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Wearable Paper-Based Microfluidic Biomarker Sensor Patch

Jeff Morse, Jim Watkins, Vince Rottello, Zewen Jiang, Sam Nugen Center for Personalized Health Monitoring

UMass Amherst

Azar Alizadeh, Nandini Nagraj, Ralf Lenigk, Matthew J. Misner GE Global Research, Niskayuna NY 12309

Jason Heikenfeld

Novel Devices Laboratory University of Cincinnati

ACIM Project FA86501327311 -1

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Objectives

Ø Development of low cost non-invasive wearable sensors for continuous monitoring of cognition and stress protein biomarkers from sweat.

Ø  Integration of sensors and paper-based microfluidics to enable fully wearable and small footprint device formats

Ø  Development of ultrasensitive electrical sensors to detect Orexin-A at nM-pM levels under application relevant conditions (example simulated sweat)

Ø  Development of novel functionalization and patterning techniques on paper fluidics to enable on-demand (continuous) sensing

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Background

Courtesy of R. Naik, AFRL

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Background

Courtesy of R. Naik, AFRL

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Background: Orexin A Sensor

Courtesy of R. Naik, AFRL

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Current Challenges with Orexin-A Sensors

•  AFRL: Demonstrated Orexin A biomarker sensors based on interdigitated ZnO FETs, Graphene FETs and SiNWs.

•  Sensitivity levels are within the desired range when probing the biomarker in buffer

•  Challenges associated with transitioning from buffer to sweat-like media– need to improve sensor stability & selectivity

•  Challenges associated with sensor integration with the sweat patch (sweat collection & transport to the sensor site)- need to implement

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Development / optimization & down-selection of robust and high performing electrical sensors •  Multivariable resonance (RF) sensors •  Electrical impedance spectroscopy (IES) sensors •  Optimization of sensor surface affinity to the bio-marker System level design / integration & testing

•  Integration of the sweat sensors and the fluidic components on the patch for on-demand (continuous) measurements

•  Device characterization under application relevant conditions

Current NBMC-UMass Project Focus

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Schematic of Integrated Sweat Sensing Device with a Resonance RF Sensor

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2-10 um width/spacing

Integrated RF Sweat Sensing Device

Sensing surface- Gold interdigitated electrodes

Surface immobilized bio-recognition element binding with Orexin A

Peptide bio-recognition element (OABP-Cys)

Custom synthesized by Peptide 2.0

Binding constant: KD ~ 70 nM

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Goal: Conjugate the biological recognition element (BRE) peptide sequence onto the gold surface.

-  Synthesize a heterobifunctional linker and use it to get a self- assembled monolayer (SAM) of peptide and filler on gold surface.

-  Immobilize the BRE sequence by the reaction between its thiol group and the heterobifunctional linker.

Advantages:

-  The design of the ligand provides rigidity, flexibility and biocompatibility for the SAM.

-  The linker maximizes presentation of the peptide recognition element

Integrated RF Sweat Sensing Device

Sensing surface- Immobilization of BRE on the interdigitated electrodes

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Schematic illustration of gold surfaces

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Comparison of XPS Multiplex results for Au, C, O, N and S

elements

“Au-BRE” surface “Au-linker” surface “Au” surface

Integrated RF Sweat Sensing Device

Sensing surface- Immobilization of BRE on the interdigitated electrodes

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Integrated RF Sweat Sensing Device

Orexin A detection with RF sensors (BRE has been immobilized on the Au IDE sensing surface)

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4 106 6 106 8 106 1 107 1.2 107 1.4 107 1.6 107 1.8 107 2 107

Full Spectra Au-M1-S1 with ssweat09262014

DI Water0.1 uM Orexin-A1 uM Orexin-A10 uM Orexin-A100 uM Orexin-A500 uM Orexin-A1000 uM Orexin-A

Impe

danc

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hm)

Frequency (Hz)

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Counter

Ref

W1

W2

Tolerance

2mm

2mm

EIS Sweat Sensing Device Au sensor arrays on a PET substrate

Student Xiao Wang: Support AFRL ORISE (Hagen) and NSF EAGER #1347725

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EIS Orexin A Sensors Current LOD: 25nM Orexin-A

EIS Sweat Sensing Device

Orexin A Detection (Bulk electrodes surfaces functionalized with the OABP-Cys BRE)

Xiao Wang, Dr. Selva Kumar: Funding Source AFRL ORISE (Hagen), NBMC, and NSF EAGER #1347725

Note! Expected 1st results coming on Oct. 16th with IDE electrodes, expected to further lower the LOD.

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Schematic of Integrated Sweat Sensing Device with a Resonance RF Sensor

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Concept: To control the flow on a paper fluidic channel, Ag electrowetting valves are inkjet printed and functionalized with a thiolated self-assembled monolayer

Electrowetting: Change in contact angle from hydrophobic (>90°) to hydrophilic (<90°)

Integrated Sweat Sensing Device

Adaptive sweat flow control

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Challenge: Ag electrowetting valves on paper requires high sintering temperatures to be conductive. Also, Ag oxidizes easily and can clog up nozzles in the inkjet printer and the pores in nitrocellulose. Proposed Method: Inkjet print PEDOT:PSS, a conductive polymer, to replace Ag electrode/ valves and to functionalize it with a thiolated self-assembled monolayer

Integrated Sweat Sensing Device

Adaptive sweat flow control

Patterning PEDOT:PSS electrodes/valves on front side of nitrocellulose with inkjet printing

Patterning PEDOT:PSS electrodes/valves on back side of nitrocellulose with inkjet printing à 5 valves on each device

Au electroplating of electrodes/valves

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Summary & Next Steps

•  Development of robust in-situ processes for immobilization of

BRE on the sensor chip surface •  Characterization of the integrated devices in both buffer and

simulated sweat •  Characterization and benchmarking of electrical impedance

sensors

•  Characterization of non-specific binding on down-selected micro-fluidic papers

•  Development and characterization of electrowetting vales on the downselected microfluidic papers

•  Refinement of the “adaptive flow control” design

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This material is based on research sponsored by Air Force Research Laboratory under agreement number FA8650-13-2-7311. The U.S Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation theron. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of Air Force Laboratory or the U.S. Government.

Acknowledgements