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Polymerization Synthetic polymers used in medicine Department of General Chemistry UMS Poznan • History of polymers • Chemistry of polymers – definition – structure – properties – polymerization • Polymers used in medicine • Biomaterials and composites History of polymers • Prior to the early 1920's, chemists doubted the existence of molecules having molecular weights greater than a few thousand. • Hermann Staudinger, a German chemist with experience in studying natural compounds such as rubber and cellulose proposed they were made up of macromolecules composed of 10,000 or more atoms. • He formulated a polymeric structure for rubber, based on a repeating isoprene unit (referred to as a monomer). • For his contributions to chemistry, Staudinger received the 1953 Nobel Prize. The terms polymer and monomer were derived from the Greek roots poly (many), mono (one) and meros (part) A brief timeline of polymers in medicine 1860’s Aseptic surgery introduced 1900’s Metal bone plates used for breaks and fractures 1940’s PMMA used in cornea replacement surgery 1950’1960’s Artificial heart and dialysis machines introduced polymers eventually make units better 1970’1980’s Eye glass lens are made of PMMA, contact lenses revolutioni -ze industry made of PHEMA 1990-2000 More than half of biomaterial aplications are made of or contain some polymer Beyond 2000 Artificial skin derived from skin in labolatory, Internal kidney dialysis machine developed due to mambrane advancements Polymers in medicine Until recently, most medical devices are still made from homogenous and isotropic materials such as polymers, metals, and ceramics. A large number of polymers is used in many medical applications. This is mainly becouse they are available in a wide variety of compositions, properties and forms (solid, fibres, fabrics, films and gels) and can be fabricated readily into complex shapes and structures. Definition Polymer – a chemical compound consisting of giant molecules „MACROMOLECULES“ formed by union of many „POLY“ small repeating units „mers“ MONO“MER“ molecules POLY“MER“ chain, macromolecule What controls polymer properties? 1. Chemical composition of polymers, type of monomer, its structure CH2=CH Vinyl polymers R Examples: R = H : polyethylene hydrophobic, semicrystalline polymers R = OH : poly(vinyl alcohol), hydrophilic water soluble polymer with gelling properties What controls polymer properties? Writing Formulas for Polymeric Macromolecules The repeating structural unit of most simple polymers not only reflects the monomer(s) from which the polymers are constructed, but also provides a concise means for drawing structures to represent these macromolecules. What controls polymer properties? 2. Topology of polymer chains Linear polymers A-A-A-A-A-A-ANonlinear (branched) polymers What controls polymer properties? Cross-linked polymer (polymer networks) Cross-links (permanent connections between chains restricting motion of chains rigidity) Temporary cross-links entanglements What controls polymer properties? 3. Monomer distribution in copolymer chains • Homopolymers (one type of monomer - A) A-A-A-A-A-A-A- linear/branched • Copolymers (2-3 comonomers) A-B-A-B-B-B-A- statistical (random) A-A-A-B-B-B-B-A-A- block A-B-A-B-A-B-A- alternating -A-A-A-A-A- graft/branched -B-B-B-B-B What controls polymer properties? 4. Polymer molecular weight Two experimentally determined values are common: – Mn , the number average molecular weight, is calculated from the mole fraction distribution of different sized molecules in a sample, and – Mw , the weight average molecular weight, is calculated from the weight fraction distribution of different sized molecules. Definitions of molecular weight averages Since larger molecules in a sample weigh more than smaller molecules, the weight average Mw is necessarily skewed to higher values, and is always greater than Mn. As the weight dispersion of molecules in a sample narrows, Mw approaches Mn, and in the unlikely case that all the polymer molecules have identical weights (a pure monodisperse sample), the ratio Mw / Mn becomes unity. What controls polymer properties? 5. Supramolecular structure (molecular organization) • Amorphous polymers – coiled irregular (random) shape of polyme rchains • Semicrystalline polymers – domains with regular (crystalline) structures acting as special type of cross-links What controls polymer properties? Properties of Macromolecules • On heating or cooling most polymers undergo thermal transitions that provide insight into their morphology. These are defined as the melt transition, Tm , and the glass transition, Tg . • Tm is the temperature at which crystalline domains lose their structure, or melt. As crystallinity increases, so does Tm. • Tg is the temperature below which amorphous domains lose the structural mobility of the polymer chains and become rigid glasses. Tg • Tg