Contact-free dispensing for in-vitro diagnostics: challenges of the reagent diversity on the performance of appropriate dispensing technologies

Hochschulschrift

Zusammenfassung: Trends in the laboratory diagnostic are mainly triggered by the improvement of the medical values of the offered test parameters and the increase of the test efficiency. Improving the test efficiency and the accompanying economic added value for the healthcare system aims to reduce the costs per result. Two mayor cost factors for the IVD tests are the consumption of reagents and disposables. Hence, the trend of the industry is towards the reduction of the needed reagent volumes in future IVD analyzers, which could be achieved by better detection methods and innovative dispensing systems. A most promising method to handle reagent volumes down to the sub-µl-range is the usage of microfluidic contact-free dispensing systems. In this account it has to be ensured that the dispensing system ejects the whole spectrum of IVD reagents precisely and accurately. Aims of this work are the description of the whole IVD reagent spectrum according their fluidic properties; the evaluation of selected dispensing systems regarding their applicability as IVD reagent dispenser; and the definition of operational modes to ensure a lossless fluid transfer from the dispensing nozzle into the reaction vessel. The required energy for a contact-free fluid breakup form the dispensing nozzle is mainly determined by the fluid properties density, viscosity and surface tension. Hence, in order to ensure a reliable fluid breakup for all IVD reagents, these fluid properties have to be known. These are not disclosed in the scientific literature thus far; hence their determination is one key element of this work. To achieve this objective, a representative set of 646 IVD reagents are selected, measured and arranged in a diagram: the fluid properties landscape. Out of this landscape, eight simple and easy to prepare model fluids are developed covering almost the whole property range of the IVD reagents (offered by the Roche Diagnostics GmbH). They are aimed to evaluate dispensing systems for their applicability of dispensing the IVD reagents within the desired performance. It is demonstrated in this work that the model fluids behave like real IVD reagents when the aforementioned fluid properties are almost identical. The differences in their chemical compositions do not influence the dispensing result significantly so that instead of an evaluation with all IVD reagents, only an evaluation with these eight model fluids is sufficient.The required volume range of present and future IVD analyzers are from the sub-µl to the µl-volume range. Dispensing technologies covering this range are primarily operated with either a pressure or a flow boundary condition. Thus, in this work one dispensing system for each group is selected exemplarily in order to evaluate its applicability as IVD reagent dispenser. The dispensing systems fulfilling the required precision and accuracy for all model fluids are the Vermes dosing system (pressure boundary condition) and the cartridge for dispensing a fluid (CDF) (flow boundary condition). The experimental results show that the robustness of the system with a flow boundary condition is better compared to that with a pressure boundary condition. For instance, for the CDF the volume variations are within-a-day ± 0.9 % and due to reassembling of the dispenser components ± 1.0 %, while these values are ± 1.3 % and ± 2.8 % for the Vermes dosing system (two sigma confidence interval). In order to assess the error-proneness of a dispensing system during operation in an IVD analyzer, all factors influencing the dosing performance have to be known. For the two selected dispensing systems they are described by the derived calculation model. This model presents the dispensed volume as a function of the fluid properties as well as the specific geometrical dimensions and the setting parameters of the dispensing system. A special challenge, hereby, is the theoretical system description of the complex dispensing system with a pressure boundary condition. This could be solved with the help of the fluidic network calculation including the pressure drop at a channel constriction.On the basis of the calculation models, error propagations by Taylor are performed for each of the selected systems. They present the total volume error in case that all influencing parameters vary maximal within their tolerance limits. Depending on the operational mode of the dispensing system at the analyzer, the influencing parameters can be different. Most promising for an IVD application is the CDF with a total volume error of ± 1.3 % (1 µl), if the system is primed, while it can be operated without a fluid or cartridge specific calibration. In comparison, the Vermes dosing system leads to a total volume error of ± 5 % (1 µl) for a primed system with a fluid and cartridge specific calibration by a maximal temperature variation of ± 1.9 °C. To profit from the good performance of a contact-free dispensing system in IVD applications, it has to be ensured that all reagents are transferred completely into the reaction vessel and take part in the detection reaction. The formation of satellites, bouncing droplets and foam in the vessel are only some examples of adverse events which may cause unacceptable wrong test results. Two countermeasures are presented in this work. Firstly, a new vessel shape is introduced featuring an inclined wall, a bigger vessel opening and a constriction at the bottom to avoid the formation of foam as well as the volume loss of already captured fluid. The second measure, which is based on theoretical and experimental studies of the satellite formation, describes the need of a carefully adjustment of the maximum distance between the end of the dispensing nozzle to the upper vessel opening in order to avoid volume losses due to satellites failing the vessel. The fluid properties (viscosity, surface tension), the surrounding as well as the length of the dispensing nozzle are investigated as parameters influencing the satellite formation. It is shown that the formation of satellites is favored by the combination of a low viscosity and a high surface tension. Thus, water builds the most satellites within the tested properties range of the model fluids. If water is used as fluid, satellites will not fail the vessel in a calm surrounding if the maximum nozzle-vessel distance is ≤ 30 mm (12 mm long nozzle) or ≤ 20 mm (2 mm long nozzle). In a more turbulent surrounding, as it occurs in laboratories, the nozzle-vessel distances should be shorter. Experiments show that for the longer nozzle a distance ≤ 20 mm is suitable, while for the shorter one satellites fail the vessel already at a distance of 10 mm

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Albert-Ludwigs-Universität Freiburg, Dissertation, 2015

Klassifikation und Themen

• Klassifikation: Physik
• Schlagwort: Mikrofluidik ; Diagnostik ; Rheologie ; Fehlerrechnung ; Dosiereinrichtung ; Tropfenform ; Poiseuille-Strömung ; Strömungselement

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2015
• Urheber: Losleben, Nadine
• Beteiligte Personen und Organisationen: Zengerle, Roland

Weitere Informationen

• DOI: 10.6094/UNIFR/10396
• URN: urn:nbn:de:bsz:25-freidok-103968
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:50 MEZ