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BioMEMS and micro-/nano-processing of polymers- An overview
Abstract
The miniaturization of biomedical and biochemical devices for micro-electromechanical systems (BioMEMS) has gained a great deal of attention in recent years. Products include biochips/biosensors, drug delivery devices, tissue scaffolds, and bioreactors. In the past, MEMS devices have been fabricated almost exclusively in silicon, glass or quartz because of the similar technology available in the microelectronics industry. For applications in the biochemistry and biomedical field, polymeric materials are a desirable choice because of their lower cost, good processibility, and biocompatibility. Polymer micro-/nanofabrication techniques, however, are still not well developed. In this paper, we briefly introduce various BioMEMS applications, basic microfluidic principles and functions, and processing techniques for micro-/nano-scale structures.
... I n recent years, microfabrication techniques have received great attention in biotechnology, such as biochips, biosensors, scaffolds in tissue engineering, drug delivery systems, and fundamental studies of cell biology [1]. Positioning of cells on substrate is also important for cell-based diagnostic screening. ...
... Patterning techniques that control both the size and shape of regions on a substrate surface with difference in chemistry or topology, are extremely useful in understanding the influence of the cell-materials interface on the behavior of cells [1,4]. The technique can also benefit cell co-culture that helps one better understand the interaction of cells with other cells [5]. ...
The influence of the properties and surface micropatterning of chitosan-collagen-gelatin (CCG) blended membranes on C3A cell's activities has been investigated. It is aimed to guide the cell growth and improve the growth rate in vitro for the application in tissue engineering. Masters with micropatterns are prepared on stainless steel plates by photolithography. The CCG membranes with surface micropatterns are then fabricated by soft lithography and dry-wet phase inversion techniques. The morphology and metabolic activity of cultured C3A cells on the membranes are recorded. When the C3A cells are seeded on the membranes with micropattern spacing of 200 microm width and 80 microm depth, they adhere and aggregate in the groove of the membranes in a few minutes. The aggregated cells migrate up to the surface of the ridge later. This phenomenon, however, is not found on membranes with a micropattern spacing of 500 microm width. In addition, it is demonstrated that the cells on the CCG membranes with micropatterns have higher metabolism and growth rates than those on the flat CCG membranes and on T-flask discs. Micropatterning on the membrane surface can affect the distribution of cells and the communication among cells, and results in a difference in cell adhesion, morphology, mobility, and growth activity.
Several advantages of microfluidic systems such as rapid control, reduced size, low costs, large-scale integration and in vivo simulation of cellular microenvironments make them suitable for diverse bionanotechnological applications. This chapter reviews major current and potential microfluidic applications in bionanotechnology, including miniaturized devices related to common molecular biological techniques such as polymerase chain reaction (PCR), DNA microarray and electrophoresis; microfluidic bioreactors; and monitoring microbial behaviour by microfluidics. Additionally, present applications and future potential of microfluidics in microbial strain development and single cell analysis/characterization are discussed.
Nanofabrication techniques for feature sizes less than 100 nm are available for silicon-based materials using high cost, cleanroom-based
methods. The high cost may be acceptable for large-throughput manufacturing in the IC industry, but the broader needs and
lower volumes in biomedicine require more cost-effective mass-production methods capable of replicating nanostructures in
a wide range of materials. However, the properties of silicon (poor impact strength/toughness, poor biocompatibility) are
inappropriate for many biomedical devices. For example, the conductivity of silicon is problematic in many micro/nanofluidic
applications that require high voltage for electrokinetic flows. Non-conductive glass or quartz devices can be made using
the same lithography/etching fabrication techniques. These materials, although less costly than silicon, are still much more
expensive than most polymeric materials. In contrast, polymeric materials possess many attractive properties such as high
toughness and recyclability. Some possess excellent biocompatibility, are biodegradable, and can provide various biofunctionalities.
Proper combination of functional polymers and biomolecules can offer tailored properties for various biomedical applications,
but the ability to process them at the nanoscale to form well-defined functional structures is largely underdeveloped. Nanofabrication
techniques for feature sizes less than 100 nm are available for silicon-based materials using high cost, cleanroom-based methods.
The high cost may be acceptable for large-throughput manufacturing in the IC industry.
The use of supercritical carbon dioxide as a processing solvent for the physical processing of polymeric materials is reviewed. Fundamental properties of CO2/polymer systems are discussed with an emphasis on available data and measurement techniques, the development of theory or models for a particular property, and an evaluation of the current state of understanding for that property. Applications such as impregnation, particle formation, foaming, blending, and injection molding are described in detail including practical operating information for selected topics. The review concludes with some forward-looking discussion on the future of CO2 in polymer processing.
The influence of surface micropatterning of the chitosan–collagen–gelatin (CCG) blended membranes on the activities of human mesenchymal stem cells (hMSCs) has been investigated. It is aimed to regulate the growth activity in vitro and to guide the spatial arrangement of hMSCs on the membranes for the application in tissue engineering. Masters with micropatterns were prepared on stainless steel plates or silicon wafer by photolithography. The CCG membranes with topological surface micropatterns were then fabricated by soft-lithography. The morphology and growth activity of hMSCs on the membranes were recorded. When MSCs were seeded on the membranes with micropattern spacing size of 200μm in width and 80μm in depth, they adhered and aggregated in the grooves of the membranes in a few minutes. The aggregated cells would migrate up to the surface of the ridge later, and the cells on the ridge align with the direction of the ridge-groove patterns. Some of the cells would form bridge-like structure between two adjacent ridges. When the pattern spacing size was smaller than the size of cell, the proliferation of hMSCs would be limited. Micropatterning on membrane surface could affect the distribution of hMSCs and resulted in difference of cell behaviors such as cell alignment, morphology, proliferation, and growth activity.
