BG4231&BG6001-Lect 1- Intro to polymeric Biomaterials.pdf

Introduction to polymeric biomaterials Lecture 1 Introduction to polymeric biomaterials Asst. Prof. Dang Thuy Tram [email protected] Office N1.3-B3-09 BG 4231/BG6001 – Advanced Biomaterials 1 Introduction to polymeric biomaterials Lecture Outline 1. Definitions & Market of biomaterials 2. Ba...

Introduction to polymeric biomaterials Lecture 1 Introduction to polymeric biomaterials Asst. Prof. Dang Thuy Tram [email protected] Office N1.3-B3-09 BG 4231/BG6001 – Advanced Biomaterials 1 Introduction to polymeric biomaterials Lecture Outline 1. Definitions & Market of biomaterials 2. Basic principles in polymer science 3. Polymerization mechanisms 4. Synthetic polymeric biomaterials • Degradable polymers • Non-degradable polymers 2 Introduction to polymeric biomaterials – part 1 What is a biomaterial ? • “Biomaterial” is a non-viable material used in a medical device, intended to interact with biological systems. https://www.pravhakar.com.np/2022/07/common-biomaterials-question.html 3 Introduction to polymeric biomaterials – part 1 Growing medical demand and expanding market for biomaterials 4 Introduction to polymeric biomaterials Classes of biomaterials • • • • Metallic Ceramic Polymeric Composites (physical combinations of 2 or more of the above three basic materials classes) • Fabrication of a medical devices often requires use of multiple classes of biomaterials to achieve desired functional outcome 5 Introduction to polymeric biomaterials – part 1 Application of biomaterials 6 Introduction to polymeric biomaterials Application of biomaterials Cardiovascular applications Dermal applications Dental applications Orthopedic applications Tissue engineering applications Opthamologic applications 7 Introduction to polymeric biomaterials – Part 2 Basic principles in polymer science Why is it important for biomaterial scientists to understand the basics of polymer science? • Molecular characteristics are directly related to the physical and chemical properties of the macroscopic materials • Biomaterial scientists aware of structure-property relationship can rationally engineer a polymer system to fit the specific requirement of an application What characteristics are required of bone cements? Dental fillings? Drug delivery systems? 8 Introduction to polymeric biomaterials – Part 2 Basic principles in polymer science Molecular structure Polymer : a long-chain molecule comprising a large number of repeating units with identical structure Copolymer : polymer that contains more than one chemically distinct repeat units repeat unit n “n”: degree of polymerization Network polymer : formed when individual polymer chains are covalently crosslinked into a network cross-linkers styrene/butadiene rubber (SBR) crosslinked by sulphur into one giant network polymer 9 Introduction to polymeric biomaterials Basic principles in polymer science Examples of common polymeric biomaterials 10 Introduction to polymeric biomaterials Basic principles in polymer science Tacticity : stereochemistry of the repeat units in polymer chains Tacticity is classified based on the spatial arrangement of substitutent groups on asymmetric atoms. • Isotactic : same side of the plane containing the extended-chain backbone • Syndiotactic : regularly alternate from one side of the plane to the other • Atactic : random arrangement Tacticity affects the physical behavior of the polymer system including ability to crystallize. • Isotactic and syndiotactic : crystalline • Atactic : amorphous 11 Introduction to polymeric biomaterials Basic principles in polymer science Average Molecular Weights of a polymer system • During polymerization, polymer chains are built up from low molecular weight monomers. • Most polymer system consists of multiple polymer chains of a distribution of molecular weights Mixture of monomers Polymerization PDI : measurement of the breadth of MW distribution Polymer chains with different molecular weight 12 Introduction to polymeric biomaterials Basic principles in polymer science • Polymer chains are held together by Van der Waal’s forces, dipole-dipole interaction, hydrogen bonding • Polymers are mechanically weaker than other class of materials (metal, ceramics). • Polymer display physical behavior more similar to native tissues Structure-Property Relationship Physical properties of a polymer system arises from the Molecular characteristics • Molecular structure • Chemical composition • Tacticity • Molecular weight Macroscopic properties • Tensile properties • Hydrophilicity/Hydrophobicity • Biodegradability Vascutek® grafts fabricated from polyesters or ePTFE 13 Introduction to polymeric biomaterials Basic principles in polymer science Physical states of a polymer system Crystalline structure • Highly ordered polymer chains • Higher mechanical properties • Favored by symmetrical chain structures (tactic) and specific chain interactions (eg. Hbonding) Amorphous structure • Unorganized random coils interpenetrating with neighboring polymer chains • Lower mechanical properties • Favored by asymmetrical chain structures (atactic) Amorphous Semi-crystalline https://www.ptonline.com/ 14 Introduction to polymeric biomaterials Basic principles in polymer science Physical states of a polymer Semi-crystalline Tg Tg Glass transition temperature Tg - Characteristic of amorphous region - Below Tg, only molecular vibrations, chains can’t rotate or move in space glassy state, hard, rigid, and brittle, molecular disorder - Above Tg, chain segments can rotate/move  rubbery state, soft and flexible, retain molecular disorder Melting temperature Tm - Characteristic of crystalline region - As temperature increases above Tm, loss of crystallinity : ordered solid to disordered melt Tm injectionmoldingonline.com 15 Introduction