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Single Cell Technologies for SMEs

Periodic Report Summary 1 - SICTEC (Single Cell Technologies for SMEs)

Project Context and Objectives:
SICTEC focusses on the development of technologies for separation and manipulation of single biological cells for life science research and medical applications. The single cell manipulation technology (SCM technology) developed within the a former EC-funded project (PASCA, Platform for Advanced Single Cell Manipulation and Analysis) bases on inkjet-like printing of single biological cells confined in free flying micro droplets. It constitutes a universal platform for single cell analysis with proven potential for many life science applications. The objective of this project is to support the participating SMEs and companies to take up the SCM technology, to realize their own applications and to develop them into innovative products for the medical, biomedical and pharmaceutical markets. Central element of the research is the SCM prototype instrument and the single cell dispenser as presented in numerous publications.
The SICTEC project aims to provide validation and extension of the use of this prototype instrument and deal with necessary improvements and modifications of pre-production prototypes towards the specific needs and applications of the SME partners. In particular also topics affecting commercial exploitation like e.g. application development, design for manufacturability, reliability issues, cost and throughput optimization, extension of technical specifications, and preparation of CE IVD labeling are being investigated. Applications targeted by the individual SMEs are considering fast pathogen detection for clinical use by combining the SCM technology with MALDI TOF mass spectroscopy of single bacteria, instruments for single cell cancer and stem cell research, methods for monoclonal cell line development and other in-vitro medical diagnostic applications. The anticipated innovations stemming from this research will be exploited by the involved SMEs individually as well as jointly through several innovative products targeted for different markets and applications.

The team conducting the project consists of five SME and two RTD partners:
BioFluidix GmbH is a micro technology company focused on low volume liquid handling. Their proprietary non-contact technologies are based on micro machined components providing highest quality, throughput and functionality. Their long-standing expertise in working with liquid droplets, jets and sprays in the picoliter to nanoliter range inspired our unique product portfolio which comprises hardware and consumables as well as R&D services. Within SICTEC, BioFluidix provides the base printing technology and will be marketing both the printing module as well as the cell handling device to end customers.
BiosparQ B.V. aims at providing sensors microbial sensors with response times in the order of minutes from taking a sample to allow informed intervention and application of feedback loops to control the dynamic behavior of various systems. BiosparQ has previously developed a 'Single-cell' MALDI-TOF mass spectrometry device which has the capability to analyze mixtures of microbes without the need for time-consuming culturing and isolation steps. As these steps determine the turnaround time, BiosparQ's solution has the potential to transform MALDI-TOF mass spectrometry into a game changer for a wide variety of medical and industrial applications. The key aspect of our technology is its ability to present cells one by one to a MALDI-TOF mass spectrometer. Together with its complementary single-cell data processing algorithms, it transforms streams of single-cell spectra to microbial information. Within SICTEC, the single cell dispensing technology will be adopted to allow printing of single bacteria into the MALDI-TOF system, which BiosparQ intends to market later.
PrimaDiag SAS is a company which develops instruments for research and diagnostic laboratories. In particular, PrimaDiag has developed the PrimaRWS system, a modular platform allowing scientists to easily automate their biological processes. PrimaRWS consists of a set of simple and robust robotic bases on which, depending on the users' experimental needs, different tools can be mounted (pipettes, spectrophotometer, camera, thermostated block, vacuum pump,...). PrimaDiag will benefit from SICTEC project by having its platform further optimized and characterized towards its use in CE-IVD applications.

