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Data Minimization Techniques for the Bio-Medical

Application of Ion Sensitive Field Effect Transistor


using Deep learning Methods

Presentation by Under the Guidance of

Tulasi Radhika Patnala Madhavi Tatineni


Research Scholar, Department of EECE, Professor, Department of EECE,
GITAM Deemed to be University,
Hyderabad, India GITAM Deemed to be University,
Hyderabad, India
Contents
• Research Objectives
• ISFET Characteristics
• pH detection using ISFET
• Literature Survey
• pH vs Voltage Characteristics
• Data Minimization (Future work)*
Objective
To design and simulate ISFET using Transistion metal oxides by using
Comsol Multi-physics

To use ISFET as a pH Sensor and to perform pH detection in blood.

Data can be minimised using deep learning based the data


minimization methods.
Workflow
Evaluation of ISFET
What is pH ?
• pH is the measurement of acidity (hydrogen ion concentration)

pH = -log10[H+]
for [H+] =1.8 x 10-5 M, pH = 4.745

• An important example of pH is that of the blood. Its nominal value of


pH = 7.4 is regulated very accurately by the body.

• If the pH of the blood gets outside the range 7.35 to 7.45 the results
can be fatal.
ISE: Glass PH electrode 
• Glass pH electrode: pH sensitive glasses are manufactured typically with a composition ~22% Na 2O, ~6% CaO and ~72%
SiO2.
• Oxygen atoms within the lattice that are not bound to two Si atoms possess a negative charge. Cations(primarily Na+) pair
with these oxygen atoms and are able to diffuse slowly in the lattice, moving from one charge pair site to another. This
movement of cations within the glass allows a potential to be measured across it.
• Advantages: Its potential is essentially not affected by the presence of oxidizing or reducing agents.
• Operates over a wide pH range.
• Fast • Functions well in physiological systems.
Gas-sensing electrodes
• A thin membrane that separates the sample from an inner solution containing an ISE.
• The membrane is permeable to the gaseous analyte, but impermeable to other components. The gaseous
analyte passes through the membrane where it reacts with the inner solution, producing a species whose
concentration is monitored by the ISE.
• For example, CO2 diffuses across the membrane where it reacts in the inner solution to produce H 3O+. The
change in the activity of H3O+ in the inner solution is monitored with a pH electrode.
• CO2(aq) + 2H2O(l) ⇋ HCO3−(aq) + H3O+(aq)
• CO2, HCN, HF, H2S, NH3, NO2, SO2are commonly measured in this manner.
Why ISFET?
• Why do we need ISFET?
• Strong demand in biomedical sensing (H, K, Na ions)
• Miniaturized versions of the glass-membrane ion-selective electrode (ISE) appear to
be less stable
• For in vivo monitoring, glass-membrane ISE is fragile and cannot be used
• Goals
• Reduced dimensions to probe biology
• Fast response
• Simple integration with measurement electronics
• Solution
• Modify a common electrical engineering device (MOSFET) and use as a sensor (ISFET)
Classification based on Receptor

ISFET
pH ISFET ChemFET BioFET
DNA-FET
Structure of ISFET
• The ion-sensitive membrane replaces metal
gates, which are typically utilised as inputs in
an ISFET.
• ISFETs are comparable to MOSFETs with the
former devoid of the gate material.
• The gate insulator which is the sensing layer
of an ISFET is in direct contact with the
electrolyte and requires a reference electrode
to complete the gate to source circuit.
• The ability of an ISFET device to be integrated
with biologically active material helped it to
explore into the field of biosensors.
Applications of ISFET
• Bio medical applications
Detection of DNA
Biomarker detection from blood
Antibody detection
Glucose measurement
pH sensing.
• Electro sensing and imaging application
• Environmental Applications
Environmental Monitoring
Soil and Crop Measurements
• ISFET in Wearable Point-of-Care Applications
• ISFET in Soil Analysis
Zeng et al. 2018

