A modified microfluidic chip for fabrication of paclitaxel-loaded poly(l-lactic acid) microspheres

In this article, we present a simple PDMS surface modification method based on poly(vinyl alcohol)/glycerol (PVA/Gly) solution immersion, self-assembled absorption, and heat treatment. The results of contact angle and ATR-FTIR demonstrate the superhydrophilic surface in modified PDMS. It can allow for the stable production of monodisperse droplet in a highly reproducible manner. In addition, we demonstrate the fabrication of monodisperse paclitaxel (PTX) loaded poly(l-lactic acid) (PLLA) microspheres on this kind of modification chip with solvent evaporation. The PLLA microspheres can be adjusted to a range of different sizes depending on the system flow rate. Determination of microsphere size is carried out by optical microscopy and image analysis to reveal less than 4% variation in microsphere size. Compared with the results of published papers, the presented data demonstrate that PTX-loaded PLLA microspheres show good physical properties (spherical and discrete), high-drug loading, encapsulation efficiency, a small initial burst, and sustained-release behavior due to outstanding monodispersity. With the characteristic to prepare high-quality, monodisperse, biodegradable microspheres, the versatile and simple microfluidic method facilitates the development of more reliable and reproducible drug delivery systems, which have great potential to benefit pharmaceutical and biological applications.     

Silicon microneedle array with biodegradable tips for transdermal drug delivery

This paper presents the fabrication process, characterization results and basic functionality of silicon microneedle array with biodegradable tips for transdermal drug delivery. In order to avoid the main problems related to silicon microneedles; the breaking of the top part of the needles inside the skin, a simple solution can be the fabrication of microneedle array with biodegradable tips. A silicon microneedle array was fabricated by deep reactive ion etching (RIE), using the photoresist reflow effect and RIE notching effect. The biodegradable tips were successfully realized using the electrochemical anodization process that selectively generated porous silicon only on the top part of the skin. The porous tips can be degraded within a few weeks if some of them are broken inside the skin during the insertion and release process. The paper presents also the results of in vitro release of calcein with animal skins using a microneedle array with biodegradable tips. Compared to the transdermal drug delivery without microneedle enhancer, the microneedle array had presented significant enhancement of drug release.     

Integrated microfluidic drug delivery devices: a component view

Research on drug delivery devices is progressing rapidly with the main objective being the delivery of precise quantity of drugs into the target area of the body. A drug delivery device (DDD) needs to accurately control the flow rate of drug delivery and protects the body from undesired additional doses. An integrated microfluidic drug delivery device (IMDDD) is a miniature device that can regulate and monitor the delivery of the right amount of drug using micro-scale components. IMDDDs offer several advantages including ease of use, electro-chemical controllability, low power consumption, simplicity, fast fabrication, and good bio-compatibility. Various IMDDDs have been developed for treatment of cancer, cardiovascular disorder, eye and brain diseases, stress, and diabetes. This paper presents a generic architecture for IMDDDs, discusses the existing drug delivery methods, summarizes the specifications of the components, and identifies a number of performance evaluation parameters. The operation of IMDDDs is presented through fourteen potential internal components. In addition, recommendations on how enhance the design and fabrication process of IMDDDs are given.     

Bulk Micromachined Titanium Microneedles

Microneedle-based drug delivery has shown considerable promise for enabling painless transdermal and hypodermal delivery of conventional and novel therapies. However, this promise has yet to be fully realized due in large part to the limitations imposed by the micromechanical properties of the material systems being used. In this paper, we demonstrate titanium-based microneedle devices developed to address these limitations. Microneedle arrays with in-plane orientation are fabricated using recently developed high-aspect-ratio titanium bulk micromachining and multilayer lamination techniques. These devices include embedded microfluidic networks for the active delivery and/or extraction of fluids. Data from quantitative and qualitative characterization of the fluidic and mechanical performance of the devices are presented and shown to be in good agreement with finite-element simulations. The results demonstrate the potential of titanium micromachining for the fabrication of robust, reliable, and low-cost microneedle devices for drug delivery     

