This document discusses the evolution of microfluidics and biosensors towards systems with revolutionary analytical capabilities. It covers topics such as continuous monitoring sensors, implantable glucose sensors, commercial products like Abbott's Freestyle Libre, Google's contact lens project, and challenges around long-term reliable sensing. The document also examines autonomous platforms for water quality monitoring and reagent-based techniques versus direct sensing approaches.

1. The Evolution of Microfluidics to Bio-Inspired
Systems with Revolutionary Analytical Capabilities
Dermot Diamond
Insight Centre for Data Analytics, National Centre for Sensor Research
Dublin City University, Dublin 9, Ireland
Presented at
8th Conference on Analytical Sciences Ireland (CASi)
Dublin City University
April 14, 2016

2. Keynote Article: August 2004, Analytical Chemistry (ACS)
Dermot Diamond, Anal. Chem., 76 (2004) 278A-286A
(Ron Ambrosio & Alex Morrow, IBM TJ Watson)

3. !"
Insight Centre for Data Analytics
•! Biggest single research investment ever by Science Foundation
•! Biggest coordinated research programme in the history of the state
•! Focus is on ‘big data’ related to health informatics and pHealth

4. What is a Chemo/Bio-Sensor?
‘a device, consisting of a transducer and a chemo/bio-sensitive
film/membrane, that generates a signal related to the
concentration of particular target analyte in a given sample’
Signal out Transducer surface
Conducting cable/track
Chemo/Bio-sensing involves selective BINDING & TRANSDUCTION on the
device surface; this also implies the target analyte MUST meet the device
surface (LOCATION & MOVEMENT). It provides a signal observable in the
macroscopic world (COMMUNICATION)
Chemo/bio-sensitive
film

5. Single Use vs. Continuous
Monitoring
#"
Single/short term
Use
Measurements
and Diagnostics
Continuous
Monitoring &
Sensor
Networks
Physical Sensors
& Transducers
Chemical Sensors
& Biosensors
Can we do long-term in-situ sensing with Chemical
Sensors & Biosensors

6. Blood Analysis; Implantible Sensors
Anal. Chem., 64 (1992) 1721-1728.
Ligand (and variations of) used in many
clinical analysers for blood Na+ profiling
1985: Catheter Electrodes for
intensive care – function for 24 hrs
Dr. David Band, St Thomas’s
Hospital London
1985: Catheter Electrodes for1985: Catheter Electrodes for
intensive care – function for 24 hrsintensive care – function for 24 hrs
1985: Catheter Electrodes for1985: Catheter Electrodes for
intensive care – function for 24 hrsintensive care – function for 24 hrs
In 1985, the use model for reliable
in-vivo continuous monitoring with
an implantable chemical sensor was
restricted to a day or two

7. The (broken) promise of biosensors!..
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C*+,*-"4'7%-:45"3"7,'&*738"/'37(%-")*88"9'>*-"3+"+,'"(6"%0"+,'")*/'DDD""
"
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0'':937G"+%"*-418*-"61&6"
@*>,"H'7,-%8%>25"I%=;"JKL!5"MJAMK"

8. Abbott Freestyle ‘Libre’
L"
•! ‘Small fibre’ used to access
interstitial fluid
•! Data downloaded at least
once every 8 hr via 1s
contactless scan (1-4 cm)
•! Waterproof to 1 metre
•! Replace every 2 weeks

