failure analysis for update

Michael N. Helmus, Ph.D., Consultant
mnhelmus@msn.com
Failure Analysis: Reevaluating Functional
Requirements of Medical Devices
Invited Speaker, “Failure Analysis: Reevaluating Functional Requirements of
Medical Devices”, Opportunities for Next Generation Medical Devices,
Aug 5-7, 2008, Cleveland Clinic and ASM International.
New devices require diverse skills while utilizing biocompatible, biomechanical,
bioactive, & nanoenabled mat'ls. http://tpx.sagepub.com/content/36/1/70.full.pdf+html
These disruptive technologies will drive personalized medicine.
http://www.iscpubs.com/Media/PublishingTitles/a0306hel.pdf Understanding the design
process & failure analysis will facilitate & accelerate medical device development (M. N.
Helmus, "Biomaterials in the design and reliability of medical devices", Kluwer & Landes
Bioscience, 2003).
Let me help you with your development efforts (contact me for a special
one day rate during Dec. 2010 ).
cell (508) 269 6021 fax (508) 519 6140
mnhelmus@msn.com
Medical Devices, Biomaterials,
Drug Delivery, and Nanotechnology
(508) 767 0585

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Agenda
• Introduction: Failure with focus on Materials and Design
• Biologic Reactions and Biocompatibility
• Biologic Issues
• Explant analysis paradigm
• Failures
• Personal anecdotes
• Commercial products
•Emerging Technologies and New Failure Modes

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The Wall Street JournalThe Wall Street Journal
Fri. Aug 22, 2003Fri. Aug 22, 2003
Need for joint replacements at younger ages!

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M. N. Helmus, ed., "Biomaterials in the design and reliability of medical devices", Kluwer
Academic/Plenum Publishers and Landes Bioscience, NY, NY and Georgetown, TX, 2003.
BiocompatibilityBiocompatibility

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FAILURE ANALYSIS AND THE
MEDICAL DEVICE VALUE CHAIN
Bench/
Anim
al
Testing
D
istribution
Clinical
Application
Com
ponents/
D
evices
Clinical
Trials
RawM
aterials
Technology Medicine
Develop IP Strategy: Composition of Matter Applications
File IP
Redesign Redesign Post Market Surveillance
Redesign

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Commercializing Technology
Medical Centers
Investors
Physician
IP Uncertainties
Competition
Resource
Limits
Regulatory
barriersReimbursement
Limited life-cycle
Technical Challenge/FAILURE

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Endovascular
Peripheral Grafts
ePTFE Vascular Graft
Textile Vascular Grafts
Collagen Coated PET
Heart Valves
Annuloplasty rings
Scaffolds for
Tissue engineering
Mesh
for Hernia Repair
Biomaterials in Devices
Coils
Brain Aneurysms
Prosthetic joints
Bone repair - bone plates
Vertebroplasty -
Bone cement filling of
Compressed vertebrae
Implantable
Defibrillator

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Materials Selection Guide
Identify:
• Predicate Devices
• Corporate/Institutional Predicate Devices, Testing, and
Regulatory Approvals (510(k)s, PMA’s, and NDA’s)
• Corporate/Institutional Guidelines, Procedures and Protocols
• FDA Guidelines, CEN Guidelines, and
Standards (ASTM, ANSI, ISO)
• Corporate/Institutional R&D Reports
• Materials, Uses, Properties, ASTM and ISO Standards
Develop an Approach for Selection and Testing
M. N. Helmus, ed., "Biomaterials in the design and reliability
of medical devices", Kluwer Academic/Plenum Publishers
and Landes Bioscience, NY, NY and Georgetown, TX, 2003.

mnhelmus@msn.com
MATERIALS SELECTION IN
DEVICE DESIGN AND TESTING
Functional Requirements
Prioritization of Requirements
Brain Storming
Medical Literature and Patents Non-Medical Literature and Patents
Networking
Design and Processing Approaches
Predicate Devices/Tissue/and Cell Processing and Failure Modes
Corporate/Institutional 510(k)s, PMA’s, NDA’s, Tissue transplants

