Working Group for BME Education in Innovation, Design and Entrepreneurship

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Working Group for BME Education in Innovation,
Design and Entrepreneurship

• Advisory Board Member Perspective
• Art Coury
• Genzyme Corporation
• Nashville, TN 10/01/03

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Advisory Board Memberships

• Boston University- BME Industrial Advisory Board
  
• Case-Western Reserve University-BME Industrial
  Advisory Board
• Duke University- BME Industrial Advisory Board
• Harvard/MIT- HST Graduate Committee
• UMASS Boston- Industrial Scientific Advisory
  Board

3
Contributions of Industrial Advisory Boards

• Advice on Curriculum
• Advice on New Programs, e.g., Masters Degrees
• Advice on Approaches to Fund Raising
• Interactions with Professors and Students (Board
  Meetings, Collaboration Opportunities,
  Internships, Co-ops)
• Recruiting Advantages
• Teaching (Courses, Seminars, Tours)
• Program Support (Donations, ABET Reaccreditation)
  

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Medical Device Development Quality Systems,
Standards, Design and Process Control

• Arthur J. CouryGenzyme CorporationCambridge,
  MA

Senior Projects in Biomedical Engineering Boston
University
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Biodegradation/Biostability of Biomaterials
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Biomaterials and Medical DevicesStatus and
Outlook

• Arthur J. Coury
• Genzyme Corporation
• Cambridge, Massachusetts
• BU
  9//24//03

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Overview of BiomaterialsPast, Present and Future

• Arthur J. Coury
• Genzyme Corporation
• Cambridge, Massachusetts

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Quality Systems

• In order to gain approval to market regulated
  medical devices, manufacturers must conform to
  the requirements of quality systems as mandated
  by regulatory agencies worldwide.
• Regulatory agencies worldwide are collaborating
  for the systematic harmonization of medical
  device regulations under the umbrella of the
  International Organization for Standardization
  (ISO).

FDA 21 CFR 820,30
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ISO Quality Systems

• The US Food and Drug Administration (FDA) which
  regulates medical devices has adopted major
  elements of the ISO quality standards
• ISO 9001 1994 Quality Systems Model for Quality
  Assurance in Design, Development, Production,
  Installation and Servicing
• ISO/DIS 13485 Quality Systems Medical Devices
  Particular Requirements for the Application of
  ISO 9001 (April, 1996)
• FDA 21 CFR 820.30

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Design and Development Planning

• Regulated device development requires a plan
  which describes activities and responsibilities
  of individuals and groups.
• The plan establishes tasks, timetables,
  resources, personnel, responsibilities,
  prerequisite information, interrelationships
  among tasks, deliverables and constraints.
• The plan provides for reviews to update and
  modify the schedule.
• Management support and oversight is required and
  helps ensure an effective planning process.

FDA 21CFR 820.30
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Definitions

• QUALITY- The totality of features and
  characteristics that bear on the ability of a
  device to satisfy fitness-for-use including
  safety and performance.
• QUALITY SYSTEM - The organizational structure,
  responsibilities, procedures, processes and
  resources for implementing quality management.
• DESIGN CONTROL - Element of quality system that
  provides the process to assure that devices meet
  user needs, intended uses and specified
  requirements.
• PRODUCTION/PROCESS CONTROL - Control of the
  manufacturing process so that devices
  consistently meet specifications.
• FDA 21 CFR 820,30

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Definitions

• SPECIFICATION - Any requirement with which a
  product, process, service or other activity must
  conform.
• VERIFICATION - Confirmation by examination and
  provision of objective evidence that specified
  requirements have been fulfilled (Performance
  Specifications).
• VALIDATION - Confirmation by examination and
  provision of objective evidence that the
  particular requirements for a specific intended
  use can be consistently fulfilled (Functional
  Specifications).
• FDA 21 CFR 820,30

