Integrated Chemical and Biological Microsystems for Discovery and - - PDF document

▶
integrated chemical and biological microsystems for
SMART_READER_LITE
LIVE PREVIEW

Integrated Chemical and Biological Microsystems for Discovery and - - PDF document

Sep 30, 2023 162 likes •307 views

Integrated Chemical and Biological Microsystems for Discovery and Process Development Klavs F. Jensen Departments of Chemical Engineering and Materials Science and Engineering Massachusetts Institute of Technology Cambridge, MA 02139, USA

slide-1
SLIDE 1

Integrated Chemical and Biological Microsystems for Discovery and Process Development

Klavs F. Jensen

Departments of Chemical Engineering and Materials Science and Engineering Massachusetts Institute of Technology Cambridge, MA 02139, USA kfjensen@mit.edu MIT

Microsystems and Drug Development

Discovery – hits Lead Optimization Trials Product

Robotics, arrays, and combinatorial approaches have revolutionized the discovery process Lead optimization, process development remain challenges

I mages: beckmancoult er.com, t ecan-us.com, appliedbiosyst ems.com

slide-2
SLIDE 2

MIT

Reactor

ENIAC

Biochemical and Chemical Microsystems

Microfabrication has revolutionized electronic and optical information technology Microfluidic systems are emerging for analysis (microTotal Analysis Systems) Instrumented microchemical systems could revolutionize chemical research and production by

  • speeding up time to production with

reduced need for upfront capital investment

  • btaining chemical information (e.g.,

kinetics) and optimize chemical processes more efficiently

  • providing timely, efficient synthesis

platforms

  • providing safe and environmentally

friendly research and production tools

MIT

~2000

micro Total Analysis Systems (mTAS)

Laboratory equipment and facilities have changed Workflow - individual, separate

  • perations - has not evolved as

rapidly

~1930

Air Lines THERMAL REACTION DROP METERING SAMPLE LOADING GEL LOADING PC Board Glass Silicon Wire Bonds DETECT

Burns et al. Science, 282, 484 (1998)

SEPARATE

www.caliper.com

µ µ µ µTAS integrate fluid manipulations, reactions, separations, and analysis Ultimately information management must also be included

slide-3
SLIDE 3

MIT

µ µ µ µTotal Analysis Systems - Biological Applications

Applications

  • DNA identification
  • Assays
  • Synthesis

Advantages:

  • small volumes of

expensive reagents,

  • parallel operation,
  • integration of flow,

reactions, separation, and detection

  • integration with

information management

J.D. Harrison (Univ. Alberta)

www.gyrosmicro.com www.nanogen.com www.micronics.com Andreas Manz, Imperial College

MIT

Why Micro Systems?

Reduced length scales

  • Improved heat and mass transfer
  • Increased surface to volume ratio
  • Smaller reagent volume

Microfabrication

  • Controlled contacting of reagents
  • Integration of sensors and actuators
  • Ease of replication

Chemical research and development

  • Safe handling of reactive, hazardous chemistry
  • Small amounts of expensive materials
  • Ease of performing experiments on new chemistry
  • New methods for high throughput screening
  • Scalable manufacturing by “numbering up”
  • Chem/bio information and faster development
  • 0.002

0.038 0.078 0.118 0.158 0.198 0.238 490 530 570 610

Wavelength (nm) Absorbance

slide-4
SLIDE 4

MIT

Fabrication Methods

Si - MEMS LIGA (lithography + electroplating) Lamination of patterned glass,ceramic, polymer, and metal layers Rapid Prototyping (soft lithography) Micromachining (CNC, µ µ µ µEDM, …) Si advantages:

  • Si and coatings compatible with chemicals
  • wide range of tools for micromachining
  • ease of integration of actuation and sensing

Combination of new techniques and materials will be needed to realize advanced designs

50 µm

PDMS G.M. Whitesides Harvard

MIT

Microreactor for Liquid Phase Chemistry Integrated Heat Exchangers and Temperature Sensors

Thin-Film Temperature Sensor U = 1500 W/m2°C Heat Exchanger air gap cooling fluid reaction mixture

300µm

Optical fiber visible spectroscopy

Simulation Experiment

~ 20 ms mixing time Low Re flows - mixing by diffusion Accurate computational fluid dynamics predictions

slide-5
SLIDE 5

MIT

Microreactors Integrated with IR Spectroscopy Provide Rapid Optimization and Reaction Parameters

5 mm

0.1 0.2 0.3 0.4 0.5 0.6 1720 1745 1770 1795 1820 Wavelength (wavenumbers) Absorbance 2.43 s 4.86 s 48.6 s 81.0 s 243 s 1791 1738

H2O O Cl O OH → + HCl +

Silicon MIR crystal PDMS channels epoxy connectors 0.5 cm

1000 1200 1400 1600 1800 Wavenumbers (cm-1) Absorbance 5 x 10-3 Acetic acid, Ethyl acetate Ethanol

MIT

Microreactors for Photochemistry

Potential advantages:

