implantable polymers
TRANSCRIPT
Implantable Polymers
Mai Nguyen-Misra Medtronic, Inc Biointerface Conference, 2012
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In 2008 36 million people died from noncommunicable diseases worldwide
NCDs are projected to rise to 52 million and cause a global output loss of $30 Trillion by 2030
Source: U.S. Census Bureau, International Data Base (IDB), June 2011
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Focus of Presentation …
Material & Testing Considerations for Selection of
Chronic Implantable Polymers to
Ensure Product Reliability
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Selection and Testing of new biomaterials
• Opportunities for new development?
• Acknowledgements & Questions
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Applications of Biomaterials
• Many Classes of Biomaterials: – Metals – Ceramics – Polymers – Composites
Examples in CV Applications: • CRDM leads • Heart valves • Drug Eluting Stents • Vascular grafts • PTCA balloons • Catheters, Sutures, etc.
• Benefits: Easy fabrication; wide range of compositions & properties
• Challenges: Biostability; biocompatibility
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Major Materials Used in CRDM Leads Examples of Common Uses
Polyurethanes • Uses on leads:
– Primary and redundant insulation – Connectors – Adhesives/primers
• Advantages – Biocompatible, High Tear Strength – Low friction coefficient
• Limitations – Chemical biostability issues with some
compositions in certain design configurations: ESC (Environmental Stress Cracking) and MIO (Metal Ion Oxidation)
Silicones • Uses on leads:
– Insulation – Trifurcation / Anchoring sleeve – Adhesive
• Advantages – Biocompatible, Chemically Biostable – Chemically Inert – Soft and flexible
• Limitations – High friction coefficient (sticky) – Susceptible to Mechanical Degradation
and Handling Damage (creep, crush, compression set, abrasion)
Fluoropolymers (e.g., PTFE and ETFE) are also used in leads, e.g., as liner, redundant insulation on cables and coils
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Synthetic Polymers Used in Heart Valves : Examples of Common Uses
• Sewing ring/skirt in Mechanical and Biological Valves: PET and PTFE
– PET (Polyethylene Terephthalate)
• High melting (Tm = 260C) crystalline polymer • High tensile strength (~70MPa)
– PTFE (Polytetrafluoroethylene) • High melting (Tm ~ 325C) polymer • High modulus and tensile properties with negligible elongation • Excellent chemical resistance, very hydrophobic and lubricious • Biostable
• Polymers showing promise for Polymeric trileaflet heart valves: PVA, fiber-reinforced SIBS, and POSS-PCU nanocomposites
– Potentially combining the durability of mechanical valves with hemocompatibility and hydrodynamics of tissue valves
Source: Gallogher, S., Durability assessment of polymer trileaflet heart valves
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Selection and Testing of new biomaterials
• Unmet Needs & Opportunities for new development?
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Materials-Tissue Interface
Leachables or migration of polymer additives to surface may lead to:
Hemolysis, toxicity, sensitization, mutagenicity, carcinogenicity
Interface In polymer, host can potentially cause
In tissue, presence of polymer can potentially cause
Thrombosis Inflammation Fibrous encapsulation
Protein adsorption Cell adhesion Device encapsulation
Swelling, strength, geometry,
Hydrolysis Oxidation Wear Release of moieties
Debris which can cause Inflammation Osteolysis
Device Calcification
Biology is a science of surfaces and interfaces - It is never at equilibrium
Adapted from “Biostability and biocompatibility of polymeric materials for long term implantation” presentation, SuPing Lyu, Medtronic
37 oC aqueous environment Electrolytes, proteins, cells …
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Issues of Biomaterials in Medical Devices
• Physical properties – Mechanical properties (tensile,
compressive, fatigue, etc.) – Transport properties – Degradation rate & byproducts – Surface properties, chemistry,
morphology, rougness, etc. • Biological interactions
– Materials-Body interactions – Toxicity, decomposition
• Process & Design Considerations
Materials under constant & severe chemical/mechanical stresses in the body • Mechanical Stresses (cyclic bending, abrasion, shear, compression, tension, etc.) • Environment (temperature, cellular, water, proteins, enzymes, etc)
Device needs to function as intended over the life of device
• Understanding targeted performance
• Controlling material properties to obtain desired performance & reliability
• Requiring testing relevant material performance under biological conditions
• Initial biological response • Long term material durability and
biological response
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Design & Testing by Anatomical Zones CRDM Leads
Zone 5: Tissue Interface
Zone 1: Pocket
Zone 2: First Rib-Clavicle
Zone 3: Vasculature
Zone 4: Intracardiac Zone differences
• Lead curvature • Rate of lead cycling/flexing • Anatomical structures
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Selection and Testing of new biomaterials
• Unmet Needs & Opportunities for new development?
