Challenges Associated with Developing Diagnostic Technologies for Global Public Health: Development

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Challenges Associated with Developing Diagnostic
Technologies for Global Public HealthDevelopmen
t of a Point-of-Care Diagnostic System for the
Developing World

• Paul Yager, Ph.D.
• Professor and Acting Chair
• Department of Bioengineering
• University of Washington
• Seattle, WA

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Biomedical Diagnostic Technologies
20th Century
21st Century

• In centralized laboratory
• Required trained personnel
• Consumed large volumes of reagents
• Required large expensive equipment
• Sample to result in gt1 day
• Required disruptive trips for outpatients
• Not much use for outpatient clinical research or
  clinical trials

• At the point of care (e.g., ER, doctor's office,
  workplace, home)
• Anyone can operate them
• Small volumes of samples and of reagents
• Low cost disposables, possible inexpensive reader
• Sample to result in lt10 minutes
• Rapid data connectivity
• Enabling new and personalized types of
  theranostics, closed-loop therapies, clinical
  trials, field medicine

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Distributed Diagnosis and Home Healthcare
(D2H2)--A New Doctor-Patient Interface
Where the patient is
Home, nursing home, work or vacation
Physiological sensors including home ultrasound,
fluid chemistries
2-way audio/video link
Assay modules
Handheld station
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Potential Uses of Chemical D2H2

• Monitoring hospital inpatients (underway with
  existing devices)
• Clinical trials of new medications
• Monitoring hospital outpatients (cancer,
  post-surgery)
• Monitoring chronic conditions (cancer, arthritis,
  AIDS, diabetes, heart disease, via metabolites
  and drugs)
• Monitoring chronic or critical drug treatment
• Pregnancy (abnormal and normal)
• Early warning for emergent health conditions
  (e.g. heart attack, stroke, cancer, heat stress,
  infection, food poisoning, etc.)
• Anticipating, preventing and managing outbreaks
  of infectious disease (epidemiology)

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The Appeal of Microfluidics

• Potential to automate very complex procedures
• Compatibility with small sample volumes
• Potential for packing many tests to operate in in
  small spaces--parallel processing
• Possible integration with pumping, detection and
  processing components
• Little waste
• Reproducibility of function
• Potential for mass fabrication
• Potentially low inherent cost

devices and systems that move fluids that have
at least one dimension smaller than 1 mm, formed
using microlithography or any of several
polymeric forming techniques
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Properties of Fluid Flow in Microchannels

• Viscous forces dominate
• Fluid flow is laminar
• Adjacent miscible fluids do not mix
• Mass transfer between fluid streams is by
  diffusion only

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Microfluidic Technologies Developed at UW or
Micronics

• Microfluidic methods and devices
• H-filter
• T-sensor
• Electrokinetic Fractionation
• Electrokinetic concentration
• Mixers
• Valves
• Switches
• Flow cytometers
• Immunoassays
• These are components that could be used for
  diagnostic systems

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Fabrication of Disposables
Laser cutter
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Yager Lab Diagnostic System Goals

• A disposable polymeric laminate cartridge that
• uses 1- 2 drops of easily accessible samples
  (blood, urine, tears, saliva)
• costs less than 5 (in the US)
• contains all chemistry needed for multiple
  quantitative bioassays
• can be left in the glove compartment of a car all
  summer in Texas or winter in Alaska
• requires only insertion in a handheld device and
  addition of water--usable by anyone over the age
  of 5
• gives all results in under 5 minutes
• provides laboratory-quality quantification of
  analytes
• IF NECESSARY, a portable inexpensive (!)
  measurement system that supports the use of
  laminate cartridges

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Thinking Globally

• The developed world is not the only part of the
  world with health problems amenable to a
  technological fix.
• Problems of health in the third world can VERY
  RAPIDLY become problems for all of us.
• Solutions to public health issues in less
  fortunate areas of the world must be inexpensive
• We focus our on technology that can be
  inherently inexpensive to be affordable in both
  developed and developing worlds

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The Developing World Environment(s)

• Conditions in the developing world vary
  enormously
• The wealthy may have facilities similar to the
  best in the US, Europe and Japan
• The poorest may have little or no medical
  resources at all
• Some countries (such as India, as shown here)
  have the full range of medical diagnostic
  capabilities within a few miles
• Designing things that will work in such varied
  and low-resource environments is a challenge

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Indian lab supply courier service

• Getting supplies such as disposables and reagents
  to the end-users is not simple in the developing
  world.
• Refrigeration may be sporadic or worse.
• Ambient temperatures above 40C are common in
  many countries.

