G4 Bio Medical Sensing

8/3/2019 G4 Bio Medical Sensing

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BIOMEDICAL SENSING(Nano-bio-sensors)

Diego A Gomez-Gualdron

Texas A&M University

February 23rd, 2010


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Introduction

Sensing means becoming aware of


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What if I can see?

Add instrumentation


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Sensors applications

The primary goal is detect danger so an action can betaken Pressure sensingGas concentration

sensing

We need a property that correlates to what I want to measure


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What I want to measure in medicine?

The concentration of a biomarkers can tell me the

nature of a disease and what stage it is in

WHITE CELLS INFECTION

CREATININEKIDNEY

MALFUNCTION


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Sensibility range

Antigen Concentration Organ Confinement

PSA 4-10 ng/ml 75%

PSA >10ng/ml >50%

PSA (prostate specific antigen) is a biomarker

related to the existence of prostate cancer


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Nanosensors

If I want to measure

something small, I needsomething small


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Nanosensor technology

LABEL-FREE LABEL

In labeled technology, some sort of label has to be

attached to the biomarker, which otherwise would

pass by undetected


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Labeled technology examples

Quantum dots

Gold nanoparticles

Radioactive inks

labeled Non-labeled


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Why would I prefer a label-free

approach?

1. One fewer step to worry about (labeling)

2. I do not need a device to excite and image the

sample

3. I might create a lab-on-a-chip device

4. I would end-up with point of care (POC) testing


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Point of care testing

test results treatment

SCENARIO A

SCENARIO B

Wait results treatment


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FET Nanosensor

Based on a conventional MOSFET

Source:wikipedia


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Proof-of concept

Performed by Lieber et al(Science 293, 1289, 2001)

nanowire

Science 293, 1289, 2001


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pH Sensing

It is a good start to demonstrate the sensibility to

superficial charge changes

Science 293, 1289, 2001


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Antibody sensing

Study of the biotin-streptavidin system

biotin

streptavidin

Science 293, 1289, 2001

250nM Unmodified

SiNW

d-biotin 25 pM


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Why it works

Antigens appear during

disease and can be used

as biomarkers

Nature has made the binding

between antibodies and

antigens very specific


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A simple model

Analytical Chemistry (2006), 2093-2099


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Some thoughts

Nanowires are sensitive to the antigen-antibody binding, because the

local charge transfer is a strong enough effect for the nanowire

dimensions

Building nanosensors is complicated, involving either top-downapproaches using sophisticated litographic techniques, or bottom up

techniques

Residual effects during fabrication causes spurious effects duringfunctioning

Find a more process friendly substitute, but that is expected to be as

sensitive


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Si Nanoribbons as nanosensors

Introduced by Linnros et al (Nanoletters, 8, 3, 945-949 (2008))

Nanoletters, 8, 3, 945-949 (2008)

It behaves like a Schottky

barrier


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Antibody sensing

Once again, the biotin-streptavidin system is studied the nanoribbon is

functionalized with biotin (biotinalized) and the solution contains streptavidin

at different concentrations

biotin

streptavidin

Si Nanoribbon

Nanoletters, 8, 3, 945-949 (2008)

Modified from Science 293, 1289, 2001


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Good newsOnly there was response to

Streptavidin

There is a concentration dependant

response

Sensitivity can be

manipulated

Nanoletters, 8, 3, 945-949 (2008)


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Are we done yet?

The short answer is NO!!!...

For the nanosensor to be effective, the sensing has to be

performed in the presence of a pure buffer solution. On theother hand, the human blood is nothing like it.

The long answer is ...


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The device

Two separate chambers. The big one has a chip functionalized with

antibody-photocleavable groups. The small one has the nanosensors.

chip

Nature Nanotechnology, 5, 153 (2010)


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First blood

Spiked blood containing the antigens PSA (prostate cancer) and

CA15.3(breast cancer) flow into the big chamber



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Wash and sunbathe

The buffer solution is added to leave the chamber blood-free. UV

light breaks the photocleavable-antigen pair.

Now I have a buffer solution of antigen!!!



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The happy ending

The content of the big chamber flows toward the small chamber,

where sensing takes place



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Verifying the capture


A modified ELISA test is performed


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The sensor

Sensor geometry and behavior similar to the one reported by Linnros

et al(2008)

Schottsky barrier



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The performance

The performance described in previous studies is retained


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Conclusions

The advances in label-free nanosensing havebeen plausible during the last decade

Nanoribbon sensors appears to have thenecessary sensitivity and are less troublesomethan nanowires

The current sensitivity of nanosensors is in theappropriate range for early cancer detection


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Specific Assessment

Fahmy et al did not performed a control with an antigennot specific to the selected antibodies.