9. K"
‘Over the past year, Apple has snapped up at
least half a dozen prominent experts in
biomedicine, according to LinkedIn profile changes.
Much of the hiring is in sensor technology, an
area Chief Executive Tim Cook singled out last
year as primed "to explode."
Industry insiders say the moves telegraph a vision of
monitoring everything from blood-sugar levels
to nutrition, beyond the fitness-oriented devices
now on the market.’
"This is a very specific play in the bio-sensing
space," said Malay Gandhi, chief strategy officer at
Rock Health, a San Francisco venture capital firm
that has backed prominent wearable-tech startups,
such as Augmedix and Spire.
May 7th 2014
biomedicine, according to LinkedIn profile changes.
Much of the hiring is in sensor technology, an
area Chief Executive Tim Cook singled out last
year as primed "to explode."
Industry insiders say the moves telegraph a vision of
monitoring everything from blood-sugar levels
to nutrition, beyond the fitness-oriented devices
now on the market.’
biomedicine, according to LinkedIn profile changes.
Much of the hiring is in sensor technology, an
area Chief Executive Tim Cook singled out last
year as primed "to explode."
Industry insiders say the moves telegraph a vision of
monitoring everything from blood-sugar levels
to nutrition, beyond the fitness-oriented devices
now on the market.’
Much of the hiring is in sensor technology, an
area Chief Executive Tim Cook singled out last
year as primed "to explode."
Industry insiders say the moves telegraph a vision of
monitoring everything from blood-sugar levels
to nutrition, beyond the fitness-oriented devices
now on the market.’
How will they integrate
biosensing with the
iWatch!..?
HYPEwatch: Apple, iWatch & Health
Monitoring

10. Google Contact Lens
United States Patent Application 20140107445
Kind Code A1 Liu; Zenghe April 17, 2014
Microelectrodes In An Ophthalmic Electrochemical
Sensor
Abstract
An eye-mountable device includes an electrochemical
sensor embedded in a polymeric material configured for
mounting to a surface of an eye. The electrochemical
sensor includes a working electrode, a reference
electrode, and a reagent that selectively reacts with an
analyte to generate a sensor measurement related to a
concentration of the analyte in a fluid to which the eye-
mountable device is exposed.
JN"
http://www.gmanetwork.com/news/story/
360331/scitech/technology/google-s-smart-
contact-lenses-may-arrive-sooner-than-
you-think
A contact lens with embedded sensor for
monitoring tear glucose level, H. F. Yao, A. J. Shum,
M. Cowan, I. Lahdesmaki and B. A. Parviz,
Biosensors & Bioelectronics, 2011, 26, 3290-3296.
A contact lens with embedded sensor for
monitoring tear glucose level
M. Cowan, I.
Biosensors & Bioelectronics
electrode, and a reagent that selectively reacts with anelectrode and a reagent that selectively reacts with an
Kind Code
Microelectrodes
Sensor
Abstract
An
sensor
mounting
sensor
electrode
Kind Code A1 Liu; Zenghe April 17, 2014
Microelectrodes In An Ophthalmic Electrochemical
Sensor
Abstract
An eye-mountable device includes an electrochemical
sensor embedded in a polymeric material configured for
mounting to a surface of anof anof eye. The electrochemical
sensor includes a working electrode, a reference
electrode and reagent that selectively reacts with
•! Contact lens use model is 24 hours;
•! Leverage Google Glass*;
•! Novartis now working with Google.
electrode, and a reagent that selectively reacts with anelectrode, and a reagent that selectively reacts with an, reagent selectively
analyte
concentration
mountable
, reagent selectively
analyte to generate a sensor measurement related to a
concentration of the analyte in a fluid to which the eye-
mountable device is exposed.*Google Glass project abandoned!
(Jan 15 2015) see
https://plus.google.com/+GoogleGlass/posts/9uiwXY42tvc

11. ACS Nano Cover and Editorial
‘Grand Plans for Nano’, (9) 12 December 2015

12. Cover Article: ACS Nano 9 (12) (2015) 12174–12181

13. Materials – great! Sensing - ????
•! ‘CHEMFET’ configuration (same as 1984 paper) pH response not great
•! Glucose sensor responds to pH – selectivity issue
•! No integrated reference or counter electrodes

