Microfluidics – Services for Design, Manufacturing, Instrumentation

Sandwich structures for microfluidic manifolds

GeSiM offers different approaches for micromachining of 3D structures. Microfluidic devices are easily made from silicon/glass sandwiches. However, many applications require optical transparent channel structures. Glass/glass sandwiches are precise but more expensive and give high accuracy.

PDMS microfluidics keeps prices close to disposables but requires more initial instrumentation. Please refer to the GeSiM MicCell or even the Micro-Contact-Printers. The latter one prints your microfluidic devices (NIL – Nano-Imprint-Lithography) including sample handling by onboard pipettors.

Different sandwich methods for microfluidic devices

3D Microfluidics from hard materials

• Anisotropic wet-chemical etching of Si with KOH: inexpensive batch process, smooth surface, side wall angle depends on crystal orientation
• Anisotropic plasma-enhanced dry Si etching (ASE/Bosch process): single wafers, dense structures, vertical side walls
• Super-rough surfaces by etching in SF₆/C₄F₈ plasma
• Isotropic wet etching of glass with HF: round channels, 3 – 700 µm deep
• Ultrasonic drilling and micro-blasting for 150 – 1000 µm thick glass, Si, quartz

Etched channel structure of a micromachined sieve

KOH etched sieve structure

Micro pores, realized by ASE at presence of insulated platinum electrodes

GeSiM dispenser structure: View from the pump chamber of the fluid inlet

Photoemulsion Masks with your Design

We supply cost effective photo emulsion masks for patterns down to 25 microns. Smaller features are available with chrome masks from an external source. The photo emulsion masks are based on glass substrates 5″ x 5″ as well as on films of diverse sizes.

If desired we also offer CAD services for your particular application.

Design Guidelines – Technical Information on the GeSiM Mask Service

We accept CAD data accordingly to the following rules, as well as create plot files based on your specs.

Supported data formats

• AutoCAD™ DXF up to release 12 (preferred),
• Gerber RS 274X,
• GDS-II, CIF.

Lithography equipment (Left), photoemulsion mask (Right)

Design guidelines

For 5” masks, the plotting area is restricted to 100 mm x 100 mm. For a centered image on the mask, the outer dimensions of the drawing must be exactly 100 mm x 100 mm. Placing of four small squares (e.g. 50 microns x 50 microns) in the corners of the layout supports this contraint.

In DXF files, please use only solids, circles and closed polylines with a width of zero. These patterns will be filled by our software. Do not try to fill them with the hatch command. Avoid “islands”, try to split complex figures in separate parts instead. For text information, use only the text command, never dtext or mtext. Please set the font to txt.shx.

Download our sample file as a design template.

Thin Film Services – Coating Technologies

GeSiM offers the deposition of conducting and insulating films by

• Physical Vapor Deposition
• Plasma-Enhanced Chemical Vapor Deposition
• Screen Printing

PVD and PECVD applies to all kind of substrates up to 4 inch diameter.

Screen Printing

• Dispensing of the state of the art adhesives on printed circuit boards and micro system substrates for surface mounted device packaging.
• Dispensing of silicon rubber.
• Includes sieve design and production.
• Typical thickness of printed materials in the range of 15 to 35 Microns.

Bonding – Connecting Microfluidic Chips with and without Glue

In order to achieve closed fludic channels MEMS technologies offers different – material dependent – methods. The GeSiM engineering service covers:

• Anodic bonding
• Silicon fusion bonding
• Die bonding using adhesives
• Wire bonding

Wafer Dicing Service

GeSiM accepts flat wafers with diameters up to 6 inch, furthermore tubes and objects of other geometries (please ask).

Instrumentation Service for R/D – Integrating the Worlds of Micro and Macrotechnology

The exchange of material and information with MEMS is more complex than with standard microelectronic chips. GeSiM offers customized solutions for packaging, liquid handling and instrument design.

• Hybrid integration of Si or glass chips in ceramic of other wire bonding mounts,
• Innovative electrical, fluidic and mechanical joining technology,
• Integration of macrofluidic components (E.g. valves, pumps) or custom-specific parts,
• Development of hard- and software,
• Customization of GeSiM standard instruments.

