biomaterials in medical devices

Biomaterials in Medical DevicesMedtronic, Inc. [email protected]
– Biomaterials and Biocompatibility • Overview of Medical Devices
– Focus on implantable, therapeutic devices • Heart Valves
– Mechanical valves and Bioprosthesis • Stents
– Stent delivery system – Bare metal stents and Drug eluting stents
• Pacemakers and ICDs – Components – MRI compatibility issues
• Surface Properties – Surface energy – Surface treatments and coatings
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Introduction
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What are biomaterials?
• Materials used to make devices to replace a part of a function of the body in a safe, reliable, economic, and physiologically acceptable manner. (Hench and Erthridge, 1982)
• A nonviable material used in a medical device intended to interact with biological systems. (Williams 1987)
Biomaterials are used in medical devices in direct contact with biological systems. Biomaterials are defined by their application, NOT chemical make-up.
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• Interdisciplinary, integrated, sophisticated – materials science + biology + physiology +
biochemistry + clinical science + …
biological materials
known – High mechanical strength – Stiff and strong – Fatigue resistance, wear
resistance – Joining technologies known
Metallic Biomaterials
• Readily sterilized
• Low to high bioreactivity
• Disadvantages • Difficult to fabricate
BioCeramics
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– Silicone
Polymer Biomaterials
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• Advantages – Easy fabrication – Wide range of compositions and properties – Many ways to immobilize biomolecules/
cells
• Mobility
fixation; bone grafts
• Dental – enamels, fillings, prosthetics, orthodontics
• Soft tissue – wound healing, reconstructive and augmentation, intra-ocular lens
• Surgical – staples, sutures, scalpels, surgical tools
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• Have required physical/chemical properties and maintain these properties over desired time period.
• Do not induce undesirable biologic responses.
• Should be manufactured and sterilized easily and reproducibly.
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• Biological interactions – Materials-Body interactions – Toxicity, Decomposition
• Formability • Design Issues • Liability
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• Relevant material performance under biological conditions – 37 C, aqueous, saline, extracellular matrix (ECM)
– Material properties as a function of time • Initial negative biological response - toxicity
• Long term biological response – rejection
• Biology is a science of surfaces and interfaces and it is never at equilibrium.
Cont’d
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Value Location pH 6.8 Intracellular 7.0 Interstitial 7.15-7.35 Blood pO2 2-40 Interstitial (mm Hg) 40 Venous 100 Arterial Temperature 37 Normal Core 28 Normal Skin Mechanical Stress 4x107 N m-2 Muscle (peak stress) 4x108 N m-2 Tendon (peak stress) Stress Cycles (per year) 3x105 Peristalsis 5x106 - 4x107 Heart muscle contraction
Length of implant: Day, Month, Years
Test Conditions:
allergenic, etc.
– New Definition • The ability of a material to perform with an
appropriate host response in a specific application. » D. Williams
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Biocompatibility
• Is a collection of processes involving interactions between the materials and the tissue.
• Refers to the ability of the material to perform a function.
• Refers to the appropriate host responses. – Does not stipulate that there should be no responses.
• Is NOT an intrinsic material property.
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• Question: Will this material stimulate the appropriate biological response for the intended use?
• In vitro tests • In vivo/Usage tests
• Clinical Trials
• Nature of cell/biomaterial interactions
• Cell number, growth rate, metabolic rate, cell function, protein expression
• Simple, repeatable, inexpensive, rapid
• Expensive, logistically complicated
Response, Infection, Necrosis
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nontoxic and nearly inert a fibrous tissue forms
nontoxic and bioactive an interfacial bond forms
nontoxic and dissolves the surrounding tissue replaces it
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Why do Medical Devices Fail?
