OSTE polymers create novel opportunities in biomedical microsystems Tommy Haraldsson

Transcription

1 OSTE polymers create novel opportunities in biomedical microsystems Tommy Haraldsson Fredrik Carlborg, Reza Shafagh, Alexander Vastesson, Xiamo Zhou, Jonas Hansson, Weijin Guo, Niklas Sandström, Mikael Hilmering, Gaspard Pardon, Wouter van der Wijngaart

2 Outline of my talk Why a new material? What is OSTE? Core benefits of OSTE Prototype to medium scale fabrication of OSTE devices Reaction injection molding Photolithography

3 The starting point of OSTE Thermoplastic chip (microfluidic ChipShop) Manufacturability PDMS Chip Karlsson et al.transducers 11, Beijing, China, June 5-9, 2011

4 Requirements on a bridging material The material needs to: Be easy to micromachine (molding, lithography etc.) Easy to align and bond layers to fabricate multilayer devices Easy to surface modify Mimimum of re-engineering to obtain a thermoplastic device Optional: Production of devices (medium quantity-1000 s of devices/year)

5 OSTE OSTE is a material composed of Thiol and Ene monomers TATATO- a triallyll PETMP- a tetrathiol

6 OSTE Mixed in an Off Stoichiometric fashion Ene -CH=CH 2 Mix off-stoichiometrically UV / thermal Click chemistry Thiol -SH Liquid precursor Solid with active surface thiol or ene groups [Carlborg, Lab Chip, 2011]

7 OSTE core features OSTE has a number of unique features including: Dry bonding at low temperatures High compatibility polymer chemistry

8 OSTE core features OSTE has a number of unique features including: Dry bonding at low temperatures Sealing to almost any substrate at low temperatures ( C) High compatibility polymer chemistry Glass, silicon, metal, paper OSTEMER

9 OSTE core features OSTE has a number of unique features including: Dry bonding at low temperatures Surface: built-in anchors provides easy surface modification High compatibility polymer chemistry Bulk: polymerization process with very low internal stresses

10 OSTE Device Manufacture Reaction injection molding RIM Photolithography

11 OSTE(+): thiol-ene-epoxy dual cure systems Before curing After First cure (UV 405 nm) After Second cure (thermal or UV 310 nm) Bulk: Liquid SH O SH O Bulk: Soft and deformable adjusts to nanorough surfaces Surface: Unreacted epoxy and thiols Ready for functionalisation / bonding Bulk: Stiff (~3 GPa) and heat resistant possible to drill Surface: Inert surfaces, OH-groups Saharil et al., JMM, 2012

12 RIM in an aluminum mold QCM-cartridge layer

13 RIM in an aluminum mold 10 Sec Glass Release slide liner Bottom-cartridge mold 16

14 RIM in OSTE+ for QCM cartridges Inlet Outlet Top part Microfluidic chamber QCM Bottom part

15 SH O SH O SH O C C C C C C O H O H O H

16 QCM OSTE chip

17 QCM multipart mold

18 Reaction Injection Molded Microfluidic Chip

19 Unique replication accuracy and range: Simultaneous manufacturing of cm, milli, micro, and nano- features

20 In OSTE systems there is reflow during cure Silicone mold Reflow

21 Surface energy mimicking OSTE Copying the mold structure, and the mold surface energy in a single replication step [Pardon, Adv. Mat. Int., 2016]

22 Specialty composite polymer OSTE precursor + Hydrophobic methacrylate + Hydrophilic methacrylate = Replica mixture [Pardon, Adv. Mat. Int., 2016]

23 Surface energy mimicking during replication UV light Specialty polymer Hydrophobic Hydrophilic Hydrophobic Hydrophilic MASTER REPLICA [Pardon, Adv. Mat. Int., 2016]

24 Surface energy mimicking during replication

25 PoC Lateral flow tests use capillary pumping Easy to use Low cost But only YES / NO answers

26 Device and sample variability make quantitative measurements difficult Readout signal Measurement result We must reduce variability to improve performance Analyte concentration Where you assume your analyte concentration is 31

27 Where does variability come from? Addressed in our research on synthetic microfluidic paper Addressed in our research on capillary design Channel geometries Sensing area geometries Material surface properties Receptor density Sample surface energy Sample viscosity Concentration of analyte Diffusivity of analyte Binding constants Etc

28 Where does variability come from? Addressed in our research on synthetic microfluidic paper Addressed in our research on capillary design Channel geometries Sensing area geometries Material surface properties Receptor density Sample surface energy Sample viscosity Concentration of analyte Diffusivity of analyte Binding constants Etc

