Development and Commercialization of a High Pressure ... · Solutions • Medical Devices LIFE...

1 © 2015 AB Sciex. GEN-MKT11-2066-B

Development and Commercialization of a High Pressure Platform for nano- and micro-HPLC

Don W. Arnold, PhD

VP, R&D and Principal Scientist

International MicroNano Conference 2015,

Amsterdam, December 8, 2015


FORENSICS

CLINICAL

DIAGNOSTICS

• IVD Testing

Solutions

• Medical Devices

LIFE SCIENCE

RESEARCH

FOOD AND

ENVIRONMENT

PHARMA AND BIOPHARMA

Markets We Serve

• Toxicology

• Forensics

• Proteomics

• Metabolomics

• Lipidomics

• Clinical Research

• Contaminations and Safety

• Quality and Authenticity

• Water and Soil Testing

• Biologics Discovery & Development

• Small Molecule Discovery and

Development



iChemistry™

Solutions Integrated

chemisties to

boost MS workflows*

Powerful Software Service and

Support New Mobile

Monitoring from a

partner you can

trust

High

Performance

Mass Spec Exceedingly

sensitive. Sharply

focused

Innovative

CESI 8000

INTEGRATED SOLUTIONS

Liquid

Chromatography Reliable standard,

micro and nano with

cHiPLC® systems*

Front-end

Partners E.g. Advion,

Phytronix, Beckman

Coulter

iMethods™

& Cliquid™ Instant methods

for accelerated

results*

* Research use only. Not for use in diagnostic procedures.

Workhorse Mass

Spectrometry LC-MS/MS workhorses,

intelligently

re-engineered

Strong Portfolio for Advanced and Routine Workflows

piston

bypass

1mm

Open

Closed

Open

Closed

Microfluidics Roots at Eksigent Technologies

4

Life science research and product development built upon micro- and nano-flow fluid delivery and analysis technologies

Core Technologies – Micro-/Nano-flow fluid delivery, sensitive microscale detection and analysis, system integration

Liquid chromatography

• Separate a complex mixture into

components according to chemical

properties

• Based upon partitioning between mobile

phase (liquid) and stationary phase (solid)

• Gold-standard for liquid phase analyses

(Pharmaceutical, fine chemicals, food and

beverage, agriculture, petroleum,

proteomics, etc.)

Conventionally - 4.6 mm diameter columns

Conversion to 2.1 mm with Ultra High Pressures

Eksigent – Nano- and Micro-flow HPLC focus

time

sig

nal

Motoyama and Yates, AChem 80, 7187 (2008)

nanoLC-MS for Proteomics

nanoLC-MS is powerful tool for proteomics

Separation of complex sample

Small sample consumption

Sensitivity

Positive ID

Flexible and sophisticated

Top-Down and Bottom-Up Approaches

Utility in longer-term will require increased

precision, improved robustness, ease-of-use, …

For nanoLC portion, this means:

Flow control

Columns

Overall system stability

System-to-system repeatability

Ease-of-use

Wehr, LCGC 24(9), (2006)

time

sig

na

l

Focus on two components

Fluid delivery Microfluidic Chips

EK Flow Control

1550 1600 1650 1700 1750 1800 1850 1900

0

1

2

3

4

5

6 Flowrate Setpoint

Measured EKFC Flowrate

Flo

w R

ate

[u

L/m

in]

Time [s]

• Inherently microscale (nm’s-thick double-layer)

• No moving parts or seals

• Precision, voltage controlled fluid delivery

• Large dynamic range (nL – 10’s mL)

• High pressure capability

• Excellent performance

EKFC Flow Meter

Flow Restrictor

Pressure Source

Injector

Column

Detector

US Patent 8795493

Microfluidic Flow Control

• Electropneumatic amplifier pumping system

• Direct flow rate feedback to rapidly adjustable pressure source

• Precise flow control at moderate to low flow rates

• Enables highly reproducible and accurate analytical separations

US Patent 8685218

Family of nanoLC prototypes and products to Market

EKPump-based Nanoflow metering system (2002)

Similar platform for first EP-based pumps (2004)

Second generation –

optimized EP pump

system. Two configs,

nano and micro (2006)

Third generation –

self-priming,

UHPLC, several

configurations

(2009)

Fourth generation – higher

precision, lower cost, user

changeable flow ranges (2012).

