微机电系统发展及其应用

本文介绍了MEMS国内外发展状况和关键技术,并对MEMS在医学和军事领域的应用作了详细阐述。     

Microneedle-based drug delivery systems: Microfabrication,drug delivery,and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500?Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.     

Innovation requirements for telemetric sensor systems in medicine: results of a survey in Germany

Although first telemetric microsystems have been marketed for medical applications, the entry into the healthcare market represents a considerable challenge for many companies working in the field of microsystems technology. The Institute of Healthcare Industries (IHCI) at the Steinbeis University Berlin has conducted a study among experts in medicine, technology, and industry. The goal of the study was to investigate on innovation requirements and the market for telemetric microsystems in medicine. This article reviews selected results of the “Study on market and innovation requirements for telemetric microsystems in medicine”. It was performed in context with the project IMEX (Implantable and Extracorporeal modular microsystem platform), funded by the German ministry of science and research.     

High-performance,low-voltage electroosmotic pumps with molecularly thin silicon nanomembranes

We have developed electroosmotic pumps (EOPs) fabricated from 15-nm-thick porous nanocrystalline silicon (pnc-Si) membranes. Ultrathin pnc-Si membranes enable high electroosmotic flow per unit voltage. We demonstrate that electroosmosis theory compares well with the observed pnc-Si flow rates. We attribute the high flow rates to high electrical fields present across the 15-nm span of the membrane. Surface modifications, such as plasma oxidation or silanization, can influence the electroosmotic flow rates through pnc-Si membranes by alteration of the zeta potential of the material. A prototype EOP that uses pnc-Si membranes and Ag/AgCl electrodes was shown to pump microliter per minute-range flow through a 0.5-mm-diameter capillary tubing with as low as 250 mV of applied voltage. This silicon-based platform enables straightforward integration of low-voltage, on-chip EOPs into portable microfluidic devices with low back pressures.Electroosmotic flow results from the interaction between an electric field and the diffuse layer of ions at a charged surface. In capillaries or pores, the migration of the diffuse layer toward the oppositely charged electrode causes the bulk fluid within the channel to flow through viscous drag. Electroosmotic pumps (EOPs) are designed to generate high flow rates in microchannels using these principles (1, 2). EOPs present a number of advantages over mechanical pumps, including the lack of mechanical parts, pulse-free flows, and ease of control through electrode actuation. EOPs have been suggested as pumps for cooling circuits (3) and microfluidic devices that aid in drug delivery (4, 5) or diagnostics (2, 6). Microfluidic devices enable the miniaturization of multistep laboratory processes into small, low-cost, disposable units (6, 7). The inclusion of multiple steps into a single device increases the need for the precision pumping of fluids on-chip.High voltages (>1 kV) are often required for direct current (dc) EOPs to achieve sufficient flow rates in microchannels (8, 9). However, devices with high-voltage EOPs require bulky external power supplies and a skilled technician to operate, which defeats the ease of use and portability aims of a microfluidic diagnostic tool. For these reasons, the development of a low-voltage EOP is a current focus in the literature. Several recent low-voltage EOPs have been fabricated from porous silicon (10), alumina (11–13), track-etched polymer (14), and carbon nanotube membranes (15). These low-voltage EOPs are much thinner than their high-voltage predecessors (60–350 μm compared with >10 mm). Yao et al. suggest that further thinning of EOPs will enable better voltage-specific characteristics (16). Here, we examine the electroosmotic pumping by nanoporous membranes that are more than two orders of magnitude thinner than any membrane material previously used in an EOP.We have recently developed an ultrathin (15–30 nm), nanoporous membrane material called porous nanocrystalline silicon (pnc-Si) (17). pnc-Si membranes are fabricated on silicon wafers using techniques standard to the microelectronics industry. The silicon platform enables control of freestanding membrane area (Fig. 1A) and industrial-scale manufacturing (18). Pore distributions are controlled by fabrication temperatures and ramp rates during a rapid thermal crystallization step (19). Pores can be directly viewed in the ultrathin membrane and characterized with transmission electron microscopy (TEM). The silicon platform also enables the integration into a number of devices and fluidics systems. Previously, pnc-Si membranes have been shown to present little resistance to the diffusion of small molecules (17, 20–22) and have high permeability to water (18) and air (23).Open in a separate windowFig. 1.pnc-Si membranes and testing devices. (A) pnc-Si chips with one, three, six, or nine 200 × 200-μm windows of freestanding membrane. A 15-nm-thick pnc-Si membrane extends over each window on the silicon chips. (B) Transmission electron micrograph of pnc-Si membrane. White spots are pores and black regions are diffracting nanocrystals. (C) Pore diameters as determined by MATLAB image processing of a 1.7 × 1.1-μm TEM image of the membrane depicted in B. (D) Electroosmosis testing device. pnc-Si chips are sealed between two PET chambers, and a dc power supply maintains a constant voltage across two Pt electrodes. KCl solution that flows into the receiving chamber was continuously removed and weighed at intervals to determine electroosmosis rate. (E) Streaming potential testing device. pnc-Si chips are sealed between two threaded polycarbonate chambers. Ag/AgCl electrodes measure voltage difference between cells as KCl is pressurized through chamber.In this work, we show that pnc-Si membranes with low active areas (0.36 mm²) generate electroosmotic flow rates of 10 μL/min at voltages of 20 V or lower. These flow rates are compared with electroosmotic theory by calculating electroosmotic flow using pore distributions from TEM micrographs. Surface modifications are shown to change the zeta potential of the material and influence the electroosmotic flow rates. EOPs developed using pnc-Si membranes and Ag/AgCl electrodes were shown to pump fluids through capillary tubing at applied voltages as low as 250 mV. The thermodynamic efficiency of pnc-Si EOPs was shown to be less than 0.01% due to low stalling pressures. Theoretically, the thermodynamic efficiency could be improved orders of magnitude by bringing the electrodes closer to the membrane and reducing the applied voltage. Our work suggests pnc-Si EOPs can provide ultralow voltage and on-chip pumping in microfluidic systems with low back pressures.     

