Post on 13-Nov-2014
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Biodegradable MaterialsBiodegradable Materials
Eliminates additional surgery to remove an Eliminates additional surgery to remove an implant after it serves its functionimplant after it serves its function
Ideal when the “temporary presence” of Ideal when the “temporary presence” of the implant is desiredthe implant is desired
replaced by regenerated tissue as the replaced by regenerated tissue as the implant degrades implant degrades
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Biodegradable MaterialsBiodegradable Materials
Degradation Degradation Short term applications Short term applications suturessutures drug deliverydrug delivery orthopaedic fixation devices (requires orthopaedic fixation devices (requires
exceptionally strong polymers)exceptionally strong polymers) adhesion prevention (requires polymers that adhesion prevention (requires polymers that
can form soft membranes or films)can form soft membranes or films) temporary vascular grafts (development temporary vascular grafts (development
stage, blood compatibility is a problem)stage, blood compatibility is a problem)
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Biodegradable MaterialsBiodegradable Materials
Four main types of degradable implants:Four main types of degradable implants: the temporary scaffoldthe temporary scaffold the temporary barrierthe temporary barrier the drug delivery devicethe drug delivery device multifunctional devicesmultifunctional devices
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Biodegradable: Scaffold Biodegradable: Scaffold
provides support until the tissue healsprovides support until the tissue heals weakened by disease, injury or surgery weakened by disease, injury or surgery healing wound, broken bone, damaged blood vesselhealing wound, broken bone, damaged blood vessel sutures, bone fixation devices, vascular graftssutures, bone fixation devices, vascular grafts
Rate of degradation: Rate of degradation: implant should degrade at the rate the tissue healsimplant should degrade at the rate the tissue heals
Sutures are most widely usedSutures are most widely used polyglycolic acid (PGA) - Dexonpolyglycolic acid (PGA) - Dexon®®
copolymers of PGA and PLA (polylactic acid), Vicrylcopolymers of PGA and PLA (polylactic acid), Vicryl®® polydioxanone (PDS)polydioxanone (PDS)
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Biodegradable: Barrier Biodegradable: Barrier
Prevent adhesionPrevent adhesion caused by clotting of caused by clotting of blood in the extravascular tissue spaceblood in the extravascular tissue space clotting clotting inflammation inflammation fibrosis fibrosis adhesions are common problems after adhesions are common problems after
cardiac, spinal and tendon surgerycardiac, spinal and tendon surgery barrier in the form of thin membrane or filmbarrier in the form of thin membrane or film
Another barrier use is Another barrier use is artificial skinartificial skin for for treatment of burnstreatment of burns
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Biodegradable: Drug Delivery Biodegradable: Drug Delivery
Most widely investigated application Most widely investigated application
PLA, PGA used frequentlyPLA, PGA used frequently
Polyanhydrides for administering Polyanhydrides for administering chemotherapeutic agents to patients chemotherapeutic agents to patients suffering from brain cancer suffering from brain cancer
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Biodegradable: Multifunctional Biodegradable: Multifunctional Devices Devices
Combination of Combination of several functions several functions mechanical function + mechanical function +
drug deliverydrug delivery : : biodegradable biodegradable bone bone nailsnails and screws made and screws made of ultrahigh-strength of ultrahigh-strength PLA and treated with PLA and treated with BMP & TGF-BMP & TGF- for for stimulation of bone stimulation of bone growthgrowth
SEM image of biodegradable polyurethane
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Biodegradable: Multifunctional Biodegradable: Multifunctional Devices Devices
Combination of several Combination of several functionsfunctions mechanical support + mechanical support +
drug deliverydrug delivery: : biodegradable biodegradable stentsstents to to prevent collapse and prevent collapse and restenosis (reblocking) restenosis (reblocking) of arteries opened by of arteries opened by balloon angioplasty and balloon angioplasty and treated with anti-treated with anti-inflammatory or anti-inflammatory or anti-thrombogenic agents thrombogenic agents
Biodegradable intravascular stent molded from a blend of polylactide and trimethylene
carbonate. Photo: Cordis Corp. Prototype Molded by Tesco Associates, Inc.