This paper describes the generation of monodisperse calcium alginate (Ca-alginate) microcapsules on a microfluidic platform using the commercial optical disk process. Our strategy is based on combining the rapid injection molding process for a cross-junction microchannel with the sheath focusing effect to form uniform water-in-oil (w/o) emulsions. These emulsions, consisting of 1.5% (w/v) sodium alginate (Na-alginate), are then dripped into a solution containing 20% (w/v) calcium chloride (CaCl2) creating Ca-alginate microparticles in an efficient manner. This paper demonstrates that the size of Ca-alginate microparticles can be controlled from 20 µm to 50 µm in diameter with a variation of less than 10%, simply by altering the relative sheath/sample flow rate ratio. Experimental data show that for a given fixed dispersed phase flow (sample flow), the emulsion size decreases as the average flow rate of the continuous phase flow (sheath flow) increases. The proposed microfluidic platform is capable of generating relatively uniform emulsions and has the advantages of active control of the emulsion diameter, a simple and low cost process and a high throughput.
Micro/nanotechnology is initiated from the electronics industry. In recent years, it has been extended to micro/nanoelectromechanic system for producing miniature devices based on silicon and semiconductor materials. However, the use of these hard materials alone is inappropriate for many biomedical devices. Soft polymeric materials possess many attractive properties such as high toughness and recyclability. Some possess excellent biocompatibility, are biodegradable, and can provide various biofunctionalities. Proper combinations of micro/nanoelectronics, polymers, and biomolecules can lead to new and affordable medical devices. In this paper, we briefly review several cleanroom and noncleanroom techniques related to micro/nanomanufacturing of polymeric materials. © 2009 Wiley Periodicals, Inc. Adv Polym Techn 27:188–198, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/adv.20134
In the early 21st century, nanotechnology is a field in rapid flux and development, and definition of its boundaries can be elusive. Aspects
of multiple disciplines, ranging from physics to computer science to biotechnology, legitimately contribute to the endeavor.
This breadth of field allows many interested parties to contribute to nanotechnology, but the same ambiguity can effectively
render the field indistinct. The precise definition of nanotechnology remains debatable, so consideration of the present scope
of the field may be useful.
Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes,
features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties
associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation
of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is ahallmark
of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes,
with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum
to acogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing
measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external
clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals.
Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation
techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition
inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics.
Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer
and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection
of nanotherapeutic design and assembly protocols.
In this chapter, we have presented an overview of microfluidic enzyme-linked immunosorbent assay (ELISA) by first introducing the principle of immunoassay, ELISA, and microfabricated devices, followed by a discussion of microfabrication technology and the characterization of microfluidic components. Significant advances in laboratory technology are contributing to the further understanding of microfluidic function, surface modification and immobilization, which lead to the development of improved biomolecule detection methods and prospective applications. For the future, the exploitation of more robust-manufacturing processes and integrated assay systems in an automatic fashion with much reduced assay time and reagent consumption will allow for the effective detection and quantification of biological agents that are of interest in medical diagnostics, food safety surveillance, and environmental monitoring.
The hot embossing microreplication microfabrication, HEMM, systems are gaining popularity in the MEMS and more specifically the BioMEMS area due to their capability to quickly and inexpensively replicate microstructures on various types of polymers or used for thermal bonding of BioMEMS substrates. Control issues associated with a HEMM system include temperature, heat and force control for process control. This manuscript discussed the procedure for the development of an artificial intelligence based controller using neural networks and fuzzy logic with application to the heating and temperature control of a HEMM system. Subsequently, the controller development in LabVIEW and MATLAB, and its implementation and performance verification on a testbed is presented
A high-throughput lithographic method with 25-nanometer resolution and smooth vertical sidewalls is proposed and demonstrated.
The technique uses compression molding to create a thickness contrast pattern in a thin resist film carried on a substrate,
followed by anisotropic etching to transfer the pattern through the entire resist thickness. Metal patterns with a feature
size of 25 nanometers and a period of 70 nanometers were fabricated with the use of resist templates created by imprint lithography
in combination with a lift-off process. With further development, imprint lithography should allow fabrication of sub-10-nanometer
structures and may become a commercially viable technique for manufacturing integrated circuits and other nanodevices.
We have investigated pattern formation of thin PMMA films during both hot embossing and demoulding of micro- and nanostructures. During filling of the stamp cavities, compressive and capillary effects were observed, and under certain conditions periodic patterns with characteristic length scales formed. In unstructured stamp regions the form of these patterns is affected by local differences in the pressure. For structured stamps, the self-assembly is strongly influenced by the size and the shape of the stamp cavities. Rapid expansion of trapped air resulted in viscous fingering patterns and a dewetting behaviour of the polymer could be observed.