to polymeric biomaterials Basic principles in polymer science Physical states of a polymer Effect of cross-linking Effect of copolymerization 16 Introduction to polymeric biomaterials Basic principles in polymer science Polymer classification – by thermal processing behavior • • Thermoplastics : polymers that can be heat-softened to process into a desired form Eg : polystyrene, polyethylene, poly(vinyl chloride) Thermosets : polymers whose individual chains have been chemically linked by covalent bond into crosslinked network that resists softening, creeping, solvent attack and cannot be thermally processed. Eg : unsaturated polyesters – by polymerization mechanism • • Step-growth polymerization Chain-growth polymerization – by degradability • • Degradable polymers Non-degradable polymers – by sources • • Synthetic polymers Naturally derived polymers 17 Introduction to polymeric biomaterials Polymerization mechanism Step-growth polymerization • Random reaction of two molecules of any combination (monomer, oligomer, longer chain molecules) • Higher MW polymer formed near the end Chain-growth polymerization • Attachment of a monomer to an active chain • High MW polymers formed in the early stage of a chain growth polymerization 18 Introduction to polymeric biomaterials Polymerization mechanism Step-growth polymerization - Condensation polymerization https://chem.libretexts.org/ 19 Introduction to polymeric biomaterials Polymerization mechanism Step-growth polymerization – Addition polymerization 20 Introduction to polymeric biomaterials Polymerization mechanism Chain-growth polymerization – Free radical polymerization 21 Introduction to polymeric biomaterials Polymerization mechanism Chain-growth polymerization – Ionic polymerization 22 Introduction to polymeric biomaterials Polymerization mechanism Synthesis strategies to design desired polymers • Selection of appropriate polymer e.g bulky pendant groups for glassy polymer or polar pendant group for hydrogel hydrophilicity • Controlling crystallinity: using catalyst to produce isotactic or syntactic addition polymers that can crystallize • Controlling cross-linking : (i) adding a small amount of monomers with three or more functional groups during condensation polymerization (ii) Linear polymers can be crosslinked after synthesis by vulcanization or UV radiation 23 Introduction to polymeric biomaterials Degradability Degradation vs Erosion • Degradation : a chemical process resulting in the cleavage of a covalent bond. Causes : hydrolysis, oxidative, photodegradative, enzymatic mechanism • Erosion : physical changes in size, shape or mass of a device. Causes : degradation, dissolution, ablation or mechanical wear. • Note : Degradation can occurs in the absence of erosion and erosion can occur in the absence of degradation. • Degradable polymers degrade within the time scales of their expected service life or shortly thereafter. • Non-degradable polymers have degradation times that are significantly longer than their service lifetime. • “Bio” (biodegradation, bioerosion, bioresorption/bioabsorption) – occurring under physiological conditions – caused by a biological agent (cells, enzymes, etc..) 24 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Why degradable polymers? • Some implants need to serve a temporary rather than a permanent purpose e.g delivery a drug for a short time, structural support while a damaged tissue is being regenerated. • Benefits of degradable implants (i) No requirement for a second surgery to remove a temporary device, avoiding another wound with possibility of surgical complication and infection (ii) Long-term safety of permanent implants i.e long-term immune rejection, chronic inflammation at implant-tissue interface, device failure • Safety concerns of degradable implants (i) Potential toxicity of degradation products (ii) Mechanical integrity, degradation-related, premature failure of the implant 25 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Degradation mechanisms • Polymers are cleaved by a variety of chemical reactions into low molecular weight byproducts which are metabolized and excreted. • Diffusion of water molecule into the polymer is the first step of the degradation process. 26 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Degradation mechanisms – Abiotic degradation • Abiotic degradation often precedes biotic degradation • Abiotic degradation often precedes biotic degradation - Hydrolysis - Oxidation • The rate of an abiotic process is dominated by the physical accessibility (diffusion) of the polymer structure to the biotic attacker (i.e water or oxygen molecules) • Crystalline regions are mostly impermeable to water and oxygen. Degradation of the amorphous regions occur prior to the degradation of cross-linked and crystalline regions. 27 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Degradation mechanisms – Biotic degradation • Biotic degradation refers the metabolic breakdown of materials into simpler components by living organisms • Biotic degradation always proceeds on polymer surfaces in a layer-by-layer manner because a polymer chain network is too dense to allow immigration of enzymes or cells. • Example : hydrolysis mediated by hydrolase enzymes following the colonisation of cells on polymer surface. • An enzyme is a catalyst which accelerates the rate of a chemical reaction by reducing the energy barrier, but it doesn’t change the reaction mechanism • Both abiotic and biotic hydrolysis involve the same chemical reaction, resulting in the same polymer cleavage products. The latter increases the reaction rate at the polymer surface where the enzyme acts as a catalyst. 