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Office for Technology Licensing and Industry Collaboration ● http://techtransfer.tufts.edu
Tufts School of EngineeringTufts School of Engineering
Polymer Discovery Via Polymer Discovery Via Microfluidic Enzymatic SynthesisMicrofluidic Enzymatic Synthesis
Prof. Peter Y. WongProf. David KaplanTufts University - Medford, MA
October 3, 2006
Tufts School of EngineeringTufts School of Engineering
OverviewOverview
• Markets• Needs• Problems• Solution• Team• Next Steps• Summary
Biochemical Science
Enzyme Polymer science 1970-
Synthesis 1990-
Micro-fabrication
Microsystems Technology
Engineering
Mechanical Electronics
Tufts School of EngineeringTufts School of Engineering
Many MarketsMany Markets
• Any market that benefits from new biochemicals• Improved Foods
– Additives, Modification, Nutrition
• Green Chemistry– Agricultural, Packaging, Analysis
• New Medicines– Topical, Digested, Structural
Tufts School of EngineeringTufts School of Engineering
Markets Needs vs.WantsMarkets Needs vs.Wants
• New products– Better– Faster– Cheaper– Differentiated
• Macro and Micromolecules needed– New material– New processes
• Focus on new polymers and processes
Tufts School of EngineeringTufts School of Engineering
Problems and RisksProblems and Risks
• Current Polymer Discovery Process– Long time with process and people– High costs and large resources needed– FDA, EPA stringent regulations– Limited research to commercialization
• Alternate Approaches– Nanoscience/technologies - far in future?– Biomimetics/Bioinspiration - hit or miss?– Microengineering/fluidics - scalability?
Tufts School of EngineeringTufts School of Engineering
Our SolutionOur Solution
• Achieve “Green ( ) Polymer Chemistry” through – Enzymatic Synthesis and– Microfluidics
• Enzymatic polymerizations can produce products– via mild reaction conditions w/o toxic reagents– in an environmentally friendly synthetic process– that can be scaled from microscale to macroscale
• Target macromolecules include– polysaccharides, polyesters, polycarbonates, poly(amino acid)s,
polyaromatics, and/or vinyl polymers.
Tufts School of EngineeringTufts School of Engineering
Microfluidic Enzymatic CascadeMicrofluidic Enzymatic Cascade
• Universal Lab-On-Chip is very far away• Application Specific Integrated Microfluidic
(ASIM) device • Example ASIM –
– produce vitamin C enriched polymers (PMMA) polymer – has both scientific and market value.
Antioxidant Polymer
Natural antioxidant
Monomer
Enzyme 1
Enzyme 2
Tufts School of EngineeringTufts School of Engineering
PMMA PolymerPMMA Polymer
• Disruptive Technology in Packaging– Vitamin C enriched polymers can replace butylated hydroxy
anisole (BRA) and butylated hydroxy toluene (BHT) - FDA limits conc. To 0.02%.
• New Topical Medicine – Antioxidants are considered important in reducing aging-related
phenomena by providing protection against free radicals.
• Nutraceutical Supplementation– Ascorbic acid may have an overall positive impact on public
health because humans lack the ability to synthesize vitamin C
Tufts School of EngineeringTufts School of Engineering
ASIMASIM
– Goals:
– Two enzymatic cascade reactions to produce PMMA
– low cost devices made of poly(dimethylsiloxane) (PDMS)
– efficient method to optimize process with external controls
Tufts School of EngineeringTufts School of Engineering
Translation from Abstract to HardwareTranslation from Abstract to Hardware
Reaction Vessel #1
React with lipase
Reaction Vessel #2
React with HRP
Input:
monomer
in solvent
Input:
ascorbic acid
Input : hydrogen
peroxide
Output: unreacted
ascorbic acid
Output: unreacted
hydrogen peroxide
OutputReaction Vessel #1Input:
in solvent
Input: ascorbic acid
Input
: hydrogen peroxide
Output: unreacted
ascorbic acid
Output: unreacted
hydrogen peroxide
Output
polymer
::
ascorbic acid
lipase
HRP
monomer
AA-Monomer
P-AA-MMA
Check Valve#1 #2
AA- Ascorbic Acid
MMA- Methyl Methacrylate
PMMA- Poly (Methyl Methacrylate)
P-AA-MMA – Ploy L-Ascorbic Methyl Methacrylate
HRP – Horse Radish Peroxidase
monomer
Antioxidant polymer
ascorbic acid
lipase
AA-Monomer
Hydrogen peroxide
HRP
AA-Monomer
Tufts School of EngineeringTufts School of Engineering
Improved VersionImproved Version
Vessel 2 Poly L-Ascorbyl Methyl methacrylate(P-AA-MMA) (G.2)
Vessel 1 L-Ascrbyl Methyl methacrylate(AA-MMA) (G 1)
1.77ul2,4-pentanedione(trigger)
Mix 22 hours(G2.3) Shaking 1 hr
2.5mg2,6-di-tert-butyl-4-methylphenol+10% Diox.