Lean MFG; SG plant (2013)

System performance

Challenge: Bridging the nanoLC-to-MS gap

nanoLC

Columns,

valves,

fittings,

tubing,…

MS

Need easy-to-use, cost effective nanoconnectors with low dead volume

and compatibility with high pressures and solvents

Apply microfabrication here to integrate

Focus on two components

Fluid delivery Microfluidic Chips

The engineering challenges in microfabricating HPLC

A

B

Injection Pre-heat Column Detection

Sample

Temp - control

Mix

Pump

Pump

Wide range of solvents, acids, bases, buffers

100’s bars operating pressure

Sample injection at high pressure

High pressure chip-to-world interface

Low dispersion requirements

Microfabrication

Fused silica – Isotropic wet-etch procedures

– Cylindrical channels

– Separation columns

– Multiple channels dimensions

– Injectors

– Fusion bonding

High pressure compatible structures (>4,000 psi)

• On-chip functionality:

• Valves (pL volumes)

• Injectors (precise 5 nL injections)

• Columns (variety of phases)

• Detectors (UV, Echem, MS, …)

• Connectors (high pressure, user-friendly)

• Sample Preparation (filters, traps, …)

Injector

Column

piston

bypass

1mm

Open

Closed

Open

Closed

J. E. Rehm, T. J. Shepodd and E. F. Hasselbrink, MicroTAS 2001 Proceedings, pp. 227-229

Chip-to-World Interface

• Microfabrication enabled

• Automatic alignment of multiple

simultaneous connections

• Excellent performance

• > 5000 psi demonstrated

• 4500 psi routine operation

• Robust - many make/break cycles

• Chip caddy – “Jump-drive-like”

• Excellent chemical compatibility

• Thermal control (0.2 C stability)

Connector port

Jig

Chip

US Patent 8021056

3-chip platform for using chip-based nanoLC traps and columns

Simple column/trap changes for different stationary phases

Direct injection, trap-elute, dual column and serial two column nanoLC-MS workflows

Excellent column-to-column reproducibility (<2%);

Independent temperature control for each chip

Microfabrication-enabled tool for easier, precise proteomics

nanoLC cHiPLC MS

Change the chips – change the workflow

Standard

Dirty

sample

Multiplexing

Exhaustive

1

2

3

4 Serial 2-column

2-column switching

Trap and elute

Direct inject

Offline Wash and Load

Sample

Injection

Online MS Acquisition Online MS Acquisition


Sample

Injection


Sample

Injection

Online MS Acquisition

Double Sample Throughput Two Column Switching

column 1

connector connector

column 2

LC SYSTEM

MS

VALVE

Customer feedback – longer columns, more phases

Mix-n-Match traps and columns to carry out different experiments

Carbon-phase for glycan separations

PGC

Human IgG

HILIC

Human IgG

Underivatized N-glycan mixtures from

bovine fetuin and human immunoglobulin G (IgG) (ProZyme,

Hayward, CA) were used to test the two separation phases.

Porous Graphitic Carbon (PGC)

and

HALO HILIC phases

Chip columns 75 um x 15 cm

300 nL/min flow rate

Water / ACN (formate); pH 4

Customer cross-site validation

Nature Methods 11, 149-155 (2014)

Same results from systems in Boston, Seattle and Seoul

23 © 2015 AB Sciex. GEN-MKT11-2066-B

• 200 µm ID chip with three well-defined regions (for MudPiT workflow)

• 1cm x 1cm x 1cm RP-SCX-RP (3µm-120A C18, 5µm PolySulfoethyl)

Advanced workflows - multiphase trap chips for MUDPIT

Goal: Simplify and improve 2D LC/MS for complex proteomics

Typical workflow (automated) consists of:

1. Load sample onto multiphase trap

(LOAD)

2. Load salt plugs to fractionate the

peptides (LOAD)

3. Separate the fractionates on

analytical column (Inject)

4. Repeat step 2 and 3 to separate all

fractions

Motoyama and Yates, AChem 80, 7187 (2008)

Mol Cell Proteomics. 2015 Jun;14(6):1708-19.

24 © 2015 AB Sciex. GEN-MKT11-2066-B

500mM 1500mM

50mM 2mM desalt

Reproducibility


25 © 2015 AB Sciex. GEN-MKT11-2066-B

Complex sample analysis with multiphase chips

Melanoma cells were cultured, lysed and digested with

trypsin prior LC-MS/MS and LC-SWATH-MS on

TripleToF 5600 MS (AB SCIEX) with cHiPLC® System

(Eksigent, part of AB SCIEX).