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Identification of relevant standards/ guidelines and Test Methods
Corporate/Institutional Guidelines, Protocols, and Master Files
Regulatory: FDA, CEN
Standards Organizations: ISO, ANSI, AAMI, ASTM
Biomaterials, Scaffolds, Tissue, and Cell/Tissue Selection and Processing:
Requirements
Biomechanical, Physiochemical, Surface, Durability, Biostability, Biocompatibility,
Immunology (autografts, allografts, xenografts, and cellular engineering), Viability and
Thromboresistance
Approach 1 Approach 2 Approach 3 Approach 4
Prototype Component Modeling/Processing and Testing
New Materials and Processes - Yes
Existing Data - No
Determine Sterilization/Antimicrobial Methods and Testing
Biocompatibility Screening

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In Memory of Oscar Ratnoff
Hageman Factor (FXII) and Clotting Cascade
“Failure”of Blood to Clot in a Glass Tube
New Understanding
For Biomaterials and
Blood Contacting
Devices

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M. N. Helmus, ed., "Biomaterials in the design and reliability
of medical devices", Kluwer Academic/Plenum Publishers
and Landes Bioscience, NY, NY and Georgetown, TX, 2003.

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ISO 10993-1
ISO 10993-2
ISO 10993-3
ISO 10993-4
ISO 10993-5
ISO 10993-6
ISO 10993-7
ISO 10993-8
ISO 10993-9
ISO 10993-10
ISO 10993-11
ISO 10993-12
ISO 10993-13
ISO 10993-14
ISO 10993-15
ISO 10993-16
ISO 10993-17
ISO 10993-18
ISO 10993-19
ISO 10993-20
Guidance on selection of tests
Animal welfare requirements
Tests for genotoxicity, carcinogenicity, and reproductive toxicity
Selection of tests for interactions with blood
Tests for cytotoxicity: In vitro methods
Tests for local effects after implantation
Ethylene oxide sterilization residuals
Withdrawn: Clinical investigation of medical devices
Evaluation of biodegradation of medical devices
Tests for irritation and sensitization
Tests for systemic toxicity
Sample preparation and reference materials
Identification and quantification of degradation products from polymers
Static test to quantify in vitro degradation of ceramics
Identification and quantification of degradation products from metallic materials
used in medical devices
Toxicokinetic study design for degradation products and leachables
Glutaraldehyde and formaldehyde residues in industrially sterilized medical
devices
Characterization of materials – EXHAUSTIVE EXTRACTION
Physico-chemical, morphological and topographical characterization of materials
Principles and methods for immunotoxicology testing of medical devices
INTERNATIONAL STANDARDS FOR MEDICAL DEVICES

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Biocompatibility Issues of Biomaterials
Synthetic Plastics, Engineering Plastics, Textiles, and
Hydrogels
• Extractables
• Hypersensitivity reactions (e.g. latex materials)
• 2 part systems and cytotoxic residuals
• Lipid uptake
• Hydrolytic stability
• Biostability
• Biodegradation by-products
• Calcification
• Sterilization residuals
• Fatigue and wear particulates
• Protein adsorption: hydrophilic, hydrogel and hydrophobic
M. N. Helmus, D. F. Gibbons, D. Cebon, "Biocompatibility: Meeting a
key functional requirement of next-generation medical devices”,
Toxicol Pathol 36 (1):70-80, 2008

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Guidance for Industry and FDA Staff - Saline, Silicone
Gel, and Alternative Breast Implants
Document issued on: November 17, 2006
This document supersedes “Guidance for Saline,
Silicone Gel, and Alternative Breast Implants” dated
February 11, 2003.
The draft of this document was issued on January 13,
2004.
http://www.fda.gov/cdrh/ode/guidance/1239.html

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A design that considers rupture to be
inevitable in trauma would suggest that
a gel-like filler in any mammary prosthesis
must be inherently biocompatible.

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Biodegradation
An alteration of the biomaterial or medical device
involving loss of integrity or performance
in a physiological or simulated environment.

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Example Biostability
Polyurethanes
Poyesterurethanes - hydrolytically unstable
Polyetherurethances – ofter grades prone to oxidative
enzyme degradation, e.g. 1) acute inflammation, 2) metal
ion catalyzed in pacer leads
Polyureaurethanes - generally stables, high fatigue life, not
thermally processable, I.e. solution cast
Polycarbonate urethanes - generally stable, low level of
hydrolytic degradation possible.