14. What about the environment – water
quality monitoring!
JM"

15. Change in Electrode Function
over Time
J#"
Day 0: y = 28.739x + 51.806
R! = 0.99981
Day 4: y = 28.029x + 48.261
R! = 0.99705
Day 8: y = 27.076x + 40.137
R! = 0.99892
-200
-150
-100
-50
0
50
100
-11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
EMF/mV
log a(Pb2+)
Mean (new)
Mean (4-d)
Mean (8-d)
stored in 10-9M Pb2+, pH=4
Continuous contact with
river water
Conventional PVC-membrane based ISEs
See Electrochimica Acta 73 (2012) 93–97

16. Biofilm Formation on Sensors
•! Electrodes exposed to local river water (Tolka)
•! ‘Slime test’ shows biofilm formation happens
almost immediately and grows rapidly
JO"
New electrode

17. Control of membrane interfacial
exchange & binding processes
JP"
Remote, autonomous chemical sensing is a tricky business!

18. Argo Project (accessed March 20 2016)
•! Ca. 4,000 (3918) floats: temperature and salinity
•! Bio/Chem: Nitrate (64), DO (280), Bio-optics (115), pH (25)
DO is by Clark Cell (Sea Bird Electronics) or Dynamic fluorescence quenching (Aanderaa)
‘calibration of the DO measurements by the SBE sensor remains an
important issue for the future’, Argo report ‘Processing Argo OXYGEN data
at the DAC level’, September 6, 2009, V. Thierry, D. Gilbert, T. Kobayashi
@"60K ea!
See https://picasaweb.google.com/JCOMMOPS/ArgoMaps?authuser=0&feat=embedwebsite
DO is by Clark Cell (Sea Bird Electronics) or Dynamic fluorescence quenching (
https://picasaweb.google.com/JCOMMOPS/ArgoMaps?authuser=0&feat=embedwebsite
DO is by Clark Cell (Sea Bird Electronics) or Dynamic fluorescence quenching (
@"@"@ 60K ea!
https://picasaweb.google.com/JCOMMOPS/ArgoMaps?authuser=0&feat=embedwebsite

19. What is the core issue??
•! Simple, bare chem/biosensors do not function
reliably EXCEPT as single shot or short-term
use devices – regular recalibration required (if
they manage to keep functioning)
•! Sensor surfaces change as soon as they are
exposed to the real world – biofouling,
interferents, leaching of components!.
•! Current systems work for days (after decades of
research)
•! Implants must work for 10 years!
•! Environmental Sensors are far too expensive
JK"

20. Direct Sensing vs. Reagent
Based LOAC/ufluidics
sensor
sample
molecular interactions
signal
outside world
sample,
standards
reagents
Reaction manifold
detector
waste
source
sample
blank
BL BLBL
s
t
Direct Sensing LOAC Analyser
QN"

21. Autonomous platform – water Analysis
Sampling port

22. Phosphate: The Yellow Method
Mixture (Reagent)
+
(NH4VO3 ) + (NH4)6Mo7O24.4H2O,
HCl conc.
(KH2PO4)
Sample
(NH4)3PO4.NH4VO3.16MoO3
• yellow vanaomolybdophosphoric acid is formed when ammonium metavanadate
and ammonium molybdate (mixture) reacts with phosphate (acidic conditions)
•! In conventional (molybdate) method, ascorbic acid is used to generate the well-
known deep blue complex (v. fine precipitate)

23. Deployment at Osberstown WWTP
•! Phosphate monitoring unit deployed
•! System is fully immersed in the treatment tank
•! Wireless communications unit linked by cable
•! Data transmitted to cloud
$8*:'"Q!"

