Lecture 16: Biosensors

498Bio: Introduction to Biophysics MOS Capacitor

p = NA in neutral bulk

-

+

Threshold voltage: the volume density of electrons in the inversion layer is the same as the volume density of holes in the body MOSFET

OFF ON Modes of operation

Cut-off or Sub-threshold

V GS < Vth: Limited by carriers

Linear Region:

VGS > Vth and VDS < ( VGS - Vth)

Limited by VDS

Saturation Mode, VGS > Vth and VDS > ( VGS - Vth) ) Limited by carriers (pinch-off near the drain) Field-effect gating of ionic current

Nanotubes are 40–50 nm in inner diameter and 15 µm in length PRL 95:086607

gate voltage Vg shifts the distribution of the electrostatic potential in a nanotube

Doping: p-type n-type Protein transistor Neutral surface, charged protein

30nm gap in transistor

Avidin (positive charge)

[avidin] = 30µM [KCl] 10µM λD=30-100nm Gate potential modulates diffusion Protein transistor

1V (off)

1V (off)

-1V (on)

-1V across the channel; Modulate potential of the left gate, keep the right gate at 0

Applied Physics Letters 88, 123114 Ion-Sensitive Field Effect Transistor

pH sensor Sufficiently positive bias induces an n-type inversion layer in the channel between source and drain.

Upper layer of the gate Insulator can bind specific analytes

The drain current is determined by the effective electrical resistance of the surface inversion layer and the voltage between source and drain EnFET ImmunoFET Requires very low salt concentrations

Measures surface charge

Dynamics measurements changing ion concentration Bio FEDs

Capacitive EIS (electrolyte- insulator-semiconductor) sensor Bio FEDs

Light-Addressable Potentiometric Sensor

By sweeping the applied voltage, inversion to accumulation transition happens at the semiconductor Inversion surface

Accumulation Cell/FET hybrids

“Glucose sensor”

Metabolic activity changes pH Neurons on chips

Action potential modulates source-drain current

Small 1 (2005) 206-210 Label-free detection of DNA hybridization

Hybridization effectively modulates the charge applied to the gate

Alters capacitance, threshold voltage source-drain current Questions: Why less DNA gives more signal? How can it work without the reference electrode? Electroanalysis 18:1893 Taste Sensor Sourness: H+of HCl, acetic acid, citric acid and so on; Saltiness: NaCl; Bitterness: quinine, caffeine, L-tryptophan and MgCl2; Sweetness: sucrose, fructose, glucose, L-alanine and so on; Umami (Japanese for deliciousness’): monosodium glutamate (MSG) in seaweeds, disodium inosinate (IMP) in meat and fish and disodium guanylate (GMP) in mushrooms.

Meas. Sci. Technol. 9 (1998) 1919–1936. Taste Sensor Taste-sensing FET (TSFET) Does is work? Coffee Beer

“Carbon dioxide in the standard beer was removed by stirring it for one night” Sake Miso Simple physical model of FET sensor

Nanowires

Further examples Electronic Detection of Biopolymers

PRE 70, 031906 ID = f(USD, US)

Fix point measurement: keep ID, USD constant by varying US Theoretical model Nanowires

Charles M. Lieber, Harvard U. Nanowire electronics Making nanowires

Produced using metal clusters as catalysts via a vapour-liquid-solid process from an eutectic mixture Can be only 3 nm in diameter High aspect ratio 5 nm J. Phys. D: 39:R387 Heterogeneous nanowires

A change in the reactant leads to either (c) axial heterostructure growth or (d) radial heterostructure growth Nanowire FET

Top gated FET Source and drain are metal Assembly Langmuir-Blodgett assembly

Fluidic flow-directed assembly

The pattern depends on the flow

Uniaxially compress NW-surfactant Monolayer (aqueous subphase) Nanowires can be used as bioFET

Nanomedicine 1:51 What is so great? They are 1D!

No label, electronic read out, watch as it binds Drug design

Electronically monitor competitive binding of a drug

Chronic leukemia drug

PNAS 102:3208 Does it work? 500 nm

0.1 3 20 nM ATP

Gleevec is less charged than ATP Electronic detection of DNA

M

W

Goal: Distinguish F508 mutation (cystic fibrosis) Nano Lett. 4:51 Protein detection antibodies

p-type

n-type

0.9, 0.9, 0.009, 0.0009, 5 ng/ml Nat. Biotech. 23:1294 Prostate specific antigen (PCA) Protein detection

PSA CEA mucin-1 1: 0.9 ng/ml PSA 2: 1.4 pg/ml PSA Multiplex, real-time, label-free 3: 0.2 ng/ml CEA marker protein detection 4: 2 pg/ml CEA 5: 0.5 ng/ml mucin-1 Femtomolar sensitivity 6: 5 pg/ml mucin-1 Compete selectivity

Nat. Biotech. 23:1294 Electrical detection of viruses

PNAS 101:14018 Carbon Nanotubes

ChemPhysChem 5:1084 Fullerene Discovery: 1985

Water soluble fullerene

C60

Kroto, Curl, and Smalley were awarded the 1996 Nobel Prize in Chemistry Fundamentals

Rolling up a (10,10) nanotube armchair zigzag chiral (10,10) (15,0) (12,7) z

Ch Shigeo Maruyama, University of Tokyo

r =na+mb Metallic: n-m=3p, where p is integer Semiconductor: all other Band gap is proportional to the diameter a roll-up vector r and a chiral angle θ Multiwall CWNT

A) SWCNTs with a triangular cross- section fabricated in a porous alumina template

B) SEM images of the a carbon bulb and flask (by means of explosion) Synthesis Techniques:

Arc discharge between graphite electrodes the method first nanotubes were produced (1991)

Laser abilation (vaporize graphite with a laser pulse) produces primarily single-walled carbon nanotubes

Chemical vapor deposition (really long tubes)

Wendy Beckman, U of Cincinnati Use for electronics

STM image of band structure

Electrical conductivity up to a 1000 times greater than copper Cees Dekker, Delft Kink junction (metal-semiconductor). Acts as a molecular nonlinear diod

Nanotube transistor Nanotube is bucked as a straw Nano-RAM (NRAM)

Nanotube is pulled into ON state by an electric field

Van der Waals interactions are sufficient to stabilize the the ON state

Reverse potential switches the state back to OFF Functionalizing CNT

Covalent

noncovalent

hybrid

More in Nanotechnology 18:412001 Field-effect immuno-sensor

presence

absence Cees Dekker Biological Applications as Biosensors

Biological systems are known to be highly transparent to 700- to 1,100-nm near-infrared (NIR) light.

Change in the emission spectra indicates DNA damage produced by interaction with melphalan (chemotherapeutic agent)

Courtesy of the Strano group Gene delivery

+ plasmid DNA

= vaccination Intracellular protein transport

1. Nonspecific adsorption of proteins to SWCN

2. Transport through cell wall via endocytosis: i. uptake ii. break away from endosomes

3. Release using chloroquine cytochrom-c induced apoptosis

JACS 127:6021 Nanobombs (new cancer treatment)

folate moiety is for selective internalization by tumor cells

5 x 2 minute pulses kill cancerous cells normal cells live Toxicity ?