Learning GP-BayesFilters via Gaussian process latent variable models

GP-BayesFilters are a general framework for integrating Gaussian process prediction and observation models into Bayesian filtering techniques, including particle filters and extended and unscented Kalman filters. GP-BayesFilters have been shown to be extremely well suited for systems for which accurate parametric models are difficult to obtain. GP-BayesFilters learn non-parametric models from training data containing sequences of control inputs, observations, and ground truth states. The need for ground truth states limits the applicability of GP-BayesFilters to systems for which the ground truth can be estimated without significant overhead. In this paper we introduce GPBF-Learn, a framework for training GP-BayesFilters without ground truth states. Our approach extends Gaussian Process Latent Variable Models to the setting of dynamical robotics systems. We show how weak labels for the ground truth states can be incorporated into the GPBF-Learn framework. The approach is evaluated using a difficult tracking task, namely tracking a slotcar based on inertial measurement unit (IMU) observations only. We also show some special features enabled by this framework, including time alignment, and control replay for both the slotcar, and a robotic arm.     

ASPECS: an agent-oriented software process for engineering complex systems

Holonic multiagent systems (HMAS) offer a promising software engineering approach for developing complex open software systems. However the process of building Multi-Agent Systems (MAS) and HMAS is mostly different from the process of building more traditional software systems as it introduces new design and development challenges. This paper introduces an agent-oriented software process for engineering complex systems called ASPECS. ASPECS is based on a holonic organisational metamodel and provides a step-by-step guide from requirements to code allowing the modelling of a system at different levels of details using a set of refinement methods. This paper details the entire ASPECS development process and provides a set of methodological guidelines for each process activity. A complete case study is also used to illustrate the design process and the associated notations. ASPECS uses UML as a modelling language. Because of the specific needs of agents and holonic organisational design, the UML semantics and notation are used as reference points, but they have been extended by introducing new specific profiles.     

MEMS-based micropumps in drug delivery and biomedical applications

This paper briefly overviews progress on the development of MEMS-based micropumps and their applications in drug delivery and other biomedical applications such as micrototal analysis systems (μTAS) or lab-on-a-chip and point of care testing systems (POCT). The focus of the review is to present key features of micropumps such as actuation methods, working principles, construction, fabrication methods, performance parameters and their medical applications. Micropumps have been categorized as mechanical or non-mechanical based on the method by which actuation energy is obtained to drive fluid flow. The survey attempts to provide a comprehensive reference for researchers working on design and development of MEMS-based micropumps and a source for those outside the field who wish to select the best available micropump for a specific drug delivery or biomedical application. Micropumps for transdermal insulin delivery, artificial sphincter prosthesis, antithrombogenic micropumps for blood transportation, micropump for injection of glucose for diabetes patients and administration of neurotransmitters to neurons and micropumps for chemical and biological sensing have been reported. Various performance parameters such as flow rate, pressure generated and size of the micropump have been compared to facilitate selection of appropriate micropump for a particular application. Electrowetting, electrochemical and ion conductive polymer film (ICPF) actuator micropumps appear to be the most promising ones which provide adequate flow rates at very low applied voltage. Electroosmotic micropumps consume high voltages but exhibit high pressures and are intended for applications where compactness in terms of small size is required along with high-pressure generation. Bimetallic and electrostatic micropumps are smaller in size but exhibit high self-pumping frequency and further research on their design could improve their performance. Micropumps based on piezoelectric actuation require relatively high-applied voltage but exhibit high flow rates and have grown to be the dominant type of micropumps in drug delivery systems and other biomedical applications. Although a lot of progress has been made in micropump research and performance of micropumps has been continuously increasing, there is still a need to incorporate various categories of micropumps in practical drug delivery and biomedical devices and this will continue to provide a substantial stimulus for micropump research and development in future.     