LC-MS/MS (5 μg):

- multiphase trap chips using 5-step salt fractionation

(0, 2, 50, 500 and 1500 mM ammonium acetate)

- 60 min ACN gradients (15 cm, 75 μm ID RP chip)

LC-SWATH-MS (5 μg):

- RP trap chip (0.5 mm, 200 μm ID)

- 60 min ACN gradients (15 cm, 75 μm ID RP chip)


26 © 2015 AB Sciex. GEN-MKT11-2066-B 2

6

Summary – proteomics tools

• Commercialized technologies driven by customer needs with clear value propositions

• Provides valuable data not easily obtained in other ways

• Much easier to use

• Flexibility to address a range of workflows

• Performance for quantitation

• Eksigent pump platform delivers state-of-the-art flow precision at low flow rates

• cHiPLC platform for nano/micro LC analyses is

• Enabled by microfabrication

• Excellent run-to-run repeatability on a single cHiPLC column

• Low variability between cHiPLC column

• Flexible platform enables multiples workflows with one device and minimal

reconfiguration time

27 © 2015 AB Sciex. GEN-MKT11-2066-B

Collaborators Reginald Beer (LLNL) Chris Welch (Merck) Mark Molloy (APAF) Christof Crisp (APAF) Funding NIST Advanced Technology Program Merck Pfizer

Colleagues

Dave Neyer Ken Hencken Nicole Hebert David Wyrick (IntegenX) Doug Cyr (Chevron) Patrick Leung (Illumina) Sammy Datwani (Labcyte) David Rakestraw (LLNL) Guifeng Jiang (Thermo) Jason Rehm Remco van Soest Phillip Paul Christopher Hoyle (UK) Bryce Young Erika Lin Christie Hunter Tom Covey

Thank you for your attention.

Advanced proteomics workflows Proteomic Analysis of E. coli Cell Lysates (1D vs 2D Workflow).

General micro and nanoscale HPLC challenge - variance

Loss of separation efficiency from instrumental components

‒ Large injection volumes

‒ Connection tubing

‒ Dispersion from fittings and connectors

‒ Detector cell

s2 = scol2 + sinj

2 + stube2 + sfittings

2 + sdet2

Column Type Column ID Column length s2extra

nL2

Micro LC 1.0 15 45,300

Capillary LC 300 15 370

Nanoscale LC 75 15 1.4

Proteomics data

5 replicate injections of yeast cell lysate

nanoLC 400 (300 nL/min) and TripleTOF 5600

70 transitions in E. coli lysate nanoLC 400 / QTRAP 5000

Enabled by precision of fluid delivery system,

sample introduction and detection systems

Set of tryptic peptide standards run at nanoflow rates from 200 nL/min and 1.5 µL/min

Shorter run times and higher throughput can be achieved using 200 µm cHiPLC columns

Discovery to Quantitation – customer transition

Other enabled applications

Nanoflow homogeneous biochemical assay

• Mix Incubate Detect (all on chip)

30nL <30 min 2-color FL

• Programmable Titration of Reagent / Compounds

Detection

• Absorbance

• Electrochemical

• Mass Spectrometry Interface

• Fluorescence

• Imaging

Field Corrected

counter electrodes

reference electrodes

working electrode

8 cm x 6 cm x 1.5 cm

Two-Color Fluorescence Detection

Fluorescence Intensity

TR-FRET

Coulometric Array – Series of coulometric detection

cells in which the applied potential used for detection is

monotonically changing.

Electrochemical Detection

Eksigent Potentiostat

Dual electrochemical cell chip

A/D

550 600 650 700 750 800 850 900 950 1000

-50

0

50

100

150

200

250

300

350

nA

pe

ak h

eig

ht

Eapp (mV vs Pd)

160 180 200 220 240 260

0

200

400

Time (sec)

Cu

rre

nt (n

A)

Cell 1 (900 mV vs Pd)


120 140 160 180 200 220

0

100

200

300

Cu

rre

nt (

nA

)

Time (sec)



Phenol (100 uM, 40 nL)

Uracil

Future work for transition to EC detection product:

• Refine cell fabrication to reduce dead volume – Degrades RC time constant

– Does not increase efficiency

• Further reduce Ru

– Promising results with 1 reference electrode cell

– Internal resistance of electrode

• Remove oxygen from mobile phase

• 2 and 4 cell chips – Interaction between cells

• Smaller particles – Transition to flow rates used with Express

• Lifetime testing – Fouling?

