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2016 | Buch

Microsystems for Pharmatechnology

Manipulation of Fluids, Particles, Droplets, and Cells

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Über dieses Buch

This book provides a comprehensive, state-of-the-art review of microfluidic approaches and applications in pharmatechnology. It is appropriate for students with an interdisciplinary interest in both the pharmaceutical and engineering fields, as well as process developers and scientists in the pharmaceutical industry. The authors cover new and advanced technologies for screening, production by micro reaction technology and micro bioreactors, small-scale processing of drug formulations, and drug delivery that will meet the need for fast and effective screening methods for drugs in different formulations, as well as the production of drugs in very small volumes. Readers will find detailed chapters on the materials and techniques for fabrication of microfluidic devices, microbioreactors, microsystems for emulsification, on-chip fabrication of drug delivery systems, respiratory drug delivery and delivery through microneedles, organs-on-chip, and more.

Inhaltsverzeichnis

Frontmatter
Chapter 1. A Brief Introduction to Microfluidics
Abstract
With the enormous developments in micro- and nanofabrication, a new research field for scientists and engineers called micro- or nanofluidics was opened. While printer cartridges from which an ink-jet nozzle can shoot picoliter volume droplets of ink onto a sheet of paper are still one of the most prevalent microfluidic devices, this book focuses on the pharmaceutical and biochemical applications of microfluidics. Picoliter (10−12 L, equivalent to the volume within a cube of 10 μm edge length) droplets already appear very small, but are still large compared to functional entities in biology and chemistry. A picoliter water droplet consists of nearly 1013 molecules. In the same volume 104 bacteria and approximately ten red blood cells would only fit. To design, build, and operate devices that can manipulate drugs, particles, and biological materials like proteins and cells in miniaturized fluid volumes can be considered as a central theme of microfluidics. Such devices also known as Lab-on-a-chip systems (LOC), bio-microelectromechanical systems (BioMEMS) or miniaturized total analysis systems (μTAS) allow us bridging the gap between volumes which are familiar in classical laboratories or pilot factories and the microscale volumes common in biology. They can be the key to automated drug formulation, fast screening, protein crystallization, drug delivery, microbiorectors, organ-on-chip, and many other applications.
A. Dietzel
Chapter 2. Fabrication of Microfluidic Devices
Abstract
Microfluidics could not be thought about without advances in micro- and nanofabrication. Following an approach that has been adapted from microelectronics fabrication is carried out in a cleanroom environment using monocrystalline silicon as base material. It typically involves mask-based photolithography, dry and wet etching and thin film deposition. Glass can be used as an alternative or in combination with silicon and allows optical access to the fluid in the microdevices. A different approach using the so-called soft lithography and PDMS (polydimethylsiloxane) material has found widespread applications because it is relatively cheap and easy to use. In most cases the manipulation of fluids at microscales takes place in closed volumes or channels. Several bonding techniques have been developed allowing closure by a lid which in many cases can be transparent. Recently, maskless techniques like inkjet- or 3D-printing, laser micromachining, and microelectrical discharge machining get more and more attention.
M. Leester-Schädel, T. Lorenz, F. Jürgens, C. Richter
Chapter 3. Surface Functionalization of Microfluidic Devices
Abstract
Internal surfaces of pharmatechnological or biomedical microfluidic components may be functionalized—i.e., tailored or adapted to fulfill one or more specific physicochemical functions within a lab-on-chip system—by surface-technological methods selected from a number of available coating or modification processes.
Among various potential functions of a surface, its wetting behavior is of particular importance if two different phases (e.g., water and air, water and oil) are involved during operation of the system. Adhesive properties of internal walls are of major relevance in applications where particulate matter (cells, micro- or nanoparticles) plays a role: It may be necessary to prevent the adhesion of such particles on the surfaces in order to prevent clogging; on the other hand, the adhesion of cells may be aspired on certain parts of the surface. Adhesion promotion may, however, not only be an issue for the operation of an MF device but also for its manufacturing, for example for sealing or bonding processes. Frequently an undesired wall deposition of proteins or other constituents of the fluid has to be prevented by an antifouling coating or a suitable pretreatment of the surface. Coatings or surface modifications generating chemically reactive groups may be utilized to bind small molecules, polymers, biomolecules, or nanoparticles covalently to a surface. Controlling the density of charged functional groups, the ζ potential of a surface can be adjusted in order to influence, e.g., the charge of droplets dispensed from a pipette.