The correlation between the introduced concentration and

the captured/release concentration must be improved

An exploration of the optimal operation parameters(potentials, thickness, etc..) must be done

The technique can be assembled in a self-containedcompact design


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General assessment to the topic

Silicon nanowire/nanoribbons are ideally suitedfor nanosensing, due to sensitivity and ease offunctionalization

A successful implementation of the techniqueawaits for significant advances in the detection ofsuitable biomarkers

Charge screening effects (Debye length) are still apoint to be addressed through more clever designof the nanosensors


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General assessments

The research for new and more sensitive materials must not

be discarded

Complete charting of a disease needs more than one antigen,

so improvements in microarray arrangements must be made,

as well as independent signal detection

Microfluidics studies must be made to set the fluid

parameters to optimize binding, diffusion effects and

response times


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References

Science 293,1289 (2001) Lieber, et al. Nanowire Nanosensorsfor highly Sensitive and Selective Detection of Biological and

Chemical Species

Nanoletters 8, 3, 945 (2008) Linnros, et al. Silicon Nanoribbons

for Electrical Detection of Biomolecules Nature Nanotechnology, 5, 138 (2010) Fahmy, et al. Label Free

biomarker detection from whole blood

Clinical Chimica Acta, 381, 93 (2007) Chan & Liang. Enzymes

and related proteins as cancer biomarkers (REVIEW) Clinical Chimica Acta, 385, 37 (2005) Jain, Nanotechnology in

clinical laboratory diagnostics (REVIEW)


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G4

Rebuttal: Biomedical Sensing

Diego A. Gmez-Gualdrn


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Comments G2: It was not mentioned in the introduction any of the design

considerations for a sensor like accuracy, repeatability, resolution,hysteresis, linearity etc

A:/ I decided to make a much more friendly introduction to the topic, instead

of going on technical details that might have done the introduction more

obscure. Notice that a high percentage of the audience is at the

undergraduate level and they are not so familiar with the nanotechnologyworld. I think that the audiences academic background guarantees that they

have a feel of what to expect from a sensing device (accuracy and so on..)

My main focus in the introduction was to give the audience just the

necessary information to be able to follow through the presentation of the

paper results. The paper results were not focused in the sensor calibration(resolution, accuracy, etc), but on the ability to actually sense at such small

concentration.

C t


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Comments G2: Some technical terms were not defined, like Schottky Barrier,

nanoribbon, streptatividin, photocleavable-antigen pair, some

terminology was confusing, like 1 anti-PSA, 1 anti-CA15.3

A:/ The 2-dimensional character of the nanoribbon was mentioned incontrast to the 1-dimensional character of the nanowire. Moreover, itwas pointed that this was one of the reasons why was easier to workwith nanoribbons.

It was mentioned that strepatavidin/biotin is an antibody/antigen pairwidely used in this kind of studies

Photo=light, Cleavable=break. A photocleavable antigen pair whereinan antigen breaks loose under UV light. This was explained since thisis what enables the transfer of antigen from the big chamber to the

small chamber 1 anti-PSA: the antibody corresponding to the antigen PSA. Use the

same reasoning for 1-anti-CA15.3

The point of the Schottky barrier was only brought up to point thesimilarities of the electrical behavior of the presented nanosensor tothat of a conventional Schottky barrier FET


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Comments G2: The microfabrication process was not illustrated, and the

nanowire functionalization procedure was also not shown. Thetechnical challenge implied on making the nanodevice and making it

work was not explained

a) The focus of the presentation was centered on the functioning of the

device, not on the fabrication of the devices. Therefore, only I few

remarks about the fabrication process were done.

b) The presentation showed three mile-stone papers on the development

of nanosensors since 2001 up to date. Throughout the presentation, it

was constantly discussed the challenges at-the-paper-date and the

approach used in the paper to solve it. Moreover, some of these

challenges were pointed to explain the transition from a nanowire- to

a nanoribbon based sensor. All the three papers were about making

it work. If the technical challenges refer to their fabrication, answer

a) applies


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Comments

G6: How effective are nanowires in nanoFET in detecting such charge

transfer?

Nanowire technology correspond to the first paper presented. The

plots shows that concentrations in the order of picomolar were

detected. This corresponds to the binding of about six antigens to the

functionalized nanowire. It is noteworthy, though, that this sensitivityoccurs under specfic conditions. For instance, the presence of a buffer

solution is a must. However, there are ways around this, as shown in

the third paper


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Comments

G6: What methods are currently being used to fabricate these

nanosensors?