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Biodegradable: Terminology Biodegradable: Terminology
Confusion between Confusion between biodegradation, bioerosion, biodegradation, bioerosion, bioabsorption and bioresorption!bioabsorption and bioresorption!Consensus Conference of the European Society for Consensus Conference of the European Society for BiomaterialsBiomaterialsBiodegradationBiodegradation: : A biological agent (an enzyme, microbe A biological agent (an enzyme, microbe or cell) responsible for degradationor cell) responsible for degradationBioerosionBioerosion: Bioerosion contains both physical (such as : Bioerosion contains both physical (such as dissolution) and chemical processes (such as backbone dissolution) and chemical processes (such as backbone cleavage). A water-insoluble polymer that turns water-cleavage). A water-insoluble polymer that turns water-soluble under physiological conditions. soluble under physiological conditions. Bioresorption, BioabsorptionBioresorption, Bioabsorption: Polymer or its degradation : Polymer or its degradation products removed by cellular activity (e.g. phagocytosis)products removed by cellular activity (e.g. phagocytosis)
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Biodegradable PolymersBiodegradable Polymers
Variety of available degradable polymers Variety of available degradable polymers is limited due to stringent requirementsis limited due to stringent requirements biocompatibilitybiocompatibility free from degradation related toxic products free from degradation related toxic products
(e.g. monomers, stabilizers, polymerization (e.g. monomers, stabilizers, polymerization initiators, emulsifiers)initiators, emulsifiers)
Few approved by FDAFew approved by FDA
PLA, PGA, PDS used routinelyPLA, PGA, PDS used routinely
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Biodegradable PolymersBiodegradable Polymers
ester bond
o
coo
anhydride
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Biodegradable PolymersBiodegradable Polymers
Effect of molecular weight on the mechanical
strength????
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Biodegradable PolymersBiodegradable Polymers
Most degradable Most degradable polymers are polymers are polyesterspolyesters
ester is a covalent ester is a covalent bond with polar bond with polar nature, more reactivenature, more reactive
can be broken down can be broken down by hydrolysisby hydrolysis
the C-O bond breaksthe C-O bond breaks
ESTER BOND
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Biodegradable PolymersBiodegradable Polymers
contain a contain a peptide (or peptide (or amide) amide) linklink
can be broken down can be broken down by hydrolysisby hydrolysis
the C-N bond breaksthe C-N bond breaks
can be spun into can be spun into fibres for strengthfibres for strength
AMIDE BOND
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Biodegradable Polymers: Biodegradable Polymers: HydrolysisHydrolysis
Breakdown of a molecule Breakdown of a molecule in the presence of waterin the presence of water
Hydrolysis of the ester Hydrolysis of the ester bond results in formation bond results in formation of an acid and an alcoholof an acid and an alcohol
Inverse of reaction to Inverse of reaction to hydrolysis is hydrolysis is condensation (remember condensation (remember condensation condensation polymerization)polymerization)
hydrolysis
condensation
Hydrolysis of ester
Hydrolysis of anhydride
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Biodegradable PolymersBiodegradable Polymers
polyhydroxybutyrate (PHB), polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and polyhydroxyvalerate (PHV) and copolymerscopolymers polyesters synthesized and used by polyesters synthesized and used by
microorganisms for intracellular energy microorganisms for intracellular energy storagestorage
70% PHB-30% PHV copolymer commercially 70% PHB-30% PHV copolymer commercially available as Biopolavailable as Biopol®®
rate of degradation controlled by varying rate of degradation controlled by varying copolymer compositioncopolymer composition
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Biodegradable PolymersBiodegradable Polymers
polyhydroxybutyrate (PHB), polyhydroxyvalerate polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and copolymers (cont)(PHV) and copolymers (cont) in vivo in vivo PHB degrades to hydroxybutyric acid which is PHB degrades to hydroxybutyric acid which is
a normal constituent of human blood a normal constituent of human blood biocompatible, nontoxicbiocompatible, nontoxic