In this paper we describe components for integrated microliquid handling systems such as fluid injection analysis, and first results of planar integration of components. The components discussed are channels, passive and active valves, actuators for micropumps, micromixers, microflow sensors, optical detectors, pumps and dosage systems. The dosage system described comprises a flow sensor and a pump micromachined on a single silicon wafer sandwiched between Pyrex wafers. The liquid pump is of the reciprocating type with a thermo-pneumatic actuator. The microliquid flow sensor is based on the thermal anemometer type. Both pump and flow sensor are realized in a 3 inch (100)- Si wafer using a KOH bulk etch from both sides of the wafer. The dosing system allows accurate dosing of liquid in the mu l regime and can easily be integrated with components as mixers and detectors to microliquid handling systems. A new concept for micromixing of liquids is introduced and its feasibility is demonstrated. The mixer allows fast mixing of small amounts of two liquids and it is applicable to microliquid handling systems. The mixer has a channel for the liquid, an inlet port for the reagent, and a mixing area, the bottom of which has 400 micronozzles (15 mu m*15 mu m). Through these nozzles, a reagent is injected into the sample liquid, making many microplumes. These plumes speed up mixing by diffusion over a short distance.
The ability to create well-defined and controlled interfaces has been an area of great interest over the last few years, particularly in the biomedical arena. This paper will describe the development of technology for the fabrication of nanopore membranes, and their operation in biological environments. With monodisperse pores sizes as small as 10 nanometers, these membranes offer advantages in their reproducibility, and their ability to be integrated with controlled biochemical surface modification protocols. A comprehensive review of results in the areas of nanopore and biocapsule microfabrication technologies, biocompatibility of nanomembrane materials, biologically appropriate post-processing protocols (bonding, sterilization), surface modification protocols, and appropriate mass transport models will be presented. The results point to the potential of using such technologies for therapeutic applications including immunoisolation biocapsules, drug delivery devices, and targeted biorecognition platforms.
In this paper, the design of a polymer based microfluidic compact disk (CD) platform is presented. Several microfluidic functions such as flow sequencing, cascade micro-mixing, and capillary metering can be integrated into the CD by balancing the centrifugal force and the capillary force. These functions are demonstrated experimentally. For flow sequencing, a two-point calibration design is used as an example to show how the release and flow of fluids can be precisely controlled by the rotation speed of the CD. For cascade micro-mixing, a typical application is reconstituting lyophilized protein. A simple metering technique based on bubble snap-off in the two-phase flow is also described.
Tissue engineering scaffolds play a critical role in regulating the reconstructed human tissue development. Various types
of scaffolds have been developed in recent years, including fibrous matrix and foam-like scaffolds. The design of scaffold
materials has been investigated extensively. However, the design of physical structure of the scaffold, especially fibrous
matrices, has not received much attention. This paper compares the different characteristics of fibrous and foam-like scaffolds,
and reviews regulatory roles of important scaffold properties, including surface geometry, scaffold configuration, pore structure,
mechanical property and bioactivity. Tissue regeneration, cell organization, proliferation and differentiation under different
microstructures were evaluated. The importance of proper scaffold selection and design is further discussed with the examples
of bone tissue engineering and stem cell tissue engineering. This review addresses the importance of scaffold microstructure
and provides insights in designing appropriate scaffold structure for different applications of tissue engineering.
This Letter reports the measurement of electro-osmotic flows (EOF) in microchannels with surface charge patterned on the 200 mu m scale. We have investigated two classes of patterns: (1) Those in which the surface charge varies along a direction perpendicular to the electric field used to drive the EOF; this type of pattern generates multidirectional flow along the direction of the field. (2) Those in which the surface charge pattern varies parallel to the field; this pattern generates recirculating cellular flew, and thus causes motion both parallel and perpendicular to the external field. Measurements of both of these flours agree well with theory in the Limit of thin double layers and low surface potential.
Electrochemical methods were combined with redox-active surfactants to actively control the motions and positions of aqueous
and organic liquids on millimeter and smaller scales. Surfactant species generated at one electrode and consumed at another
were used to manipulate the magnitude and direction of spatial gradients in surface tension and guide droplets of organic
liquids through simple fluidic networks. Solid microparticles could be transported across unconfined surfaces. Electrochemical
control of the position of surface-active species within aqueous films of liquid supported on homogeneous surfaces was used
to direct these films into periodic arrays of droplets with deterministic shapes and sizes.
The advantage of a low voltage approach to lithography and surface modification is that a more spatially localized energy deposition can be achieved than with a focused high energy charged particle beam. Proximal probes, such as the scanning tunnelling microscope or atomic force microscope with a conductive tip, are convenient ways to realize this approach. We summarize here research performed over the past few years at the Naval Research Laboratory directed towards materials studies and lithographic fabrication of structures and devices using proximal probes.
Economic success of microsystems technology requires a wide range of materials as well as the related manufacturing processes. A suitable technology for medium/large scale production is micro injection molding which actually allows the manufacturing of plastic microstructures with 20 microns minimum thickness, structural details of approximately 0.2 microns or maximum aspect ratios of more than 20. These microstructures are, for example, applied as components in micro optics, micro fluidics or minimally invasive surgery. This is demonstrated by microparts that are currently available or will be available soon. For higher economic efficiency and cost reduction, fully electrical injection modeling machines of higher accuracy have been applied. Also, micro insert injection molding reduces mounting costs. Manufacturing of metal or ceramic microparts by powder injection modeling allows large-scale production of complex shaped microstructures with a wide range of materials. Typical examples are sintered structured like stepped LIGA- gear wheels with minimal dimensions of 50 microns in different metal and ceramic materials. Micro Precision Casting originating from conventional investment casting is a suitable process for small/medium-scale production. Examples are microturbine housings made of precious metal alloys. An approach similar to rapid prototyping applies photocurable reactive resins. Photoinduced molding of low viscous resins under ambient conditions leads to significantly reduced cycle times. Additionally, rapid testing of new composite materials can be performed easily. Microcomponents molded from polymers and different composites like dyes with nonlinear optical properties and nanosized ceramic powders will be presented.