  • Continuous flow
  • Enhancement of mass and heat transfer
  • Large surface area-to-volume ratio
  • No deposition on window

O

+

H O H H O O

hν (366 nm)

+

O

Model reaction: benzopinacol formation UV Lamp

Conversion Immediately Following Irradiation

0% 10% 20% 30% 40% 50% 2 4 6 8 10 12 flowrate (µl/min) conversion

Subsequent dark reactions

slide-6
SLIDE 6

MIT

Multiphase Microreactors

Traditional multiphase packed-bed reactors: KLa = 0.001 - 0.08 s-1 Dominated by mass transfer

G L L G

Microreactor KLa = 2-15 s-1 Mass transfer improved 100X

36-38 µm Particle size

100µ µ µ µm MIT

Multiphase Microreactors - Hydrogenation

k a K ] H [ Rate

i L SAT

η 1 1

2

+ =

Traditional multiphase packed- bed reactors: KLa = 0.001 - 0.08 s-1 10-8 10-7 10-6 10-5 10-4 0.001 0.01 0.1 1 10 100

KLa (s

  • 1)

Reaction Rate (mol/s/g catalyst)

Typical KL a values

Cyclohexene Hydrogenation Microreactor KLa = 2-15 s-1 Mass transfer improved 100X

Microreactor Results

G L L G

slide-7
SLIDE 7

MIT

Handling Reactive and Toxic Chemistry

0.2 0.4 0.6 0.8 1 50 100 150 200 250 300

Conversion Temperature (°C)

On demand synthesis of phosgene

  • 10 multichannel reactors: ~ 2 g/min.

R N C O R NH2 + COCl2 R NHCOCl

  • HCl

R NHCONH R

  • HCl

R N C O R N C O R N C O R NH2 + COCl2 R NHCOCl

  • HCl

R NH2 + COCl2 R NH2 + COCl2 R NHCOCl R NHCOCl

  • HCl

R NHCONH R R NHCONH R

  • HCl

Point-of-use synthesis of isocyanate Phosgene synthesis CO + Cl2

  • COCl2 (∆

∆ ∆ ∆H = -109 kJ/mol Shipping and storage restrictions

  • Distributed production

MIT

Microreaction Technology for Direct Fluorination

NH2 NaNO2/HCl HBF4 N N

+

BF4

−

∆ F + N2 + BF3 R

F R + F2 R + HF H (l) (g) (l) (l)

Hazardous HF and F2 Heat management

  • low temperature
  • diluted reactants

Obstacles for direct fluorination scale-up Multi-step process Low yields Not suitable for all aromatics Current routes to fluorinated aromatics

Pyrex glass Interchannel wall Silicon Nickel Ni coating makes device compatible with F2 and HF

Microreactor for direct fluorination Room temperature

  • peration gives similar

results as experiments at very low temperature

Microreactors expand operating regimes – allowing reactive chemistry to be performed safely under optimal conditions

slide-8
SLIDE 8

MIT Gas Phase Catalyst Gas Phase Catalyst Test System Test System 0.55 m 0.55 m 0.65 m 0.65 m

Demonstration of Scale-Up and Integration

Replace walk-in chemical fume hood space with desktop system System integration raise significant challenges x 2

Jim Ryley et al. DuPont David Quiram MIT

MIT

µ µ µ µFluidic Integration with Soft Lithography

PMDS based systems are flexible, but not compatible with most organic solvents Applications are primarily for biological systems

Peristaltic Pump

Quake et al. Science, 288, 113 (1999)

3D Microfluidic Networks

Whitesides et al. Anal. Chem. 72, 3158 (2000)

Microfluidic Arrays

Whitesides et al. Anal. Chem. 73 5207 (2000) fluid in fluid out air pressure

slide-9
SLIDE 9

MIT

µ µ µ µFluidic Systems for Biological Applications

Soft lithography methods provide opportunities for realizing microsystems with unique properties for biological applications

Microfabricated Fluorescence- Activated Cell Sorter

Quake et al. Nature Biotech. 17, 110 (1999)

Patterning Cells in Laminar Flow

Whitesides et al.

  • Acc. Chem. Res. 33, 841 (2000)

MIT

Example – Isolation of Mitochondria

Would like to explore role of specific organelles in cell signaling Conventional approaches

  • potential artifacts with mechanical
  • r chemical cell lysis
  • large samples and time

consuming

  • study of average of large

population (~106)

Microsystems

  • novel cell lysis and organelle

separation approaches

  • small cell populations (~103)
  • probe a subpopulation
  • integrate functions
slide-10
SLIDE 10

MIT

Lysing by Electroporation (HT-29 cells)

nucleus nucleus Intact cell Dissolving membrane Bare nucleus

Electroplated gold structure Channel on glass substrate SU-8 wall Gold thin film electrode Bond pad 200 µm 50 µm

µ µ µ µFluidic electroporation device

MIT

IsoElectric Focusing of Mitochondria

end of channel middle of channel beginning of channel

pH gradient Flow

slide-11
SLIDE 11

MIT

This experiment used full content of cell lysate and whole cells. Other fractions are not labeled, therefore not visible. Mitochondria and cells were in a homogeneous mixture at the start of the channel. Separation of mitochondria from whole cells in lysate achieved.