24. Autonomous Chemical Analyser
QM"

25. Q#"
Osberstown – 3 week deployment
Biofouling of sensor surfaces is a major challenge for remote chemical
sensing – both for the environment and for implantable sensors

26. Origins of microfluidics: Inspired by
Electronic ‘Chips’
•! Tremendous success of
‘integrated circuits’ in
1960s 1970s
•! Integrated Fluidics
would do the same for
Analytical Science
•! ‘Lab on a Chip’:
inherently 2D!
www.gesundheitsindustrie-bw.de

27. But not everything is integrated!..
•! Fluidic Interconnects can get
very messy
•! Most of the ‘Chip’ has no function
•! Many components are
located off-chip
•! Detectors, pumps, valves!.
•! Hard Materials
http://www.eetimes.com/document.asp?doc_id=1171478

28. How does Biology do it?
•! Inherently 3D
•! Soft, flexible materials
•! Everything is fully integrated
•! All available space is functional
•! Channel walls play an active role
http://www.wisegeek.org/what-is-an-open-circulatory-system.htm

29. Extend Lifetime by Making Systems
‘Self-Aware’, Capable of Detecting and
Repairing Damage

30. Lets Make a Start: Extend Period of Use
via Multiple short-use Sensors!.?
•! If each sensor has a
functional lifetime of 1
week!.
•! And these sensors are very
reproducible!.
•! And they are very stable in
storage (up to several years)
!N"
Then 50 sensors when used sequentially could provide
an aggregated in-use lifetime of around 1 year
But now we need multiple valves integrated into a
fluidic platform to select each sensor in turn
Sample, reagent in
Valves
Sensors

31. How to advance fluid handling in LOC
platforms: re-invent valves (and pumps)!
•! Conventional valves cannot be easily scaled down -
Located off chip: fluidic interconnects required
–! Complex fabrication
–! Increased dead volume
–! Mixing effects
•! Based on solenoid action
–! Large power demand
–! Expensive
!J"
Solution: soft-polymer (biomimetic) valves fully integrated
into the fluidic system

32. 0
0.5
1
1.5
2
2.5
3
400 450 500 550 600 650
NM
ABS
Off (spiropyran) On (merocyanine)
MerocyanineSpiropyran
-
+UV
VIS, #
Photoswitchable Soft Actuators

33. Famous Molecule!.
From Prof. Thorfinnur Gunnlaugsson, TCD School of Chemistry
Spotted on Nickelodeon Cartoons February 2015

34. Poly(N-isopropylacrylamide)
•! pNIPAAM exhibits inverse solubility upon heating
•! This is referred to as the LCST (Lower Critical Solution Temperature)
•! Typically this temperature lies between 30-35oC, but the exact
temperature is a function of the (macro)molecular microstructure
•! Upon reaching the LCST the polymer undergoes a dramatic volume
change, as the hydrated polymer chains collapse to a globular
structure, expelling the bound water in the process
pNIPAAM
Hydrophilic Hydrophobic
Hydrated Polymer Chains Loss of bound water
-> polymer collapse
#T

35. Photo-actuator polymers as
microvalves in microfluidic systems
trihexyltetradecylphosphonium
dicyanoamide [P6,6,6,14]+[dca]-
Ionogel-based light-actuated valves for controlling liquid flow in micro-fluidic manifolds, Fernando Benito-Lopez, Robert
Byrne, Ana Maria Raduta, Nihal Engin Vrana, Garrett McGuinness, Dermot Diamond, Lab Chip, 10 (2010) 195-201.

36. Optimisation of valve dimensions
First example of actuating polymer gels as reusable valves for
flow control on minute time scales (> 50 repeat actuations)
0 200 400 600 800 1000
0,0
0,5
1,0
1,5
2,0
Time (sec)
Flowrate(µl/min)
0
1
2
3
4
5
Cummulativevolume(µl)
0 5 10 15 20
0
2
4
6
8
Time (min)
Flowrate(µl/min)
0
20
40
60
80
Cummulativevolume(µl)1.7 mm mask 1.6 mm mask

37. ACS applied materials & interfaces, 6 (2014) 7268-7274
!"
#" 0 0.5 1 1.5 2 2.5 mm
mm
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 0.5 1 1.5 2 2.5 mm
mm
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
!m
0
5
10
15
20
25
30
35
40
45
50
! !"#$$"%&
! !"#$$"%&
High crosslink density
Low crosslink density
Light source
Photocontrol of Surface Features – Channel
Surfaces Become ‘Active’
!P"
!"
#"
!"!"
!"
#"