Electron beam lithography (EBL) and scanning probe lithography (SPL) are electron exposure techniques capable of high resolution patterning of organic resists. This article compares the exposure properties of these two systems. We consider the resist sensitivity to EBL and SPL electrons, exposure tolerances, patterning linearity, and proximity effects. It is possible to print sub-50 nm features using both systems, but SPL has a wider exposure latitude at these small feature sizes. SPL requires a significantly higher incident electron dose for exposure than does EBL. In EBL, lithography control is most limited by proximity effects which arise from backscattered electrons whose range is considerably larger than the forward scattering range in the resist film. As a result, the exposed feature dimension depends strongly on the local feature density and size, leading to unacceptable linewidth variations across a wafer. These limitations are alleviated in the case of SPL exposures. We demonstrate improved linearity and reduced proximity effects with SPL. We have patterned 200 nm pitch grids with SPL where all individual features are resolved. The linewidth of features in these grids is the same as the width of an isolated line at the same dose. Finally, we suggest that the SPL exposure mechanism may be different than that for EBL. © 1998 American Vacuum Society.
Pore size distributions and pore densities of track-etched polycarbonate ultrafiltration (UF) membranes with pore sizes ranging from 10 to 100 nm (0.01–0.10 μm) were characterized by image analysis of field emission scanning electron micrographs (FESEM) of membranes. Porosity data obtained from image analysis compared well with those derived from manufacturer's specifications, but this may have been coincidental, as pore size and pore density results differed by 20–40% and 25–70%, respectively. The experimentally determined flux through each membrane type varied by up to 30–45% within a batch, and were about 8–46 times higher than the theoretical over the range of membranes. The disparity between theoretical and experimental flux was beyond the bounds of physical variability of the membranes. The membranes with smaller pore size tended to show a greater disparity. Water flux of all membranes increased with increasing temperature, generally in accord with the decreasing viscosity of water. However, unlike the linear increase for the membranes with larger pores (> 50 nm), the membranes with smaller pores (10 and 30 nm) showed exponential increase with temperature. Water flux also increased with a pressure increase from 50 to 300 kPa. Raised pressure appear to enlarge pores resulting in exponential flux enhancement at higher pressure, particularly for membranes with smaller pores (PC10). The pores may have stretched open under pressure to deliver the higher than expected fluxes due to flexibility of polycarbonate films, although FESEM showed no visible evidence of fracturing or tearing of the membranes. The flux results from filtration of aqueous protein solution were a little lower and correlated well with water permeability of the membranes, but remained in discord with the pore size distribution results.
Scanning probe lithography based on localized current injection using the probe tip of atomic force microscopy (AFM) has been applied to nanoprocessing of an insulating substrate. An electrically conductive resist film composed of triple layers was developed for this current-injecting AFM lithography. The bottom layer of the resist, which served as a current pass during patterning, consisted of amorphous silicon (a-Si) with 20 nm in thickness prepared by ion-beam sputtering. An organosilane monolayer, that is, octadecylsilyl self-assembled monolayer (ODS-SAM) of 2 nm in thickness, was used as the top layer of the resist, therefore, as the imaging layer in which nanoscale patterns were drawn by AFM. In order to bind the a-Si and the ODS-SAM together, the intermediate layer of the resist, that is, Si oxide of 2 nm in thickness, was prepared by photooxidation of the a-Si layer. Through an AFM-lithographic process using this multilayered resist, nanofabrication of fine grooves on a Si oxide substrate was demonstrated. The minimum feature size about 50 nm was successfully fabricated. © 1999 American Vacuum Society.
Macroscopic orientational ordering of the pores of condensed hexagonal mesostructured silica (MCM-41) was achieved through
alignment of an unpolymerized, hexagonal, lyotropic silicate-surfactant liquid crystal in a high magnetic field. This alignment
was preserved after polymerization of the silicate species by acid treatment. Subsequent calcination to remove the surfactant
yielded a mesoporous silica solid that retained both macroscopic pore alignment and mesoscale periodicity. Potential applications
of such liquid crystal processing strategies range from the formation of anisotropic silica-based bulk ceramics to the production
of oriented mesoporous thin films for chemical sensors, separations, catalysis, or host-guest applications.
A microactuator for rapid manipulation of discrete microdroplets is presented. Microactuation is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass. A prototype device consisting of a linear array of seven electrodes at 1.5 mm pitch was fabricated and tested. Droplets (0.7–1.0 μl) of 100 mM KCl solution were successfully transferred between adjacent electrodes at voltages of 40–80 V. Repeatable transport of droplets at electrode switching rates of up to 20 Hz and average velocities of 30 mm/s have been demonstrated. This speed represents a nearly 100-fold increase over previously demonstrated electrical methods for the transport of droplets on solid surfaces. © 2000 American Institute of Physics.
Pumping of fluids in microchannels using the movement of a single or multiple vapor bubble(s) is proposed, analyzed, and demonstrated. The pumping mechanism requires no micromechanical moving parts for actuation by utilizing asymmetric heating which creates a variation in vapor pressure and surface tension due to the heater-induced temperature gradient along the channel. A heat and mass transfer analysis was performed to understand the pumping mechanism and estimate the pumping capability of the micropumping device. To verify the concept and our analysis, a pumping device with a transparent microchannel with a hydraulic diameter of 3.4 μm was fabricated on a silicon wafer using surface micromachining. Experimental results with the first generation device have shown pumping of isopropanol at velocities as high as 160 μm/s (0.5 nl/min flow rate) with a pressure head of approximately 800 Pa. © 1998 American Institute of Physics.