often depends on the history of the sample, particularly previous heat treatment, mechanical manipulation and annealing. It is sometimes interpreted as the temperature above which significant portions of polymer chains are able to slide past each other in response to an applied force. • The introduction of relatively large and stiff substituents (such as benzene rings) will interfere with this chain movement, thus increasing Tg (note polystyrene below). • The introduction of small molecular compounds called plasticisers into the polymer matrix increases the interchain spacing, allowing chain movement at lower temperatures. with a resulting decrease in Tg. Rubber is a elastomer Elastomers are amorphous polymers that have the ability to stretch and then return to their original shape at temperatures above Tg. At temperatures below Tg elastomers become rigid glassy solids and lose all elasticity. A tragic example of this caused the space shuttle Challenger disaster. The heat and chemical resistant O-rings used to seal sections of the solid booster rockets had an unfortunately high Tg near 0 ºC. The unexpectedly low temperatures on the morning of the launch were below this Tg, allowing hot rocket gases to escape the seals. Glass transition (softening temperature) Temperature Tg Temperature at which rigidity of polymer decreases Influence of cross-links on physical properties of polymers Linear or branched polymers - flow when heated, can be easily reshaped upon heating – thermoplastic polymers (usually soluble in organic solvents) Cross-linked polymers - they cannot be reshaped on heating, do not melt, but decompose on heating, insoluble in organic liquids(thermosetting polymers). Thermosetting vs. Thermoplastic Polymers • Most of the polymers are classified as thermoplastic. This reflects the fact that above Tg they may be shaped or pressed into molds, spun or cast from melts or dissolved in suitable solvents for later fashioning. Because of their high melting point and poor solubility in most solvents, Kevlar and Nomex proved to be a challenge, but this was eventually solved. • Another group of polymers, characterized by a high degree of cross-linking (Bakelite), resist deformation and solution once their final morphology is achieved. Such polymers are usually prepared in molds that yield the desired object. Because these polymers, once formed, cannot be reshaped by heating, they are called thermosets. Bakelite, one of the first completely synthetic plastics to see commercial use (circa 1910). Synthesis of Polymers used in medicine Prepared via polymerization reactions: • Addition (chain-growth) polymerization of monomers with a double bond • Condensation (step-growth) polymerization of bifunctional monomers, frequently with release of low molecular compounds (analogous reaction to low molecular weight compounds) Addition polymerization Characteristics – Starts from an active center (only these molecules are capable to react) – π-bond of monomer is converted to σ-bond in the polymer – Monomers add sequentially to the end of a growing chain – Is very fast and exothermic – Produces high molecular weight polymers Types of addition polymerization • Free-radical polymerization – active center is a radical (contains unpaired electron) and the propagating site of reactivity is a carbon radical. • Cationic polymerization - the active center is an acid, and the propagating site of reactivity is positively charged • Anionic polymerization - the active center is a nucleophile, and the propagating site of reactivity is negatively charged Synthesis of Addition Polymers All the monomers from which addition polymers are made are alkenes or functionally substituted alkenes. Since a pi-bond in the monomer is converted to a sigma-bond in the polymer, the polymerization reaction is usually exothermic by 8 to 20 kcal/mol. Indeed, cases of explosively uncontrolled polymerizations have been reported. A. Stages of free radical polymerization 1. Initiation/induction – process starts - Primary radical formation – When radical polymerization is desired, it must be started by using a radical initiator, such as a peroxide or certain azo compounds 2. Propagation – the addition of monomer to an active center (free radical) to generate a new active center 3. Termination – the growing chain is stopped - Radical coupling/recombination (most common) In principle, once started a radical polymerization might be expected to continue unchecked, producing a few extremely long chain polymers. In practice, larger numbers of moderately sized chains are formed, indicating that chain-terminating reactions must be taking place. The most common termination processes are Radical Combination and Disproportionation. B. Anionic polymerization Initiated with e.g. n-butyllithium, alkaline metals. Used in superglues for methyl 2 cyanoacrylate polymerization. C. Cationic polymerization Polymers used in medicine and