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

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Acknowledgements

•  Medtronic Management •  Medtronic Colleagues

mai.t.nguyen-misra@medtronic.com