38

• Only a few types of biodegradable polymers such as polyanhydrides and poly (ortho esters) show surface erosion characteristics

PLA and PLG bulk