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Molecular Weight Distribution: Balancing of Properties
– Tensile strength – Brittleness / Toughness – Stress-crack resistance – Hardness
– Processability – Melt viscosity – Softening temperature
Distribution of molecular weights to obtain good properties while permitting reasonable processing conditions
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Solid Bulk State Polymers can be either thermoplastic or thermoset, amorphous or semi-crystalline, branched or linear
• Amorphous – No melting point
• Semi-crystalline – Exhibit a melting point - crystal formation when cooled below Tm – Crystals act as:
• Physical crosslinks that constrain mobility of the amorphous phase • Physical barriers to chemicals
• Crosslinked networks – Permanent - Covalent crosslinks – Temporary - H-bonding; entanglements – Increased in apparent molecular weight; Permanent networks swell in solvents
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Onset of long-range molecular motion – variable upon rate and thermal history • Abrupt and significant changes to properties at Tg → Upon heating above Tg:
– Modulus decay of 3 - 4 orders of magnitude over a 20 to 40°C range – Volumetric expansion increases in a discontinuous manner – Viscosity drops nearly 10 orders – Creep rises
• Factors affecting Tg: – Molecular weight – Chemical structure (e.g., side groups, tacticity) – Additives interfere with bonding and chain movement – Intermolecular interactions, copolymers, etc.
1Tg
=ω1Tg,1
+ω2
Tg,2
Glass transition temperature, Tg
Source: Sperling, L. Introduction to Physical Polymer Science
Tg = Tg,∞ −KM n
Non-crystallizable
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Crystallinity & Polymer Properties
Polymer Properties Crystallinity affecting: • Density • Hardness • Strength • Creep resistance • Durability/stability • Transport properties
Extent of Crystallinity variable dependent upon: • Cooling rate • Annealing • Simplicity of chain structure and monomer chemistry • Side branching • Chain regularity
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Thermal Expansion
• Materials expand when heated and contract when cooled ‒ αpolymers typically an order of magnitude
higher than αmetals – Polymers more sensitive to temperature
and humidity
• Thermal stress may occur due to: – Uneven heating/cooling – Mismatch in thermal expansion
Material α (10-5/K) at room temp
• Polymers
Silicone 250-300
PTFE 130-220
TPU 80-180
Polystyrene 90-150
Nylon 70-100
• Metals
Aluminum 23.6
Steel 12
Titanium 8.6
Tantalum 6.5
Incr
easi
ng α
Generally the stronger the interatomic bonding the smaller is the thermal expansion α
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Polymer Viscoelasticity - Temperature/time Dependence
• Polymers exhibit both viscous (liquid) and elastic (solid) properties: – Brittle (glassy and stiff) behavior below Tg and/or at high frequencies or short times – short range molecular motions (e.g., vibrations, rotations) – Viscous (soft and rubbery) behavior above Tg or Tm and/or low frequencies or long times – large-scale molecular motions (chain sliding)
• The temp-time superposition principle enables construction of larger data set over timescales and temperatures otherwise out of reach
Low MW
Increased Crystallinity
Amorphous
Increasing MW
Cross-linked
Temperature T (oC) or log (time)
Log
Sto
rage
Mod
ulus
G’ (
Pa)
Terminal (long-time relaxation)
Transition (short-time relaxation)
Glassy Region
Rubbery plateau
Stre
ss
Strain
Properties need to be measured at end-use conditions
τT~Mm, m ≈ 3.4
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Polymer stress-strain
Types of Strain or Deformation in response to applied stress • Elastic : A temporary change in shape or size that is recovered when the applied stress is removed. • Ductile (Plastic) : A permanent change in shape or size that is not recovered when the stress is removed (i.e. it flows or bends) • Brittle (Rupture) : the loss of cohesion of a body under the influence of deforming stress (i.e. “it breaks”)
Measurements highly dependent on rate of deformation and temperature
Resilience - Area under elastic region Toughness - Area under whole curve
Irreversible deformation
• Critical consideration in material designing/selecting for end application
• Factors that influence stress-strain can affect upstream operations
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Creep and Strain Recovery (Long-Term Test) Materials flow under load and recover upon load removal
σ
• Polymers, in the amorphous regions, behave as viscous liquids above Tg
• Creep increases at higher temperatures, at higher applied loads, in the presence of plasticizers (including moisture, etc.)
