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Separation Technology for A Million Peaks

Periodic Reporting for period 4 - STAMP (Separation Technology for A Million Peaks)

Berichtszeitraum: 2021-03-01 bis 2022-02-28

The field of liquid chromatography (LC, i.e. liquid phase separations of mixtures) is challenged with increasingly complex mixtures. The current set of LC methods present a trade-off between separation time and the ability to separate complex samples: fast LC methods, with typical separation times in the order of minutes, fall short in their ability to handle complex mixtures by several orders of magnitude. On the other hand, the current state-of-the-art in separating complex mixtures, known as 2D-LC, requires separation times in the order of hours.

The overall objectives of the STAMP project were to create high-resolution two- and three-dimensional spatial- liquid-chromatography devices, ultimately capable of reaching a peak capacity of one million. While the ultimate goals have not yet been achieved, a number of significant steps were taken and achievements were shared with the scientific community through 0open-access publications and presentations at conferences.

Various new analytical methodologies were published from within the STAMP project. ) A number of scientific (sub-) disciplines came together in the project, including analytical chemistry, synthetic organic and polymer chemistry (to create stationary phases and for stereolithographic 3D-printing), mechanical engineering and microfluidics (3D-printing), chemical engineering (transport phenomena, CFD), applied physics (optical detection).
Two patents were applied for, i.e. EP18184801.1 Device for Multi-Dimensional Liquid Analysis, by T. Adamopoulou*, S. Deridder, G. Desmet, P.J. Schoenmakers* (* denoting a STAMP-team member) and EP19170376.8 Stereo-lithographic 3D-printing assembly and stereo-lithographic 3D-printing method, by S. Nawada*.
The overall objectives of the STAMP project were to create high-resolution two- and three-dimensional spatial- liquid-chromatography devices, ultimately capable of reaching a peak capacity of one million. While the ultimate goals have not yet been achieved, a number of significant steps were taken and achievements were shared with the scientific community through 0open-access publications and presentations at conferences.

Objective #1 of the STAMP project involved the creation of multidimensional separation devices by the use of 3D-printing and computer-aided design. Dorina (Theodora) Adamopoulou published several papers (Adamopoulou et al., 2019, 2020) on the design of devices based on computational fluid dynamics (CFD). The computational aspects of the project produced results fastest, because (i) they did not meet any experimental obstacles (unlike the other work packages), (ii) both Dorina Adamopoulou and Suhas Nawada had significant experience with CFD when they started working on the project, (iii) collaboration with Prof. Gert Desmet at the Vrije Universiteit Brussels (B), as stipulated in the action, was very fruitful and (iv) Covid-19 barely (if at all) affected the computational effort in the project. Several possible designs of devices came out of this part of the project (Adamopoulou et al., 2020).

Objective #2 was the exploration and development of 3D-printing technology for the purpose of the STAMP project. In the first year of the project we started to realize that buying printers and making prototypes in-house was not the best approach. Many initial prototypes were made in-house using stereolithography (SLA) or fused-deposition-modelling (FDM) printers. Promising prototypes were designed within the project, but ordered from printing hubs operating with selective-laser-melting (SLM) printers. Suhas Nawada produced a breakthrough patent on hybrid stereolithography, a technique that allows for a much greater spatial resolution of printed objects, without increasing the printing time substantially (Nawada and Budel, 2021).

Objective #3 concerned design optimization and flow control, both in practice and through computational simulations. Much effort was devoted to this work package. Dorina Adamopoulou et al. published a paper that described a band-broadening investigation by CFD, and testing of 3D printed devices (Adamopoulou et al., 2019) and another paper entitled "Flow confinement in 3D-LC devices by employing permeability differences between dimensions" (Adamopoulou et al., 2020), while Suhas Nawada et al. described "Temperature controlled flow confinement by creation of freeze-thaw valves" (Nawada, Aalbers and Schoenmakers, 2019). Both the permeability-differences method (PDM) and the freeze-thaw valves (FTV) were promising, but met with serious obstacles. Preparing stationary materials with very different permeabilities is possible, but difficult. The low-permeability materials may not have desirable properties from a separation-science perspective. The FTV process could be used to isolate regions and to prepare stationary phases is specific regions of devices, but the flow control was not sufficiently precise to allow robust confinement of the flow. The best option may be TWIST- or SLIT-type devices, as patented by Dorina Adamopoulou (Adamopoulou et al., 2018).

Objecgtive #4 concerned the introduction of stationary phases and testing of devices. This was also an intensively investigated subject. Noor Abdulhussain et al. published on the creation of monolithic stationary phase in 3D-printed polypropylene columns (Abdulhussain et al., 2020). Polypropylene is an example of a chemically highly inert materials and connecting stationary materials to the surface with covalent bonds is a challenge that was overcome. Noor Abdulhussain et al. published on the creation of monolithic frits and introduction of particles in a glass chip (Abdulhussain et al., 2022) and Liana Roca et al. described the introduction of particles in a transparent 3D -printed device with multiple outlets (Roca et al., 2022). In the former case monoliths were synthesized in situ through photopolymerization. In the latter case a packed bed was created in the device. Creating stationary materials in an optically non-transparent device is even more challenging, as described by Marta Passamonti et al. in a paper entitled " Confinement of Monolithic Stationary Phases in Targeted Regions of 3D-Printed Titanium Devices Using Thermal Polymerization " (Passamonti et al., 2020).

Objective #5 was to develop understanding and realize combinations of retention mechanisms. This is essential for realizing orthogonal separations in multi-dimensional separations systems. Liana Roca et al. published on the retention mechanism of hydrophilic-interaction liquid chromatography (HILIC) (Roca et al., 2020) and later on the comprehensive two-dimensional separation of peptides by a combination of HILIC and reversed-phase liquid chromatography (RPLC) (Roca, Gargano and Schoenmakers, 2021).

Objective #6 concerned detection techniques suitable for the analytes and devices in use. This work package suffered most from the Covid-19 pandemic, as we intended to investigate aspects of this issue at different locations. Martina Komendová et al. published a system for the parallel electrochemical detection for 3D printed device with multiple channels (Komendová et al., 2020).
Left: Basic schematic of a STAMP device's operation showing the proposed separation method in three
SEM image of an EDMA stationary phase synthesized in-chip in a channel 3D-printed using a polypropyl
Left: CFD Simulation of freeze-thaw setup, Center: 3D-printed freeze-thaw device with hot and cold z
Left: A comparison of two device designs’ analyte transfer characteristics using CFD simulations and