Design and microfabrication of new automatic human blood sample collection and preparation devices
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For self-sampling or collection of blood by health personal related to point-ofcare diagnostics in health rooms, it may often be necessary to perform automatic collection of blood samples. The most important operation that needs to be done when handling whole blood is to be able to combine automatic sample collection with optimal mixing of anticoagulation liquid and weak xatives. In particular before doing any transport of a sample or point-of-care nucleic acid diagnostics (POCNAD) it is very important to x the gene expression at the time of collection. It is also important to concentrate and separate out the white blood cells of interest from the whole blood before further detection. An automatic sample collection module with a microneedle array in combination with a micromixer is proposed for the blood collection in typical nurse or health rooms. An automatic human blood preparation module is also suggested that could be used for pre-mixing, concentration and lyses. Despite that the concept of microneedle has been intensively studied since several decades ago, the fabrication still remains very challenging. Major challenges concern the high aspect ratio of microneedle structure. In addition, the microneedles have to be su ciently strong to avoid fracture and cracks during practical implementation. The other challenge with small microchannel dimensions on a chip is the lack of turbulences (including fluids that operate with Reynolds number smaller than 2000). Hence a long mixing length is required for good mixing quality. This doctoral thesis focus on the following challenges: (i) design and optimize a continuous concentration and separation unit, (ii) optimize and improve the fabrication process of high aspect ratio metallic microneedle, (iii) develop and investigate the mixing performance of a passive planar micromixer with ellipse-like micropillars, (iv) integrate and demonstrate the pretreatment system. Article I reported the design and optimization of non-clogging counter-flow microconcentrator for enriching epidermoid cervical carcinoma cells. The counter-flow concentration unit with turbine blade-like micropillars were proposed in microconcentrator design. Due to the organization of these micropillar units the functionality cause a unique system of continuous concentration and separation. Due to the unusual geometrical-pro les and extraordinary micro fluidic performance, the cells blocking does not occur even at permeate entrances. The excellent concentration ratio of a fi nal microconcentrator was presented in both numerical and experimental results. Article II proposed a simple and low cost micromixer for laminar blood mixing. The design of micromixer unit was modifi ed from the counter-flow concentration units which mentioned in Article I. The e ciency of the splitting and recombination (SAR) micromixer was examined by theoretical methods, including finite element method and verifi ed by measurement results. Numerical results show that micromixer with ellipse-like micropillars have a well mixing status when its mixing effi ciency is higher than 80% as Re 6 1. Article III presented that the e ciency of the SAR micromixer for cell lysis. Some bacteria, especially gram-positive, may be diffi cult to lyse with conventional lysis bu er. If the cells are not properly lysed, the quality of the analysis results might suff er. With a splitting and recombination concept, homogeneous mixing can be obtained in short distance. Hence, the quality of the sample after lysis for further process (Nucleic Acid Purifi cation, Nucleic Acid Sequence Based Ampli fication) is also improved. The treatment in the SAR micromixer is comparable lysis by long ultrasound exposure. Hence, SAR micromixer proved to be a good alternative method for cell lysis. Moreover, SAR micromixer has the advantage that it can easily be integrated into an automatic system for lysis and sample treatment. Article IV investigated the mixing performance at the outlet of SAR micromixer. The outlet channel of SAR micromixer was split into four sub-channels. Absorbance testing was used to implement to evaluate the outlet concentration of four subchannels. The homogeneous of fluids are varied with the inlet velocities. Article V presented the optimized fabrication process of the template of extremely long microneedles for blood extraction. Backside lithography with a UVlight source was employed to build the high aspect ratio SU-8-based microneedle template. Some major challenges on fabrication process were also shown and discussed in this article. Article VI covers a total process chain from design, fabrication to performance evaluation of the hollow microneedle design. The contribution of this article is a highly applicable theoretical model for the microneedle geometry. The proposed model has been developed to predict the fracture forces. A good agreement was observed between the results obtained from analytical solution and practical measurements of fracture force.
Has partsArticle I. Nhut Tran-Minh, Tao Dong, Qianhua Su, Zhaochu Yang, Henrik Jakobsen, Frank Karlsen. Design and optimization of non-clogging counter-flow microconcentrator for enriching epidermoid cervical carcinoma cells. Biomedical Microdevices, 13 (2010), 179-190
Article II. Nhut Tran-Minh, Tao Dong, Frank Karlsen. An e cient passive planar micromixer with ellipse-like micropillars for continuous mixing of human blood. Computer Methods and Programs in Biomedicine, 117 (2014), 20-29
Article III. Nhut Tran-Minh, Birgitte Kasin Hønsvall, Frank Karlsen. Integrated microfluidic device for cell lysis in a continuous flow mode. Journal of Medical and Bioengineering, 4 (2015)
Article IV. Nhut Tran-Minh, Erik Andrew Johannessen, Frank Karlsen. Numerical and experimental mixing studies in a split and recombine micromixer with ellipselike micropillars. IFMBE Proceedings, 46 (2015), 11-14
Article V. Nhut Tran-Minh, Hugo Nguyen, Frank Karlsen. Design and fabrication of the template of extremely long microneedles for blood extraction applications. Submitted to Journal of Micromechanics and Microengineering (Print ISSN: 0960-1317).
Article VI. Nhut Tran-Minh, Hugo Nguyen, Frank Karlsen. Fabrication, analysis and testing of high aspect ratio metallic microneedles for blood extraction applications. Submitted to Journal of Micromechanics and Microengineering (Print ISSN: 0960-1317).