• The types of materials failure in the failure of biomedical devices – Mechanical – Physico-chemical – Chemical (biochemical, electrochemical) – Device Design
• Device failure can be catastrophic to the patient and, at the least, costly and risky – We often don’t have good long term descriptive tests for
medical devices in-vivo – High risk nature precludes new device adoption
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Physico-chemical Adsorption of biomolecules (fouling),
Absorption of water (softening), Desorption of low MWs (weakening), Dissolution
Biochemical Hydrolysis, Oxidation, Reduction, Mineral deposition
Electrochemical Corrosion
• Mechanisms: – Creep: Long term deformation under load – Wear/Abrasion: Surface failure during working – Stress cracking: Stress relief in local environment – Fatigue: Breaking under cycling load – Tensile/Torsion/Compression failure
• Issues: – Material choice – Testing – Failure analysis: fractography
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• Protein/cell adsorption on the surface - fouling • Property decay through water interactions –
softening, crazing • Leaching of plasticizer, filler, etc. in bio environment • Dissolution of component/device • Materials degradation of device - hydrolysis of
esters or amides • Corrosion - oxidation or reduction • Calcification - “growing unwanted bone” or Ca
deposits • Catastrophic fibrous encapsulation
• Electrical resistance, contact, power supply, earthing, insulation, electromechanical
compatibility • Thermal
product life span, shelf life, humidity, manufacturing waste, recyclability • Surface
finish, wear, friction, tactility (“feel”) • Aesthetic
Cosmetic appearance, colors, visual clarity • Economic
Material cost, process introduction
– Damages DNAs
– E-beam causes crosslinking and chain scissoring of polymers (Teflon, PP, etc.)
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gamma rays
– Quick turnaround; easy penetration
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– Disrupts DNAs
– Takes long time: pre-condition (T, humidity), sterilization, aeration
– Aeration is particularly a problem for polymers (absorbed must be desorbed)
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gamma – Radiation affects materials with
low binding energy. • Energy of radiation breaks the
molecular bonds.
– For some polymers (acetyls, Teflon, PP), crosslinking or scissoring occurs.
– It also affects batteries and electronic components.
– Gamma radiation changes the color grade of ceramics.
• ZrO2 hip balls turn dark after sterilization.
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Effects of Sterilization
• Ethylene oxide (EtO) – Aeration is particularly a problem for polymers and porous
materials.
– Polymers absorb EtO easily. Sterilization is effective, however, all absorbed EtO must be removed (aeration).
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BIOmaterials
time
bioMATERIALS
BIOMATERIALS
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1960’s
2000
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What is not?
Definition of a Medical Device (by US FDA)
• “An instrument, apparatus, or implant intended for diagnosis, treatment, or prevention of disease …… affect the structure or function of the body without chemical action or metabolism”
• Range from simple tongue depressors to complex programmable pacemakers with micro-chip technology and laser surgical devices
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Classification of Medical Devices (by US FDA)
• Classification depends on three factors – Intended use - What disease, symptom, or
condition is the device intended to treat? How will the device be used?
– Indications for use - What kinds of patients should this be used on? Can be based on age, disease state, medical history, allergies, etc.
– Level of risk - Is the device life-saving? Is the device life-sustaining? Is there an unreasonable risk of illness or injury associated with use of the device?
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• Class I: General Controls – Present minimal potential for harm to the user
– Devices whose safety & effectiveness are well- established
– Registration with the FDA, GMP, proper labeling, notification of FDA before marketing
– About 40% of all devices are Class I
– Tongue depressor, bandages, exam gloves
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• Class II: General controls with specific controls – Subject to special controls of special labeling,
mandatory performance standards, postmarket surveillance, preclinical testing
– About half of all devices are Class II
– Contact lenses, x-ray machines, powered wheelchairs, infusion pumps, surgical needles, suture materials, acupuncture needles
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• Class III: General controls and Premarket Approval – Premarket approval, scientific reviews to ensure
the device’s safety and effectiveness
– Life-supporting or life-sustaining devices
– Heart valves, pacemakers, breast implants, stents
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• For a “Me Too” device – 510(k) Notification
– Manufacturer must show substantial equivalence to already marketed device.
• For a new device – Pre-market Approval (PMA)
– Manufacturer must show safety and effectiveness of new device.