Modeling and simulation of drug delivery from a new type of biodegradable polymer micro-device

In this paper, modeling and simulation of a new type of controlled drug delivery micro-device based on biodegradable polymers is reported. The micro-device consists of micro-chambers arrays for drug storage to achieve linear release. The micro-chambers are fabricated with polyanhydrides (CPP-SA) using the UV-LIGA technology and the controlled release process are the combined results of the design of the micro-chambers and the biodegradable characteristics of the polymer. This type of drug delivery system has some unique advantages in controlled long-term drug delivery, such as larger loading volume than the matrices release systems, easier control for the release rate, etc. It is necessary to optimize the structure for the long-term and zero-order drug release. Based on the Monte Carlo erosion model, the drug release model is founded for the drug delivery system and using the new model, the drug release profiles from the delivery systems with different structures are simulated. The simulated results indicate that the effect of the drug delivery is dependent on the micro-structure of the delivery system and the simulated drug profiles of coaxial rings micro-cavity shape equal to zero-order released model approximatively. The simulated results are very important to the application research of the new biodegradable polymer micro-device.     

生物分子识别响应性水凝胶及其智能给药系统

生物分子识别响应性水凝胶是模拟生命活动过程中的分子识别现象，能识别特定生物分子而产生刺激响应性的智能高分子材料．用它构筑的智能系统类似于具有反馈和平衡功能的生物系统，在生物工程和生物医学领域有非常诱人的应用前景．对能识别特定生物分子，如葡萄糖、酶、抗原、核酸等，产生刺激响应的智能水凝胶的制备及其在智能给药系统中的应用研究情况进行了详细介绍．这些内容有助于更好地理解生物分子识别响应性水凝胶的结构和功能，另外也为发展新型智能给药系统提供了很好的思路．     

Inertial effects on cylindrical particle migration in linear shear flow near a wall

Micro-/nanoparticle-based systems are regarded as one of the possible candidates due to the engineerability and multifunctionality to maximize the accumulation of the nano-/microparticle-based drug delivery system on the target. Recent advances in nanotechnology enable the fabrication of diverse particle shapes from simple spherical particles to more complex shapes. The particle dynamics in blood flow and endocytosis characteristics of non-spherical particles change as the non-sphericity effect increases. We used a numerical approach to investigate the particle dynamics in linear shear flow near a wall. We examined the dynamics of slender cylindrical particles with aspect ratio γ = 5.0 in terms of particle trajectory, velocity, and force variation for different Stokes numbers over time. We identified the rotating inertia of particle near a wall as the source of inertial migration toward the wall. The drift velocity of slender cylindrical particles is comparable to that of discoidal particles. We discuss the possibilities and limitations of using slender cylindrical particles as a drug delivery system.     

Fabrication Methods and Performance of Low-Permeability Microfluidic Components for a Miniaturized Wearable Drug Delivery System

In this paper, we describe low-permeability components of a microfluidic drug delivery system fabricated with versatile micromilling and lamination techniques. The fabrication process uses laminate sheets which are machined using XY milling tables commonly used in the printed-circuit industry. This adaptable platform for polymer microfluidics readily accommodates integration with silicon-based sensors, printed-circuit, and surface-mount technologies. We have used these methods to build components used in a wearable liquid-drug delivery system for in vivo studies. The design, fabrication, and performance of membrane-based fluidic capacitors and manual screw valves provide detailed examples of the capability and limitations of the fabrication method. We demonstrate fluidic capacitances ranging from 0.015 to 0.15 $muhbox{L}$/kPa, screw valves with on/off flow ratios greater than 38 000, and a 45$times$ reduction in the aqueous fluid loss rate to the ambient due to permeation through a silicone diaphragm layer. $hfill$[2008-0148]      

Checking the reliability of socket based communication software

Locating potential execution errors in software is gaining more attention due to the economical and social impact of software crashes. For this reason, many software engineers are now in need of automatic debugging tools in their development environments. Fortunately, the work on formal method technologies during the past 25 years has produced a number of techniques and tools that can make the debugging task almost automatic, using standard computer equipment and with a reasonable response time. In particular, verification techniques like model-checking that were traditionally employed for formal specifications of the software can now be directly employed for real source code. Due to the maturity of model-checking technology, its application to real software is now a promising and realistic approach to increase software quality. There are already some successful examples of tools for this purpose that mainly work with self-contained programs (programs with no system-calls). However, verifying software that uses external functionality provided by the operating system via API s is currently a challenging trend. In this paper, we propose a method for using the tool spin to verify C software systems that use services provided by the operating system thorough a given API. Our approach consists in building a model of the underlying operating system to be joined with the original C code in order to obtain the input for the model checker spin. The whole modeling process is transparent for the C programmer, because it is performed automatically and without special syntactic constraints in the input C code. Regarding verification, we consider optimization techniques suitable for this application domain, and we guarantee that the system only reports potential (non-spurious) errors. We present the applicability of our approach focusing on the verification of distributed software systems that use the API Socket and the network protocol stack TCP/IP for communications. In order to ensure correctness, we define and use a formal semantics of the API to conduct the construction of correct models.     