While so far mentioned functions of the MF device walls largely depend on their chemical composition close to the interface, specific geometrical and physical characteristics of surfaces and surface coatings may also be desired. Examples are the role of topography and Young’s modulus for the attachment of cells and microorganisms, coatings with specific electrical or optical functions involved in sensing and detection, electrowetting, or electrophoresis, and, last but not least, permeation barriers preventing the leaching of polymer constituents into the fluid or controlling gas transport through a polymer.
The present article gives an introduction to surface modification and coating processes which are established or under development in order to attain the above-mentioned surface functions. An emphasis will be laid on special requirements of microfluidic devices to be used with two-phase fluids and particulate matter.
M. Eichler, C.-P. Klages, K. Lachmann
Chapter 4. Microbioreactors
Abstract
In the last decade, microbioreactor (MBR) technology has allowed for rapid advances in biotechnology process development and the investigation of various biological systems from the industrial biotechnology and pharmaceutical biotechnology. Many of the devices that have been reported in the literature are being applied for early-stage bioprocess research. This research makes it possible to perform comprehensive experiments with very expensive substances that are only available in limited quantities.
Microtechnologically fabricated MBRs range in complexity from simple microtiter-based systems to complex automated parallel bioreactors designed to allow meaningful scaling up/scaling down of conventional pilot and large-scale bioprocesses. MBR technology and the capability to monitor cultivation process variables in situ, such as the optical density, dissolved oxygen, pH and fluorescent protein expression, provide real-time and quantitative data from a microliter cultivation broth. Currently, the majority of MBR systems have been designed for batch and fed-batch processing; there are a few efforts directed at developing MBRs for continuous chemostat mode operation.
This overview of microtechnologically fabricated MBRs, their design and application presents the advantages, different strategies for manufacturing and biotechnological applications of these tiny devices in different operation modes. The report discusses the possibility of design versatility and maintaining key aspects, for example, single-use and fluidic connections, as well as the application of MBRs in versatile and different biotechnological fields.
R. Krull, S. Lladó‐Maldonado, T. Lorenz, S. Demming, S. Büttgenbach
Chapter 5. Microsystems for Emulsification
Abstract
Emulsions are important pharmaceutical preparations that are traditionally prepared by techniques like high-shear mixing and high-pressure homogenization. In recent years, microstructured devices have attained increasing importance with regard to emulsion preparation. In particular, the possibility of preparing emulsions with very precisely controlled particle size distribution and/or of continuous manufacturing makes such devices interesting. This chapter introduces microsystem-based techniques operating at low to moderate pressure and high-pressure-based methods. The former comprise direct microchannel and membrane emulsification as well as premix membrane emulsification. The latter particularly focuses on emulsification in a customized microchannel system but also covers aspects of conventional high-pressure emulsification devices. Apart from explaining the respective principles and devices, their use for the preparation of pharmaceutical formulations is outlined.
H. Bunjes, C. C. Müller-Goymann
Chapter 6. On-Chip Fabrication of Drug Delivery Systems
Abstract
The chapter provides an overview about the fabrication of drug delivery systems with microfluidic devices. Different microfluidic approaches are presented, describing the basic fabrication principles and highlighting representative examples. Diffusive mixing is preferentially used for controlled precipitation of small particles down to nanometer size. Particles can be collected in suspension or directly be spray dried with specific devices. Emulsion-based approaches are utilized for direct use of liquid emulsions and as templates for semisolid or solid systems ranging from polymer particles and hydrogels up to complex capsules and vesicles. In addition, scale-up approaches for microfluidic devices and recent development of delivery systems based on microfluidic devices for attachment to or implantation into the human body for controlled drug delivery over longer time intervals are presented. Finally, a future perspective is given discussing advantages and challenges of microfluidic approaches for safe and effective drug delivery.
M. Windbergs
Chapter 7. Microsystems for Dispersing Nanoparticles
Abstract
Typically in the production of nanoparticles via bottom-up syntheses, agglomerates or even strong aggregates are formed which have to be redispersed in a subsequent dispersion process. Especially for the processing and screening of aggregated highly potential and cost-intensive biotechnological or pharmaceutical products, microsystems are advantageous due to high stress intensities, narrow residence time distributions, and high reproducibility as well as low volume flow. Depending on the geometry and the operating conditions of dispersing units within microsystems, various stress mechanisms have an effect on the dispersion process. However, in contrast to emulsification processes, the effect of cavitation is disadvantageous for high-pressure dispersion processes and can be avoided by applying backpressure. For the characterization and optimization of the stress intensity distribution and stressing probability in microchannels at various operating conditions, microparticle image velocimetry (μPIV) as well as single- and two-phase CFD simulations are well suited.