PHB homopolymer is highly crystalline and brittlePHB homopolymer is highly crystalline and brittle copolymer of PHB with hydroxyvaleric acid is less copolymer of PHB with hydroxyvaleric acid is less
crystalline, more flexible and more processiblecrystalline, more flexible and more processible used in controlled drug release, suturing, artificial used in controlled drug release, suturing, artificial
skin, and paramedical disposablesskin, and paramedical disposables
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Biodegradable PolymersBiodegradable Polymers
polycaprolactonepolycaprolactone semi-crystalline polymersemi-crystalline polymer slower degradation rate than PLAslower degradation rate than PLA remains active as long as a year for drug deliveryremains active as long as a year for drug delivery CapronorCapronor®®, implantable biodegradable contraceptive, implantable biodegradable contraceptive
implanted under skinimplanted under skin
dissolve in the body and does not require removaldissolve in the body and does not require removal
degradation of the poly(degradation of the poly(epsilonepsilon-caprolactone) matrix occurs -caprolactone) matrix occurs through bulk hydrolysis of ester linkagesthrough bulk hydrolysis of ester linkages
autocatalyzed by the carboxylic acid end groups of the autocatalyzed by the carboxylic acid end groups of the polymer, eventually forming carbon dioxide and waterpolymer, eventually forming carbon dioxide and water
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Biodegradable PolymersBiodegradable Polymers
CapronorCapronor®®, implantable biodegradable , implantable biodegradable contraceptive (cont.)contraceptive (cont.)
Capronor II consists of 2 rods of poly(e-Capronor II consists of 2 rods of poly(e-caprolactone) each containing 18 mg of caprolactone) each containing 18 mg of levonorgestrellevonorgestrelCapronor III is a single capsule of copolymer Capronor III is a single capsule of copolymer (caprolactone and trimethylenecarbonate) filled (caprolactone and trimethylenecarbonate) filled with 32 mg of levonorgestrelwith 32 mg of levonorgestrelthe implant remains intact during the first year of the implant remains intact during the first year of use, thus could be removed if needed. use, thus could be removed if needed. Over the second year, it biodegrades to carbon Over the second year, it biodegrades to carbon dioxide and water, which are absorbed by the bodydioxide and water, which are absorbed by the body
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Biodegradable PolymersBiodegradable Polymers
polyanhydridespolyanhydrides highly reactive and hydrolytically unstablehighly reactive and hydrolytically unstable degrade by surface degradation without the degrade by surface degradation without the
need for catalystsneed for catalysts aliphatic (CHaliphatic (CH22 in backbone and side chains) in backbone and side chains)
polyanhydrides degrade within dayspolyanhydrides degrade within days aromatic (benzene ring as the side chain) aromatic (benzene ring as the side chain)
polyanhydrides degrade over several yearspolyanhydrides degrade over several years
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Biodegradable PolymersBiodegradable Polymers
polyanhydrides (cont.)polyanhydrides (cont.) aliphatic-aromatic copolymers can be used to aliphatic-aromatic copolymers can be used to
tailor degradation ratetailor degradation rate excellent biocompatibilityexcellent biocompatibility used in drug deliveryused in drug delivery drug loaded devices prepared by drug loaded devices prepared by
compression molding or microencapsulationcompression molding or microencapsulation insulin, bovine growth factors, angiogenesis insulin, bovine growth factors, angiogenesis
inhibitors, enzymesinhibitors, enzymes
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Biodegradable PolymersBiodegradable Polymers
polyorthoesterspolyorthoesters formulated so that degradation occurs by formulated so that degradation occurs by
surface erosionsurface erosion drug release at a constant ratedrug release at a constant rate
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Biodegradable PolymersBiodegradable Polymers
polyaminoacidspolyaminoacids poly-L-lysine, polyglutamic acidpoly-L-lysine, polyglutamic acid aminoacid side-chains offer sites for drug aminoacid side-chains offer sites for drug
attachmentattachment low-level systemic toxicity owing to their low-level systemic toxicity owing to their
similarity to naturally occurring amino acidssimilarity to naturally occurring amino acids investigated as suture materialsinvestigated as suture materials artificial skin subtitutesartificial skin subtitutes