• Dispersion through cell (array of 12)

Results with Eksigent Potentiostat

Electrochemical Detection

On-chip MS Interface

Column Weir

Electrode

To ESI tip

30 um channel

Figure A – Chip connector assembly for electrospray

interface chip

Modified connector design

Dual tips, ease of use

Newer designs underway in 2013

(not shown)

Interface Comparison

New Objective Simple chip interface Plug-n-play interface

Cytochrome C Digest

2-60% B in 60 min

500 nL/min

LCQ Deca MS

75 um capillary column

On-chip valves for sample manipulation

Eksigent Proprietary and Confidential

Loop

W

EKFC MP Inj - Col - Det

Loop

W


Fill

Run

Loop

W


Loop

W


Fill

Run

S

Col

MP

W

S

Col

MP

W

S

Col

MP

W

S

Col

MP

W

Trap chip preconcentration of

5 standard peptides (2.5 pmol/uL each),

MS detection

2 4 6 8 10 12 14 16 18

Time (min)

15.42 17.32 1.56

16.36

15.21 1.90 1.33

0 2 4 6 8 10 12 14 16 18 Time (min)

12.26

13.31

12.14 1.16

6.5 E 8

1.4

E 9

500 nL

2 uL

Integration - Mixers

H2O + C5H12O2 + HCl 2 CH4O + C3H6O + HCl

NaOH + HCl H2O + NaCl

k1

k2

Characterize Mixer using Competitive-Consecutive Reactions:

Fourth Bourne Reaction

k1 = 1.4 x 108 m3/mol/s

k2 = 0.6 m3/mol/s tr = 1/k2[DMP]

X = [MeOH] out

[DMP] in

X = 1 tr < tmixing slow mixing

X = 0 tr > tmixing fast mixing

• Working with Merck collaborators to characterize mixing designs – GC-FID Analysis

• Initial results inconsistent with calculations – Herringbone and tee mixer tested

• Identified material compatibility problem – Strong acid not compatible with stainless steel in microfluidic format

• Testing system has been built with compatible materials

On-chip flow-based assay

• Homogeneous biochemical assays • Mix Incubate Detect (all on chip)

30nL <30 min 2-color FL

• Programmable Titration of

Reagent / Compounds

IC50/Ki: 4 – 30 min. depending upon application

Mechanistic studies: 20 min.

P

ATP

PKA

enzyme

TAMRA

fluorophore

+

+

ADP

Flow assay benefits

• Data quality

• Integrated liquid handler, incubator reader

• Reduced turnaround time for single compound

• Reduced operator time / error through

automation

• 100- to 1000-fold reduction in reagent

consumption

• Facile protocol to carry out simultaneous of

multiple reagents to determine

mechanism of action

MoA Studies with flow assay

Figure 10

Figure 10. Simulated initial rate data versus fraction gradient of inhibitor and substrate

modeled to the three classical inhibition mechanism types (competitive (black line),

uncompetitive (red line), and noncompetitive (blue line)) using eq 2. The following fixed

values were used to generate the simulated data: maximum substrate concentration = 10,

maximum inhibitor concentration = 10, Vmax = 10, and Km = 5. The values for the

inhibition constants for the three mechanism types are as follows: competitive inhibition

(Kis = 2, Kii = not applicable), noncompetitive inhibition (Kis = 4, Kii = 4), and

uncompetitive inhibition (Kis = not applicable, Kii = 2)

Fraction Gradient

0 0.2 0.4 0.6 0.8 1

Rel

ativ

e R

ate

0

0.5

1

1.5

2

2.5

3

Figure 10

Figure 10. Simulated initial rate data versus fraction gradient of inhibitor and substrate

modeled to the three classical inhibition mechanism types (competitive (black line),

uncompetitive (red line), and noncompetitive (blue line)) using eq 2. The following fixed

values were used to generate the simulated data: maximum substrate concentration = 10,

maximum inhibitor concentration = 10, Vmax = 10, and Km = 5. The values for the

inhibition constants for the three mechanism types are as follows: competitive inhibition