Model checker aided design of a controller for a wafer scanner

For a case-study of a wafer scanner from the semiconductor industry it is shown how model checking techniques can be used to compute (1) a simple yet optimal deadlock avoidance policy, and (2) an infinite schedule that optimizes throughput. in the absence of errors. Deadlock avoidance is studied based on a simple finite state model using Smv, and for throughput analysis a more detailed timed automaton model has been constructed and analyzed using the Uppaal tool. The Smv and Uppaal models are formally related through the notion of a stuttering bisimulation. The results were obtained within 2 weeks, which confirms once more that model checking techniques may help to improve the design process of realistic, industrial systems. Methodologically, the case study is interesting since two models were used to obtain results that could not have been obtained using only a single model. Supported by the European Community Project IST-2001-35304 (Ametist), http://ametist.cs.utwente.nl/.     

Arrays of hollow out-of-plane microneedles for drug delivery

Drug delivery based on MEMS technology requires an invasive interface such as microneedles, which connects the microsystem with the biological environment. Two-dimensional arrays of rigid hollow microneedles have been fabricated from single-crystal silicon using a combination of deep reactive ion etching and isotropic etching techniques. The fabricated needles are typically 200 /spl mu/m long with a wide base and a channel diameter of 40 /spl mu/m. The fabrication process allows creating either blunt needles or needles with sharp tips. Their shape and size make these needles extremely suitable for minimally invasive painless epidermal drug delivery. MEMS technology allows for batch fabrication and integration with complex microsystems. Fluid has been successfully injected 100 /spl mu/m deep into sample tissue through arrays of microneedles. Needle breakage did not occur during this procedure. Experiments have shown that the modified Bernoulli equation is a good model for liquid flowing through the narrow microneedle lumen.     

A novel polymer microneedle fabrication process for active fluidic delivery

In this article, we explore a new fabrication process for a flexible, all polymer, active fluidic delivery system, incorporating a fusion of laser micromachining and microfabrication techniques as well as rapid prototyping technology. Here, we show selective fluidic delivery from isolated microchannels through an electrochemically driven pumping reaction, demonstrate the dispensing of dose volumes up to 5.5 μl, and evaluate the device’s performance in terms of its delivery speed and ejection efficiency. Finally, we move this work toward an implantable microfluidic drug delivery device by investigating the device’s biocompatibility through a statistical approach that overviews the viability of bovine aortic endothelial cells on polyimide and silicon substrates.     

On the Systematic Analysis of Natural Language Requirements with CIRCE

This paper presents Circe, an environment for the analysis of natural language requirements. Circe is first presented in terms of its architecture, based on a transformational paradigm. Details are then given for the various transformation steps, including (i) a novel technique for parsing natural language requirements, and (ii) an expert system based on modular agents, embodying intensional knowledge about software systems in general. The result of all the transformations is a set of models for the requirements document, for the system described by the requirements, and for the requirements writing process. These models can be inspected, measured, and validated against a given set of criteria. Some of the features of the environment are shown by means of an example. Various stages of requirements analysis are covered, from initial sketches to pseudo-code and UML models.     

Structural and microfluidic analysis of hollow side-open polymeric microneedles for transdermal drug delivery applications

