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Miniaturized System for Screening of Primary Cells based on Droplet Microarray

Periodic Reporting for period 1 - Droplet Microarray (Miniaturized System for Screening of Primary Cells based on Droplet Microarray)

Reporting period: 2020-02-01 to 2021-01-31

Current cell screening systems based on micro plates are mainly used to perform drug discovery experiments. However, performing a larger number of therapeutic tests on patient derived (primary) cells is yet impossible due the high consumption of reagents and especially cells when using microplates. In the clinical context, personalized drug screenings for optimal medical treatment are not possible due to the scarcity of precious primary cells. In pre-clinical drug discovery, the extremely
high cost of primary cells limits the innovation potential as researchers hardly have access to screening models which are relevant for human physiology. The possibility to use scarce cell types like primary cells or stem cells therefore is the future of basic life science research, drug discovery (replacing animal models) as well as personalized medicine applications (individual precision therapies) and will have significant impact for a healthy society.

Further miniaturization of current assays would inevitably allow the wide use of scarce cell types and at the same time reduce costs, increase throughput, and increase biological relevance of screening results. DMA allows researchers and clinicians to perform meaningful experiments with primary cells and circulating tumor cells – alternative technologies hardly work with low cell numbers.

Aquarray is in a position to produce the DMA (Droplet Micro Array) in a semi-automated process in the meantime. The production capacity is in the range of 20 000 – 50 000 DMAs per year. Further automation would cost more money than expected. So it was decided not to invest in further automation at the moment. To become competitive to the existing micro plates, Aquarray started to manufacture cartridges in the same dimensions as micro plates. These cartridge should be able to take up / include the DMA, which would allow the usage in automated systems.

The DMA Cartridge and also the disruptive Cell Screening System that integrates the DMA Cartridge with a nanoliter dispenser, an incubator and a read-out apparatus are configured and the first demo machine will be produced within one year with the help of our subcontractor. First contacts to potential users were established.

Aquarray developed partnerships into different directions to make even more use of the DMA technology and the DMA cartridges. For example Aquarray generated interest from manufactures of mass spectrometric instruments, which also might use DMAs as screening platform.
The overall objective was to screen for the different substrate materials to find a substitute to glass. The available materials were tested against the physical forces that occur during the production process, like heat, solvents, and UV irradiation. The results show that an alternative to glass that withstands all necessary parameters would be more expensive than glass. Additionally, Aquarray wanted to address the scale up of the production process. The tools for the patterning process were redesigned to create a higher throughput and fix problems from the existing tools. This will lead to an improvement in produced throw-outs.

The Droplet Microarray (DMA) slides in their current state bring a lot of advantages to the user but a major drawback is the microscope slide format. It is not easy to adapt it in lab instruments and the manual handling is not user-friendly. An overall objective was to design a DMA cartridge in the ANSI microtiter plate format. This format is used in common laboratory automation systems. It is highly important to adapt the DMA slide to this format. A company was chosen to produce the DMA cartridge prototypes. These prototypes were tested for the implementation in a biological assay workflow. The results show that the precision of the molded cartridges was not high enough to fit our standards. Aquarray still can distinguish the parameters that need to be changed to have a fully functional DMA cartridge.

The overall objective was to reduce the time for QC after the production of DMA slides maintaining a functional and reliable readout. The quality check of the DMAs has been optimized by comparing different techniques to visualize the hydrophilic spots on a hydrophobic background. After optimization of the protocol the QC can be performed manually by applying steam instead of the dispensing water in each individual spot. This leads to a time reduction of at least 50 %.

A market study was done to evaluate pricing and availability of the different units required for the assembling of the ISS. These units comprise a cell incubator, a cell dispenser, a readout system (either scanner, plate/image reader, automated microscope/image platform). For specifications of the units required for automation. Aquarray received some support from subcontractors. A list of suitable units was generated in house by contacting the corresponding suppliers and asking for specifications, technical data sheets and quotations.

The designing of the integrated screening system was the main objective of this task using the created market overview. Aquarray started with a basic description of the system, that was sent to the possible partners. In several discussion rounds they were able to receive quotations for the system integration and defining the needed parts. The drawings were delayed as they were part of the work of the subcontractor, who started already later than expected. The task was completed so far without drawings, which were completed when the subcontractor starts to work on the integrated screening system.

The delivery of a 2D and 3D drawing for the Aquarray Screening System (ASS) for personalized medicine was one of the main objective in the first reporting period. OEM parts were chosen due to their qualification for the system considering the following aspects: suitability for integration in this system, size, price and availability.
A concept for automation was developed together with the subcontractor for systems integration. The prototype of the Aquarray screening system consists of a dispenser, cell incubators, a handling unit and two readout units: a scanner and an automated microscope. Based on the chosen OEM parts a CAD model and top-view of Aquarray’s Integrated Screening system was generated. Due to its relatively compact size the decision was taken to develop the system as a benchtop unit.
Aquarray and first users of the DMAs were able to create screenings at an unknown density in comparison to micro plates. These leads to new possibilities in cell screening especially whenever cell material is rare and/or expensive.
DMA Platform vs. existing solution