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Definitions

• PERFORMANCE SPECIFICATIONS - Specify how much or
  how well the device must perform in quantitative
  terms (Basis for verification).
• FUNCTIONAL SPECIFICATIONS - Specify how the
  device meets user requirements in qualitative
  terms (Basis for validation).
• INTERFACE SPECIFICATIONS - Specify
  characteristics of the device critical to
  compatibility with external systems - ie user
  and/or patient interface and possibly other
  interfaces (Validated by clinical studies).
• PRODUCTION SPECIFICATIONS - Drawings and
  documents used to procure components, fabricate,
  test, inspect, install, maintain and service the
  device.
• FDA 21 CFR 820,30

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Device ClassesClass I - General Controls

• General Controls Requirements
• Company registration with FDA
• Medical device listing
• Good manufacturing practice conformance
• Submission of premarket notification (510K)
• Many Class I devices exempted
• Examples
• Elastic bandages, examination gloves, hand-held
  surgical instruments

www.fda.gov/cdrh/devadvice/3132.html
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Device ClassesClass II - Special Controls

• Special Controls Requirements
• Apply general controls
• Special labeling
• Mandatory performance standards
• Postmarket surveillance
• Etc.
• Examples
• Powered wheelchairs, infusion pumps, surgical
  drapes

www.fda.gov/cdrh/devadvice/3132.html
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Device ClassesClass III - Premarket Approval
(PMA)

• Support or sustain life, substantially prevent
  impairment of health or present a potential,
  unreasonable risk of illness or injury
• Require scientific review to ensure safety and
  effectiveness
• Can gain approval through premarket notification
  (510K) if substantially equivalent to devices
  marketed before May 28, 1976
• Examples
• PMA - Silicone-filled breast implants,
  prosthetic heart valves, implanted brain
  stimulators
• 510K - Implantable heart pacemakers, certain
  vascular grafts, endosseous implants

www.fda.gov/cdrh/devadvice/3132.html
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Design Control Regulations

• All Class II, III devices require design
  control. Most Class I devices are exempt except
  software automated devices, surgeons gloves,
  protective restraints, tracheobronchial suction
  catheters, radionuclide applicators and sources.

www.fda.gov/cdrh/devadvice/3132.html
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DESIGN INPUT - The physical and performance
requirements of a device that are used as a basis
for device design.

• Requirements include functional, performance and
  interface specifications.
• Design inputs should be comprehensive,
  unambiguous, self-consistent, realistic and
  appropriate.
• Design inputs are subject to modification during
  the development process.

FDA 21 CFR 820,30
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DESIGN OUTPUT - The results of a design effort at
each design phase and at the end of the total
design effort.

• Includes results of verification tests and
  conclusions regarding validation requirements.
• Total finished design output consists of the
  device, its packaging and labeling and the device
  master record.
• Device master record holds documents the device,
  packaging and labeling.

FDA 21 CFR 820,30
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Medical Device Development Protocol
User Need
Medical Device Concept
Proof of Concept
Preliminary Research (Discovery)
Development Project Initiation Under Design and
Documentation Control
Design and Development Planning
Design Input
Design Review
Design Output
Design Changes
Design Verification
Design Validation
Production Control
Design Transfer
Product Marketing
Product Servicing
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Project Description

• (H) Status
• As of Current Date

(A) Title (Project )

• (B) Project Coordinator(s)
• Technical
• Administrative

• (I) Issues
• Technical Barriers
• Competition
• Alternatives
• Logistics
• etc.

(C) Objective 1 or 2 Sentences

• (D) Rationale
• User Need
• Business Opportunity
• Improvements Over Competition
• Technical Feasibility

• (J) Resources
• Internal Staff (FTEs, Names, Function)
• Collaborators (Institution, Relationship)
• Major Space (Preclinical, Lab, etc.)
• Major Equipment

• (E) Approach
• Technical

• (K) Tasks
• Details of Science, Preclinical,
• Clin/Reg.