Micromolding is a key technology for the economic production of micro-components for microsystems. It is applied in several microstructuring techniques including the LIGA process which was invented and developed at Forschungszentrum Karlsruhe. Injection molding of multiple-use LIGA tool inserts produced by deep-etch x-ray lithography and electroforming allows the economic production of components for most applications using microsystems technology. Such microstructures are produced in small and large series and commercialized by Forschungszentrum Karlsruhe and the microParts Company, Dormund, Germany, cooperating within the framework of a license agreement. Special molding machines are applied for the production of single- or multi-stepped microstructures of a few micrometers in lateral dimension and structural details in the submicrometer range. Maximum aspect ratios of several ten up to 600 are achieved. In contrast to compact disc production, the machines are equipped with a special control unit, by means of which tool temperature is often kept above the melting temperatures of the plastics processed during injection. Evacuation of the tool cavity is required for the complete filling of the microstructurized nest area of the mold. Cycle time is mainly determined by the heating and cooling of the whole molding tool. Recently, novel techniques were developed for the production of ceramic LIGA or LIGA-similar microstructures at Forschungszentrum Karlsruhe, where further development of the LIGA technique has been performed for more than a decade. Using lost plastic microstructures and sometimes even metal tools, microstructures are made of structural (e.g., aluminum oxide, zirconium oxide) and functional ceramics (e.g., PZT). Current development activities are aimed at producing lost plastic molds for metal microstructures by injection molding. Molding tests with conductively filled thermoplastics have been carried out to manufacture lost molds for e.g. spin nozzles.
Nanotip arrays have been fabricated on the distal faces of coherent fiber-optic bundles. A nanotip array comprised ∼6000 individual optical fibers that were etched chemically. Individual tips were ∼4 μm long with radii of curvatures as small as 15 nm. Nanotip arrays served as a template for a novel polymeric patterning process called photoimprint lithography. This lithographic method generated an array of polysiloxane microwells on glass surfaces. Individual wells had ∼1 μm diameters and were dispersed regularly ∼4 μm apart (center-to-center). Nanotip arrays were also used as templates for an imprint patterning process. This lithographic method generated an array of polystyrene microwells on glass surfaces dispersed regularly ∼4 μm apart with ∼1 μm diameters and ∼4 μm well depths. Both lithographic methodologies provide a simple, technically-expedient method to pattern surfaces with arrays of picoliter-volume wells suitable for microanalytical device utilization. © 1999 American Institute of Physics.
Economic success of microsystems technology requires cost- effective fabrication in large series as well as a great diversity of materials processing technologies. The different techniques of micro molding meet all these requirements. An important economic factor is the reduction of cycle time by process and tool optimization with simulation techniques. Actually, minimal cycle times are about two minutes in certain cases. Evolution of thermoplastics processing technologies is demonstrated by application of technical or even high- performance polymers like PEEK, PMMA or PSU. For manufacturing of metal microstructures, we develop three possibilities: microstructures like stepped LIGA gear wheels are obtained from galvanization on lost molds, which have been injection molded using conductively filled polymers. Additionally, electroless plating is used to replicate nonconducting plastic microstructures and the metal injection molding (MIM) process is under development. A quite different approach uses polymer precursors containing monomer/polymer mixtures in reaction injection molding. We chose photoinduced polymerization without any preheating step using photopolymerizable resins. Avoiding the time consuming thermal cycle, molding takes place at ambient temperature. Due to the low viscosity, the microcavities should be filled completely. The process is characterized by the integration of a powerful UV-source and a partially glass made molding tool.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
Polymer microfabrication methods are becoming increasingly important as low-cost alternatives to the silicon or glass- based MEMS technologies. We present in this paper hot embossing as a replication method for planar microstructures based on polymer substrates. Several chips containing microchannels for capillary electrophoresis applications with a range of channel widths between 0.8 micrometers and 100 micrometers have been produced by this method, yielding a very good structural replication and short production times.© (1998) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
Diagnostics for point-of-care (POC) and field use requires the integration of fluid processes with means of detection in a user-friendly, portable package. A drawback to the use of many current analyzers for POC and field applications is their reliance on expensive and fragile robotic technology for automation, lack of portability, and incomplete integration of sample processing into the device. As a result, a number of microfluidic technologies are being developed for diagnostics applications outside of central laboratories. We compare several of these technologies with our own preferred centrifugal flow system, the LabCDTM, with an emphasis on fluid propulsion. LabCDTM has been developed to perform a variety of fluidic processes necessary in diagnostics while dispensing with traditional pumps and valves. The use of the CD-ROM model provides a natural division of the system into an instrument and a disposable component, each with well-defined functions. The CD format also allows for the use of encoded information to integrate process control, data acquisition, and analysis. Finally, the `solid state' nature of the microfluidics and use of standard manufacturing techniques should yield a low- cost platform.© (1998) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