Further MEMS Services

Microgalvanics: Galvanic deposition of thick layers of Ni (70 µm), Au (70 µm), Au (10 µm), after lift-off microstructuring

Screen Printing:

• Printing of SMD adhesives or silicone rubber on PCBs and microsystem substrates
• Including sieve design and production
• Typical thickness: 15 – 35 µm

Multi-Organ Chips (MOCs)

In collaboration with Fraunhofer IWS (Dresden), TissUse GmbH (Berlin) and others, flow cells were designed (Materne et al., 2015; Maschmeyer et al., 2015; Günther et al., 2017) in which overpressure or vacuum are exerted on cells or organoids, e.g. to monitor chondrocyte differentiation. As a variation on this theme, micropumps with valves made of thin elastomeric (PDMS) membranes simulate heartbeat and thus drive artificial blood circulation. The multi-layer plastic chips are mounted in modified MicCells.

Various cells types (2D, organoids, 3D-printed cellular scaffolds) can be tested in different layouts. Nutrients, growth media or test substances are added via wells or O2 diffused into the organ-on-chip devices, e.g. to study toxicity or hypoxia. Requirements:

• Prolonged cultivation in a biocompatible circulation system
• Pulsatile fluid flow within physiological boundaries
• Low media-to-cells ratio → little dilution
• Measurement of flow rate, temperature, oxygen, pH etc.
• Continuous monitoring using microscopy, fluorescence etc.

In projects funded by BMBF, SAB and IGF, we have built a robot (See tab MICROFLUIDIC WORKSTATION) with a liquid handling/pneumatic environment for MOCs in the upper level and a fluorescence microscope in the lower level. The special nature of this instrument justifies its name, 2-LEVEL-LAB.

Possible applications:

• Long term cultivation/perfusion of 3D-printed cell-laden scaffolds and tissue slices
• Long-term cultivation of scaffolds with cells and integrated artificial blood vessels
• Long-term studies of endothelial regeneration (after laser-cut lesions)
• Biocompatibility/toxicity/hypoxia tests using microscopy

Chip for 3D cell cultures with pump and oxygenator

Schematic drawing of MOCs for liver and skin on a slide-sized chip with simple “blood circulation” (by integrated peristaltic pumps)

Flowthrough cell assembly

MOC ready to use (Courtesy Fraunhofer IWS and TissUse GmbH)

Alternatively you can use 12 or 24-well microwell plates into which cells, organs or cellular scaffolds are printed with the GeSiM Nano-Plotter or the BioScaffolder. Wells are covered by PDMS membranes (cast in the MicCell moulding station) that are deflected by air pressure. Nutrients, drugs or signal molecules can be added via tubes, all with automatic analysis in a microscope.

Design and Prototyping of a novel “Organs-on-a-Chip” Bioreactor System for Substance Testing

This work was conducted by
Fraunhofer IWS Dresden, TU Berlin, ProBioGen AG Berlin, GeSiM mbH

Introduction

The prototype of this “organs-on-a-chip” (OOC) platform is supposed to enable studies of the interaction of consumer-relevant synthetic or natural substances with the human body in its typical environments and with its individual genotypic specificities. It has been designed for the long-term culture of human sub-organoids in small cavities of a microfludic flow-through cell.

Design of the Multi-Bioreactor Chip

A double sided micromachined silicon chip at the size of a standard glass slide is the heart of the bioreactor. It contains the growth segments and the cavities for the stem cells. The silicon chip is than enhanced with a PDMS layer shaping fluidic structures for supply and removal of reagents.

Multiorgan chip

Bioreactors on the Multi-Organ-Chip

The micromachining department at GeSiM contributed to the development by:

• Lithography and mask design
• Development of a new deep RIE etching process for micro patterning of silicon wafers
• Adaptation of the PDMS casting technology for the fluidic reservoirs (Layer 1)
• Development of a three layer glass/silicon/glass sandwich with embedded heater/sensor arrays (Accuracy of temperature control 0.1 K)

Instrumentation

GeSiM developed a docking station for unattended operation of the bioreactor chip. Laboratory compatibility was ensured by sticking to the common micro titer plate format (Approx. 125 mm x 83 mm). Therefore the bioreactor docking station fits to common laboratory robots, shakers, incubators, microscope stages and others.

Features:

• Data exchange with PC
• Battery based operation for at least 2 hours
• Automatic charging in the docking station
• Data acquisition and logging for at least 14 days (E.g. temperature)
• Monitoring and alerting function for limit values