Polymer Degradation and Synthesis Quiz

Lecture Plan

• Dates: 15.10.2024 - 18.02.2025
• Topics: Fundamentals of Biomedical Materials, Physicochemical properties of polymer materials, Synthetic biomedical polymers (resorbable and non-resorbable), Biomedical hydrogels, Additive Manufacturing of biomedical polymers, Protein adsorption, Immune response, Smart textiles, wearable devices, biosensors, Case studies on medical devices, and student presentations.
• Lecturers: del Campo, Müller, Asensio, Steudter, Sankaran, Trujillo

Lecture 3: Synthetic, Resorbable Biomedical Polymers

• Topic: Synthetic, resorbable biomedical polymers
• Lecturer: Aránzazu del Campo

Outline

• Degradation & Clearance mechanisms: Degradation and clearance mechanisms of biomedical polymers.
• Resorbable aliphatic polyesters: Resorbable aliphatic polyesters.
• Other resorbable polymers: Other resorbable polymers (to be covered in a later lecture)

Classification of Polymeric Biomaterials

• Resorbable: Poly(lactic-co-glycolic acid) (PLGA)
  • Vicryl sutures, 6–0, V-18 needle, 70 cm purple filament.
  • Tensile strength:
    • 2 weeks: 75%
    • 3 weeks: 50%
    • 4 weeks: 25%
  • Complete absorption within 56–70 days
• Durable: Nylon
  • Ethilon sutures, 2–0, FS needle, 45 cm blue filament.
  • Non-absorbable, sterile monofilament suture of long-chain aliphatic polymers (Nylon 6 and Nylon 6,6).

Example Resorbable Biomedical Polymer

• Polymer: Poly(D,L-lactide-co-glycolide) (PLGA) (Resomer®)
• Applications: Dental membrane, bone & tissue regeneration, tracheal implant, cardiovascular stents, breast implants, shoulder balloon, tissue scaffold, and more.
• Other examples of applications: Craniomaxillofacial implants, suture anchors, Spinal fusion, fixation plates, and more.

Resorbable Material

• Definition: Breakdown of a structure and subsequent assimilation of resulting components into the environment.
• Breakdown mechanisms: Hydrolytic, enzymatic, oxidative degradation and Dissolution
• Assimilation: Clearance by the body through metabolic processing or excretion.

Degradation

• Hydrolytic Degradation: Cleavage of water-labile bonds (glycosides, carbonates, esters, or amides) in the polymer backbone by water molecules.
• Enzymatic Degradation: Breakdown of polymers by enzymes
• Oxidative Degradation: Deterioration of polymers through oxidation by atmospheric oxygen or other oxidants in the biological environment.

Factors Influencing Degradation Rate

• Material Parameters: Polymer backbone chemistry, molar mass, hydrophobicity/hydrophilicity, crystallinity, water adsorption, diffusion, degradation products solubility and diffusion.
• Device and External Conditions: Device size and geometry, pH, temperature, tissue type, pathology, and environmental conditions.

Factors Influencing Degradation of Bioresorbable Devices

• Processing: Sterilization, annealing, machining, additive manufacturing, compression molding, injection molding, and extrusion.
• Material Properties: Chemical composition (monomer ratio, crystalline/amorphous, molecular weight, stereoisomerism), secondary ingredients, geometry, additive, interfacial reaction, and dispersion/orientation.

Degradation Mechanisms

• Surface Erosion: Polymer degradation and mass loss primarily at the water-biomaterial interface. Water diffusion rate is slower than the degradation rate.
• Bulk Erosion: Water diffusion into the biomaterial is faster than degradation at the surface, leading to degradation throughout the bulk material.

Hydrolytically Degradable Polymers

• Polymers: Polymers possessing water-labile bonds in their backbone for breakdown in an aqueous environment (the body).
• Hydrolytic Degradation: Scission of water-labile bonds (glycosides, carbonates, esters, amides) in the polymer backbone.