Fluid flow in capillary microchannels is used in numerous applications in biotechnology (such as protein separation, fast DNA analysis, drug deliveries systems and viral filtration), in solid-state devices, and in catalytic devices. The current work presents the experimental validation for the electrokinetic theory in microchannels. Retardation of polar liquids, including de-ionized water, ethanol and propyl alcohol, is studied in microfabricated channels of several diameters. It was found that polar liquids flow about 6 percent more slowly than predicted by the classical hydrodynamic theory in microchannels, with the hydraulic diameter equal to 90 microns. For small microchannels with a hydraulic diameter of several microns, observed retardation is on the order of 70 percent. Collected experimental data have good correspondence with the electrokinetic model presented. Electrokinetic retardation of polar liquids in microchannels is based on the charge separation principle. Electrical charges are separated at the interface (near the channel wall). When liquid is forced downstream, it causes charge accumulation at one end of the microchannel. The streaming potential produced causes an upstream current that creates upstream counterflow. The resultant fluid flow is less than it would be for non-polar liquids. The higher the zeta-potential at the microchannel wall and the smaller the channel, the larger the resulting retardation. Modifications for the friction factor, as applied to microfluidics, are suggested. Recommendations to improve fluid flow in microchannels are made.© (1999) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
In this paper, we review the approaches developed in our laboratory for polymer-based micro/nanofabrication. For fabrication of microscale features, UV-LIGA (UV-lithography, electroplating, and molding) technology was applied for low-cost mass production. For fabrication of sub-micron or nanoscale features, a novel nano-manufacturing protocol is being developed. The protocol applies a novel nano-lithography imprinting process on an ultra-precision motion-control station. It is capable of economically producing well-defined pores or channels at the nanometer scale on thin polymer layers. The formed thin layers can be used as nano-filters for chemical or bio-separation. They can also be integrated into miniaturized devices for cell immunoprotection or tissue growth. For bonding of polymer-based microfluidic platforms, a novel resin-gas injection-assisted technique has been developed that achieves both bonding and surface modification. This new approach can easily seal microfluidic devices with micron and sub-micron sized channels without blocking the flow path. It can also be used to modify the channel shape, size, and surface characteristics (e.g., hydrophilicity, degree of protein adsorption). By applying the masking technique, local modification of the channel surface can be achieved through cascade resin-gas injection.
pH-sensitive hydrogels are suitable candidates for oral drug delivery of peptides due to their ability to respond to their environment. We have developed new hydrogels composed of poly(methacrylic acid) (PMAA) grafted with poly(ethylene glycol) (PEG) (P(MAA-g-EG)) which can be used as drug delivery carriers for salmon calcitonin. P(MAA-g-EG) hydrogels were prepared by free radical solution polymerization. The monomer mixture was diluted using a 50% w/w solution of ethanol and water. The percentage of monomer in solution was varied from 84% to 45% v/v. Swelling studies were conducted to investigate the effects of solvent content used during polymer preparation in the swelling behavior. The effects of dilution on the swelling behavior were not observed until the monomer mixture was diluted to approximately 50%. Salmon calcitonin was successfully incorporated and released in vitro from the system. Solutions of approximately 0.1 mg/mL of salmon calcitonin were used to load the protein into the gels at pH = 7 and constant ionic strength of 0.1 M. The loading efficiency was affected by the amount of solvent used during hydrogel preparation. In vitro release studies were performed at pH = 7 and 37 °C, while keeping an ionic strength of 0.1 M. The release behavior was found to be not very much affected by the amount of diluent used during polymer preparation. The transport mechanism was found to be relaxation controlled for all cases, and the diffusion coefficient was estimated using a heuristic Fickian/relaxational model.
Graft copolymer networks of poly(methacrylic acid-g-ethylene glycol) exhibiting pH-dependent swelling behavior due to the formation of interpolymer complexes were prepared by free radical solution polymerization of methacrylic acid and poly(ethylene glycol) monomethacrylate. Dynamic swelling studies established the swelling/deswelling process due to hydrogen bonding. Additionally, the effects of copolymer composition, graft chain molecular weight, and environmental pH on network structure were studied. The average network correlation length changed significantly due to changes in environmental pH. The largest changes in network structure were observed in gels containing nearly equimolar amounts of methacrylic acid and ethylene glycol and the longest molecular weight poly(ethylene glycol) grafts. Water diffusion coefficients, determined through dynamic swelling analysis, varied by 2 orders of magnitude between the uncomplexed and complexed states.
A novel approach to highly ordered and modular nanoelectrode arrays (NEAs) has been developed using block copolymer self-assembly. Variable scan rate cyclic voltammetry studies were performed to characterize the NEA. At low scan rates, the NEA behaves similar to a macroelectrode, while at high scan rates the nanoelectrodes act independently. This is an important feature for real-time in vivo sensing and other electroanalytical applications.
This paper, aimed at delineating the significant changes in polyaniline (PAN) upon going from external protonic doping to internal doping, describes results on preparation and characterization of a self-doped conducting polymer: sulfonic acid ring-substituted polyaniline (SPAN). This polymer has a wide range of solubility, which improves the processibility of the polymer. Elemental analyses and spectroscopic data show that approximately 50% of the total number of phenyl rings in the polymer are monosubstituted by -SO3- groups. SPAN has an intrinsic acid that is capable of doping the polyaniline backbone. Little correlation between the conductivity and pH is observed, the conductivity of approximately 0.1 S/cm being independent of pH for pH less than 7.5. Transport, magnetic, and electrochemical properties of SPAN provide insight into both the structural and electronic properties and the role that -SO3- and -SO3-Na+ groups play in affecting the solubility, doping mechanism, and charge transport in the polyaniline system. Comparative studies of SPAN and PAN show similarities due to the same backbone structure and differences because of the -SO3- groups on the phenyl rings.