dentistry Natural polymers - polysaccharides (agar and alginates) - poly(isoprene) SOME COMMON ADDITION POLYMERS NAME(S) FORMULA MONOMER PROPERTIES USES Polyethylene low density (LDPE) –(CH2-CH2)n– ethylene CH2=CH2 soft, waxy solid film wrap, plastic bags Polyethylene high density (HDPE) –(CH2-CH2)n– ethylene CH2=CH2 rigid, translucent solid electrical insulation bottles, toys Polypropylene (PP) different grades –[CH2-CH(CH3)]n– propylene CH2=CHCH3 atactic: soft, elastic solid isotactic: hard, strong solid similar to LDPE carpet, upholstery Poly(vinyl chloride) (PVC) –(CH2-CHCl)n– vinyl chloride CH2=CHCl strong rigid solid pipes, siding, flooring Poly(vinylidene chloride) (Saran A) –(CH2-CCl2)n– vinylidene chloride CH2=CCl2 dense, high-melting solid seat covers, films Polystyrene (PS) –[CH2-CH(C6H5)]n– styrene CH2=CHC6H5 hard, rigid, clear solid soluble in organic solvents toys, cabinets packaging (foamed) Polyacrylonitrile (PAN, Orlon, Acrilan) –(CH2-CHCN)n– acrylonitrile CH2=CHCN high-melting solid soluble in organic solvents rugs, blankets clothing Polytetrafluoroethylene (PTFE, Teflon) –(CF2-CF2)n– tetrafluoroethylene CF2=CF2 resistant, smooth solid non-stick surfaces electrical insulation Poly(methyl methacrylate) –[CH2-C(CH3)CO2CH3]n– (PMMA, Lucite, Plexiglas) methyl methacrylate CH2=C(CH3)CO2CH3 hard, transparent solid lighting covers, signs skylights Poly(vinyl acetate) (PVAc) –(CH2-CHOCOCH3)n– vinyl acetate CH2=CHOCOCH3 soft, sticky solid latex paints, adhesives cis-Polyisoprene natural rubber –[CH2-CH=C(CH3)-CH2]n– isoprene CH2=CH-C(CH3)=CH2 soft, sticky solid requires vulcanization for practical use Polychloroprene (cis + trans) (Neoprene) –[CH2-CH=CCl-CH2]n– chloroprene CH2=CH-CCl=CH2 tough, rubbery solid synthetic rubber oil resistant Step-growth polymerization Characteristics • Proceeds by conventional functional group reactions (condensation, addition) • Needs at least 2 functional groups per reactant • Any monomer molecule has the „same“ probability to react • After an elementary reaction – ability to grow remains • Combines two different reactants in an alternating structure Synthesis of Step-growth Polymers • Polymers are formed more slowly than by addition polymerization • Polymers are generally of lower molecular weight • Types of step-growth polymerization – Polycondensation – Polyaddition The polyester Dacron and the polyamide Nylon 66, shown here, are two examples of synthetic condensation polymers, also known as step-growth polymers. In contrast to chain-growth polymers, most of which grow by carbon-carbon bond formation, step-growth polymers generally grow by carbonheteroatom bond formation (C-O & C-N in Dacron & Nylon respectively). Although polymers of this kind might be considered to be alternating copolymers, the repeating monomeric unit is usually defined as a combined moiety. Step-growth polymerization Step-growth polymerization 2. Setting reaction of epoxies Step-growth polymerization • Polyaddition Step-growth polymerization polyaddition cont. 2. Setting reaction of A-silicone impression materials Some Condensation Polymers Formula Type Components Tg ºC Tm ºC ~[CO(CH2)4COOCH2CH2O]n~ polyester HO2C-(CH2)4-CO2H HO-CH2CH2-OH <0 50 polyester Dacron Mylar para HO2C-C6H4-CO2H HO-CH2CH2-OH 70 265 polyester meta HO2C-C6H4-CO2H HO-CH2CH2-OH 50 240 polycarbonate Lexan (HO-C6H4-)2C(CH3)2 (Bisphenol A) X2C=O (X = OCH3 or Cl) 150 267 polyamide Nylon 66 HO2C-(CH2)4-CO2H H2N-(CH2)6-NH2 45 265 53 223 ~[CO(CH2)4CONH(CH2)6NH]n~ ~[CO(CH2)5NH]n~ polyamide Nylon 6 Perlon polyamide Kevlar para HO2C-C6H4-CO2H para H2N-C6H4-NH2 --- 500 polyamide Nomex meta HO2C-C6H4-CO2H meta H2N-C6H4-NH2 273 390 polyurethane Spandex HOCH2CH2OH 52 --- Biocompatibility Biocompatibility - describes how well a material (regardless of source) works with a living system. In any living system only the host's own tissues are truly inert - all other materials (synthetic or natural) will illicit some level of response. Successful integration of a health product with a patient's own tissues is therefore absolutely critical. Biocompatibility and the risk of rejection due to the hosts' immunological response is a significant challenge. This is becoming a growing challenge since those awaiting replacement / transplantation of organs greatly outnumber the number of available donors. Polymers in Medicine Transdermal Patch Biodegradable Polymer Drug: Fentanyl (pain killer) Nicotine Name: Duragesic, Nicoderm, Habitrol, Prostep, Nicotrol Dosis: 72 hours (fentanyl) Implantable medical devices • Permanent implants that saves livespacemakers,vascular grafts, central nervous system shunts for hydrocephalus • Permanent implants that enhance livesreplacement eye lenses for cataracts, hip prosthesis, incontinence implants • Temporary implants that save livesemergency airways, catheters, balloon angioplasty devices • Temporary implants that enhance livesbone growth stymulators, wound healing patches, fracture