Hydrolytic Degradation Rates of Biomedical Polymers

• Polymers': Polycarbonates, polyesters, polyamides, polyphosphoesters, polyurethanes, polyacetals, poly(ortho esters), polyanhydrides, and polyphosphazenes.
• Degradation rates: Rates for each category of polymers are listed according to degradation time in 1 cm thickness.

Degradation Rates of Biomedical Polymers

• Classifications: Polymers are categorized by the rates and conditions causing the breakdown and degradation
• Characteristics: Tables list degradation rates, compositions, structures, and applications for different polymer groups, including polyphosphazenes, polyanhydrides, polyacetals, poly(ortho esters), and polyphosphoesters.

Clearance of Biomedical Polymers by the Body

• Biodegradable polymers: Cleave bonds in the backbone, producing small molecules absorbed in the body's biochemical pathways. Examples include Poly(L-glutamic acid) and poly(aspartic acid), producing monomeric amino acids.
• Semi-degradable polymer backbones: Composed of non-degradable blocks with degradable linkers.
• Renal elimination: Rate inversely correlates with the molecular weight (MW).

Aliphatic Polyesters

• Wide Use: Widely used in degradable biomedical polymers.
• Primary Processes:
  • Hydrolysis of ester bonds (autocatalytic process): water diffuses into amorphous regions & cleaves ester bonds.
  • Degradation proceeds at the surface and/or in the bulk of the polymer
  • Degradation is influenced by various factors such as chemical composition, stereochemistry, monomer sequence, molecular weight, etc.

Synthesis of Aliphatic Polyesters

• Polycondensation: Hydroxyacids or diols with diacids/diesters yield aliphatic polyesters.
• Ring-opening Polymerization (ROP) of lactones: Synthesis method for aliphatic polyesters.
• Bacterial Synthesis: A synthesis method for aliphatic polyesters.

Ring Opening Polymerization of Lactones

• Lactones: Monomers of ring sizes exhibiting substituents.
• High Molecular Weight Polymer: Obtainable from living/controlled polymerization.
• Ratio-dependent Molecular Weight: Molecular weight determined by the initiator to monomer ratio.

Coordination-insertion ROP

• Organometallics: Typical initiators, such as Sn(Oct)2.
• Mechanism: Initiator coordinates to the carbonyl group, followed by acyl-oxygen bond cleavage and monomer insertion into the metal-alkoxide bond.
• Catalyst: In the presence of nucleophiles, the organometallic acts as a catalyst.

Polyglycolide (PGA)

• Monomer: Glycolide, derived from glycolic acid (from sugar fermentation).
• Molar Mass: > 100 kDa
• Tg (°C): 36 °C
• Tm (°C): 223 °C
• Crystallinity (%): 45–55%
• Degradation: 1–6 months
• Modulus: 7–8.4 GPa
• Strength: ~900 MPa in oriented fibers
• Elongation at Break (%): 30%
• Polymer Type: Thermoplastic

PGA Biomedical Devices

• Examples: Degradable sutures (DEXON®), internal bone pins (Biofix®)
• Limitations: Rapid degradation leads to loss of mechanical strength and significant local glycolic acid production, potentially resulting in adverse inflammatory responses.

Polylactide (PLA)

• Monomer: L-lactide (from bacterial fermentation of starch/sugar; biobased) or L-lactide + D-lactide
• Molar Mass: > 100 kDa
• Tg (°C): 50–65 °C
• Tm (°C): 170–190 °C (amorphous)
• Crystallinity (%): 37%
• Degradation: >4 years
• Modulus: 3.5 GPa
• Strength: 80 MPa
• Elongation at Break (%): 30–40%

Poly(L-lactide-co-glycolide (PLGA)

• Random copolymer of PLLA and PGA: Degradation rates faster than pure PGA and PLLA, with the fastest rate at a 50/50 ratio.
• Semi-crystalline structure: Crystallinity decreases as the copolymerization ratio moves away from pure homopolymer structures.

Applications of Bioresorbable Implants (PLA and PLGA based)

• Orthopedic Applications: Various uses in orthopedic applications such as implants, and more.