A novel procedure has been developed for the synthesis of spongelike silica membranes with three-dimensional meso-macrostructures. The process utilizes multiphase media comprised of a mesoscopically ordered block copolymer/silica phase that macroscopically separates from an electrolyte phase. This results in hierarchically organized composite structures whose different characteristic length scales can be independently adjusted.
Mesoporous silica fibers with accessible, highly ordered large periodic pores are directly drawn from a highly viscous surfactant/silicate solution. Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) triblock copolymers are used as the structure-directing agents under acidic conditions during the syntheses. These fibers have uniform exterior diameters of submicron to several hundred micron and no apparent limit on aspect ratios. They are made up of either supercage arrays or 2-dimensional channel arrays with pore sizes as large as 63 Angstrom.
Large, hard, transparent, mesoporous silica spheres are synthesized in one step by using oil-in-water emulsion chemistry under basic conditions with cationic surfactants and (n-BuO)(4)Si. The pores are shown by TEM and nitrogen absorption studies to be monodispersed in size, with total surface area over 1000 m(2)/g.
i-STAT devices are now in use in 1000 hospitals in North America, Japan, and Europe. i-STAT blood testing technology has been integrated into other patient-side monitoring tools offered by Hewlett-Packard Co. In about 100 hospitals our blood testing technology has been adopted as an institution-wide, multidepartment program. In the past few years, patient-side testing of critical blood values has become an accepted procedure; indeed it is now a significant growth sector of the in vitro diagnostics industry. For the test menu available for patient-side use (fully developed and performing robustly), the fraction of testing actually restructured to patient-side relative to the total tests amenable to restructuring is still quite small, so that the opportunity for growth of this sector is still enormous. Restructuring to patient-side blood testing activities is no longer limited by availability of technology.
Using the LIGA technique prototypes of twelve-fibre-wide ribbon connector ferrules have been developed that provide low-loss physical-contact multimode connections for parallel interfaces. The ferrules are injection moulded and the modular mould insert has been fabricated by means of microtechnology (LIGA) and electro-discharge machining. After assembling, mated couples of these ferrules show average insertion loss values of 0.35 dB and have been used to successfully transmit data with a transfer rate of 250 Mbit per fibre over a 100 m distance.
The application of microfabrication techniques to problems involving fluids is reviewed. A number of scientific issues have been addressed using microstructures designed to confine and manipulate fluids. These problems include studies of fluid motion in percolative structures, chemical applications involving small volumes of reactants and products, biologically inspired experiments involving the manipulation of individual molecules, and studies of fundamental properties of liquids in extremely small geometries. Representative work is described, along with the ingenious fabrication methods which have been developed.
We believe that there are many opportunities for interesting basic physics and also interdisciplinary work in this area. The primary goal of this article is to bring this message to the general physics community.
A process for the fabrication of microvalve systems by thermoplastic molding and membrane techniques has been developed. The valve system consists of three individual valves formed by two parts molded from polymethylmethacrylate PMMA and a polyimide membrane. The mold inserts were manufactured by milling of a brass substrate using a 300 mu m diameter head. The three-dimensional microstructure of the inserts consists of four different levels for valve seats, orifices, alignment pins and cavities. The overall diameter and height of the whole valve system is 7 mm and 1.9 mm, respectively. The valves are designed to be normally open. To close the valves, the pressure in an actuator chamber above the membrane is raised by a heater coil and the membrane is pressed onto the valve seat. First measurements at a difference pressure of 1000 hPa showed a rate of water flow through a single valve of 171 mu l s-1. An actuator pressure of 180 hPa was reached by heating air with a resistive heater and continuous electrical power of 158 mW. A valve supplied with nitrogen at 130 hPa was closed by an electrical power of 116 mW.
Microsystems are gaining more and more interest in several technological areas. The complete integration of different basic elements like pumps, valves and reaction chambers is possible by the use of microtechnologies. In the field of micro analysis systems a mixing procedure of different solutions is often required. A static micromixer built up in silicon has been developed. The design and fabrication procedures of the micromixer allow the integration of other microcomponents like pumps, valves or sensors. The micromixer consists of two structures silicon wafers. The structured surfaces are bonded together by using a low temperature silicon direct bonding process. The structure of the mixer consists of several identical mixing elements. The size of one element is about . Each element consists of two or more microchannels for different liquids to be mixed. The arrangements of the microchannels in the elements lead to a mixing of the liquids. We found a homogeneous mixing after about 5 mixing elements for mixable liquids. Not mixable liquids will be emulsified after about 16 - 20 mixing elements.
A short overview of the technology and physics of semiconductor quantum dots is given. Different methods of creation of quantum dots and mechanisms of carrier confinements are described. The fundamental properties of these systems are discussed including current attempts for applications in new ultra-small opto-electronic semiconductor devices.
An electrostatically actuated polymer microvalve with a movable membrane electrode is presented. The microvalve cases are made by thermal injection molding of conductive polyamide. The movable membrane acting as an electrode consists of two insulating layers with a conductive layer in between. The three layers are patterned differently and transferred from a silicon wafer to the valve case in a batch process. The case of the microvalve and the three-layer membrane are joined by adhesive injected into cavities in the case. The three-layer membrane is moved electrostatically by a suitable voltage applied between the case and the membrane. The membrane of thickness is attracted to the upper or the lower valve chamber, thus opening or closing the inlet of the microvalve. The microvalve has an outer diameter of 5 mm and is 3 mm thick. The membrane electrode is moved when the voltage applied is approximately 60 - 150 V. Volume flows of up to 0.2 are attained at a differential pressure of 1100 hPa.