• This paper presents a 128 × 128 ISFET array with current mode readout peripherals for real-time ion
imaging. Current-mode operation is employed to achieve very high speed and frame rate and provide a
linear mapping between the ion concentration at the sensing layer (typically hydrogen ions - pH) to the
drain current of the device. To this effect, a single device biased in the triode region can serve as both the
sensing and readout device in the pixel ensuring a very small area footprint per pixel. Compensating for
known non-ideal effects of the ISFET, namely trapped charge and drift, is implemented by resetting the
gate voltage whereas any additional circuit offsets are eliminated by auto-zeroing. Auto-zeroing and
sampling takes place on a row-parallel basis which is then multiplexed to 8 current mode ADCs
• Drawbacks:
Low Sensitivity of the ISFET

J. Zeng, N. Miscourides, and P. Georgiou, “A 128x128 Current-Mode Ultra-High Frame Rate ISFET Array for
Ion Imaging,” in 2018 IEEE International Symposium on Circuits and Systems (ISCAS), 2018, pp. 1–5.
Moser et al. 2018
Moser et al. paper reviews the field of ISFET arrays for Labon-Chip applications from the
early age of ISFET instrumentation to the current state-of-the-art. We provide an overview of
the last decades of research by describing three eras which range from early steps in
instrumentation to integration with autonomous Lab-on-Chip platforms for biochemical
applications. We expect the future of ISFET arrays to be dictated by the new wave of
detectable molecular targets, which will provide new specification to designers.
Drawback:
Lower array size.

N. Moser, L. Keeble, J. Rodriguez-Manzano and P. Georgiou, "ISFET Arrays for Lab-on-Chip


Technology: A Review," 2019 26th IEEE International Conference on Electronics, Circuits and
Systems (ICECS), 2019, pp. 57-60, doi: 10.1109/ICECS46596.2019.8965034.
Cacho Soblechero et al. 2019
Cacho soblechero presented a novel 32x32 ISFET array for DNA amplification detection. Each pixel
contains a highlylinear ISFET-based OTA and a sawtooth oscillator, converting the solution pH into a
digital clock with chemically controlled duty cycle. By employing a differential measurement
between a DAC-generated voltage and the pH solution on the OTA, a highly linear, PVT-insensitive
response is achieved, while opening the possibility of real-time pixel-wise compensation of trapped
charge and chemical drift. The proposed architecture paves the way towards a new generation of
ISFET imagers, capable of learning from data and correcting their measurements in real time.

Drawbacks: Low Detection Sensitivity of the chip.

M. Cacho-Soblechero and P. Georgiou, “A programmable, highly linear and pvt-insensitive isfet array
for poc diagnosis,” in 2019 IEEE International Symposium on Circuits and Systems (ISCAS), May 2019,
pp. 1–5.
Miguel Cacho Soblechero et al. 2020

This paper discusses about the ISFET array that amplifies the on chip DNA detection by picture dual sensing.
The pixel architecture provides thermal and chemical sensing by encoding temperature and ion activity in a
single output PWM, modulating its frequency and its duty cycle respectively. Fabricated in 0.18 µm standard
CMOS process, the system demonstrates a quadratic thermal response and a highly linear pH sensitivity, with
a trapped charge compensation scheme able to calibrate 99.5% of the pixels in the target range, achieving a
homogeneous response across the array. The architecture suitability for on-chip DNA amplification detection
is proven by performing Loop-mediated Isothermal Amplification (LAMP) of phage lambda DNA, obtaining
a time-to-positive of 7.71 minutes with results comparable to commercial qPCR instruments. This architecture
represents the first in-pixel dual thermo-chemical sensing in ISFET arrays for Lab-on-a-Chip diagnostics.
Drawbacks: The architecture designed on chip for DNA detection is complex to implement .