fixation devices TYPICAL USES OF POLYMERS AS BIOMATERIALS PMMA-bone cement, contact lenses PTFE-artificial vasculature PU-facial protheses, blood/device interfaces PVC-blood vessels, gastrointestinal grafts, heart components PDMS-ear and ear parts,heart components, bones and joints POLYESTERS-lungs, kidneys, livers, blood vessels NYLONS-joints, blood vessels, kidneydialysis Cellophane • Cellophane is regenerated cellulose. It is in the form of a film; as opposed to rayon, which has the same properties yet is a fiber. • In the 1960’s Brandenberger’s original cellophane was put to use as the membrane that filters and separates the dialysis fluid from the blood. The precursor to the saran wrap that we use today had properties that are so desirable because of its ultra small permeability. • The production of cellophane as stated earlier is simply the regeneration of cellulose. Obtained naturally from wood and cotton fiber. Cellulose is reacted with NaOH and carbon disulfide to produce cellulose xanthate. Cellulose xanthate is then treated with sulfuric acid. The result of the reaction is extruded to a sheet and after a small “aging” period, a thin clear film of cellophane can be peeled. The process by which cellophane is known is viscose . Cellophane Today dialysis machines save thousands of lives daily. The only true alternative to dialysis is kidney transplant. Even in the very unlikely case of a successful transplant (over 50% rejection rate) dialysis is continued for many month or years, to ensure stability. The future of cellulose membranes in the treatment of renal failure has no limits. How dialysis membranes work. A dialysis membrane is a semi-permeable film (usually a sheet of regenerated cellulose) containing various sized pores. Molecules larger than the pores cannot pass through the membrane but small molecules can do so freely. The main inconvenience with dialysis is the actual administration of the lengthy procedure. With improvements in the engineering of the membrane in dialysis, the result has been healthier patients and longer lives for the unfortunate victims. The polymer polyglycolic acid (PGA), and polylactic acid (PLA,PLGA) • The polymer polyglycolic acid, PGA, initially started out as an absorbable suture named Dexon. Dupont, under the direction of Norton Higgins, first synthesized PGA by a three-step process from glycolic acid by manipulating temperature and pressure. • These polymers are then used for drug-delivery systems, to construct synthetic scaffolding, etc. • The amorphous form of PLA is used for drug delivery applications. The latest treatment in treating brain tumors involves attaching dimesized wafers directly into the skull. The wafers are made out of PLA or PLGA and slowly distribute cancer-killing reagents directly into the location where it’s needed. Polymers delivery systems EPR Effect Tumors have “leaky” blood vessels, which allow relatively large nano-sized “pills” to enter. This is called Enhanced Permeability and Retention (EPR) Effect. Normal blood vessels are not “leaky” and nano-particles are prevented from entering. This allows one to selectively target tumors. Duncan, R. Nature Reviews Cancer 2006, 6, 688-701 Tumors Grow Blood Vessels Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760 Polydimethyl siloxane (PDMS) •The polymer polydimethyl siloxane (PDMS) is used in pacemakers, the delivery of vaccines, and the construction cerebrospinal fluid shunts. PDMS is an amorphous structure with low cross-linked elasticity. •For the delivery of the vaccine, biodegradable pellets made of PDMS are used. The pellets are very small in diameter and generally contain soluble antigens to be released within the body. The pellets consist of vulcanized rubber and have a mean diameter of 188 um which allows for the particles to stay in the localized region. Pacemaker •One method for the production of dimethyl siloxane starts with the monomer, dichlorodimethylsilane. Hydroxyl groups, through hydrolysis, replace the two chlorines in the monomer. To achieve a higher molecular weight, however, a different approach is used. This new method is done by a base catalyzed ring-opening polymerization of the siloxanes. CSF shunts Polyethylene and Polymethylmethacrylate (PMMA) Many common thermoplastics, such as polyethylene and polyester, are used as biomaterials. Hip-joint replacements are principally used for structural support. Consequently, materials that possess high strength, such as metals, tough plastics, and reinforced polymer-matrix composites dominate them. In addition, biomaterials used for orthopedic applications must have high modulus, long-term dimensional stability, high fatigue resistance, and biocompatibility A typical modern artificial hip consists of a nitrided and highly polished cobaltchromium ball connected to a titanium alloy stem that is inserted into the femur and cemented into place by in situ polymerization of