• (F) Functional Specs
• General Goals of Project
• (How user needs are met I.e. validated)

• (L) Cost Estimates
• Project Initiation to Product Introduction

• (G) Performance Specs
• Quantitative Requirements
• (Verified to fall within stated range)

• (M) Schedule
• Gantt Chart (Project Initiation to
• Product Introduction)

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Case Study

• Development of a sealant for use in
• lung surgery

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Project Description

• Title
• Development of a Lung Sealant
• Project Coordinators
• Technical - Leonardo DaVinci
• Administrative - Julius Caesar
• Objective
• To develop a sealant for sites on a lung
  undergoing resection which demonstrate
  intraoperative leakage or are at risk of
  post-surgical leakage.

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Project Description

• Rationale
• Lung resection surgery produces intra-operative
  air leaks in the majority of cases using standard
  techniques of closure such as staples and
  sutures.
• Lung air leaks often require extended use of
  percutaneous chest drainage, tubes and hospital
  stays until adequate healing occurs.
• Tumor resection and lung reduction surgery occurs
  at the rate of 400,000 worldwide, annually, and
  almost every patient would be a candidate for a
  treatment to assure pneumostasis intra or
  post-operatively.
• There is currently no intra-operative therapy for
  sealing or preventing leaks.
• We hypothesize that the use of a resorbable
  sealant applied intra-operatively will be
  technically feasible and reduce the time, pain,
  and costs associated with extended lung air leaks.

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Project Description
Approach

• Technical
• An adherent, bioresorbable hydrogel results
  from the use of a tissue primer and sealant
  topcoat which convert from fluid to solid form by
  a photopolymerization process. The resultant
  coating provides a barrier to prevent leakage
  while tissue healing occurs underneath. The
  composition resorbs by dissolution and clearance
  through normal metabolic pathways after
  appropriate healing assures a leak-free lung.

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Photocurable Hydrogels Macromer Based
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Vision for Interventional Therapeutics
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Macromer Structure
A Water Soluble/Biocompatible Core B
Biodegradable Moieties C
Photopolymerizable End Caps

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Formation and Degradation of Hydrogel
Micelles of Macromer in Solution
Acrylate Lactate PEG
Illumination
Crosslinked Hydrogel
Hydrolysis
Hydrolytic Dissolution of Hydrogel
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Visible Light Initiating System
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Hydrogel Sealant Application
Brush on Primer
Drip
Illuminate
Brush on Sealant
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FocalGelTM Customized Properties
Low
Days Low
Liquid Soft
Low Microns
Non-Adherent Seconds
High Months (Years) High Paste Hard High Centimet
ers Adherent Minutes

• Adherence to Tissue
• Degradation Time
• Drug Loading
• Stiffness
• - Macromer Formulation
• - Hydrogel Formulation
• Fatigue Resistance
• Thickness
• Cellular Attachment
• Cross-linking Rate

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Tissues to Which Strong or Moderate Acute
Bonding of Hydrogels was Achieved In-Vivo

• Lung Parenchyma
• Parietal Pleura
• Visceral Pleura
• Blood Vessels
• - Media
• - Endothelium-Denuded Intima
• Nerves
• Liver Capsule
• Liver
• Dura Mater
• Cortical Bone
• Mouth Floor

• Mucogingival Flap
• Ear Cartilage
• Articular Cartilage
• Epicardium
• Small Intestine
• Urinary Bladder
• Spleen
• Pelvic Sidewall
• Uterine Horn
• Kidney
• Pancreas
• Esophageal Muscularis

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Characteristics of Focal Hydrogels

• Formation
• In Situ Curable
• Can form in bulk or interfacially
• Can fill void or coat surfaces
• Conformal
• Biocompatibility
• Blood compatible
• Tissue compatible

• Physical Properties
• 95 water at equilibrium
• Transparent
• Adherent to moist tissue
• Drug loadable
• Degradation
• Degrades by dissolution,
• not fragmentation
• Moderate molecular weight,
• soluble products
• Bioresorbable

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Project Description
Functional Specifications(Provide Validation of
Conformance to User Needs)

• The sealant shall arrest or prevent leaks under
  the sites to which it is applied.
• The sealant shall allow healing to occur to the
  attached tissue so that subsequent leaks do not
  occur.
• The sealant shall not interfere with the normal
  function of the lung to which it is attached.
• The sealant shall be resorbed innocuously after
  performing its function.
• The sealant shall be biocompatible for its
  lifetime in the body.
• The sealant shall be easy to prepare and apply by
  practitioners functioning normally in the
  lung/surgery suite.
• The sealant shall be readily producible, storable
  and transportable under conditions available at
  source and destination.
• The sealant shall be cost effective to supplier
  and user.