C. Schilde, T. Gothsch, S. Beinert, A. Kwade
Chapter 8. Particles in Microfluidic Systems: Handling, Characterization, and Applications
Abstract
This chapter gives a tour of the fascinating opportunities for handling and characterizing solid particles by microfluidic methods. First, attention will be given to the hydrodynamic, electrical, and magnetic forces which may be used to manipulate suspended particles at small scales. Second, important methods for the detection and characterization that have been proposed in the literature are illustrated and discussed. The third and last part of the chapter will give the reader a sense of the exciting applications of these methods in different fields, in particular flow cytometry, particle synthesis, and bioanalytical measurement. These applications exemplify the subtle invasion of particle-based microfluidics into many areas of the life sciences, pharmaceutical technology, chemistry, and materials science. In the future, the trend towards miniaturization will continue, and we are likely to see an increasing number of technologies and products using some of the principles reviewed here.
T. P. Burg
Chapter 9. Respiratory Drug Delivery
Abstract
The treatment of diseases by respiratory drug delivery offers a noninvasive route to deliver either topically active medications or systemic drugs. Nose and lung are target organs which provide opportunities for aerosol drug delivery by deposition on the right surface. However, filter and clearance mechanisms of the body must be overcome in order to achieve successful applications. Basic mechanisms of deposition and their interplay with the particle size (aerodynamic diameters, approx. 40–80 μm (nose) and 2–5 μm (lung)) and the patient’s inhalation flow profile are discussed. The required particle size motivates the technological approaches for aerosol generation by different inhalers. Among them are nebulizers, dry powder inhalers (DPI), pressurized metered dose inhalers (p-MDI), and non-pressurized metered dose inhalers (np-MDI). Two recently designed examples of non-pressurized liquid inhalers are presented in more detail as they make direct use of microfluidic structures in their nozzle and filter designs.
H. Wachtel
Chapter 10. Drug Delivery Through Microneedles
Abstract
Drug delivery through microneedles is a new form of a pharmaceutical dosage system. While single microneedles have been clinically applied already, the out-of-plane integration of a multitude of microneedles in a pharmaceutical patch is a disruptive technology. To take advantage of micro- and nanofluidics, such active patches utilize microneedle array (MNA) technology. MNAs are microsystems that adopt their technical uniqueness by the choice of a fabrication technology. MNAs can be made of solid, hollow, porous, or dissolvable materials in a cost-effective manner by the so-called MEMS technology. However, key to their success will be a proof-of-concept in the clinic, which must demonstrate that the intradermal (nano)release of drugs and vaccines serve an unmet medical need. In this chapter, we discuss recently established MNA platform technologies and by means of a case study we assess novel opportunities for MNAs in drug and vaccine delivery arising from this novel skin interface.
R. Luttge
Chapter 11. Organ on Chip
Abstract
The process of new drug development is both time and cost intensive. Therefore, all test systems, in particular during the pre-clinical phase, have to provide reliable results to minimize the risk of failure at a later stage of drug development. However, current pre-clinical studies are mainly performed using experimental animals and in vitro cell culture models, which both are not able to reliably emulate human physiology. As a consequence, the common test procedures may be one reason for late-stage drug failures. Hence, improved test systems are needed, which mimic the diverse and dynamic human physiology and are well controllable and suitable for high-throughput screening.
High expectations have been raised by the development of organ on chip (OOC) systems. These novel microdevices combine the benefits of an engineered, physiological-like microenvironment with the advantages of well-characterized human cells. Furthermore, due to the small dimensions of OOCs, it is possible to work with small amounts of drugs, so OOCs are suitable for high-throughput screening. Moreover, OOCs can include biosensors that allow online measurements of the viability and functionality of the cells in real time. Additionally, OOCs containing tissues from different origins can be connected by microfluidic techniques to form multiple OOCs.
This chapter takes a closer look at the technical as well as the cellular aspects of OOC technology. Subsequently, the presentation of various already developed OOCs and promising future applications in pharmaceutical research and development shall underline the enormous potential of OOCs in the reduction of animal experiments and the precise emulation of human physiology.
N. Beißner, T. Lorenz, S. Reichl
Backmatter
Metadaten
Titel
Microsystems for Pharmatechnology
herausgegeben von
Andreas Dietzel
Copyright-Jahr
2016
Electronic ISBN
978-3-319-26920-7
Print ISBN
978-3-319-26918-4
DOI
https://doi.org/10.1007/978-3-319-26920-7

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