The use of silicon nanoribbons makes it preferable to use top-down

approaches as e-beam litography and selective etching, using silicon

on insulator wafers as starting materials.

G6: Could this be batch processed for cost reduction and large scaleproduction?

Yes, but it is not the main concern just now. The current primary

objective is to make the technology work properly


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Comments

G6: What are the methods in detecting which antigen is binding withwhich antibody in the nano-scale sensing

If your question refers as to what antibody must the sensor befunctionalized with in order to detect an specific antigen, I must say

that usually labeled technology (fluorescence assays) has been

traditionally used to determine what antigen binds with what

antibody. However, the implementation of better biosensors like the

one presented in this study significantly would speed up the screeningof these pairs, which itself would help to create more selective

nanosensors


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G6: Is the number of charge transferred different fordifferent antigen-antibody combination?

Yes, it is different because different compounds modifythe electron density in the neighborhood of nanosensorsurface in slightly different ways. As you can see for thersults of the third paper, identical concentration ofdifferent antigen produces a different slope in the

response curve

Comments


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General Comments

I agree with comments pointing to the length of

presentation and the use of filler words. I will work

on improving my presentation skills. Also I will

improve the graphic labels There was some mixed feelings about the informal

approach used in the presentation. So I guess I will

use a more formal approach in the up coming

presentation


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G1

Review : Biomedical Sensing

By Edson P. Bellido Sosa


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The presenter described in detail what a bio-sensors is and what we want to detect in

biomedical applications. He explained why one wants a label free detection. He analyzed 3

papers. The first is based on a silicon nanowire functionalized with amine group and

bioting in a FET configuration, they measured the change in pH and he explained how the

nanosensor works. In the second paper they test a silicon nanoribon and measured thechange in conductivity according to the concentration of streptavidin. Finally in the third

paper they used microfluidic channel technology to include a filtering step in the process

of sensing, in this paper they measure the concentration of PSA and CA15.3, which are

biomarkers for prostate cancer and breast cancer respectively, using the change in

conductivity in a silicon array.

Future research would be about the use of

other nanomaterials for nanosensing to

increase the sensitivity and selectivity. Also

more research needs to be done in the area of

design optimization of the lab on a chip

structures to avoid false positives or negatives.Also other interesting area is the discovery of

new biomarkers which are directly related to a

disease.

http://image.absoluteastronomy.com/images/encyclopediaimages/f/fr/free_psa.png


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G2

Review Biomedical Sensing

by Alfredo Bobadilla

Review of biomedical sensing lecture


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It was shown how a functionalized Si nanowire can be usedfor electrical detection of very low concentration of molecularbiomarkers. The working principle and performance of thebiosensing device was illustrated.

Nevertheless it was not mentioned in the introduction any ofthe design considerations for a sensor like accuracy,repeatability, resolution, hysteresis, linearity, etc.

Some technical terms were not defined, like Schottky barrier,nanoribbon, streptatividin, or photocleavable-antigen pair. Andsome molecular biology terminology was also confusing like

1 anti-PSA, 1 anti-CA15.3 which was shown together withpictures.

The microfabrication process was not illustrated, and thenanowire functionalization procedure was also not shown.The technical challenge implied on making the nanodevice andmaking it works was not explained.

Alfredo D. Bobadilla


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G3


by Mary Coan


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Review

Overall a great presentation

Nanosensors are used for early cancer

detection

Nanosensors using nanoribbons are moreeasily fabricated than nanowires and

have similar sensitivity Explained in detail sensors and

nanosensors Graphics were used as aids


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Review

Presented a significant amount ofinformation about bio-nanosensors in a

fun and educational way Assessment of the paper and topic was

spot on


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G5


by Norma Rangel

Biomedical sensing (Nano-bio-sensors),


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Biomedical sensing (Nano bio sensors),

by Diego A. Gomez-Gualdron

Diego did a very educational and organizedpresentation about sensors for biomedicalapplications, with an emphasis on biomarkers

used to detect cancer. The presentation is very self explanatory and

didactic, the papers chosen are state of the art

and very promising for early detectionbecause they are able to detect inconcentrations in the range of 4-10 ng/ml


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G6


By Jung Hwan Woo


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How effective are nanowires in

nanoFET in detecting such charge

transfer?

What methods are currently beingused to fabricate these

nanosensors? E-beam litho? X-ray?

Could these be batch processed for

cost reduction and large-scale

production?

What are the methods in detecting

which antigen is binding with which

antibody in the nano-scale sensing?

Is the number of transferred chargedifferent for different antigen-

antibody combination?

G4 Bio Medical Sensing

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