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Substantial Equivalence
• A device is found substantially equivalent (SE) if, in comparison to a legally marketed device, it: – Has the same intended use, and – Has the same technological characteristics as the
pre-existing (predicate) device; or – Does not raise new questions of safety and
effectiveness, or demonstrates equal safety and effectiveness
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• Premarket Approval (PMA) requires – Valid Scientific Evidence showing safety and
effectiveness
---------------------------- • External Devices
• Implanted Devices ----------------------------
• Devices for Acute Care (short-term use) • Devices for Chronic Care (long-term use)
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• Imaging (X-ray, CT, MRI) • DNA-base diagnostics; POC devices • Cardiac marker-base diagnostics
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• Monitoring Devices
– Determine the progress of therapy and the state of the patient in response to therapy
– Examples • Blood pressure • ECG • Blood oxygen monitor
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• Therapeutic Devices
– Change structure and function of the biological system to alter the course of disease
– Examples • Pacemakers
---------------------------- • External Devices
• Implanted Devices ----------------------------
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Most Advanced Technologies=
Heart failure Cardiac resynchronization systems (CRT)
Arrhythmias Pacemakers
Disease management Internet-based information technology system
For full safety information, visit medtronic.com
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Acute tibial fractures Bone morphogenetic proteins
Fixation Systems
Aortic disease Implantable stent grafts
Heart valve disease Artificial valves
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Chronic pain Implantable neurostimulation systems, drug-infusion systems
Hydrocephalus Implantable shunts (cerebrospinal fluid)
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Overactive bladder/urinary retention Implantable sacral stimulation systems
Enlarged prostate Radio frequency ablation systems
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Diabetes
Disease management Internet-based information technology system
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BIOmaterials
time
bioMATERIALS
BIOMATERIALS
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Drugs
Biologics
Devices
•Steroid eluting pacemaker
•Drug eluting stents
• Transdermal patch for ADHD
• Transdermal patch for Depression
• Inhaled insulin for diabetes
• Surgical mesh with antibiotic coating
• Dermal iontophoresis system
Prosthetic Heart Valve
• A prosthetic (artificial) heart valve is a replacement for a diseased or dysfunctional heart valve.
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•Heart Pump: Atrial contraction (RA/LA->RV/LV)
Ventricular contraction (RV/LV->Lung/Body)
When is it used?
• Two conditions that may require a heart valve replacement are – Stenosis (smaller opening)
• Leaflets thicken or stiffen
– Regurgitation (incompetence) • Valve doesn’t close properly and blood leaks backward
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• Mechanical heart valves
• Biological heart valves
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– Occluder in restraining cage – 1960’s – Very durable, but suboptimal
hemodynamics
• Tilting disc valve – Single leaflet on a central strut – Good hemodynamics
• Bileaflet valve – Two leaflets rotate on pivots
St. Jude medical
Mechanical Heart Valves • Advantages
– The main advantage of mechanical valves is high durability. They usually last a lifetime.
• Disadvantages – Mechanical heart valves can increase the risk of blood
clots. Because of this, patients must take anticoagulant (blood thinners) for the rest of their lives.
– Even though blood thinners are relatively safe, they do increase the risk of bleeding in the body.
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calcification) – Sewing ring provides structural stability – Some hemodynamic issues
• Stentless – Primarily made from aortic valves – Implanted on native valvular annulus w/o
a sewing cuff – Provides native anatomical and
hemodynamic profiles Medtronic Freestyle ®
– Less prone to thromboembolism. Anticoagulant therapy is generally not necessary.
• Disadvantages – Biological heart valves may wear out over time. They may
need to be replaced every 10 to 15 years.
– Calcification can be a problem. (More with young patients.)
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– Valve housing • CP Ti (grade 4), PyC coated cage,
Co-Cr alloys
(W doped graphite)
• CP Ti • All α-Ti (HCP) • ~99% Ti with O
• Grade 1 ~ 4 according to O content (0.18 ~ 0.4 %).
• Oxygen has a great influence on yield/fatigue strength and corrosion resistance, with acceptable ductility.
Properties Grade 1 Grade 2 Grade 3 Grade 4
Oxygen (w/o) 0.18 0.25 0.35 0.40
Tensile strength (MPa) 240 345 450 550
Yield strength (MPa) 170 275 380 485
Elongation (%) 24 20 18 15
Area reduction (%) 30 30 30 25
Oxygen Concentration and Mechanical Properties of CP Ti
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• Co-Cr Alloys • 2 major areas of use for the Co-Cr alloys are orthopedic
(prosthetic replacements, fixation devices) and cardiovascular (heart valve).