polymethyl-methacrylate. Modern artificial hip Methyl methacrylate (MMA) polymers Most frequently used group of polymers in medicine Why? Because these materials can be easily adopted to individual purposes (fillings, prostheses) and can be in contact human body • Suitable manipulation/processing properties (easy to mix, shapable, simple to process and cure) • Good mechanical properties (rigidity, strength, wear resistance) • Biocompatible (tasteless, odourless, non-toxic or nonirritating, resistance to microbial colonization) Methyl methacrylate (MMA) polymers Most frequently used group of polymers in medicine • Aesthetic properties translucency and transparency (colour and optical properties of tooth tissues) • Chemical resistance in oral environment, to disinfectants etc. • Acceptable cost of both material and processing method Polytetrafluoroethylene PTFE is thermosetting polymer very limited application in medicine, but its characteristic properties, which combine high strength and chemical resistance, are useful for some orthopedic and dental devices. The polymer chains in this material are highly cross-linked and therefore have severely macromolecular mobility; this limits extension of the polymer chains under an applied load. Biomaterials are used in many blood-contacting devices. These include artificial heart valves, synthetic vascular grafts, ventricular assist devices, drug releases, and a wide range of invasive treatment and diagnostic systems. Artificial heart valves and vascular grafts, while not ideal, have been used successful and have saved many thousands of lives. However, the risk of thrombosis has limited the success of existing cardiovascular devices and has restricted potential application of the biomaterials to other devices. Bioprosthetic Heart Valves Mechanical Prosthetic Heart Valves Polyurethane Polyurethane is a thermoset that is also a noncondensation step growth polymer. Polyurethane has a very low molecular weight compared to many other polymers with a molecular weight average of only 47,000 g/mol. The benefits of this material lie in the basics of it visible physical properties. Polyurethane today is one of the most important materials in use for ventricular assist devices (VAD). Most commonly seen in the operating room during open-heart surgery, postoperatively, and in the cases of extreme cardiac trauma. They consist of tubing attached to the heart valves leading to a pump that can be centrifugal,electrical, or pneumatic. Polyurethane (segmented) stabilized the VAD, making not only the contact barrier of the blood and machine the safest possible, but also using the compressive properties that it exhibits made it function more like the actual heart itself. Ventricular Assist Device Composites materials • Composite materials are formed by combining two or more materials that have quite different properties. • The different materials work together to give the composite unique properties, but within the composite you can easily tell the different materials apart – they do not dissolve or blend into each other. • Most composites are made up of just two materials. One material (the matrix or binder) surrounds and binds together a cluster of fibres or fragments of a much stronger material (the reinforcement). • The greatest advantage of composite materials is strength and stiffness combined with lightness. By choosing an appropriate combination of reinforcement and matrix material, manufacturers can produce properties that exactly fit the requirements for a particular structure for a particular purpose Composites COMMON NAMES OF BIOMATERIALS AND POLYMERS ABBREVIATION NAME ABBREVIATION NAME BIS-GMA BIS-PHENOL A GLYCIDYL METHACRYLATE CARBON FIBRES GLASS FIBRES HYDROXYAPATITE HIGH DENSITY POLYETHYLENE LOW DENSITY POLYETHYLENE METHYL METAHACRYLATE POLYCARBONATE POLIDIMETHYLSILOXANE (SILICONE) POLYETHYLENE POLYETHYLENE GLYCOL PELA BLOCK COPOLYMER OF LACTIC ACID AND POLYETHYLENE GLYCOL POLYETHYLENE TEREPHTALATE POLYMETHACRYLATE POLYMETHYLMETACRYLATE POLYPROPYLENE POLYTETRAFLUOROETHYLENE CF GF HA HDP LDP MMA PC PDMS PE PEG PET PMA PMMA PP PTFE PU PVC PVP SR UHMWPE POLYURETHANE POLYVINYLCHLORIDE POLYVINYLPYRROLIDONE SILICONE RUBBER ULTRA HIGH MOLECULAR WEIGHT POLYETHYLENE Aplication of polymers POLYMER APLICATION PDMS Catheters, heart valves Polyurethane ventricular assist devices PGA, PLA, PLGA Drug delivery, devices Polytetrafluoroe, thylene Heart valves, vascular grafts, nerve repair Polyethylene Catheters, hip prostheses Polymethylmethacrylate (PMMA) Fracture fixation Cellophane Dialysis membranes Conclusion Biomaterials have already made a huge impact on medical practices. But, the opportunities that lie ahead of us are enormous. “Tissue engineering and related subjects have the potential to change paradigms” for treating diseases that today cannot be treated effectively like certain forms of liver failure, paralysis, and certain disorders. Thank you