Cytoskeletal role in differential adhesion patterns of normal fibroblasts and breast cancer cells inside silicon microenvironments

In this paper we studied differential adhesion of normal human fibroblast cells and human breast cancer cells to three dimensional (3-D) isotropic silicon microstructures and investigated whether cell cytoskeleton in healthy and diseased state results in differential adhesion. The 3-D silicon microstructures were formed by a single-mask single-isotropic-etch process. The interaction of these two cell lines with the presented microstructures was studied under static cell culture conditions. The results show that there is not a significant elongation of both cell types attached inside etched microstructures compared to flat surfaces. With respect to adhesion, the cancer cells adopt the curved shape of 3-D microenvironments while fibroblasts stretch to avoid the curved sidewalls. Treatment of fibroblast cells with cytochalasin D changed their adhesion, spreading and morphology and caused them act similar to cancer cells inside the 3-D microstructures. Statistical analysis confirmed that there is a significant alteration (P < 0.001) in fibroblast cell morphology and adhesion property after adding cytochalasin D. Adding cytochalasin D to cancer cells made these cells more rounded while there was not a significant alteration in their adhesion properties. The distinct geometry-dependent cell–surface interactions of fibroblasts and breast cancer cells are attributed to their different cytoskeletal structure; fibroblasts have an organized cytoskeletal structure and less deformable while cancer cells deform easily due to their impaired cytoskeleton. These 3-D silicon microstructures can be used as a tool to investigate cellular activities in a 3-D architecture and compare cytoskeletal properties of various cell lines.

