This document proposes integrating metabolite sensing onto CMOS chips using ion-sensitive field effect transistors (ISFETs) and microfluidics to create a portable personal metabolome machine. Current metabolite measurement requires expensive, bulky equipment like mass spectrometry. The proposed solution is to use diagnostic clinical chemistry techniques with specific enzymes to quantify metabolites on an integrated sensor chip using CMOS technology for its low cost, small size, and mass production abilities. This would allow for measuring a person's metabolome to indicate their health and integrating genomics with real-time metabolite measurements.

1. Boon Chong Cheah, Alasdair I. MacDonald, Michael
P. Barrett, David R. S. Cumming
Email: b.cheah.1@research.gla.ac.uk
Metabolomics on
Integrated Circuit

2. • Project Overview
• Complementary Metal Oxide Semiconductor (CMOS) Technology
• Ion Sensitive Field Effect Transistors (ISFETs)
• Integrated Sensors: Sequencing
• Enzyme Assays
• Microfluidics
• Bio-functionalisation
• Future Work & Conclusions
Outline
1

3. Current measurement of
Metabolome:
• Mass spectroscopy or Nuclear
magnetic resonance (NMR)
• Expensive equipment
• Bulky components
• Required special skillsets
• No single platform to for
metabolome detection
Project Overview
Proposed solution:
• Diagnostic clinical chemistry used
specific enzyme to quantify
metabolites
• CMOS integrated sensors and
microfluidics integration, together
with bio-functionalisation
technique
2

4. CMOS Technology
Applications
• It is a semiconductor technology to construct integrated circuits
• Low cost, miniturisation and mass-manufacturing capability
• Dominates the world of electronics and revolutionaries modern
computing and communications.
• Made enormous impact on sensing technology such as digital
camera
3

5. Ion Sensitive Field Effect
Transistors (ISFETs)
• First miniaturised silicon based chemical sensor
• Measured H+ concentration in aqueous solution
• ISFET array chips have been used extensively to measure ionic activity
such as Belousov-Zhabotinsky reaction, natural of artificial membranes
B. Nemeth, D. R. S. Cumming et. al, Adv. Mater. 24, 1238-1242 (2012).
4

6. Integrated Sensors:
Genome Sequencing
The FIRST
Glasgow array
Migration and
scale-up
Further scale-up
World’s first
optics-free
sequencing
system
M. J. Milgrew, D. R. S. Cumming et. al, ISSCC, 590-638 (2008).
5

7. Personal Metabolome
Machine
Genomics Metabolomics
Indicate individual’s
propensity towards
a disease
Immediate
measurement of
body function
6

8. Sensors and Sensors
System
Portable
electronic
devices
7

9. Imaging Experiments
8

10. Sensor’s Characteristics
• Ta2O5 membrane with detection sensitivity of 45 mV/pH unit
• Drift is approximately 0.8 mV/hour
• Nernstian pH response between pH 2 – pH 12
9

11. Spatial Averaging for
Noise Reduction


2
1
)(
1 2
12
2
t
t
ii dttV
tt
e 

M
i
iM tV
M
V
1
)(
1
10

12. Enzyme Assays on Chip
Buffer concentration reduction to maximise the sensitivity for ISFET
11

13. • Most enzyme reactions follow Michaelis-Menten kinetics
• The KM value is calculated to be 0.58 mM, comparable to value obtained
from spectrophotometer of 0.85 mM
Enzyme Kinetics on Chip
MKS
S
vv


][
][
max
• Hexokinase enzyme for glucose measurements encompassing
physiological range
12

14. Microfluidics on Chip
200μm
SU-8
Inlet
SU-8 microchannels Microchannels on chip
Images of flow
of enzymatic
solution on
chip
13

15. Bio-functionalisation on
Chip
Enzyme in
alginate gel
Jetlab II Inkjet Printer
0 400 800 1200
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
AmplitudeDifference(Volts)
Time (Seconds)
50
4
Hexokinase Units
On chip measurement for glucose
using alginate gel
Array Printing
14

16. Multiple Metabolites on
Chip
15

17. Conclusion
• ISFET array chip fabricated in a standard 350 nm CMOS process was
presented
• Enzyme assays for metabolites sensing and enzyme kinetics was
demonstrated on chip
• Microfluidics using SU-8 microchannels was fabricated and demonstrated
on chip
• Jatlab II inkjet printer was used to print enzyme assays on chip to be
measured
• All these abilities could be integrated and resulted in the production of a
personal metabolome machine.
16

18. Thank You!
Any
Questions?
Email:
b.cheah.1@research.gla.ac.uk