Innoprot, spin-off from the University of the Basque Country, is a biotechnology company focused on the generation of recombinant cell lines and primary cells intended for use in cell-based drug screening. Their efforts are directed to increase speed and efficiency of "in vitro" assays, allowing the collection of more information about the compounds in less time than other biological systems. The types & formats of our products fit the specific needs of the market, allowing the pharmaceutical and biopharmaceutical companies to choose between cell lines for single assays, cell lines for High Content Screening and cell lines for High Throughput Screening. Innoprot will use the technologies developed within SICTEC to further optimize their production e.g. by the integration of fluorescence detection capabilities.
Sophion Bioscience, headquartered near Copenhagen, Denmark, has the sole focus of providing state of the art products and integrated solutions for automated patch clamping. Sophion develops and sells high throughput patch clamp solutions for functional characterization of living cells. Based on advanced microtechnology, Sophion’s QPatch systems potentially increase patch clamp throughput from 100 up to 1,000 times by a high degree of parallelism and automation. Thus the QPatch combines the accuracy of traditional patch clamp with the high throughput of indirect methods. Sophions intension in SICTEC is to get a fully integrated single cell printing tool for integration into their machines including the complete disposable supply chain.
The Department of Microsystems Engineering (IMTEK), University of Freiburg, is the principal technology partner and project coordinator. It has grown to become one of the world’s largest academic institutions in the field of microsystems engineering. With 20 professors and over 300 research and technical staff, its scientific scope encompasses nearly all technical fields relevant to the highly interdisciplinary world of microsystems technology. It has years of experience striking new paths with researchers and developers from other fields. The Laboratory for MEMS Applications is an expert on micro- and nanofluidics, especially on nanoliter and picoliter liquid handling: With its contact-free dispensing technologies fluids in very small doses with high precision can be dispensed. They are even able to cope with delicate media such as dissolved particles or living cells and guarantee high throughput. Being one of the RTD performers, IMTEK is doing the main development on the printing technology for all SME partners.
The department of Medical Microbiology and Infectious Diseases at the Erasmus MC Rotterdam, provides microbiological diagnostics, infection prevention control and consultancy for a 1320-bed university medical centre. Diagnostics for bacteria, fungi and parasites is based on conventional (culture, microscopy and serology) and molecular-based nucleic acid amplification techniques. On an annual basis over 200’000 clinical samples (data from 2010) have been processed in the diagnostic laboratory. For that reason, diverse robots are used to speed up the throughput. The medical staff consists of clinical microbiologists, infectious diseases specialists and is supported by medical biologists and medical molecular microbiologists. A unit Research and Development in the department focuses on drug development, antimicrobial resistance (mechanisms), antibiotic dynamics in experimental animal models, host-pathogen interaction, development of microbial typing platforms (e.g. MALDI -TOF, Raman spectroscopy), and innovation in diagnostic platforms. The laboratory had several decades of experience in testing and validation of new diagnostic platforms, such as SICTEC. The main role of the Erasmus Medical Center in the project is therefore to provide clinical validation and consulting to the project partners that target IVD applications with their products and to help them to prepare for CE IVE labelling.

Project Results:
Within the first reporting period, the specifications for all intended applications and devices were gathered and based on that, initial designs have been created, manufactured and validated.
The core technology development in this context included work in getting the chip supply chain to a much more mature level that is has been so far. Intensive studies have been carried out to optimize the yield and quality of the disposable elements used in the single cell dispensing process. The current fabrication process allows to fabricate more than 40 disposables per week with (four time as high as in the early project phase) with an additional expected 10-fold increase within the next reporting period. For the partnering SMEs, this will result in a much more robust and plannable disposable supply. Furthermore two new dispenser prototypes have been designed and evaluated. The first one is capable to dispense objects ten times as small as the ones previously used (10 µm  1 µm) and thus allow the dispensing of single bacteria at smaller droplets than the ones which have previously been available. This print head is now operating at the SME’s facilities for further evaluation. The other print head enhances the printing technology with a fluorescence detection option and thus allows the discrimination of labelled cells. This print head will be integrated on partner devices in the near future and will enable them to expand their experimental capabilities.
A new set of liquid handling devices has been designed and initial optimization has been performed always keeping their usage in CE-IVD applications while still maintaining low production costs paired with a high robustness in mind. The documentation and initial experiments for the certification however is part of the upcoming reporting period.
For promoting the project, the team has been present at conferences and fairs and has conducted a first partnering event in form of a live lab at the MicroTas 2013 conferenec. A two hours live lab presentation and demonstration of the prototype instrument was given along with a booth at the conference exhibition. In total 56 attendants participated in the live lab and > 100 visitors were at the booth.
Being in an early research and optimization phase, the overall economic impact cannot be overseen so far. There have not been any direct sales or products arising from the project so far. The project website can be located at http://www.sictec-project.eu/.
Further publishable information is also provided in Deliverable D9.3 “Intermediate progress report”.

Potential Impact:
included above

List of Websites:

http://www.sictec-project.eu/