29 Current materials in LFIA Porous materials Micropillar arrays Paper [1] Nitrocellulose [2] Silicon [3] Polymer [4,5] = Most sensitive Surface area Large Small Structure shape Random Regular Structure repeatability Low High Optical transparency ~10 µm optical depth Transparent Surface functionalization [1] O Farrell (2009) [2] Yetisen et al. (2013) Adsorption [3] Zimmermann et al. (2006) Adsorption [4] Dudek et al. (2009) [5] GlobeNewsWire (2014)

30 Miniaturizing pillar arrays increases surface area but leads to capillary collapse Surface area Structure shape Structure repeatability Optical transparency Surface functionalization Small Regular High Transparent Adsorption

31 Synthetic microfluidic paper 100 µm Miniaturising interlocked pillars enables high surface area reduces pillar collapse OSTE allows covalent receptor binding Surface area Structure shape Structure repeatability Optical transparency Surface functionalization [Hansson, Lab Chip, 2016] Small larger Regular High Transparent Adsorption covalent

32 Uncomplicated manufacturing 1) Multidirectional 3D UV lithography (5-30s) Photo of setup: 2) Developing (30-300s) 3) Finished device in aceton + ultrasonication

33 Best master thesis in engineering in Sweden, 2016

34 Improved capillary pumping variability Blood Water (n=4) Low standard deviation σ = 1% < σ Nitrocellulose = 4% [1] [Hansson, Lab Chip, 2016]

35 The problem of receptor spotting Challenges: deposited volume of diluted biomolecules per area line width (spot morphology) Repeatable surface interaction

36 Our solution: Pillar density design Mask design Side-view Top-view [Hansson, Proc. microtas 2015]

37 Self-aligned spotting [Hansson, Proc. microtas 2015]

38 Self-aligned spotting 1.5 µl added 1.5 µl added x x x = where the liquid is added 1mm High density [Hansson, Proc. microtas 2015]

39 Self-aligned spotting 1.5 µl added 1.5 µl added x x x = where the liquid is added 1mm Equivalent spot regardless of spotting position [Hansson, Proc. microtas 2015]

40 Material transparency leads to higher signal readout Hair visible through pillar [Hansson, Lab Chip, 2016]

41 Material transparency leads to higher signal readout Blue dye added: More visible readout signal in Synthetic Microfluidic Paper [Hansson, Proc. microtas 2015]

42 110 μm A 100 µm sized drug Factory Prof. Wouter van der Wijngaart Prof. Matthias Löhr Prof. John-Inge Johnsen Sponsors:

43 A 100 µm sized drug Factory Aim at localised chemotherapy Deliver toxic cytostatic to tumor only Allow higher cytostatic dose Protect the host from side-effects.

44 A 100 µm sized drug Factory Microscale drug factory = core-shell bead + genetically modified cells Hard porous OSTE shell harmless pro-drug ifosfamide Genetically modified cells 20 µm PEG-diacrylate hydrogel Toxic cytostatic

45 Manufacturing in a droplet microfluidic platform OSTE precursor Toluene Cells PEGDA Da=6k Initiator (H2O soluble)

46 Manufacturing in a droplet microfluidic platform OSTE precursor Toluene Cells PEGDA Da=6k Initiator (Irgacure 2959)

47 Cells in PEGDA OSTE precursor in tolluene Cells in PEGDA droplet Cells in PEGDA bead Droplet formatio n Droplet separation Droplet slow-down Droplet polymerization

48 Manufacturing in a droplet microfluidic platform OSTE precursor Toluene Cells PEGDA Da=6k Initiator (Irgacure 2959)

49 Bead reservoir Waste reservoir

50 110 μm Preliminary results Cell (dead) encapsulation in polymerized OSTE-PEGDA

51 The KTH Micro and Nanofluidic systems team Research sponsors: EU via projects Norosensor, Rapp-ID, and Routine. VR Vinnova SSF SLL Barncancerfonden

52 Winter Greeting!

53 OSTE+ Biocompatibility in an advanced cell co-culture device

54 OSTE+ Biocompatibility Manufacture of a cell growth chip using OSTEmer 322 (Mercene Labs) Sticker, D., et al., Lab Chip, 2015,15,

55 OSTE+ Biocompatibility Comparison OSTEmer 322 and Polystyrene: NIH3T3 (fibroblast) and admsc (pluripotent stem cell) Sticker, D., et al., Lab Chip, 2015,15,

56 OSTE+ Biocompatibility Autofluorescence Sticker, D., et al., Lab Chip, 2015,15,

57 OSTE+ Biocompatibility Cell co-cultures The straightforward fabrication of complex device architectures in addition to the inherent hydrophilic surface, low water vapour permeability and excellent bonding properties make OSTEMER an ideal tool for microfabrication of cell-based assays and could therefore bridge the gap between proof of concept and actual industrial applications. Sticker, D., et al., Lab Chip, 2015,15,