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Biodegradable PolymersBiodegradable Polymers
polyaminoacids (cont.)polyaminoacids (cont.) limited applicability as biomaterials due to limited limited applicability as biomaterials due to limited
solubility and processibilitysolubility and processibility drug delivery (difficult to predict drug release rate due drug delivery (difficult to predict drug release rate due
to swelling)to swelling) polymers containing more than three or more amino polymers containing more than three or more amino
acids may trigger antigenic responseacids may trigger antigenic response
““pseudo”- polyaminoacidspseudo”- polyaminoacids backbone of polyaminoacids altered to circumvent backbone of polyaminoacids altered to circumvent
above problemsabove problems tyrosine derived polycarbonates developed as high-tyrosine derived polycarbonates developed as high-
strength degradable orthopaedic implantsstrength degradable orthopaedic implants
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Biodegradable PolymersBiodegradable Polymers
polycyanocrylatespolycyanocrylates used as bioadhesivesused as bioadhesives use as implantable material is limited due to use as implantable material is limited due to
significant inflammatory responsesignificant inflammatory response
polyphosphazenespolyphosphazenes inorganic polymerinorganic polymer backbone consists of nitrogen-phosphorus bondsbackbone consists of nitrogen-phosphorus bonds use for drug delivery under investigationuse for drug delivery under investigation
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Biodegradable PolymersBiodegradable Polymers
PGA and PLAPGA and PLA most widely used biodegradable polymersmost widely used biodegradable polymers PGA is the simplest aliphatic polyesterPGA is the simplest aliphatic polyester
highly crystalline, high melting point, low solubilityhighly crystalline, high melting point, low solubility
appeared with the trade name Dexonappeared with the trade name Dexon
Dexon sutures lose strength within 2-4 weeks Dexon sutures lose strength within 2-4 weeks sooner than desiredsooner than desired
used as bone screws, Biofixused as bone screws, Biofix®®
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Biodegradable PolymersBiodegradable Polymers
PGA and PLA (cont.)PGA and PLA (cont.) PLA PLA
D,L-PLA amorphous polymer; thus, used for drug D,L-PLA amorphous polymer; thus, used for drug deliverydelivery
L-PLA semicrystalline; thus, mechanical L-PLA semicrystalline; thus, mechanical applications such as sutures or orthopaedic applications such as sutures or orthopaedic devices devices
compare mechanical properties of D,L-PLA and L-compare mechanical properties of D,L-PLA and L-PLA in the Table in slide #12PLA in the Table in slide #12
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Biodegradable PolymersBiodegradable Polymers
PGA and PLA (cont.)PGA and PLA (cont.) copolymers of PGA and PLA used to adapt copolymers of PGA and PLA used to adapt
material properties suitable for wider range of material properties suitable for wider range of applicationsapplications
PLA is more hydrophobic than PGAPLA is more hydrophobic than PGA
hydrophobicity of PLA limits water uptake of thin hydrophobicity of PLA limits water uptake of thin films to about 2% and reduces the rate of films to about 2% and reduces the rate of hydrolysis compared with PGAhydrolysis compared with PGA
sutures with trade names Vicrylsutures with trade names Vicryl®® and Polyglactin and Polyglactin 910910®®
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
Bioerosion cause:Bioerosion cause: changes in the appearance of the devicechanges in the appearance of the device changes in the physicomechanical propertieschanges in the physicomechanical properties swellingswelling deformationdeformation structural disintegrationstructural disintegration weight lossweight loss loss of functionloss of function
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
Bioerosion is due to Bioerosion is due to chemical degradation chemical degradation
cleavage of backbonecleavage of backbone
cleavage of crosslinkscleavage of crosslinks
side chainsside chains physical processes (e.g. changes in pH) physical processes (e.g. changes in pH)
Two types of erosionTwo types of erosion bulk erosionbulk erosion surface erosionsurface erosion
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
bulk erosion: bulk erosion: water enters polymer water enters polymer causes hydrolytic causes hydrolytic
degradation degradation component hollowed outcomponent hollowed out finally crumbles (like sugar finally crumbles (like sugar
cube in water)cube in water) releases acid groups (slide releases acid groups (slide