• Creep decreases with crystallinity, increasing molecular weights, crosslinks
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Surface Characteristics Matter
Surface … • Energetics • Hydrophilicity/hydrophobicity • Chemistry • Electrical Properties • Morphology and topography …
Impact … • Material/Device Interactions • Surgeon Handling Characteristics • Material/Biological System Interactions
Influence … • Adhesion • Lubricity • Protein adsorption to materials • Blood coagulation/thrombosis due to material contact • Cellular response to materials
Alter Surface to impact: • Biocompatibility • Other performance factors
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Selection and Testing of new biomaterials
• Unmet Needs & Opportunities for new development?
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Potential Mechanisms of Biomaterial Breakdown
Mechanism Breakdown Examples Mechanical Creep, wear, stress cracking, fracture
Physico-chemical Adsorption of molecules (fouling) Absorption of water and other molecules (softening)
Desorption of low molecular weights (weakening) Dissolution
Bio-chemical Hydrolysis, oxidation, enzymatic, mineral deposition Fibrous encapsulation
Electrochemical Corrosion
No polymer is impervious to chemical and physical actions of the body
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Potential Hydrolytic Degradation
Hydrolyzable polymeric materials: • Esters, • Amides, • Anhydrides, • Carbonates, • Urethanes, etc.
Degradation rate dependent on: • Hydrophobicity, • Crystallinity, • Tg
• Impurities, Molecular weight & polydispersity • Manufacturing procedure, Geometry, etc.
Hydrolysis ‘split with water’ - the scission of chemical functional groups by reaction with water Bulk erosion (homogeneous), e.g.polycaprolactones, polyα-hydroxyesters
• Hydrolysis rate < diffusion rate • Uniform degradation throughout polymer process • Immediate loss in MW
Surface erosion (heterogeneous), e.g.polyanhydrides, polyorthoesters • Hydrolysis rate > diffusion rate • Polymer degrades only at polymer-water interface • Ideally no change in MW
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Potential Oxidative Degradation
• Typically involves abstraction of a highly labile H from the polymer by highly reactive peroxyl radicals
• Some possible causes of polymer oxidation: – Excessive temperature and/or shear in air, – Insufficient or poorly dispersed antioxidant, – Contact of polymer with catalytically active metal (e.g., Cu, Co)
• Direct oxidation by host and/or device – Release of superoxide anion and hydrogen peroxide by neutrophils and macrophages – Catalyzed by presence of metal ions from corrosion
Oxidation susceptibility: PP> LDPE> HDPE>Polyether > PEEK > PVDF > PTFE
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Example: Metal Ions Induced Oxidation of Polymers
Brittle cracking observed in Poly(etherurethane) 80A surface next to metal coil
In vitro • Observed in polymers in H2O2 solution, with certain metals • Cracking more prevalent with increasing ether content of polymers • Stress has a slight impact, but not necessary In vivo • Cracking has been observed with polyurethane implanted in close
proximity with certain metals (i.e. Co) • Polymer does not have to be in contact with tissue
Ebert et al, Medtronic Internal
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Selection and Testing of new biomaterials
• Unmet Needs & Opportunities for new development?