(Kis = 2, Kii = not applicable), noncompetitive inhibition (Kis = 4, Kii = 4), and

uncompetitive inhibition (Kis = not applicable, Kii = 2)

Fraction Gradient

0 0.2 0.4 0.6 0.8 1

Rel

ativ

e R

ate

0

0.5

1

1.5

2

2.5

3

Competitive (black)

Non-competitive (blue)

Uncompetitive (red)

SK

IK

SVv

ism

1

max

Competitive

iiism K

ISK

IK

SVv

11

max

non-competitive

iim K

ISK

SVv

1

max

uncompetitive

iiis KBIBS

KBIKm

BSVv

11

max

Figure 11

Figure 11. Representative NanoCF data for glycogen phosphorylase using the continuous

variation MOA method in comparison with a microtiter plate-derived orthogonal global

dataset. a) NanoCF data in which the following variables were used: maximum [glycogen] =

1 mg/mL; maximum [inhibitor] = 2 mM. Data from an independent control experiment

yielded a Vmax of 8x105 relative fluorescence units and a Km value of 0.08 mg/mL and was

used in fitting the MOA data to eq 2 (experimental data shown in red and the fit to eq 2 in

black). The calculated values for Kis and Kii are 0.29 ±0.01 mM and 0.59 ±0.01 mM,

respectively. b) A conventional microtiter plate orthogonal dataset demonstrating

noncompetitive inhibition against glycogen phosphorylase. A fit of the data to a

noncompetitive inhibition model yielded the following inhibition constants: Kis = 240 ±110

mM and Kii = 1700 ±900 mM.

1/Glycogen (mL/mg)

0 2 4 6 8 10 12 14 16

1/R

elat

ive

Rat

e

0.002

0.004

0.006

0.008

0.01

0.012

0.014b)

Fraction Gradient

0 0.2 0.4 0.6 0.8 1

Rel

ativ

e R

ate

5e5

6e5

7e5

8e5

9e5

a)

Figure 11

Figure 11. Representative NanoCF data for glycogen phosphorylase using the continuous

variation MOA method in comparison with a microtiter plate-derived orthogonal global

dataset. a) NanoCF data in which the following variables were used: maximum [glycogen] =

1 mg/mL; maximum [inhibitor] = 2 mM. Data from an independent control experiment

yielded a Vmax of 8x105 relative fluorescence units and a Km value of 0.08 mg/mL and was

used in fitting the MOA data to eq 2 (experimental data shown in red and the fit to eq 2 in

black). The calculated values for Kis and Kii are 0.29 ±0.01 mM and 0.59 ±0.01 mM,

respectively. b) A conventional microtiter plate orthogonal dataset demonstrating

noncompetitive inhibition against glycogen phosphorylase. A fit of the data to a

noncompetitive inhibition model yielded the following inhibition constants: Kis = 240 ±110

mM and Kii = 1700 ±900 mM.

1/Glycogen (mL/mg)

0 2 4 6 8 10 12 14 16

1/R

elat

ive

Rat

e

0.002

0.004

0.006

0.008

0.01

0.012

0.014b)

Fraction Gradient

0 0.2 0.4 0.6 0.8 1

Rel

ativ

e R

ate

5e5

6e5

7e5

8e5

9e5

a)

1/Glycogen (mL/mg)

0 2 4 6 8 10 12 14 16

1/R

elat

ive

Rat

e

0.002

0.004

0.006

0.008

0.01

0.012

0.014b)

Fraction Gradient

0 0.2 0.4 0.6 0.8 1

Rel

ativ

e R

ate

5e5

6e5

7e5

8e5

9e5

a)

Courtesy of GSK

Three models for inhibition re-cast to

single model

Simultaneous titration of S and I

Requires very precise and accurate

control of conc

Limited verification experimentally

Flow Assay system

Liquid handling

Reagent Storage (4 ºC-RT)

Microfabricated chip-based analyzer

• Temperature controlled (e.g., 37 ºC)

• Mix, Incubate, Read

• No evaporation

• Coatings

Fluid delivery system

• Nanoflow precision and accuracy

• Programmable continuous dilution

• Fluorescence detection

• Designed for higher data quality,

lower throughput

Particle Imaging System

Rapid Particle Analyzer

Parallel; long illumination time (up to 5 s)