15) (a.k.a. acid bursting) 15) (a.k.a. acid bursting) possible inflammationpossible inflammation
characteristic of hydrophilic characteristic of hydrophilic polymerspolymers
H2O H2O
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
surface erosion: surface erosion: water penetration limited, water penetration limited, degradation occurs on the degradation occurs on the
surfacesurface thinning of the component over thinning of the component over
timetime integrity is maintained over integrity is maintained over
longer time when compared to longer time when compared to bulk erosionbulk erosion
hydrophobic polymers hydrophobic polymers experience surface erosion since experience surface erosion since water intake limitedwater intake limited
acidic byproducts are released acidic byproducts are released gradually gradually acid burst less likely, acid burst less likely, lower chance of inflammationlower chance of inflammation
surface erosion can also occur surface erosion can also occur via enzymatic degradationvia enzymatic degradation
H2O H2O
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
Factors that determine rate of erosion:Factors that determine rate of erosion: chemical stability of the polymer backbone chemical stability of the polymer backbone
(erosion rate anhydride > ester > amide)(erosion rate anhydride > ester > amide) hydrophobicity of the monomer (addition of hydrophobicity of the monomer (addition of
hydrophobic comonomers reduce erosion hydrophobic comonomers reduce erosion rate)rate)
morphology of polymer morphology of polymer crystalline vs. amorphous: ↑crystallinity crystalline vs. amorphous: ↑crystallinity ↑ ↑ packing density packing density ↓ water penetration ↓ water penetration ↓erosion ↓erosion rate rate
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Biodegradable Polymers: Biodegradable Polymers: BioerosionBioerosion
Factors that determine rate of erosion (cont.):Factors that determine rate of erosion (cont.): initial molecular weight of the polymerinitial molecular weight of the polymer fabrication processfabrication process presence of catalysts, additives or plasticizerspresence of catalysts, additives or plasticizers geometry of the implanted device (surface/volume geometry of the implanted device (surface/volume
ratio)ratio) Polymer less permeable to water in glassy state: Polymer less permeable to water in glassy state: TTg g of of
the polymer should be greater than 37 the polymer should be greater than 37 CC to maintain to maintain resistance to hydrolysis under physiological resistance to hydrolysis under physiological conditionsconditions
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Biodegradable Polymers: Chemical Biodegradable Polymers: Chemical DegradationDegradation
Chemical degradation mediated by water, Chemical degradation mediated by water, enzymes, microorganismsenzymes, microorganisms
Mechanisms of chemical degradationMechanisms of chemical degradation cleavage of crosslinks between chainscleavage of crosslinks between chains cleavage of side chainscleavage of side chains cleavage of polymer backbonecleavage of polymer backbone combination of abovecombination of above
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Biodegradable Polymers: Chemical Biodegradable Polymers: Chemical DegradationDegradation
CLEAVAGE OF CROSSLINKS
TRANSFORMATION OF SIDE CHAINS
CLEAVAGE OF BACKBONE
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Biodegradable Polymers: Storage, Biodegradable Polymers: Storage, Sterilization and PackagingSterilization and Packaging
minimize premature polymer degradation during minimize premature polymer degradation during fabrication and storagefabrication and storagemoisture can seriously degrade, controlled moisture can seriously degrade, controlled atmosphere facilitiesatmosphere facilitiessterilizationsterilization -irradiation or ethylene oxide-irradiation or ethylene oxide both methods degrade physical propertiesboth methods degrade physical properties choose lesser of two evils for a given polymerchoose lesser of two evils for a given polymer -irradiation dose at 2-3 Mrad (standard level to -irradiation dose at 2-3 Mrad (standard level to
reduce HIV) can induce significant backbone damagereduce HIV) can induce significant backbone damage ethylene oxide highly toxicethylene oxide highly toxic
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Biodegradable Polymers: Storage, Biodegradable Polymers: Storage, Sterilization and PackagingSterilization and Packaging
Packed in airtight, aluminum-backed, Packed in airtight, aluminum-backed, plastic foil pouches.plastic foil pouches.