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M. N. Helmus, ed., "Biomaterials in the design and reliability of medical
devices", Kluwer Academic/Plenum Publishers and Landes Bioscience, NY,
NY and Georgetown, TX, 2003.

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Biodegradables
• Rate of biodegradation
• Surface vs. bulk
• Particulates
• Biodeposition
• Tissue partitioning and excretion
• Effect of infection (acidic pH) or hematoma (basic pH) on
degradation rates

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BBiioollooggiiccaallllyy DDeerriivveedd MMaatteerriiaallss:: AArrtteerriieess,, vvaallvveess,, sskkiinn,,
dduurraa--mmaatteerr,, bboonnee,, lliiggaammeennttss
• Decellularization processes
• Viability of cells in fresh or Cryopreserved Allografts
• Cytotoxic preservatives
• Cross-linking
• Sterilizability and residuals
• Biodegradation
• Calcification
• Immune responses
• Biomechanical properties
• Infectious contamination- bacterial, viral, fungal, and
prion

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Bioderived Macromolecules: eg albumin, Chitosans,
collagen, gelatin, elastin, fibrin, hyaluronic acid,
phospholipids, silk
• Purity
• Extractables
• Hydrolysis & Biodegradation
• Hypersensitivity reactions
• Lipid uptake
• Calcification
• Inflammatory and immune responses
• Permeability
• Water content
• Degree of cross-linking
• Effect of cross-linking on inflammation, immune response, and
thrombogenicity

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Tissue and BiomoleculesTissue and Biomolecules
Collagen
Impregnated
Vascular GraftPericardial
Heart Valve
Uterine Sling -Repliform ® Tissue
Regeneration Matrix, human dermis
architecture with cells removed

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Typical Bioprosthetic Failure Modes
Pericardial (stenosis)
Porcine (insufficiency & stenosis)
MN Helmus & CM Cunanan, “Mechanical and Bioprosthetic Heart Valves”,
in Biomaterials for Artificial Organs, Woodhead Publishing, in Press 4Q 2010

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1 7,008,591 Supercritical fluid extraction process for tissue preparation
2 6,964,682 Heart valve holder that resist suture looping
3 6,945,997 Heart valves and suture rings therefor
4 6,837,902 Methods of making bioprosthetic heart valves with strain matched leaflets
5 6,585,766 Cloth-covered stents for tissue heart valves
6 6,413,275 Apparatus for testing bioprosthetic heart valve leaflets
7 6,245,105 Method of testing bioprosthetic heart valve leaflets
8 6,102,944 Methods of tissue heart valve assembly
9 5,961,549 Multi-leaflet bioprosthetic heart valve
10 5,928,281 Tissue heart valves
11 5,880,242 Nonpolymeric epoxy compounds for cross linking biological tissue and
In Memory of Ralph Kafesjian
An engineer and innovator in
Heart valve design

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Failure Analysis
Bioprosthetic Valve: Stuck leaflets
Pericardial Heart valve removed shortly after
implantation
Leaflets stuck together
Surgeon (outside US) suggested patient had
antiphospholipid syndrome
- Coagulation resulted in stuck leaflets

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Failure Analysis Bioprosthetic Valve: Stuck leaflets cont.
Operating rooms notes documented the use of fibrin sealant on
the sewing ring to mitigate paravalvular leaking
Histopath on leaflets showed an acellular protein layer
PTAH staining was consistent with fibrin
Conclusion: fibrin sealant was responsible for the stuck leaflets