M. Cacho-Soblechero, K. Malpartida-Cardenas, C. Cicatiello, J. Rodriguez-Manzano and P. Georgiou, "A Dual-


Sensing Thermo-Chemical ISFET Array for DNA-Based Diagnostics," in IEEE Transactions on Biomedical
Circuits and Systems, vol. 14, no. 3, pp. 477-489, June 2020, doi: 10.1109/TBCAS.2020.2978000.
Ashkhen Yesayan et al. 2020
In this paper they present a theoretical analysis of a junctionless (JL), ion-sensitive, field-effect
transistor (ISFET), self-consistently combining the electrochemical interaction between the
semiconductor–insulator interface and the surrounding electrolyte medium. Incorporating charge-
based core relationships for the nanowire (NW) and planar double gate (DG) JL FETs with basic
relations governing the electrolyte–insulator proton exchanges, they predicted the output
characteristics of the NW and DG JL ISFETs with respect to pH for all the regions of operation. This
hybrid charge-based approach of JL ISFETs is fully validated by COMSOL Multiphysics
simulations without the need to introduce any fitting parameters. These developments are suitable
for implementation in circuit simulators as well as for fast prototyping by tuning the technological
parameters and estimate their impact on the device performances, including the electrolyte medium.
Drawbacks: It is not possible to adjust technological factors and see how they affect the device's
performance, including the electrolyte medium.

Ashkhen Yesayan, "Extended Gate Reference-FET (REFET) Using 2D h-BN Sensing Layer for pH
Sensing Applications," in IEEE Electron Device Letters, vol. 41, no. 1, pp. 159-162, Jan. 2020, doi:
10.1109/LED.2019.2952887.
Lewis Keeble et al. 2020
This paper reviews the state-of-the-art of CMOS-based LoC devices for DNA detection and discusses electric
field actuation as an opportunity for enhanced sensing capabilities. They provide an overview of reported
architectures in recent years which have led to portable ISFET-based devices for PoC diagnostics. Then they
discuss the use of dielectrophoresis (DEP) for electric field manipulation of DNA using lowpower, CMOS-
compatible microelectrodes. The technique enables positioning of DNA close to ISFET sensing regions to
localise hydrogen ion production. This provides a signal boost to the ISFETs that lowers the limit-of-detection
and time to-result of the device, as well as providing a means of on-chip sample preparation. Major challenges
include electrode spoiling reactions, hindering electro kinetic effects, and the strong dependence of trapping
efficiency on applied voltage. The combination of an ISFET LoC platform with a DEP actuation system is
expected to represent a landmark step for the next generation of PoC diagnostics devices.
• Drawbacks
The deep tool used in this detection is invaluable and importance is not given which lowers the
detection limit and detection of DNA is slower.

Lewis Keeble, "Extended Gate Reference-FET (REFET) Using 2D h-BN Sensing Layer for pH Sensing Applications,"
in IEEE Electron Device Letters, vol. 41, no. 1, pp. 159-162, Jan. 2020, doi: 10.1109/LED.2019.2952887.
Asia J.Beiga et al. 2020
In this paper, they identifies a lack of a homogeneous interpretation of the data
minimization principle and explore two operational definitions applicable in the context of
personalization. The focus of their study in the domain of recommender systems is on
providing foundational insights about the (i) feasibility of different data minimization
definitions, (ii) robustness of different recommendation algorithms to minimization, and
(iii) performance of different minimization strategies. Overall analysis uncovers the
complexities of the data minimization problem in the context of personalization and maps
the remaining computational and regulatory challenges.
Drawback
To support minimization, we need to design new protocols for user system interaction,
and new learning mechanisms that select data while respecting specific minimization
requirements..

Asia J.Beiga et al., "A Deep Learning-Based Data Minimization Algorithm for Fast and
Secure Transfer of Big Genomic Datasets," in IEEE Transactions on Big Data, vol. 7, no. 2,
pp. 271-284, 1 June 2020, doi: 10.1109/TBDATA.2018.2805687.
Panteli et al. 2021
Panteli et al. studied in this paper about the reduction of drift in CMOS ISFET pH sensors by
using monolayer and multi layer graphene sheets. Graphene blocks the ion penetration in the
CMOS passivation layers and provides the physisorption sites needed for electrical double layer
formation allowing sensing. With an in-house polymer-assisted graphene transfer (PAGT) process,
monolayer and multilayer graphene sheets were manually transferred on top of the sensing
membrane of CMOS ISFET sensors on a 2 by 4 mm chip. The average performances parameters
of capacitive attenuation, drift, trapped charge, sensitivity and noise are experimented with pH
buffers. The stretched exponential function, that describes dispersion processes in amorphous
solids such as silicon dioxide and silicon nitride, was modified to model the dynamic drift
behaviour and analyse the effect of graphene on the performance of the sensors.

