Klavs F. Jensen

Cells on chips

Microsystems create new opportunities for the spatial and temporal control of cell growth and stimuli by combining surfaces that mimic complex biochemistries and geometries of the extracellular matrix with microfluidic channels that regulate transport of fluids and soluble factors. Further integration with bioanalytic microsystems results in multifunctional platforms for basic biological insights into cells and tissues, as well as for cell-based sensors with biochemical, biomedical and environmental functions. Highly integrated microdevices show great promise for basic biomedical and pharmaceutical research, and robust and portable point-of-care devices could be used in clinical settings, in both the developed and the developing world.

Microreaction engineering * is small better?

Microfabrication techniques are increasingly used in different fields of chemistry to realize structures with capabilities exceeding those of conventional macroscopic systems. In addition to already demonstrated chemical and biological analysis applications, microfabricated chemical systems are expected to have a number of advantages for chemical synthesis, chemical kinetics studies, and process development. Chemical processing advantages from increased heat and mass transfer in small dimensions are demonstrated with model gas, liquid, and multiphase reaction systems. These case studies also serve to illustrate benefits of integrating sensors for flow, temperature, and chemical composition with microfluidic reaction and control components. The role of reaction engineering in the development of microreaction technology is described along with new approaches to scale up based upon replication of microchemical devices.

Multiphase microfluidics: from flow characteristics to chemical and materials synthesis.

We review transport characteristics of pressure-driven, multiphase flows through microchannel networks tens of nanometres to several hundred of micrometres wide with emphasis on conditions resulting in enhanced mixing and reduced axial dispersion. Dimensionless scaling parameters useful in characterizing multiphase flows are summarized along with experimental flow visualization techniques. Static and dynamic stability considerations are also included along with methods for stabilizing multiphase flows through surface modifications. Observed gas-liquid and immiscible liquid-liquid flows are summarized in terms of flow regime diagrams and the different flows are related to applications in chemistry and materials synthesis. Means to completely separate multiphase flows on the microscale and guidelines for design of scalable multiphase systems are also discussed.

Deciding Whether To Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.

Transport and reaction in microscale segmented gas–liquid flow

We use micro particle image velocimetry (microPIV) and fluorescence microscopy techniques to characterize microscale segmented gas-liquid flow at low superficial velocities relevant for chemical reactions with residence times of up to several minutes. Different gas-liquid microfluidic channel networks of rectangular cross section are fabricated in poly(dimethylsiloxane) (PDMS) using soft lithography techniques. The recirculation motion in the liquid segments associated with gas-liquid flows as well as the symmetry characteristics of the recirculations are quantified for straight and meandering channel networks. Even minor surface roughness effects and the compressibility of the gas phase induce loss of symmetry and enhance mixing across the centerline in straight channels. Mixing is further accelerated in meandering channels by the periodic switching of recirculation patterns across the channel center. We demonstrate a new, piezoelectrically activated flow injection technique for determining residence time distributions (RTDs) of fluid elements in multiphase microfluidic systems. The results confirm a narrowed liquid phase RTD in segmented flows in comparison to their single-phase counterparts. The enhanced mixing and narrow RTD characteristics of segmented gas-liquid flows are applied to liquid mixing and in sol-gel synthesis of colloidal nanoparticles.

Microchemical systems for continuous-flow synthesis

Microchemical systems have evolved rapidly over the last decade with extensive chemistry applications. Such systems enable discovery and development of synthetic routes while simultaneously providing increased understanding of underlying pathways and kinetics. We review basic trends and aspects of microsystems as they relate to continuous-flow microchemical synthesis. Key literature reviews are summarized and principles governing different microchemical operations discussed. Current trends and limitations of microfabrication, micromixing, chemical synthesis in microreactors, continuous-flow separations, multi-step synthesis, and integration of analytics are delineated. We conclude by summarizing the major challenges and outlook related to these topics.

End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation†

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

A Continuum Model of DC and RF Discharges

A continuum model of direct current (dc) and 13.56-MHz radio-frequency (RF) discharges in a parallel-plate configuration is presented. The model consists of equations for electron and ion continuity, Poissons equation for the self-consistent electric field, and an equation for electron energy. The equations are solved for a single set of conditions and a comparison is made between the structure of a dc and a 13.56-MHz RF discharge. One of the major structural differences is the emergence, under RF conditions, of large electron conduction currents in the quasi-neutral region. This results in substantially higher electron heating in the quasi-neutral region and a consequent shift in the peak ionization rate from the cathode sheath to the quasineutral region. In addition, the RF solutions suggest that equivalent circuit models and ambipolar diffusion models are promising ways to simplify predictions of discharge physics. The ultimate goal of this work is to provide an adequate description of the discharge physics so that discharge chemistry can be understood. The latter is essential in predicting the behavior of plasma film etching and deposition reactors used extensively in electronics materials processing.

Integrated continuous microfluidic liquid–liquid extraction

We describe continuous flow liquid-liquid phase separation in microfluidic devices based on capillary forces and selective wetting surfaces. Effective liquid-liquid phase separation is achieved by using a thin porous fluoropolymer membrane that selectively wets non-aqueous solvents, has average pore sizes in the 0.1-1 microm range, and has a high pore density for high separation throughput. Pressure drops throughout the microfluidic network are modelled and operating regimes for the membrane phase separator are determined based on hydrodynamic pressure drops and capillary forces. A microfluidic extraction device integrating mixing and phase separation is realized by using silicon micromachining. Modeling of the phase separator establishes the operating limits. The device is capable of completely separating several organic-aqueous and fluorous-aqueous liquid-liquid systems, even with high fractions of partially miscible compounds. In each case, extraction is equivalent to one equilibrium extraction stage.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Drug manufacturing in a fridge-sized box Commodity chemicals tend to be manufactured in a continuous fashion. However, the preparation of pharmaceuticals still proceeds batch by batch, partly on account of the complexity of their molecular structures. Adamo et al. now present an apparatus roughly the size of a household refrigerator that can synthesize and purify pharmaceuticals under continuous-flow conditions (see the Perspective by Martin). The integrated set of modules can produce hundreds to thousands of accumulated doses in a day, delivered in aqueous solution. Science, this issue p. 61; see also p. 44 Preparation of four common pharmaceuticals shows the versatility of an integrated system the size of a household refrigerator. Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.