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Nature Medicine Published online: 13 January 2008
Perfusion-decellularized matrix: using nature's platform to engineer a
bioartificial heart
Harald C Ott1, Thomas S Matthiesen2, Saik-Kia Goh2, Lauren D Black3, Stefan M
Kren2, Theoden I Netoff3 & Doris A Taylor2,4
About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22
million individuals are living with heart failure. A bioartificial heart is a theoretical
alternative to transplantation or mechanical left ventricular support. Generating a
bioartificial heart requires engineering of cardiac architecture, appropriate cellular
constituents and pump function. We decellularized hearts by coronary perfusion with
detergents, preserved the underlying extracellular matrix, and produced an acellular,
perfusable vascular architecture, competent acellular valves and intact chamber
geometry. To mimic cardiac cell composition, we reseeded these constructs with
cardiac or endothelial cells. To establish function, we maintained eight constructs for
up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By
day 4, we observed macroscopic contractions. By day 8, under physiological load and
electrical stimulation, constructs could generate pump function (equivalent to about
2% of adult or 25% of 16-week fetal heart function) in a modified working heart
preparation.

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Malone, J, et al, 1984
Acelullar vascular matrix
Was proposed as a
Vascular prosthesis
Early 1980’s

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Evaluation for potential immunogenicity
2nd
set rejection study in Baboons
acellular canine carotid artery implanted in
baboon carotid for 3 weeks
accellular canine carotid implanted in
contralateral baboon carotid
Histopath evidence of immune response

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Explant analysis paradigm
Implant History—Device, Patient/Animal, Medication (Pre-,
Peri- , Postoperative), Patient History, Removal history
(revision, autopsy), Gross Photographs in
situ and after removal (keeping device moist with saline
and limiting time of exposure to air). Blood contacting
devices can result in embolic episodes and
organs such as the brain, lungs, and kidneys are
particularly important to evaluate for infarcts. Device
removal and handling as described below.

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Biologic Analyses – An Overlooked component of expant analysis
M. N. Helmus, ed., "Biomaterials in the design and
reliability of medical devices", Kluwer Academic/Plenum
Publishers and Landes Bioscience, NY, NY and
Georgetown, TX, 2003.

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Material Properties

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Passive Coatings: eg Albumin, diamond-like,
fluorocarbons, hydrogels, PVD, CVD
• Adherence
• Wear
• Flaking
• Uniformity
• Sterilizability
• Shelf-life
• Durability
• Biostability
• Extractables
• Hypersensitivity
• Lipid uptake
• Calcification
• Fatigue

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Bioactive Coatings (heparin, antimicrobials, cell adhesion
peptides, surface charge) and Tissue Adhesives ( Collagen,
cyanoacrylates, fibrin glue, PEG)
• Degree of antithrombogenicity, cell adhesion & tissue binding
• Biostability
• Wear & Durability
• Uniformity
• Sterilizability
• Microbiologic contamination
• Shelf-life
• Calcification
• Immune responses
• Residuals
• Tissue Adhesives
- Purity
- Filtration sterilization
- Cure time
- Tissue Adhesion

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Heparin Release Coating CVC Catheters
US5447724
Medical device polymer
HELMUS MICHAEL N; TOLKOFF M JOSHUA;
RALEIGH CAROL L
HARBOR MEDICAL DEVICES INC

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2.4x10-4
mg/cm2
/hr

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Case Study: Processing and heparin release
Particulate heparin in a polyurethane
Release rate decreased (springtime on Atlantic coast)
Reformulated to increase release rate
Product released.
Reports of Hematoma. (Fall season)

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Processing and heparin release cont.
In the spring, the humidity increased causing
precipitation of the urethane during drying,
decreasing release rate.
Reformulated during the summer.
When fall came and dry weather, no precipitation
and release rate increased resulting in too high a
localized heparin concentration.

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Biocompatibilty of Coating
Coating concentration Cytotoxicity – Cell
Culture
Rabbit Intramuscular
Implant
0% No Biocompatible
.005% Not tested Biocompatible
.1% Yes Biocompatible
.3% Not tested Biocompatible
.5% Yes Necrosis
1.5 Yes Necrosis
Helmus, Michael N., Scott, Michael J., Enhanced Biocompatibility Coatings for Medical Implants,
WO99/38547, Aug. 5, 1999

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Intramuscular Rabbit Implants 7 days
Coating concentration > 0.5% DurafloTM
Necrosis and increased host response compared to uncoated controls
Coating concentrations< 0.3 %
Biocompatible
Helmus, Michael N., Scott, Michael J., Enhanced Biocompatibility Coatings for Medical Implants,
WO99/38547, Aug. 5, 1999
Ex Vivo Canine Shunt
100 ml/min flow
Bioactive Heparin Coatings