28 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Degradation mechanisms – Tuning degradation kinetics • Primary factors influencing degradation kinetics - Strength of chemical bonds in polymer chains (weak ester bond; strong C-C, C-F, Si-O bonds) - Steric interference • Secondary factors influencing degradation kinetics - Cross-linking density - Crystallinity Higher crosslinking density and crystallinity retards water diffusion into the polymer and thus slow down degradation. 29 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Examples of existing degradable polymers in clinical use or under investigation • • Safety concerns limit the number of non-toxic monomers that are considered for synthesis of degradable biomaterials. Regulatory agencies (e.g USA Food and Drug Administration) do not approve polymers or materials per se but only specific medical devices and drug delivery formulations. 30 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyester (PLGA, PLA, PGA) • • • Esters are chemical compounds derived from a carboxylic acid and a hydroxyl compound i.e alcohol Polyesters are polymers which contain the ester functional groups (-COO-) in their main chains. Ester bonds are weak bonds, and can be broken down by hydrolysis 31 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Poly(glycolic acid) (PGA) • Monomers : Glycolic acid (produced by carbonylation of formaldehyde, also found in some sugar crop) • Synthesis routes : Condensation polymerisation Ring-opening polymerization 32 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Poly(lactic acid) (PLA) • Monomers : Lactic acid (industrially produced by bacterial fermentation of carbohydrates such as sugar and starch, also naturally occurring as milk acid or produced by muscle during exercise) • Synthesis routes Condensation polymerisation Ring-opening polymerization 33 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Macroscopic physical properties of PGA and PLA • PGA : • - highly crystalline - high melting point - low solubility in organic solvents PLA : - semi-crystalline or amorphous - more hydrophobic - chiral C atoms in the backbone * • 3 commonly used, morphologically distinct forms of PLA - stereo-regular D-PLA and L-PLA :, optically active, semi-crystalline - racemic polymer : optically inactive, amorphous 34 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyester (PLGA, PLA, PGA) Poly(lactic-co-glycolic) acid (PLGA) • Synthesis route Pan et al, Interface Focus, 2012 • Controlled chemical compositions , identified by molar ratio of the monomers used (e.g. PLGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid) 35 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Factors affecting degradation kinetics 36 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Factors affecting degradation kinetics 37 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Factors affecting degradation kinetics 38 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Factors affecting degradation kinetics DL-PLG = poly(DL-lactide-co-glycolide); DL-PLA = poly(DL-lactide); L-PLA = poly(L-lactide); PGA = poly(glycolide); PCL= poly(ε-caprolactone) http://www.absorbables.com/ 39 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Factors affecting degradation kinetics In vivo biodegration of PLGA microspheres with different L/G monomer ratio http://www.absorbables.com/ 40 Introduction to polymeric biomaterials Synthetic polymers Degradable polymers Synthetic polyesters ( PLA, PGA, PLGA) Tailored properties for specific biomedical applications Sutures Local delivery of anesthetic drugs What are the desired characteristics of these devices? (mechanical properties, degradation time ? What molecular composition should be chosen for the polymers to achieve these characteristics? 41 Introduction to polymeric biomaterials Synthetic polymers Non-degradable polymers Examples of existing non-degradable polymers in clinical use or under investigation Class of polymer Example Applications Poly(acrylate) Poly(methyl methacrylate) (PMMA) bone cements, dental fillings Poly(urethane) n.a pace makers, artificial heart patch Fluorinated polymers Polytetrafluoroethylene (PTFE) artificial blood vessels Silicones n.a breast implants, catheters, vascular grafts 42 Introduction to polymeric biomaterials Synthetic polymers Non-degradable polymers Poly(Acrylates) 43 Introduction to polymeric biomaterials Synthetic polymers Non-degradable polymers Poly(Acrylates) 44 Introduction to polymeric biomaterials Synthetic polymers Non-degradable polymers Poly(Acrylates) High viscosity Less polymerization shrinkage Low viscosity More polymerization shrinkage When expose to irradiation, monomer resin is converted to a cross-linked 3D polymer network  photopolymerization by free radical mechanism 45 Introduction to polymeric biomaterials Synthetic polymers viscosity Non-degradable polymers Poly(Acrylates) What cause the change in viscosity with increasing mole fraction of base monomers? 46 Introduction to polymeric biomaterials Synthetic polymers Non-degradable polymers Poly(Acrylates) Requirements for dental restorative application - Viscosity, ease of filler loading - Rapid and efficient polymerization - Long-term performance (mechanical properties) - Absence of leaching of potentially toxic materials from cured polymers http://www.westernkentuckydental.com/services/ Selection of monomer composition to control rate and extent of conversion in polymerization 47 Introduction to polymeric biomaterials Summary 1. Definition and application of biomaterials 2. Basic principles in polymer science • Molecular structure , Molecular weight • Structure-property relationship • Polymer classification 3. Polymerization mechanisms • step-growth polymerization • Chain-growth polymerization 4. Synthetic polymeric biomaterials • Degradable polymers : degradation mechanism & example of poly(esters) • Non-degradable polymers : example of poly(acrylates) 48