The relationship among processing conditions, material properties, and part quality in hot embossing was investigated for three optical polymers: polycarbonate (PC), polymethyl methacrylate (PMMA), and polyvinyl butyral (PVB). A series of systematic embossing experiments was conducted using mold inserts having either single or multiple feature depths. The feature dimensions varied from 90 to 3000 μm. The processing conditions studied include embossing pressure, thermal cycles, and heating methods. The displacement profile, replication accuracy and molded-in stresses were measured experimentally. It was found that for isothermal embossing, both replication accuracy and birefringence pattern depend strongly on the processing conditions. For non-isothermal embossing, the molded parts showed excellent replication as long as the feature transfer was completed. The flow pattern under isothermal embossing resembles a biaxial extensional flow. Under non-isothermal embossing, the polymer deformation involves an upward flow along the wall of mold features, followed by downward compression and outward squeezing. Rheological characterization and hot embossing analysis are presented in Part II.
Injection molding of thin plates of micro sized features was studied in order to manufacture micro-fluidic devices for bioMEMS applications. Various types of mold inserts—CNC-machined steel, epoxy photoresist, and photolithography and electroplating produced nickel molds—were fabricated and tested in injection molding. The feature size covers a range of 5 microns to several hundred microns. Issues such as surface roughness and sidewall draft angle of the mold insert were considered. Two optically clear thermoplastics, PMMA and optical quality polycarbonate, were processed at different mold and melt temperatures, injection speeds, shot sizes, and holding pressures. It was found that the injection speed and mold temperature in injection molding greatly affect the replication accuracy of microstructures on the metal mold inserts. The UV-LIGA produced nickel mold with positive draft angles enabled successful demolding. Numerical simulation based on the 2D software C-MOLD was performed on two types of cavity fillings: the radial flow and the undirectional flow. The simulation and experimental data were compared, showing correct qualitative predictions but discrepancies in the flow front profile and filled depth.
This review considers the uses of biodegradable polymers in terms of their relevance within current plastic waste management of packaging materials, biomedical applications and other uses; research papers and patents are catalogued. The chemical synthesis of polyesters and the microbial production of poly(hydroxyalkanoate)s, including recent publications in these areas, are covered and methods of characterization and structural analysis are outlined. Current research into two- and three-component blends is reviewed as a method of reducing overall costs and modifying both properties and biodegradation rates of materials. Finally, there is a summary of degradation processes. Both abiotic and biotic reactions are discussed, together with the development of biodegradation test methods, particularly with respect to composting. © 1998 Society of Chemical Industry
A corner flow hydrodynamic theory is outlined for the time to snap-off of a gas bubble moving through a smoothly constricted noncircular capillary as a function of the pore geometry and the capillary number, Ca. Above a transition capillary number the time to snap-off is independent of Ca, while below it the time to snap-off is inversely proportional to the capillary number. Thin films of liquid deposited along the capillary walls are shown to play a minor role; they are accordingly neglected in the analysis. The proposed theory is compared to new experimental results for snap-off in two constricted square capillaries (dimensionless constriction radii of 0.3 and 0.5) over a range of capillary numbers (10−5 to 10−3), wetting-liquid viscosities (1.0 to 8.5 mPa · s), and surfactant types. Good agreement is found between theory and experiment.
Most conventional drug delivery systems are based on polymers or lipid vesicles. These chemically synthesized materials can be designed to be biocompatible and have good functionality, but they often lack well-defined properties, due to an inherent size and structure distribution resulting from chemical synthesis. On the other hand, micro-fabrication technology developed for microelectronic applications is capable of mechanically creating devices with more precisely defined features, in a size range similar to polymeric and lipid materials. In this paper, we describe the design of a self-regulated drug delivery device based on the integration of both mechanical and chemical methods. In this device, a constant release rate can be achieved by carefully designing the shape of the drug reservoir, while a pH-sensitive hydrogel switch is used to regulate the drug release.
A solder technology has been developed that utilizes molten solder surface tension forces to self-assemble MEMS 3-D structures. Using solder, a single batch reflow process can be used to accomplish hundreds or thousands of precision assemblies, and the cost per assembly can be reduced considerably. A model, based on surface energy minimization of molten liquids, has been developed for predicting assembly motion. The modeling, combined with experimental studies, have demonstrated ±2° assembly angle control is possible when the MEMS structures are assembled by solder alone. To improve the self-assembly angle precision, a self-locking mechanism can be added, which reduces the assembly angle variation down to ±0.3°.
Intelligent controlled release systems have been designed and constructed. The systems have a sensor-actuator gate consisting of polyelectrolyte hydrogel layer with immobilized enzymes inside fine holes of polyethylene terephthalate (PET) film and silicon wafer as base materials. Excimer-laser or ion-beam irradiation was used for the etching of holes in PET film and photo-lithography was used for the etching of silicon wafer. U.V. and γ-ray irradiations were used for the polymerization and immobilization of electrolyte layers in the holes. Various kinds of signal responsive release systems such as pH responsive, substrate responsive, Ca2+ responsive, photo-responsive and electric field responsive systems have been developed using those techniques. Some integrated systems have been designed and constructed by combination of unit systems in series and in parallel and proved the selective signal transfer and the successive signal responsive release functions.