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Summary of Some of the Problems
Technical Issues
Higher-Level Issues

• Not all technologies appropriate for DW
• Cost
• Fragile supplies
• Many diseases common only in DW (samples for RD
  stages hard to get)
• Poor DW infrastructure
• Trained clinicians, nurses, diagnosticians
• Power
• Supplies and supply chain
• Commercial reagents not always reliable

• Poverty--Little financial support other than
  philanthropy
• Burden of diseases very high in many areas
• Qualified production facilities not always
  available in DW
• Unstable and/or corrupt political infrastructure
• Regulatory and IP issues
• Occasional (civil) wars

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The Diagnostics Box (DxBox)

• Supported by the Bill Melinda Gates Foundation
  since 2005
• Grand Challenge 14 Technologies that assess
  individuals for multiple conditions or pathogens
  at point-of-care
• 15.4M, 5-year collaborative RD project led by
  UW
• Aim is to produce a system/platform for rapid
  diagnosis of diseases for use in the developing
  world

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DxBox Project Collaborators
Paul Yager UW, PI Immunoassays
Patrick Stayton UW, Biomolecular systems dev.
Walt Mahoney Nanogen N.A. Assay dev.
Fred Battrell Micronics Lab card/reader
dev. Systems integration
Gonzalo Domingo PATH Assay validation UNA,
System testing
Bill Hunter Invetech Instrument design/build
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DxBox Team

• Yager Group UW
• Elain Fu
• Kenneth Hawkins
• Turgut Fettah Kosar
• Barry Lutz
• Kjell Nelson
• Kelly Anderson
• Michael Look
• Afshin Mashadi-Hossein
• Chelsea Musick
• Sujatha Ramachandran
• Paul Yager
• Katherine McKenzie
• Jennifer Osborn
• Paolo Spicar-Mihalic
• Dean Stevens
• Gayathri Subramanian
• Rahber Thariani
• Matt Whitfield

• Nanogen
• Walt Mahoney
• Merl Hoekstra
• Eugene Lukhtanov
• Noah Scarr
• Ansel Wald
• Eric Yau
• Mark Gleave
• Irina Afonina
• Yevgeniy Belousov
• Alan Mills
• Sylvia Sanders
• Boyang Li
• Vladimir Gorn
• Alexei Vorobiev
• Dave Adams
• Nic Vermeulen

• Stayton Group UW
• Xiangchun Yin
• Lakeshia Taite
• Allison Golden
• Mitsuhiro Ebara
• James Lai
• Micronics
• Fred Battrell
• John Gerdes
• Diane Wierzbicki
• Anahita Kiavand
• Wenhao Wu
• John Williford
• Denise Hoekstra
• Sean Pennell
• Pat Maloney
• Michael Vegh
• Jason Capodanno
• Karen Hedine

• PATH
• Gonzalo J.Domingo
• Tala de los Santos
• Matt Steele
• Jay Gerlach
• Mitra Singhal
• Kate Watts
• Roger Peck
• Daniel Chang
• Kendall Magnuson
• Bernhard Weigl
• Invetech
• Rick Gardner
• Bill Hunter
• Ben Jenkins
• Bogden Arefta
• Cameron Stastra
• Graham Menhennit
• Jennifer Maschmann

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The DxBox (Diagnostics Box)

• A platform for rapid differential diagnosis of
  disease states
• Ability to detect 6 pathogens by at least 2
  methods
• PCR for amplification of nucleic acids
• Immunoassay for detection of antigens and
  antibodies
• Turnaround time of 20 minutes per sample
• Disposable contains all reagents
• On-card calibration and test validation
• Small, lightweight, rugged, battery-powered
  instrument
• Simple operation
• Low cost
• Low maintenance