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Preclinical Verification/Validation

• Examples
• The sealant shall arrest or prevent leaks under
  the sites to which it is applied (validation).
• 1. The sealant shall perform leak-free in the
  excised pig lung in vitro model for 18 hr,
  maintaining an adherence score of at least 3 out
  of 4 (verification).
• 2. The sealant shall seal the leaks produced
  from an imperfect staple line in the dog lung
  wedge resection model evaluated after 2 weeks
  duration (verification).
• 3. The sealant shall act as the sole sealing
  mechanism for a wound produced by resecting a
  lobe of a dog lung evaluated after 2 weeks
  duration. (verification).
• 4. The sealant shall effectively eliminate
  intra-operative leaks in human subjects where
  applied and shall, on average, reduce the time
  of post-operative chest drainage by 25 relative
  to controls.
• 5. Etc.

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Pre-Clinical Testing BURST STRENGTH - Rat
peritoneal tissue

FocalSeal Sealant 377.53 98.26 mmHg
Fibrin Glues 23.79 17.07 mmHg
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Pre-Clinical Testing TISSUE ADHERENCE - Porcine
lung tissue
FocalSeal Sealant 4.0
Fibrin Glues 1.0
Scoring System 0 Gel falls off when touched 1
Entire gel can be removed by lifting one edge 2
Peeling motion required to remove gel 3 Scraping
required to remove gel 4 Vigorous scraping
required to remove gel
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Control, 5 months Dog Lung Lobectomy
FocalSealR L, 5 months Dog Lung Lobectomy
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Preclinical Verification/Validation

• Examples
• The sealant shall not interfere with the normal
  function of the lung to which it is attached
  (validation).
• 1. The sealant shall be designed to have a
  Youngs modulus less than that of the
  expanding human lung (lt100KPa), and
  demonstrate an elongation in excess of the
  fully expanded human lung (gt300) (verification).
• 2. Etc.
• The sealant shall be biocompatible for its
  lifetime.
• 1. The sealant shall pass the ISO10993 test
  protocol for long term implants.
• 2. The sealant shall display, by histological
  examination, normal, viable tissue with only
  mild inflammation under the hydrogel and a thin
  or absent fibrous capsule around the hydrogel
  (verification).

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Comparison of Macromer-Based Hydrogels
Macromer Type
8,000 MW PEG
27,000 MW PEG
Viscosity Stiffness (vs Pig Lung) Elongation Lu
ng Adherence (18 hours fatigue test, 0-4)
Thick 1X 500 4
Fluid 3X 100 1
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Tensile Behavior of FocalSeal
200 150 100 50 0
Youngs Modulus
Stress 151.1 59.80 kPa Strain 768.5
255.2 mm/mm Modulus 29.4 kPa
Stress (Kpa)
200 400 600 800
Strain (mm/mm)
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Histology of FocalSeal Treated Dog Lung (14
Days)
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Definition

• Investigational Device Exemption (IDE)
• An IDE allows the performance of a clinical
  study with an investigational device in order to
  collect safety and effectiveness to support a PMA
  or a 510K submission. It requires Approval
  by an institutional review board (IRB) informed
  consent of all patients labeling for
  investigational use only monitoring of the
  study required records and reports.
• www.fda.gov/cdrh/deadvice/ide/print/index.htm
• Risk Management
• The systematic application of management
  policies, procedures and practices to identifying
  analyzing, controlling and monitoring risk.
  Methodologies include Preliminary hazard
  analysis (PHA) failure mode and effects analysis
  (FMEA) failure mode, effects and criticality
  analysis (FMECA) fault tree analysis (FTA)
  hazard analysis and critical control points
  (HACCP).
• www.devicelink.com/mddi/archive/98/10/011.html