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Metals and Metallic Alloys
• Passive layer durability
• Corrosion - pitting, fretting, stress
• Corrosion by-products
• Fracture toughness
• Fatigue life
• Stiffness compared to application
• Porous coatings
• Noble metal protein interactions;
• Antimicrobial activity, eg. Ag, Cu
• Wear
Ceramics, Inorganics, and Glasses
• Bioactivity and Degree of bone formation
• Bioresorption rate
• Biostability

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Carbons: Pyrolytic, Ultra low temp. isotropic
• Wear resistance
• Biostability
• Low heat of protein adsorption
• Thromboresistance
• Fatigue
Composites: Carbon fiber, nanoparticles,
radioopacifiers
• Surface exposure of compounded particles
• Extractables
• Residuals
• Lipid uptake
• Hydrolytic stability
• Biostability
• Calcification
• Fatigue and particulates

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Issues:
• Stress transfer, sites of highest static and impact stress
• Conformal bearing surface – adhesion & abrasion, particles < 1 micron,
osteolysis eg Total Hip
• Non-conformal, hi contact stress exceeding strength of UHMWPE ,
subsurface delamination, pitting, fatigue cracking, particles 2-20 microns,
eg Total Knee
• Abrasion of acetabular cup
• Effect of gamma/ebeam sterilization on UHMWPE
• Carboxyl formation
• Fatigue life of metal stem
• grain size, inclusions, wrought vs cast, surface defects
• Fatigue life of bone cement
• formulation - initiator in polymer beads vs monomer
• voids, inclusions, poor adhesion to stem poor filling of bone
surface

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Issues:
• Prosthesis loosening
• Noncalcified tissue adjacent to cement leading to
micromovement and loosening leading to stem
fracture
• mechanical injury to bone during bone cement
and stem placement
• chemical toxicity of monomer (PMMA)
• thermal injury due to exothermic reaction
• hypersensitivity to bone cement
• surgical technique in removing blood and debris
in order to improve penetration into bone

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Issues:
• Particles of cement leading to wear of ball and cup
• cement particles and wear particles leading to excessive
inflammation and bone resorption – particles < 1 micron
•Diffuse cytoplasmic birefringence
•Citation – T. P. Schmalzried, et al, J Applied
Biomaterials, Vol. 5, 185-190 (1994)
• Infection leading to bone resorption

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Materials’ Standards for Medical ApplicationsMaterials’ Standards for Medical Applications
ASTM Standards for Materials forASTM Standards for Materials for
Medical DevicesMedical Devices
Example -Example - F 2063 – 00 Standard
Specification for Wrought Nickel-Titanium
Shape Memory Alloys for Medical Devices and
Surgical Implants

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9.2 Non-metallic Inclusions and Porosity:
9.2.1 For all mill products, porosity and nonmetallic
inclusions such as Ti4Ni2Ox and TiC particles shall be no
larger than 12.5 µm (0.0005 in.). Furthermore, porosity and
nonmetallic inclusions shall not constitute more than 1.0 %
(area percent) of the structure as viewed at 400X to 500X in
any field of view.

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SEM to
demonstrate
Ti2Ni(Ox)
Inclusion At
Origin Of Wire
Fracture
Bend ductility and fatigue endurance limit were negatively
impacted by the presence of Ti2Ni(Ox) inclusions

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Since the failure had occurred
in the cabin area,
engineers did a huge
fatigue test of an actual
airplane. They varied the
cabin pressure
hydraulically while they
flexed the wings. After
three thousand pulsations,
a crack appeared near a
cabin window and quickly
spread. http://www.uh.edu/engines/epi1773.ht
m
http://www.rafmuseum.org.uk/hendon/exhibiti
ons/comet/comet5.cfm
Life Analysis – Comet Jet Experience

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B.A.J.704 M. de Mol et al. “Non-destructive assessment of 62
Dutch Bjork-Shiley convexo-concave heart valves”
European Journal of Cardio-thoracic Surgery 11 (1997) 703–709
L. E. Eiselstein and B. James, “Medical Device Failures—
Can We Learn from Our Mistakes?” Proceedings from the Materials &
Processes for Medical Devices Conference, M. Helmus, D. Medlin eds.,
August 25–27, 2004