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Criteria for Biomaterials as Implants
• Have required physical/chemical properties and maintain these properties over the desired time period
• Do not induce undesirable biologic responses
• Should be manufactured and sterilized easily and reproducibly
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Material Selection • Material Selection and Process Selection are strongly
interdependent, dictated by Part Geometry/dimensions and Finished Device Requirements
Material
Process Design
DEVICE
Considerations: • Part manufacturing and device
assembly conditions (e.g., heat shrinking, joining methods, etc.)
• Sterilization • Use conditions (applied
stresses, environment)
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Potential Material Selection Considerations
• Mechanical: tensile, compression, fatigue, stiffness, creep, fracture • Electrical: insulation, electromechanical compatibility • Chemical: biostability, degradation interaction/reaction • Thermal: shrinkage, expansion, dimensional stability, thermal insulation • Environmental: product life span, shelf life, humidity • Surface: finish, wear,friction, tactility, biocompatiblity, thrombogenicity • Process considerations: melt processing, sterilization, etc. • Economic: Material cost, process introduction • Aesthetic: cosmetic appearance, visual clarity
Considerations: • Function: What does the component do? How/where/how long is going to be used? • Constraints: What essential conditions must be met? • Objectives: What variables need to be maximized/minimized
Impact of choice on qualification, regulation, schedule and cost
Help to narrow down properties to probe and material down selection
Sources: Haam, S., Biomaterials; Egan, S, Choosing Materials for Medical Devices, 2012
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New Material Initial Selection Questions
• Has the material been used in long term implants? How long? Vendor experience in providing biomaterials? Process capability? Quality system, ISO-certified, GMP?
• Can the material be made/delivered consistently and reliably in volume/time needed?
• How processing-friendly and stability against processing (sterilization, extrusion, etc.) is the material?
• What data is available (toxicity assessment, biocompatibility, mechanical, biostability, Degradation mechanism and byproducts, material compatibility with metals, polymers, drugs?, etc.)
• Shelf life of material before and after processing? • Is the material on DMF? • Patent protection? • If all OK then bring in material & conduct screening
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DESIGN CONSIDERATIONS DEVICE
IN VITRO (BENCH) EVALUATION
IN VIVO (PRECLINICAL) EVALUATION
NEEDS
MATERIALS FIRST TIER TESTING
DOWN SELECTION
MATERIALS SCREENING
SECOND TIER TESTING
New Biomaterials Selection / Qualification Process
Adapted from Haam, S., Biomaterials
CLINICAL TRIAL
Paper analysis: vendors’ datasheets, databases, potential failure modes, etc.
PROCESS CONSIDERATIONS
Translating device requirement to material requirements
Material Qualification
Selecting test method and determining screening criteria
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Reliable bench testing to predict in vivo performance
Validation
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Outline
• Overview of Polymers in Implantable Devices • Where are biomaterials used? What are the current challenges? • Examples of existing biomaterials and uses
• Relevant Issues of Polymers in Implantable Devices: – Overview of fundamental polymer properties – Polymer Degradation – Identification and Selection of new biomaterials
• Opportunities for new development?
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Trends & Opportunities for Innovation
Increased globalization, aging population and advances in information technology leads to: • Increased demand & access to healthcare • Patients with more challenging health conditions • Demand for lower cost, but better quality and efficiency
Opportunities for Innovation: • Less invasive technologies
• Less chance of acute and chronic complications • Device longevity
• Improved in Material Biostability, Biocompatibility, etc. • Minimize numbers of procedures
• Remote and integrated care • Wider selection & more versatility
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Examples of Development Opportunities in Emerging CV Technologies
• Transcatheter heart valves Some potential areas for development:
– Biostable polymeric valves – Drug-eluting and/or valves with bioresorbable scaffolding
• Leadless pacemaker Some potential areas for development:
– Smaller devices – Longer life
• Bioresorbable and Polymer-free Drug-Eluting Stents Some potential areas for development: – New surface modification technologies
– New polymer chemistries – New Drugs
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Key Takeaway Opportunities exist for applying systematic critical thinking
and innovative approaches in:
• Building correlations between material properties-device performances-clinical needs,
• Formulating rational material selection/development process
• Developing more reliable and predictive in vitro and in vivo test methods
To bring innovative products that address unmet clinical
needs to the growing emerging markets faster