In this paper, we present a new design of hollow, out-of-plane polymeric microneedle with cylindrical side-open holes for transdermal drug delivery (TDD) applications. A detailed literature review of existing designs and analysis work on microneedles is first presented to provide a comprehensive reference for researchers working on design and development of micro-electromechanical system (MEMS)-based microneedles and a source for those outside the field who wish to select the best available microneedle design for a specific drug delivery or biomedical application. Then, the performance of the proposed new design of microneedles is numerically characterized in terms of microneedle strength and flow rate at applied inlet pressures. All the previous designs of hollow microneedles have side-open holes in the lumen section with no integrated reservoir on the same chip. We have proposed a new design with side-open holes in the conical section to ensure drug delivery on skin insertion. Furthermore, the present design has an integrated drug reservoir on the back side of the microneedles. Since MEMS-based, hollow, side-open polymeric microneedles with integrated reservoir is a new research area, there is a notable lack of applicable mathematical models to analytically predict structural and fluid flow under various boundary conditions. That is why, finite element (FE) and computational fluid dynamic (CFD) analysis using ANSYS rather than analytical systems has been used to facilitate design optimization before fabrication. The analysis has involved simulation of structural and CFD analysis on three-dimensional model of microneedle array. The effect of axial and transverse loading on the microneedle during skin insertion is investigated in the stress analysis. The analysis predicts that the resultant stresses due to applied bending and axial loads are in the safe range below the yield strength of the material for the proposed design of the microneedles. In CFD analysis, fluid flow rate and pressure drop in the microneedles at applied inlet pressures are numerically and theoretically investigated. The CFD analysis predicts uniform flow through the microneedle array for each microneedle. Theoretical and numerical results for the flow rate and pressure drop are in close agreement with each other, thereby validating the CFD analysis. For the proposed design of microneedles, feasible fabrication techniques such as micro-hot embossing and ultraviolet excimer laser methods are proposed. The results of the present theoretical study provide valuable benchmark and prediction data to fabricate optimized designs of the polymeric, hollow microneedles, which can be successfully integrated with other microfluidic devices for TDD applications.     

Maximum Entropy Modeling: A Suitable Framework to Learn Context-Dependent Lexicon Models for Statistical Machine Translation

Current statistical machine translation systems are mainly based on statistical word lexicons. However, these models are usually context-independent, therefore, the disambiguation of the translation of a source word must be carried out using other probabilistic distributions (distortion distributions and statistical language models). One efficient way to add contextual information to the statistical lexicons is based on maximum entropy modeling. In that framework, the context is introduced through feature functions that allow us to automatically learn context-dependent lexicon models.In a first approach, maximum entropy modeling is carried out after a process of learning standard statistical models (alignment and lexicon). In a second approach, the maximum entropy modeling is integrated in the expectation-maximization process of learning standard statistical models.Experimental results were obtained for two well-known tasks, the French–English Canadian Parliament Hansards task and the German–English Verbmobil task. These results proved that the use of maximum entropy models in both approaches, can help to improve the performance of the statistical translation systems.This work has been partially supported by the European Union under grant IST-2001-32091 and by the Spanish CICYT under project TIC-2003-08681-C02-02. The experiments on the Verbmobil task were done when the first author was a visiting scientist at RWTH Aachen-Germany.Editors: Dan Roth and Pascale Fung     

Tapered microvalves fabricated by off-axis X-ray exposures

 A method for creating angled structures for use in microvalve devices applicable to control of liquid flow is presented. This technique utilizes a modified LIGA process with successive angled and rotated exposures into free standing acrylic sheets to form a tapered valve seat structure. These valve seats are integrated with bulk micromachined silicon diaphragms and tapered PMMA valve bosses to complete the microvalve. The long term goal of this research effort is to develop a normally-closed, low power, microfabricated valve for use in an implantable drug delivery system. This paper reports on the design and fabrication of microvalves using off-axis LIGA exposures. Flow testing and fluid handling characterization results are also presented. Received: 25 August 1997 Accepted: 22 October 1997     

Neural Network Implementation of Nonlinear Receding-Horizon Control

The Receding Horizon (RH) approach is an effective way to derive control algorithms for nonlinear systems with stabilising properties also in the presence of state and control constraints. However, RH methods imply a heavy computational burden for on-line optimisation, therefore they are not suitable for the control of ‘fast’ systems, for example mechanical ones, which call for the use of short sampling periods. The aim of this paper is to show through an experimental study how a Nonlinear RH (NRH) control law can be computed off-line, and subsequently approximated by means of a neural net-work, which is effectively used for the on-line implementation. The proposed design procedure is applied to synthesise a neural NRH controller for a seesaw equipment. The experimental results reported here demonstrate the feasibility of the method.