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Replacement Heart Valve Guidance - Draft Document 10/14/94
• http://www.fda.gov/cdrh/ode/3751.htm
l
Replaced by new draft guidance:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm193096.htm

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Medical Mess: Implants in Jaw Joints Fail,
Leaving Patients In Pain and Disfigured
Teflon-Coated Disk Seemed A Boon for TMJD at First
But Had Little Testing
Bruce Ingersoll and Rose Gutfeld
Staff Reporters of The Wall Street Journal
August 31, 1993
-TMJ disorders : arthritis, jaw and facial pain,
headaches, earaches, clicking sounds in the jaw, and
restricted movement.
-The prosthesis was used to replace an oval disk of
cartilage
Image:
http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/2007091
6/Jaw_implants_070916/20070916?hub=Canada

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-Prosthesis: 2 layers laminated together - a thin sheath
of FEP & a wafer of highly porous Proplast: PTFE, and
carbon or aluminum oxide.
-Couldn't withstand the wear and tear of the lower jaw
sliding & some cases, it disintegrated within a few
months.
-1974 : implants from sheets of laminated Proplast/FEP
used to cover the tips of jawbones in TMJD patients.
-1979, sponge-like Proplast was endorsed by the
professional society of Oral and Maxillofacial Surgeons
as the "living implant" because human tissue could
grow into its pores.

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-Reported results of 50 jaw implants: "marked pain
relief and restoration of jaw movement," according to
a press release.
-Never tested in animal jaws before marketing.
Company took the position that there was no way to
reproduce in a lab animal what happens in the human
TMJ.
-No human trials.
-Tests were done on a mechanical simulator that
imitates the human jaw.
-Company did not test Proplast and FEP together, as a
laminated product

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-Simulator testing in an academic lab: sliding back and
forth over the prosthesis with 20 pounds of force, wore
through the FEP surface into the Proplast backing 100 to
200 times fasted than the wear-rate reported by the
company.
-Fractured the thin FEP layer, scattered microscopic
particles.
-Predicted "service life" of only one to three years.
-The company did wear-testing: FEP with a metal backing
that didn't give way under the 20-pound load. Not a realistic
test.

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-Only after reports failure began in around 1984 were animal
studies done. .. in dogs.
-FEP layer was "completely worn" and particles had
triggered bone erosion in the dogs after a few
months.
-Company contended the test showed mainly that the dog
wasn't a good test animal to use.
-A study at the University of Minnesota dental school in
monkeys.
-Proplast/FEP began to fragment after a year, causing
"severe degenerative joint changes

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Preclinical Efficacy and Safety Testing (Regulatory
Guidelines)
Animal implantation for function and durability
Efficacy measure, e.g. repair, functional
measurement
- In vivo methods - Radiology, NMR, Echo,
Nuclear Medicine, Assays of Blood
- Explant analysis
-- Device analysis: physical and surface
-- Organ function and Viability
-- Tissue histopathology
Clinical Evaluation (Regulatory Guidelines)

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Disruptive Technologies – New Failure Modes
Drug Delivery
Therapeutic Polymers
Bioresorbables
Tissue Engineering
Stem Cells
Smart Materials
Imaging, eg Molecular Imaging
Genomics
Proteomics
Glycomics
Computation
NanoStructures
MEMS

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Coronary Artery Disease: Drug Eluting Stents
1970’s - 1980’s Bypass Surgery
1980’s Angioplasty
1990’s Stenting (The
Problem: Instent
Restenosis)
2000’s Drug Eluting Stents
J. Biomed. Mater. Res.
71A:625-634 (2005)
www.heartsurgery-usa.com/On_Pump_
Surgery/body_on_pump_surgery.html
www.nlm.nih.gov/medlineplus/
ency/presentations/100160_5.htm
www.stormontvail.org/heartcenter/patient
_ed/ptca.pdf
Current Controversial Issues:
Delayed endothelial Healing and Late Thrombosis