Drawbacks:
Despite of reduction of sensitivity, increase in noise due to surface tap activity exists .
Lee et al. 2021
Lee et al in this paper studies about the Label-free detection of biomolecules using ion-sensitive field-effect
transistors (ISFETs) in physiological solutions which is limited by the Debye charge-screening effect of the
electrical double layer. Most ISFET measurements are therefore performed in diluted ionic-strength solutions to
detect the interface potential change on specific binding of biomolecules. The novel CMOS ISFETs proposed in
this paper have a capacitor structure in the oscillator readout to provide modulation of the surface electric field to
reduce the charge screening and non-ideal signal drift. Signal modulation was applied at frequencies higher than
the ion-strength-dependent cut-off frequency, with the highest applied frequency being approximately 100 MHz
among the four proposed designs.

Drawbacks:
The floating-gate potential changed by 52.3 to 54.4 mV/pH as a result of the measurements and sensitivity of ISFET is not ideal .

C. Lee, Y. -W. Chen and M. S. . -C. Lu, "CMOS Biosensors for the Detection of DNA Hybridization in High
Ionic-Strength Solutions," in IEEE Sensors Journal, vol. 21, no. 4, pp. 4135-4142, 15 Feb.15, 2021, doi:
10.1109/JSEN.2020.3031321.
Rodrigo Wrege et al. 2021
R.Wedge et al studied about ISFETs implemented in standard CMOS technology adopt the inherent Si3N4 passivation
as the sensing layer, and benefit from a high integration level with no need of post-processing steps. However, this
implementation is associatedwith non-idealitiessuch as output temporal drift, capacitive attenuation of the input signal
and random offsets in the threshold voltage due to trapped charges. Most of these non-idealities, which require better
understanding, are characterized through biasing a reference electrode immersed in a solution in contact with the
passivation layer. To remove electrochemical effects from the measurements, this paper proposes a dry test where the wet
test setup is replaced with a sputtered gold thin film that provides electrical contact with the ISFETs. Dry tests were
performed in arrays of n-ISFETs and p-ISFETs from chips fabricated in a standard 180 nm high voltage CMOS
technology. The dry test introduced herein allows the electrical parameters of ISFETs to be determined without the
interference of chemical contributions as well as the charges trapped in the passivation layer are estimated.
Drawbacks:
There was a large die-to-die variation in the offsets between the threshold voltages of the n- and p-ISFET intra-dies.

Rodrigo Wrege, "Enhanced pH Sensitivity of AlGaN/GaN Ion-Sensitive Field-Effect Transistor by Recess Process and
Ammonium Hydroxide Treatment," in IEEE Transactions on Electron Devices, vol. 68, no. 3, pp. 1250-1254, March 2021,
doi: 10.1109/TED.2021.3053496.
M. Aledhari et. Al, 2021

• In this paper, we present a novel deep learning-based data minimization algorithm that
• 1) minimizes the datasets during transfer over the carrier channels;
• 2) protects the data from the man-in-the-middle (MITM) and other attacks by changing the binary
representation (content-encoding) several times for the same dataset
• data minimization strategy exploits the alphabet limitation of DNA sequences and modifies the
binary representation (codeword) of dataset characters using deep learning-based convolutional
neural network (CNN) to ensure a minimum of code word uses to the high frequency characters
at different time slots during the transfer time. 