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Definition

• Failure Modes and Effects Analysis
• A method of determining, before a product is
  introduced, potential failure modes, and their
  consequences. A typical approach involves
  weighting the failure modes according to the
  following equation
• Risk Priority Severity Occurrence
  Detectability
• Number (RPN) Rating X Frequency X Rating
• Number Rating Number
• (1-10) (1-10) (1-10)
• Maximum Effect 1000
• Minimum Effect 1
• Modes are prioritized in decreasing number order.
• Thresholds of concern are low for critical
  systems, higher for general
• systems.
• www.mines.edu/academic/courses/eng/EGGN491/lecture
  

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Project Description
Status

• The program has received management approval
  to initiate design control after preliminary
  proof-of-principle research has shown promise.
  Preliminary research results have been documented
  in technical reports. Technical and business
  program managers and members of the
  multi-disciplinary program team have been
  appointed. A project initiation meeting has been
  scheduled where signoff by management, the
  program managers and leaders of each discipline
  will take place. The design and development plan
  will then be formulated for approval.

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Project Description
Issues

• Technical Barriers
• The hydrogel coating must be shown to adhere and
  stop leaks for the projected two week healing
  time. Adhesion durability has not yet been
  achieved with known tissue coatings and
  adhesives. In order to be fully functional for
  two weeks, a degradation profile of months
  results. Long lasting devices require more
  extensive testing than subchronic devices.
• Competition
• Recently-approved fibrinogen/thrombin based
  products (fibrin glues) are being used as lung
  sealants. They are two-part liquids that
  solidify when mixed. While they do not perform
  well (the lung is fibrinolytic the product is
  stiff and does not adhere well), they have the
  feature of not requiring light to effect
  crosslinking. There are rumors that other
  companies are in early-stage development of
  sealants that do not require light to polymerize.

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Project Description
Issues

• Alternatives
• Alternatives to sealants for pneumostasis have
  included staples, sutures, talcum powder (causes
  adhesions of lung to thoracic sidewall) and chest
  tube drainage. Each has significant drawbacks in
  terms of healing, pain and hospital time
• Logistics
• We manufacture the polymerizable macromer
  in-house, but clinical studies require that the
  fill and finish process for the formulation be
  performed by a contractor. Scheduling and cost
  considerations will be important during advanced
  stages of development.
• Other Issues
• If the hydrogel barrier is not substantially
  resorbed within 30 days, it is considered a
  chronic device. Preclinical, clinical and
  regulatory strategies require more complex and
  extended testing.

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Project Description
Resources
Internal Staff

• Technical Coordinator Leonardo D. Vinci,
  Biomaterials Dept.
• Administrative Coordinator Julius Caesar,
  Business Development
• Polymer Synthesis Rep Pierre Curie, Process
  Development
• Analytical Rep Marie Curie, Analytical
• Regulatory Rep Alex Hamilton, Regulatory
• Clinical Rep Alex Carrell, Clinical
• Intellectual Property Clarence Darrow, Legal

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Project Description
Resources

• Collaborators
• Preclinical Studies - Professor Harry Houdini
  will collaborate on the use of his porcine lung
  resection model to establish pre-clinical safety
  and efficacy.
• Clinical Studies - The Universities of Peoria
  and Kalamazoo have been qualified by a team from
  clinical, QC, and regulatory departments to run
  the first pilot clinical trial.
• Major Space
• Section B of the chemical labs and section C of
  the analytical labs will be dedicated to this
  project. A 2000 square foot production facility
  will be needed to service advanced clinical
  studies and worldwide marketing. Cell culture
  and small animal facilities will be used as
  needed.
• Major Equipment
• For preclinical studies, polymer synthesis will
  take place in 20 liter scale glass reactors. The
  manufacturing plant will have, as its base
  reactor, a 100 gallon glass-lined steel system
  with full accessories and safety equipment. A
  dedicated HPLC and GC will be required for all
  stages.