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Proposed Solutions
- Biodegradable Coatings
-Rapidly degradable coatings and Abluminal coatings
- New Polymeric Carriers (eg ampiphilic polymers; fluorocarbon
copolymers)
- Nonpolymeric carriers, eg porous and nanoporous Ceramics
- New pharmaceuticals for drug delivery coatings
- Bioctive coatings for enhanced healing
-RGD, cell adhesion proteins, GAGs, Heparin Sulfates, Biomimetic growth factors
-Endothelial progenitor and stem cell capture (eg antibodies)

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Adverse Publicity of Nanotechnology
THE DOWNSIDE OF NANOTECHNOLOGY Boston Globe
November 28, 2005
…Yet the very characteristics that make nanomaterials so promising are also sources
of concern about their environmental and health risks. History is littered with
technologies that once seemed benign but were discovered years later to have
devastating effects on the environment. Examples include the pesticide DDT,
marvelously effective at killing insects, but also, it turned out, lethal to birds of prey like
eagles, falcons, and osprey. ...
…But while the ability of some nano particles to pass through a cell could lead to
breakthroughs in cancer or Alzheimer's treatment, these same features can pose
environmental and health risks. Preliminary studies have shown that some
nanomaterials are able to damage skin, brain, and lung tissue. …
Nanotubes found to be as risky as asbestos
May 21, 2008
The original article is cited on the title only, and the content is ignored. It refers only to
multiwalled nanotubes fabricated to the same dimensions as asbestos, not nanotubes
that are being evaluated, for example, medical applications.
POLAND CA et al “Carbon nanotubes introduced into the abdominal cavity of mice show
asbestos like pathogenicity in a pilot study”, online Nature Nanotechnology, May 20, 2008

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Preclinical Safety Assessment for
Nanotechnologycont’d)
Our current system is expected to identify possible
hazard resulting from drug exposure, due to the
extensive pre-clinical evaluation of new drugs.
For nanotechnology drugs:
Are current required studies adequate? YES
Are new testing models needed? MAYBE
http://www.fda.gov/nanotechnology/ChBSA-nanotech-presentation06-04.ppt

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Example of
FDA guidance
covering
injectable
particles that
also pertain to
injectable
nanoparticles

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The Promise and the Challenge of Nano-enabled
technologies for Medical Applications
Enhanced functionality and biocompatibility
Potential new paradigms required for biocompatibility
and toxicity evaluations of nano-structures and particles

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Embryonic stem cells, Bone marrow & Endothelial precursor
cells
Replacing damaged myocardium and vascular tissues
Potential Failure Modes to Consider
Disease pathophysiologyand aging leading to dysfunction in
endogenous regenerative pathways
- Idiopathic dilated cardiomyopathy
- Atherosclerosis
- Myocardial Infarction
- Tumor angiogenesis
Stem Cell Therapies and Failure?

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To Engineer Is Human... Therefore,
Admiral Hyman G Rickover, father of
the nuclear navy,
“Basic Principles for Doing Your Job!”
M. N. Helmus, Details are Important,
nature nanotechnology VOL 2 | SEPTEMBER 2007
Ownership: “A person doing a job —
any job — must feel that he owns it
and that he will remain on that job
indefinitely. …
Responsibility: “Along with Ownership
comes the need for full acceptance
of full responsibility for the work.
Shared responsibility means that no
one is responsible.”
Attention to detail: “A tendency among
managers, particularly as they move
to higher positions, is to think they
no longer need to be concerned with
details. If the boss is not concerned
about details, his subordinates also will
not consider them important.”
Priorities: “If you are to manage your job,
you must set priorities. … You must
apply self-discipline to ensure your energy
is applied where it is most needed.”
Know what is going on: “You must
establish simple and direct means to
find out what is going on in detail in the
area of your responsibility.”
Hard work: “For this, there is no
substitute. ....”
Checking up: “An essential element of
carrying out my work is the need to have
it checked by an independent source.
…
Facing the facts: “Another principle for
managing a successful program is to resist
the natural human inclination to hope
things will work out despite evidence or
doubt to the contrary. […] If conditions
require it, one must face the facts and
brutally make needed changes despite
considerable costs and schedule delays.”

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