Good flow control allows particles to be trapped in well

defined positions on a channel in a microfluidic device

Laser or LED illumination

Flow Cell

Serial; short illumination time (~5

x 10-6 seconds)

Laser

Integrated cHiPLC system performance Includes microfluidic injector, column and detector

0.2 x 100 mm, 3 mm C18 Luna, 2 L/minTheophyline, Sulfamerazine, Hydrocortizone, Amitriptyline, Bumetanide, Fenoprofen

0.2 x 150 mm; 5 m C18 Jupiter; 2 L/min; 50-85% gradient; 0.1%TFA; 214 nm; Rib A, Cyt C, Holotransferrin, Apomylglobin

0

200

400

600

800

1000

1200

1400

0 5 10

Ab

so

rba

nce

(m

AU

)

Time (minutes)

Small Molecule Separations

0

200

400

600

800

1000

1200

1400

1600

1800

0 10 20 30

Protein Separations

Time (minutes)

Ab

so

rba

nce

(m

AU

)

2D cHiPLC

On-chip valves for sample manipulation

Eksigent Proprietary and Confidential

Loop

W


Loop

W


Fill

Run

Loop

W


Loop

W


Fill

Run

S

Col

MP

W

S

Col

MP

W

S

Col

MP

W

S

Col

MP

W

Trap chip preconcentration of

5 standard peptides (2.5 pmol/uL each),

MS detection

2 4 6 8 10 12 14 16 18

Time (min)

15.42 17.32 1.56

16.36

15.21 1.90 1.33

0 2 4 6 8 10 12 14 16 18 Time (min)

12.26

13.31

12.14 1.16

6.5 E 8

1.4

E 9

500 nL

2 uL

5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Time (min)

100%

50%

25%

10%

Sample: 3-protein digest

Amylose

PSA

Lactose peroxidase

1st dimension:

SCX: Polysulfo-ethyl Aspartamide SCX (silica),

5cm X 0.32 mm, 5 um, 200 A.

A: 5 mM NaOPO; B: 600 mM NaOPO

Trap: On-chip; 4 mm x 0.5 mm, C18 Luna, 3 um

2nd dimension:

RP: On-chip 5cm x 0.2 mm, C18 Luna, 3 um

A: 0.1% FA/H2O; B:0.1% FA/ACN

2% 50% B; 30min

Flow control: Eksigent NanoLC 2D; 500 nL/min

UV

Abs (

214 n

m)

2DLC Separations

Separate trap and column components

Integrated Chip Design

Trap-column combination Sample Rinse

2D Separation

Salt: 45 mM ammonium acetate


Salt: 30mM ammonium acetate



Sample: 1 pmol Lactoperoxidase digest.

1st dimension:

SCX: Polysulfo-ethyl Aspartamide SCX (silica),

5cm X 0.32 mm, 5 um, 200 A.

Trap: On-chip; 4 mm x 0.5 mm, C18 Luna, 3 um

2nd dimension:

RP: On-chip 5 cm x 0.2 mm, C18 Luna, 3 um

Flow control: Eksigent NanoLC 2D; 500nl/min

0 10 20 30

UV

Absorb

ance

Time (min)

Integrated valve, trap and RP column

On-line protein digestion and analysis

20 40 60 80

0

200

400

600

800

Abs (

21

4 n

m)

Time (min)

Cytochrome C digest (trypsin); 15 cm x 0.2 mm Zorbax (3

um SB300) column; 40 pmol injection (5ul at 8 pmol/ul),

2-50% B, 90min gradient

Cytochrome C on-line digest; immobilized trypsin column

(4 mm x 0.2 mm); 37C; 15 cm x 0.2 mm analytical

column; Zorbax (3 um SB300) column; 100 pmol injection

(5ul at 1pmol/ul), 2-50% B, 60 min gradient

20 40 60

0

500

1000

1500

2000

Ab

s (2

14

nm

)

Time (min)

ch0

UV detector RP column

Autosampler Digest column

Trap

1ST Channel

2nd Channel

UV detector RP column

Autosampler Digest column

Trap

1ST Channel

2nd Channel

Range of microfluidic capability

Fluid delivery Integration Detection Micro-Fabrication

Electropneumatic

Electrokinetic

Packed channels

Integrated valves

Microconnectors

Absorbance

Fluorescence

Electrochemical

MS Interfaces

Pump and Assay Systems

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