38. Why move the solvent at all?
•! These vehicles should be able to;
–! Spontaneously move under an external stimulus (e.g. chemical,
thermal gradient) to preferred locations
–! Report selective binding of guest species
–! Release active payload to modify local environment
!L"
[sample]/mol l-1 Ratio H2O/Sample
1.0x10-6 5.56x107
1.0x10-9 5.56x1010
1.0x10-12 5.56x1013
Strategy:
Move multifunctional micro/
nano-vehicles such as
beads, vesicles, micelles,
capsules, droplets through
the sample to perform
tasks!!

39. Chemotaxis
!K"
Chemotaxis of a Single Dictyostelium cell to cAMP
Time-lapse video microscopy (DIC optics, 60X objective) of a single cell moving toward a micropipette containing
the chemoattractant cAMP. Note that the cell changes direction in response to movement of the micropipette by
extending a new pseudopod in the direction of the pipette tip
.
Source: www.dnatube.com/video/257/Chemotaxis-of-a-Single-cell-to-cAMP

40. Chemotactic Systems
MN"
Published on Web 11/01/2010 (speed ~x4): channels filled with KOH (pH 12.0-12.3 + surfactant; agarose gel soaked in HCl
(pH 1.2) sets up the pH gradient; droplets of mineral oil or DCM containing 20-60% 2-hexyldecanoic acid + dye. Droplet
speed ca. 1-10 mm/s; movement caused by convective flows arising from concentration gradient of HDA at droplet-air
interface (greater concentration of DA- towards higher pH side); HDA <-> H+ + DA-
Maze Solving by Chemotactic Droplets; Istvan Lagzi, Siowling Soh, Paul J. Wesson, Kevin P. Browne, and Bartosz A.
Grzybowski; J. AM. CHEM. SOC. 2010, 132, 1198–1199
Fuerstman, M. J.; Deschatelets, P.; Kane, R.; Schwartz, A.; Kenis, P. J. A.;Deutch, J. M.; Whitesides, G. M. Langmuir 2003,
19, 4714.
HDA H+ + DA-HDA H
HDA
Hydrophobic Mineral Oil
HDA HHDA H
HDA
HDA H+ + DAHDA H
HDA
Acidic ! Basic "
In a pH gradient, DA- is preferentially
transferred to the aqueous phase at
the more basic side of the drop.

41. We can do the same with IL Droplets
MJ"
Trihexyl(tetradecyl)phosphonium chloride ([P6,6,6,14][Cl]) droplets with a small amount of 1-
(methylamino)anthraquinone red dye for visualization. The droplets spontaneously follow the gradient
of the Cl- ion which is created using a polyacrylamide gel pad soaked in 10-2 M HCl; A small amount of
NaCl crystals can also be used to drive droplet movement.
Electronic structure calculations and physicochemical experiments quantify the competitive liquid ion association and probe
stabilisation effects for nitrobenzospiropyran in phosphonium-based ionic liquids, D. Thompson et al., Physical Chemistry
Chemical Physics, 2011, 13, 6156-6168.
= cationic surfactant
Self-propelled chemotactic ionic liquid droplets, W. Francis, C. Fay, L. Florea, D. Diamond, Chemical Communications, 51
(2015) 2342-2344.

42. 2-Photon Polymerisation
MQ"
•! Single photon absorption
•! 2D patterns
Stereolithography Two-photon polymerisation
•! Two photon absorption
•! 3D structures