• Good corrosion resistance and mechanical properties • Co-Cr-Mo (F75, F799)
– Vitallium (Howmedica), Haynes-Stellite (Cabot), Zimaloy (Zimmer)
– Good corrosion resistance in chloride environment – Orthopedic, Dental
• Co-Ni-Cr-Mo (F562) – MP35N (SPS Technologies) – High strength/corrosion resistance – Good fatigue strength – Cardiovascular (stents)
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Pyrolytic Carbon • Similar to graphite, but with some covalent bonding
between its graphene sheets: disordered wrinkles and distortions within layers improved durability
• Belongs to turbostratic carbons • Produced by heating a hydrocarbon nearly to its
decomposition temperature, and permitting the graphite to crystallize (pyrolysis).
disordered
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of hydrocarbon (fluidized bed process)
– Coated on graphite • Pyrolysis takes place at high temperature
• Thermal expansion match
• Thromboresistant (i.e. resistant to blood clotting) – not perfect (still needs anticoagulant)
• Good durability
Pyrolytic Carbon
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• PET (polyethylene terephthalate) – High melting (Tm=260C) crystalline polymer – High tensile strength (~70 MPa) – Dacron® is a common commercial PET
• Available as woven fabric, knit graft
• PTFE (poly-tetrafluoroethylene) – PE with 4 H’s replaced with F’s – High melting (Tm=325C) polymer – Very hydrophobic and lubricious catheter, graft – Teflon®
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Aortic/Mitral
– Valve • Porcine valves or Bovine pericardium • Entire porcine aortic root and aorta
(stentless) • Stiffened with glutaraldehyde (less
calcification, stable collagen cross- links)
– Sewing ring/skirt • Wire: Co-Ni alloy, Ni-Ti alloy • PET (Dacron), PTFE (Teflon)
Materials in Biological Heart Valves
•Most commonly used materials
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Percutaneous Valves • Still in early stage of development or infant clinical studies • Ability to be delivered to the heart using traditional cardiac
catheterization techniques (balloon catheter), through femoral artery (retrograde) or cardiac apex (anterograde).
• Heart does not need to be arrested during the operation – no need to use a bypass pump.
Edwards Transcatheter Valve
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What Does it Take to Get a Surgical Valve to Market?
• Pre-Clinical In Vitro Testing (ISO 5840, FDA HV Guidance): – Hydrodynamic Performance Assessment
– Structural Testing/Analysis
– Material Assessment—biocompatibility, material property testing
• Pre-Clinical In Vivo Testing (ISO 5840, FDA HV Guidance): – Chronic animal study
• Clinical Study (ISO 5840, FDA HV Guidance): – Non-randomized study against objective performance criteria compiled
from currently marketed heart valves.
– Study not designed to show superiority, but rather safety/effectiveness against currently marketed valves.
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• ΔP vs. Q
– Flow Visualization to assess flow patterns through valve
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• Valve Durability Test (Accelerated Wear) – 200x106 cycles simulate five years implant
duration (tissue valves) – Performed at 10-15x physiologic heart rate – Periodic hydrodynamic testing and visual
examination is performed – Valve wear characteristics are compared to
clinically approved reference valve
• Valve Stent Structural Assessment – Finite Element Stress Analysis (FEA) – Fatigue analysis – Valve stent fatigue and creep testing
Leaflet Tearing--Pericardial valves
– “Control” animals implanted with clinically-approved reference heart valves for comparison
– Hemodynamic performance • Mean/peak pressure gradients,
effective orifice area, regurgitation, etc.
– Assess biological response to device
• Pathology, blood work, calcification, thrombus assessment
Biomaterials in Medical Devices
Metallic Biomaterials
Issues of Biomaterials in Medical Devices
Cont’d
In Vivo Tests
Mechanisms of Biomaterial Breakdown
Definition of a Medical Device(by US FDA)
Classification of Medical Devices(by US FDA)
Getting a Device to Market
Substantial Equivalence
Premarket Approval
Classification of Medical Devices(by EU)
3_Valves.pdf
Mechanical Heart Valves
Mechanical Heart Valves
Biological Heart Valves
Biological Heart Valves
Pyrolytic Carbon
Pyrolytic Carbon
Pyrolytic Carbon
Percutaneous Valves
What Does it Take to Get a Surgical Valve to Market?
Pre-Clinical Hydrodynamic Test
Pre-Clinical Structural Test

biomaterials in medical devices

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