Refrigeration may be necessaryRefrigeration may be necessary
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Cutting Edge…Cutting Edge…
Drug-Coated Stents Transform Heart CareDrug-Coated Stents Transform Heart Care These devices, which slowly leach medication into These devices, which slowly leach medication into
blood vessels to keep them from squeezing shut blood vessels to keep them from squeezing shut vastly better than the plain old metal stents that were vastly better than the plain old metal stents that were
standard just a few years ago. standard just a few years ago. on the market — Boston Scientific Corp.'s Taxus on the market — Boston Scientific Corp.'s Taxus
stent, and Cypher, made by Cordis Corp., a Johnson stent, and Cypher, made by Cordis Corp., a Johnson & Johnson company. & Johnson company.
very big blockages in very small vessels — some very big blockages in very small vessels — some nearly two inches long — can be fixed with such nearly two inches long — can be fixed with such stents, sometimes using overlapping ones. stents, sometimes using overlapping ones.
One novel type even dissolves in the body once its One novel type even dissolves in the body once its job is done. job is done.
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Cutting Edge…Cutting Edge…
Drug-Coated Stents Transform Heart Care (cont.)Drug-Coated Stents Transform Heart Care (cont.) metal reclogged about one-fourth of the time until drug-coated ones metal reclogged about one-fourth of the time until drug-coated ones
came along and cut the rate to around 5 percent. came along and cut the rate to around 5 percent. comparison study showed that eight months after treatment, rates of comparison study showed that eight months after treatment, rates of
heart attacks, strokes and repeat procedures were similar with both heart attacks, strokes and repeat procedures were similar with both stents, sponsored by Cypher's maker, Cordis. stents, sponsored by Cypher's maker, Cordis.
A different study led by doctors with no ties to Cordis showed Cypher A different study led by doctors with no ties to Cordis showed Cypher clearly outperformed Taxus in 250 diabetics clearly outperformed Taxus in 250 diabetics
Nearly nine out of 10 stents used in the United States now are drug-Nearly nine out of 10 stents used in the United States now are drug-coated, and two out of three are Taxus stents. coated, and two out of three are Taxus stents.
Meanwhile, Medtronic Inc. reported that its experimental drug-coated Meanwhile, Medtronic Inc. reported that its experimental drug-coated stent, Endeavor, outperformed plain metal stents in tests on 1,197 stent, Endeavor, outperformed plain metal stents in tests on 1,197 patients. patients.
Competition should make drug-coated stents more affordable, said Competition should make drug-coated stents more affordable, said Dr. Samin Sharma, co-director of the Cardiovascular Institute at Dr. Samin Sharma, co-director of the Cardiovascular Institute at Mount Sinai Medical Center in New York. They used to cost more Mount Sinai Medical Center in New York. They used to cost more than $3,000, sell for around $2,300 now, and could drop to less than than $3,000, sell for around $2,300 now, and could drop to less than $2,000, he said. $2,000, he said.