Abstract Microfluidic structures for the generation of laminar fluid diffusion interfaces (LFDIs) for sample prepa- ration and analysis are discussed. Experimental data and the results of fluid modeling are shown. LFDIs are generated when two or more streams flow in parallel in a single microfluidic structure without any mixing of the fluids other than by diffusion of particles across the diffusion interface. It has been shown that such structures can be used for diffusion-based separation and detection applications. The method has been applied to DNA desalting, the extraction of small proteins from whole blood samples, and the detection of various constituents in whole blood, among other examples. In this paper the design and manufacture of self-con- tained microfluidic cartridges for the extraction of small molecules from a mixture of small and large molecules by diffusion is demonstrated. The cards are operated without any external instrumentation, and use hydrostatic pressure as the driving force. The performance of the cartridges is illustrated by separating fluorescein from a mixture of flu- orescein and dextran of molecular weight 2×10 6 . In a sin- gle pass, 98.6% of dextran was retained in the product whereas 43.1% of fluorescein was removed. The method is adjustable for different separation requirements, and computational fluid dynamics (CFD) models are shown that demonstrate the tuning of various microfluidic pa- rameters to optimize separation performance. Other applications of LFDIs for establishment of stable concentration gradients, and the exposure of chemical con- stituents or biological particles to these concentration gra- dients are shown qualitatively. Microfluidic chips have been designed for high-throughput screening applications that enable the uniform and controlled exposure of cells to lysing agents, thus enabling the differentiation of cells by their sensitivity to specific agents in an on-chip cytometer coupled directly to the lysing structure. Introduction Microfluidics-based analysis system concepts have prolif- erated in the last few years, with the promise of enabling miniaturization, faster response times, and simplification of analysis procedures. These devices, as developed by a variety of research groups and now also being commer- cialized, generally consist of a small microfluidic chip surrounded by a substantial, typically desk-top-sized analy- sis instrument [1, 2, 3, 4, 5]. At this time, almost all com- mercial applications are in non-FDA-regulated life sci- ence areas. One of the promises of microfluidic total-analysis sys- tems is the capability to handle all steps of the analysis on-chip, from sampling, sample-processing, separation, and detection steps, to waste handling. Integrating these functions on a chip becomes considerably more challeng- ing when dealing with complex and variable samples such as whole blood or other clinical specimens. The authors have previously reported a number of mi- crofluidic devices and integrated systems for clinical di- agnostics and life-sciences applications [6, 7, 8, 9, 10, 11, 12, 13]. They fall into two general classes – machine-con- trolled disposable cartridges and passive self-contained dis- posable cards. Particle separators, particle-focusing struc- tures, microvalves, detection channels, micromixers, and diluters have been demonstrated in applications such as a hematology analyzer prototype, a stand-alone blood plasma separator, and a variety of chemical and biological assays. In this paper, we focus on microfluidic structures for the generation of LDFIs for sample preparation and analysis. Experimental data and the results of fluid modeling will be shown. LFDI are generated when two or more streams flow in parallel in a single microfluidic structure. It has been shown that such structures can be used for diffusion- based separation and detection applications [4, 10, 11]. The method has been applied to DNA desalting, the ex- Bernhard H. Weigl · Ron L. Bardell · Natasa Kesler · Christopher J. Morris Lab-on-a-chip sample preparation using laminar fluid diffusion interfaces – computational fluid dynamics model results and fluidic verification experiments Fresenius J Anal Chem (2001) 371 : 97–105 DOI 10.1007/s002160100997 Received: 20 March 2001 / Revised: 28 May 2001 / Accepted: 3 June 2001 / Published online: 24 July 2001 SPECIAL ISSUE PAPER B.H. Weigl (✉) · R.L. Bardell · N. Kesler · C.J. Morris Micronics Inc., 8463 154th Avenue, Redmond, WA 98052, USA e-mail: bernhardw@micronics.net © Springer-Verlag 2001