PLGA Biomedical Products

• Sutures: Vicryl®, Vicryl Rapide®, Vicryl Plus Antibacterial®
• Other products: Polysorb®, Purasorb®

Biological & Physiological Pathways

• PLA Degradation: Lactic acid, Krebs cycle, carbon dioxide, water
• PGA Degradation: Glycolic acid, glyoxylic acid, glycine, serine, pyruvate, kidney.
• PLGA Degradation: similar processes to those above with additional products from both the PLA and PGA portions of the polymer.

Polyhydroxyalkanoates (PHA)

• Bioplastic origins: Synthesized by microorganisms.
• Structures: Homopolymers, random, or block copolymers.
• Bacterial species variability: PHA production can depend on the bacterial species and growth conditions.

Poly(3-hydroxybutyrate) (PHB)

• Synthesis: Fermentation methods: batch, fed-batch, or continuous cultures.
• Carbon sources: Inexpensive carbon sources such as beet and cane molasses, corn starch, alcohols, and vegetable oils.
• Polymer properties: Semi-crystalline, isotactic, processability with ranges for melting and glass transition points.
• Degradation: Hydrolytic degradation results in the formation of D(-)-3-hydroxybutyric acid, a normal blood constituent. Degradation product is less acidic than PGLA.

Poly(4-hydroxybutyrate) (P4HB)

• GalaFLEX™ Scaffold: Plastic and reconstructive surgery application.
• Soft Tissue Reinforcement: Intended for soft tissue reinforcement during healing after surgery.

Poly(hydroxyvalerate-co-3-hydroxybutyrate) (PHBV)

• Copolymerization: 3-hydroxyvalerate with PHB to create PHBV.
• Crystallinity and properties: Less crystalline than PHB with melting and glass transition temperatures that vary according to 3HV content.
• Applications: Bone, cartilage, tendon, skin, and nerve tissue engineering.

Polycaprolactone (PCL)

• Properties: Semicrystalline polyester with great organic solvent solubility, low tensile strength but high elongation at breakage.
• Tg (Glass/Transition Temperature): 55-60 °C
• Tm (Melting Temperature): -54 °C
• Degradation: Degradation rates depend on molecular weight and crystallinity. Can be enzymatically degraded or copolymerized/blended with other polymers.
• Applications: Tissue engineering, scaffolds for bone, ligament, cartilage, skin, nerve, and vascular tissues.

Study of Enzymatic & Oxidative Degradation of PCL

• Materials: Semicrystalline PCL, PCL-BU (bis-urea), PCL-UPy (ureidopyrimidinone).
• Degradation phases: Materials contain separated soft blocks (semicrystalline PCL) and hard blocks (interacting H-bonding units).
• Oxidative Degradation: hydrogen peroxide and cobalt (II) chloride generate hydroxyl radicals.

Degradation of PCL in Vitro

• Mass Loss and Molecular Weight: Methods and data for testing the mass loss and molecular weight reduction during enzymatic and/or oxidative degradation for a variety of PCL variants.
• SEM Images: Microscopy analysis of the degradation of PCL fibrous structures post-treatment with various solvents, enzymes, and more.
• Quantification of Fiber Diameter: The method and resulting data are provided in graphs for the quantification of fiber diameter reduction post-treatment.

Mechanical Properties of PCL in Vitro

• Tensile test principles: Stress/strain, displacement, deformation rates, and measurement principles.
• Mechanical properties evaluation: Young’s modulus, yield strength, yield elongation, ultimate strength, and ultimate elongation are tested in this category of PCL, post-treatment with lipase or oxidative compounds..

Study of Enzymatic and Oxidative Degradation of PCL Materials

• Summary of Results: The susceptibility of each material to degradation is presented by a color scale.
• Enzymatic Degradation: PCL scaffolds are rapidly degraded, resulting in mass loss, change in fiber morphology, and weakening.
• Oxidative Degradation: Supramolecular PCLs (UPy- and BU-containing) are less prone to enzymatic hydrolysis and show either less or no mass change.