Anti-poly60C (G1.3)
9.3ulHydrogen Peroxide12.5mgAntarctica lipase (free)+ 40% Diox.
Enzyme(G1.2)
2 ul waterDissolve(G2.2)
1.5mlx2anhydrous Dioxane
1.6mg/
0.05ml
HRP
0.11 mlTetrahydrofuran (solvent)(THF) N2 flushed
0.182 mL, 1.278 mM
2,2,2-trifluoroethyl methacrylate
~0.02 g 0.082 mM
L-Ascrbyl methylmethacrylate
Mix1(G2.1) w/G2.2
150mg, 0.852 mM
L-ascorbic acid(AA)+50% Diox.
FunctionalSubstrate(G1.1)
Quantityused
MaterialStepQuantity used
MaterialStep
Stage II HRP Polymerization L-Ascrbyl Methylmethacrylate
Reaction vessel 260 min.<reaction time<90 min. 20 min.<shaking time<30 min.Flow rate<0.01 ml/min.
2Stage I Enzymatic TransesterificationSynthesis L-Ascrbyl Methyl methacrylate
Reaction vessel 150C<reaction temp <60C, 45 min.<reaction time<60 min.Flow rate<0.01 ml/min.
1
1st Vessel>50C
2nd Vessel
Hydrogenperoxide
2,6-di-tert-butyl-4-methylphenol, Dioxane.
A
BC
D
E
Initiator
HRP,THF
Ascorbicacid, Dioxane
TFM, Diox.Lipase,
AA_PMMA,/PMMA/
Function driven
Tufts School of EngineeringTufts School of Engineering
ASIM manufacturingASIM manufacturing
• DRIE Si wafer• PDMS Casting• Thermal Plasma Bonding to
glass slide• Embed fluid connectors
PDMS on Glass slide
PDMS on SI
Tufts School of EngineeringTufts School of Engineering
External HardwareExternal Hardware
Micrometer
Sample loading
Pneumatic controlling
Syringes
Tufts School of EngineeringTufts School of Engineering
Chemical AnalysisChemical Analysis
Repeat unit
Repeat unit
Molecular weight/ charge
Signal strength
Macro
Micro
• Macro vs. Micro comparison with MALDI-TOF• Need purification but polymer exists
Tufts School of EngineeringTufts School of Engineering
TeamTeam
• David Kaplan - expertise in enzymatic reactions
• Peter Wong - expertise in microfluidics
• Jin Zou - PhD graduate in Mechanical Engineering
• Martin Son - Tufts Technology Transfer Office
• Tufts Capabilities:– Enzymatic synthesis research, development, and
production
– ASIM - Microfluidic design, analysis, and fabrication
– Polymer discovery program – design of experiments and testing
Tufts School of EngineeringTufts School of Engineering
Next StepsNext Steps
• Identify 2 to 3 market products to tackle– 2 months
• Initial description of enzymatic synthesis process– 2 months
• Convert preliminary patent application to full application with these examples of synthesis– 1 month
• Develop next generation of ASIM devices for those specific market products– 6 months
• Develop new polymer products– 6 months
• Partner with companies to develop new polymers for their markets
Tufts School of EngineeringTufts School of Engineering
SummarySummary
• Food/Medicine/Biochem Markets need advantages of new polymers
• Microfluidic Enzymatic Synthesis– Make custom polymers– Faster, cheaper discovery– Scalable to mass production
• Need partners and funding to – do market analysis,– help secure IP, – develop small number of prototypes, and – expand to market
• Contact [email protected]