• M. Aledhari, M. D. Pierro, M. Hefeida and F. Saeed, "A Deep Learning-Based Data Minimization Algorithm
for Fast and Secure Transfer of Big Genomic Datasets," in IEEE Transactions on Big Data, vol. 7, no. 2, pp.
271-284, 1 June 2021, doi: 10.1109/TBDATA.2018.2805687.
Literature Survey
Author Name Year Size of the Application Description
Array
Panteli et al., 2021 [16] 2 x 4 ISFET The dynamic drift behaviour Graphene monolayer and multilayer sheets
array and analyse reduce drift in complementary CMOS ISFET pH
sensors.
Miguel Cacho- 2020 [17] 32 × 32 ISFET For the detection of on-chip Lambda DNA from the phage LAMPing shows the
Soblechero et al., array DNA amplification, dual architecture's application to on-chip DNA
sensing and programmability amplification detection.
are key features to keep in
mind.
Cacho-Soblechero et 2019 [18] 32 × 32 ISFET DNA detection With a gate switch.
al., array
Zeng et al., 2018 [19] 128 x 128 Real-time ion dynamics With a gate switch.
ISFET array

Moser et al., 2018 [20] 78 x 56 Real-time DNA detection Reset and saturation of velocity in the current
mode of operation
Lewis Keeble et al., 2020 [21] 23 x 55 DNA modification on-chip for As a result, the ISFETs receive a signal boost,
DNA detection. reducing the detection limit, time to result, and
sample preparation required on-chip.
Future work
Why data minimization
• Collecting data is easy but becoming the rightful custodian of that data is challenging. It is essential to have
proper processes and controls in place to collect the minimum amount of data for the purpose of conducting
business, protect the data and, upon completion of data usage, ensure proper mechanisms to discard the data
in the rightful manner and minimize the enterprise’s data collection footprint.
Why Deep Learning
• The data transmission is affected by channel width and amount of the data. Resource limitation and data
amount are the bottle necks of the data transmission. Deep learning based data minimisation algorithm
overcomes the limitations by
 During the transferring of data the data sets are minimised over the carrier channels and
 Protects the data from different attacks.
 Different code words to different data in different data sets.
Why Deep Learning
• The data transmission is affected by channel width and amount of
the data.
• Resource limitation and data amount are the bottle necks of the data
transmission.
• Deep learning based data minimisation algorithm overcomes the
limitations by
 During the transferring of data the data sets are minimised over the carrier channels
and
 Protects the data from different attacks.
 Different code words to different data in different data sets.
Research GAP :
• Why do we need ISFET?
• Strong demand in biomedical sensing (H, K, Na ions)
• Miniaturized versions of the glass-membrane ion-selective electrode (ISE) appear to
be less stable
• For in vivo monitoring, glass-membrane ISE is fragile and cannot be used
• Goals
• Reduced dimensions to probe biology
• Fast response
• Simple integration with measurement electronics
• Solution
• Modify a common electrical engineering device (MOSFET) and use as a sensor (ISFET)
Highlights of Simulation work (Cont..)

2D Plot
Highlights of Simulation work

Electrolyte potential (V) - solid curves: 2D model, dotted curves: 1D approx


Highlights of Simulation work (Cont..)

Drain current (uA)


Highlights of Simulation work (Cont..)

Id-Vd curves for 3 different pH values


Highlights of Simulation work (Cont..)

Vg vs. pH - sensitivity curve of the ISFET


Summary
• The ISFET sensors are widely developed with long history and sophisticated
techniques.
• Due to the excellent properties of water-proof, all solid and high sensitivity of
ISFET, the ISFET-based system offers a promising means for the fabrication of
sensors for ions, DNA molecules, antibody-antigen proteins, enzymatic substrates,
and cell-related secretions.
• These types of analytes have been achieved with very good practicality and
excellent detection limit, such as picomolar or even femtomolar level, which are
enough for the practical use of real-time, continuous and reusable detections.
• Based on this, benefited from the mature fabrication process of ISFET, packaged
and portable sensing device can be realized for the commercialization to monitor
clinical diseases and cell metabolism processes.
• Also, the outlook and facing obstacles of the ISFET-sensing system can be found in
the recent research, including the Debye screening problem, in the high ionic
solutions, the miniaturization of the ISFET system especially for the fabrication, and
the multiplexed detections for different analytes with single chip at the same time.
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