Separation of Mitochondria from Cells

Whole cells Mitochondria fraction

Enhanced contrast 100 µm

MIT

Integrated Device Concept

Integrated microfluidic devices could enable study of

  • rganelle and subcelluar response to stimuli

Lysing unit Rough separation unit Fine separation unit Buffer inlet Sample inlet /

  • utlet

Stimulus Image selection Micro Facs Buffer inlet Sample inlet /

  • utlet

Waste Sample Further analysis

slide-12
SLIDE 12

MIT

Microfermentation Techniques

Conventional approaches

  • Analytical techniques limiting
  • Large parameter spaces
  • Expensive fermentation units - time consuming experiments

Small instrumented bioreactors - µ µ µ µfermentors

  • Parallel investigations of multiple cell cultures in well defined

physiological states (steady state)

  • High throughput screen for function
  • Linking and incorporation of functional genomics
  • Optimization and translation into large scale processes

MIT

Opportunities

Integration of electronics, optics, and chemistry provide significant opportunities

Sensors

  • chemical spectroscopy - mass, IR, UV, NMR ….
  • biology - molecular, cells, tissue

Functional devices based on chemistry

  • chemical fuel based power devices
  • pharmacology
  • consumer products

Production systems

  • chemical synthesis units for on-demand, on-site production
  • materials synthesis
  • synthesis of nucleotides, proteins, sugars …
slide-13
SLIDE 13

MIT

Acknowledgements

The microreactor team Martin A. Schmidt

Leonel Arana, Sameer Ajmera, Cyril Delattre, Nuria De Mas, Aleks Franz, Tamara Floyd, Rebecca Jackman, Matthew Losey, Hang Lu, and David Quiram The staff of the Microsystems Technology Laboratories Langer Lab Sorger Lab MicroChemical Systems Technology Center DARPA, DuPont, and Novartis Foundation

MIT

Recent Relevant Publications

1.

K.F. Jensen, Microreaction engineering - is small better?, Chem. Eng. Sci. 56, 293-303 (2001).

2.

R.J. Jackman, T.M. Floyd, R. Ghodssi, M.A. Schmidt, and K.F. Jensen, Microfluidic systems with on- line UV detection fabricated in photodefinable epoxy, J. Micromechanical and Microengineering. 11 263-279 (2001).

3.

M.W. Losey, M.A. Schmidt and K.F. Jensen, Microfabricated multiphase packed-bed reactors: Characterization of mass transfer and reactions, Ind. Eng. Research, 40, 2555-2562 (2001).

4.

S.K. Ajmera, M.W. Losey, and K.F. Jensen, Microfabricated packed-bed reactor for distributed chemical synthesis: The heterogeneous gas phase production of phosgene as a model chemistry,

  • Am. Inst. Chem. Eng. J. 47, 1639-1647 (2001).

5.

S.L. Firebaugh, K.F. Jensen, M.A. Schmidt, Miniaturization and integration of photoacoustic detection with a microfabricated chemical reactor system, J. Microelectromechanical Systems, 10 232-238 (2001).

6.

  • N. de Mas, R. J. Jackman, M. A. Schmidt, K F. Jensen, Microchemical systems for direct fluorination of

aromatics, Proceedings Fifth International Conference on Microreaction Technology (IMRET5), Strasbourg, France, May 2001

7.

H.Lu, M.A. Schmidt, and K. F. Jensen, Photochemical reactions and on-line UV detection in microfabricated reactors, Lab-on-a-Chip, 1, 22-28 (2001)

8.

  • H. Lu, R.J. Jackman, S. Gaudet, M. Cardone, M.A. Schmidt, and K.F. Jensen, “Microfluidic devices for

cell lysis and isolation of organelles,” MicroTotal Analysis Systems (mTAS) 2001, J.M. Ramsey & A. van den Berg (Eds.), Kluwer Academic, Dordrecht (2001). pp. 297-8

9.

  • T. M. Floyd, M.A. Schmidt, K.F. Jensen, “A silicon microchip for infrared transmission kinetics studies
  • f rapid homogeneous liquid reactions,” ibid pp. 277-9

10.

R.J. Jackman, K. T. Queeney, M.A. Schmidt, and K.F. Jensen, “Integration of multiple internal reflection (MIR) infrared spectroscopy with silicon-based chemical microreactors,” ibid pp. 345-6

11.

D.J. Quiram, J.F. Ryley, J. Ashmead, R.D. Bryson, D.J. Kraus, P.L. Mills, R.E. Mitchell, M.D. Wetzel, M.A. Schmidt, and K.F. Jensen, “Device level integration to form a parallel microfluidic reactor system,” ibid pp. 661-3