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Tasks (2002-2003)

• Completion
• Initiate design control February, 2002
• Develop work plans March, 2002
• Synthesize polymer candidates June, 2002
• Screen polymers/formulations in vitro Sept. 2002
• Perform preclinical verification March, 2003
• Recruit clinical centers, patients March, 2003
• File IDE for pilot clinical trial March, 2003
• Perform pilot clinical trial December, 2003
• File IDE for pivotal clinical trial December,
  2003
• General tasks - more details in sub-categories

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Cost Estimates - Project Initiation to Product
Introduction

• Project 10051
• Project Title Lung Sealant Development
• Project Duration Feb., 2002 - May, 2006
• Projected Costs
• Year 2002 2003
  2004 2005 2006

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Senior Projects in Biomedical Engineering, Boston
University
Biomaterials and Tissue Engineering
Development, Manufacturing, Standards and
Quality Systems

• Problem
• A cardiac pacemaker system consists of a pulse
  generator (power source, circuitry, container,
  connector) and pacing leads (Figure 1). This
  very complex electronic device senses the
  electrical activity of the heart and responds,
  when appropriate, by delivering pulsed shocks to
  the heart to restore rhythm. Some pacemakers
  respond to body motion to modulate pulsed
  stimulation rate.
• The endocardial leads are critically important
  because they contact the heart (Figure 1
  illustrates an atrial J lead and a ventricular
  lead) and deliver the sensing signal to the pulse
  generator and the stimulation pulse from the
  pulse generator. The lead consists, minimally,
  of a conductor coil, distal electrode, proximal
  electrode with connector, insulation tubing and a
  mechanism to fix the distal electrode in the
  heart (e.g., a tine).
• (Figure 2). So that fibrous capsule formation
  around the distal electrode does not raise the
  stimulation or sensing threshold too high, some
  electrode designs contain an anti-inflammatory
  steroid reservoir for diffusion of drug to
  surrounding tissue (Figure 3) and some leads
  contain a suture sleeve for holding the lead to
  tissue (Figure 2).
• The lifetime of a pulse generator is usually
  defined by the battery it contains and may now
  reach 5-10 years. Pacing leads, ideally, would
  function for several pulse generator lifetimes
  since they fibrose into the vein and heart
  chamber in which they reside and are hard to
  remove.
• Materials of construction of the pacing leads
  shown consist of a platinum distal electrode
  (hollow or porous for drug delivery), a stainless
  steel
• crimp to hold the distal electrode to the
  MP35N, Co-Cr-Mo alloy conductor (lengthwise
  coiled wire), a proximal, crimped electrode with
  silicone connector for inserting into the
  pacemaker connector, a polyurethane fixation tine
  (distal), polyurethane insulation tubing and a
  thermoplastic polyethylene suture sleeve (Figure
  2).
• Questions
• 1. For the pacing leads of the device shown,
  describe six functional specifications.
• 2. For each functional specification, describe at
  least one performance specification. Pick a
  functional specification out of the six in which
  you describe three performance specifications.
  (Note the actual values you choose are not
  critical, although they should be reasonable.
  Understanding the concepts is most important.
• 3. Complete the analogy (Performance specs)
  (Verification) (Functional Specs) (?)
• 4. Perform an FMEA on the pacemaker lead for 5
  modes according to the handout. Refer to Art
  Courys earlier handouts on polyurethane
  degradation to describe at least one mode (see
  note above).
• 5. What class device is a heart pacemaker (I, II,
  III)? What regulatory pathway would be required
  to gain approval to sell a new pacemaker in the
  US? It is likely that some clinical trials will
  be necessary to show safety and efficacy of the
  leads. What is the name of the process leading
  to approval to run clinical trials?

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Figure 1
Figure 2
Bipolar Pacemaker System
Endocardial Pacing Lead
Figure 3
Steroid Eluting Pacing Lead (porous tip, steroid
plug, tine)