43. M!"
2-Photon Polymerisation
http://www.nanoscribe.de/

44. Near Term Goals (5Years)
Inside: Implants/In-vivo
Smart Stents Self-Aware
Transplant
Joints3D Tissue
Platforms and
Implants Post-Operative
IC (days)Medium term
Convalescence
(weeks)
Smart
Bandages
Outside: On-Body
Sensorised
Contact Lens
Sensorised
Splints/
dentures
On-Skin wearable
platforms
patches/watches
Smart Textiles/
Clothing
Inside: Implants/In-vivo
Smart Stents Self-Aware
Implants Post-OperativePost-Operative
IC (days)IC (days)
ImplantsImplantsImplantsImplants
Medium termMedium termMedium termMedium termMedium termMedium termMedium termMedium termMedium termMedium termMedium termMedium termMedium term
ConvalescenceConvalescence
(weeks)(weeks)(weeks)
Smart Stents
Convalescence
Smart
Bandages
Outside: On-Body
Sensorised
Contact Lens
Sensorised
Splints/
dentures
platforms
patches/watchespatches/watchespatches/watchespatches/watchespatches/watchespatches/watches
Smart Textiles/
Clothing
patches/watchespatches/watchespatches/watches
Smart Stents
patches/watchespatches/watchespatches/watches
Smart Stents Self-Aware
Platforms and
Post-OperativePost-Operative
Smart Stents
Platforms and
Bandages
Sensorised
Contact Lens
platforms
Smart Stents
Platforms and
Smart Stents
Transplant
Joints
Platforms and
Smart Stents
Platforms and
BandagesBandages
SensorisedSensorised
Contact Lens
platforms
Smart Stents
Platforms and
Smart Stents
Transplant
Joints3D Tissue3D Tissue
Platforms and
Smart Stents
3D Tissue3D Tissue
Platforms and
BandagesBandagesBandages
SensorisedSensorised
Contact LensContact LensContact Lens
On-Skin wearableOn-Skin wearableOn-Skin wearableOn-Skin wearable
platforms
On-Skin wearable
Smart Stents
Platforms and
On-Skin wearableDevices and Platforms
Data and Information; IOT
MATERIALS
Physics Chemistry Biology Engineering
(photonics, electronics, fluidics, 4D materials)

45. Time of EXCITING OPPORTUNITY!
•! New materials with exciting characteristics and
unsurpassed potential!
•! Combine with emerging technologies and
techniques for exquisite control of 3D morphology
•! And greatly improved methods for characterisation
of structure and activity
•! Learn from nature – e.g. more sophisticated
circulation systems for ‘self-aware’ sensing devices!
M#"
HAVE FUN!

46. Thanks to!..
•! Members of my research group
•! NCSR, DCU
•! Science Foundation Ireland & INSIGHT Centre
•! Enterprise Ireland
•! Research Partners – academic and industry
•! EU Projects: NAPES, CommonSense, Aquawarn,
MASK-IRSES, OrgBio

47. Contributions at CASi
Oral:
•! Thursday, 16:45 – 17:00: Boronic Acid Fluorophores for Saccharide Sensing, Danielle Bruen,*
Florea, L. and Diamond, D.
Flashes & Posters
•! Thursday, 17:45 – 17:50: P6: Poly(ionic liquid) Valves for Microfluidic Devices, Alexandru Tudor*
Saez, J., Benito-Lopez, F., Florea, L., and Diamond, D.
•! Thursday, 12:35 – 12:40 P32: Wearable Chemical Sensing – Optimizing Fluidics for Real-Time
Sweat Analysis, Jennifer Deignan,* Florea, L; Coyle, S; and Diamond, D
Posters:
•! P5: Photo-acid Generator Comonomer Turns pH-responsive into Photo-responsive Hydrogels,
Aishling Dunne, *; Hennessy, J., Florea, L. and Diamond, D.
•! P53: Signal and Seeker Droplets, Wayne Francis*; Colm Delaney; Larisa Florea and Dermot
Diamond
•! ‘SWEATCH’: Wearable, Real-Time Monitoring of Electrolyte Levels in Sweat, Tom Glennon*,
Conor O’Quigley, Margaret McCaul, Giusy Matzeu, Stephen Beirne, Gordon G. Wallace, Florin
Stroiescu, Niamh O’Mahoney, Paddy White and Dermot Diamond
MP"

48. ML"
Thanks for listening