Biomedical microdevices synthesis of iron oxide nanoparticles using a microfluidic system

The preparation of nanoparticles is essential in the application of many nanotechnologies and various preparation methods have been explored in the previous decades. Among them, iron oxide nanoparticles have been widely investigated in applications ranging from bio-imaging to bio-sensing due to their unique magnetic properties. Recently, microfluidic systems have been utilized for synthesis of nanoparticles, which have the advantages of automation, well-controlled reactions, and a high particle uniformity. In this study, a new microfluidic system capable of mixing, transporting and reacting was developed for the synthesis of iron oxide nanoparticles. It allowed for a rapid and efficient approach to accelerate and automate the synthesis of the iron oxide nanoparticles as compared with traditional methods. The microfluidic system uses micro-electro-mechanical-system technologies to integrate a new double-loop micromixer, two micropumps, and a microvalve on a single chip. When compared with large-scale synthesis systems with commonly-observed particle aggregation issues, successful synthesis of dispersed and uniform iron oxide nanoparticles has been observed within a shorter period of time (15 min). It was found that the size distribution of these iron oxide nanoparticles is superior to that of the large-scale systems without requiring any extra additives or heating. The size distribution had a variation of 16%. This is much lower than a comparable large-scale system (34%). The development of this microfluidic system is promising for the synthesis of nanoparticles for many future biomedical applications.     

Transdermal Delivery of Insulin Using Microneedles in Vivo

PURPOSE: The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. METHODS: Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. RESULTS: Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. CONCLUSIONS: Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.     

Micro Sensors: Linking Real-Time Oscillatory Shear Stress with Vascular Inflammatory Responses

The important interplay between blood circulation and vascular cell behavior warrants the development of highly sensitive but small sensing systems. The emerging micro electro mechanical systems (MEMS) technology, thus, provides the high spatiotemporal resolution to link biomechanical forces on the microscale with large-scale physiology. We fabricated MEMS sensors, comparable to the endothelial cells (ECs) in size, to link real-time shear stress with monocyte/EC interactions in an oscillatory flow environment, simulating the moving and unsteady separation point at arterial bifurcations. In response to oscillatory shear stress (tau) at +/- 2.6 dyn/cm2, time-averaged shear stress (tauave) = 0 at 0.5 Hz, individual monocytes displayed unique to-and-fro trajectories, undergoing rolling, binding, and dissociation with other monocyte, followed by solid adhesion on EC. Incorporating with cell-tracking velocimetry, we visualized that these real-time events occurred over a dynamic range of oscillating shear stress between +/- 2.6 dyn/cm2 and Reynolds number between 0 and 22.2 in the presence of activated adhesion molecule and chemokine mRNA expression.     

一种消化道定点药物释放工程药丸系统的研制

研究开发了一种新型的消化道定点释放工程药丸系统和基于磁标记定位跟踪技术的工程药丸体内定位跟踪系统,并成功进行了动物试验.该工程药丸系统具有可靠性高、可适应多种药物剂型的优点.     

Ultrasensitive Biomems Sensors Based on Microcantilevers Patterned with Environmentally Responsive Hydrogels

An innovative platform was developed for ultrasensitive microsensors based on microcantilevers patterned with crosslinked copolymeric hydrogels. A novel UV free-radical photolithography process was utilized to precisely align and pattern environmentally responsive hydrogels onto silicon microcantilevers, after microcantilevers were fabricated and released. Specifically, a crosslinked poly(methacrylic acid) network containing high amounts of poly(ethylene glycol) dimethacrylate was prepared and investigated. Hydrogels were patterned onto the silicon microcantilevers utilizing a mask aligner to allow for precise positioning. The silicon surface was modified with -methacryloxypropyl trimethoxysilane to gain covalent adhesion between the polymer and the silicon. The hydrogels sensed and responded to changes in environmental pH resulting in a variation in surface stress that deflected the microcantilever. The bending response of patterned cantilevers with a change in environmental pH was observed, showing the possibility to construct MEMS/BioMEMS sensors based on microcantilevers patterned with environmentally responsive hydrogels. An extraordinary maximum sensitivity of 1 nm/5×10^–5pH was observed, demonstrating the ultrasensitivity of this microsensor platform.