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.     

基于Monte Carlo模型的微型PLGA给药系统建模及仿真

多腔体的微型可降解高分子聚合物PLGA药物缓释系统是一种新型植入式给药微器件,其载体结构是结合药物释放的要求和高分子聚合物生物降解特性进行设计并利用MEMS工艺制备.为了解微型给药系统实际释药的性能,需要对其进行建模和仿真研究.基于体溶蚀的Monte Carlo溶蚀模型,建立了具有多腔体的微型PLGA给药载体的释药模型,并对腔体结构为圆形的微型给药系统进行了释药过程仿真.仿真结果表明本文建立的微系统释药模型可以较为准确的描述微系统的释药过程,仿真模型对进一步开发微型PLGA给药系统有重要的参考价值.     

Study on structural optimum design of implantable drug delivery micro-system

In this paper, design, modeling, and simulation of a new type of controlled drug delivery system based on biodegradable polymers is report. The system consists of arrays of micro-chambers for drug storage to achieve linear release. The micro-chambers were fabricated with biodegradable polymer using the UV-LIGA technology and the controlled release process is the combined results of 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 improved efficiency, reduced side effect, on-spot delivery, and convenient therapy. Mathematical model has been developed for two kind of biodegradable polymer micro-system respectively, and numerical simulations were conducted to analyze the biodegradation and the controlled release process. The mathematical model can be used to optimize the structural design for controlled-release system with the desired release characteristics.     

A directly stackable microsystem onto the cultured cells for cytotoxicity tests

Today’s pharmaceutical industry is facing several challenges resulting from a vastly increasing number of samples through a high-throughput screening. In addition, the increased demand for cytotoxicity tests have caused bottlenecks, which in turn is causing serious problems. Here we present a novel approach to performing the cytotoxicity test. This new method uses a directly stackable microsystem on the cultured cells. It also enables us to perform cytotoxicity tests with more reliability by providing exactly the same cell-culture environment for all experiments. The new approach consists of two fascinating modules: First, a serial dilution module can linearly dilute one drug solution into several diluted ones in a serial manner, and equally distribute them into independent microchambers. Secondly, a microcompartment module can firmly attach itself onto any cultured cells and divide the directly-covered cell surface into multiple well-type microchambers instantaneously. This microsystem has a strong feasible advantage. It hardly needs to modify the established cell culture protocols, and at the same time it can eliminate some repetitive and laborious processes. A quick flexible integrated microsystem would reduce many redundant efforts during on-chip cytotoxicity tests. H. Bang and W. G. Lee equally contributed to this work.     

Modeling and simulation of drug release from multi-layer biodegradable polymer microstructure in three dimensions

Multi-layer biodegradable polymer drug delivery microstructures with micro-chambers have many exceptional advantages in a long-term controlled drug delivery. In this paper, a mathematical model for the drug release from this type of three-dimensional (3D) drug delivery microstructures is presented by using 3D cellular automata and discrete iterations. The validity of the model is proved by comparing with the Gőpferich’s simulated profiles for the same composite polymer cylinder matrices. Based on this model, furthermore, the simulations are done to describe the dynamic behavior of drug release from this type of microstructures. The simulation results show that this 3D mathematical model can describe accurately the drug release behavior and therefore can provide a new optimal design tool for this kind of multi-layer biodegradable polymer drug delivery microstructure.     

Pole-assignment fixed-interval Kalman smoother with an exponential stability

Using the innovation analysis method in the time domain, based on the autoregressive moving average (ARMA) innovation model and white noise estimators, a pole-assignment fixed-interval steady-state Kalman smoother is presented for discrete-time linear stochastic systems. It avoids the computation of the optimal initial smoothing estimate, and can rapidly eliminate the effect of arbitrary initial smoothing estimate by assigning the poles of the smoother, with an exponentially decaying rate. Several simulation examples show its effectiveness.     

Equivalent area nonlinear static and dynamic analysis of electrostatically actuated microstructures

Nonlinear dynamic investigation of electrostatically actuated micro-electro-mechanical-system (MEMS) microcantilever structures is presented. The nonlinear analysis aims to better quantify, than the linear model, the instability threshold associated with electrostatically actuated MEMS structures, where the pull-in voltage of the microcantilever is determined using a phase portrait analysis of the microsystem. The microcantilever is modeled as a lumped mass-spring system. The nonlinear electrostatic force is incorporated into the lumped microsystem through an equivalent area of the microcantilever for a given electrostatic potential. Electro-mechanical force balance plots are obtained for various electrostatic potentials from which the static equilibrium positions of the microcantilever are obtained and the respective conservative energy values are determined. Subsequently, phase portrait plots are obtained for the corresponding energy values from which the pull-in voltage is estimated for the microsystem. This pull-in voltage value is in good agreement with the previously published results for the same geometric and material parameters. The results obtained for linear electrostatic models are also presented for comparison.     

Effects of Local-Lag Mechanism on Task Performance in a Desktop CVE System

Consistency maintenance is a kernel problem in Collaborative Virtual Environment (CVE) research. The approaches used in Networked Virtual Environments (e.g., DR algorithm) could not be used in CVEs, for they could not prevent short-term inconsistency. Therefore, local-lag mechanism has been proposed to eliminate short-term inconsistency in CVEs. Choosing a proper lag value is a key problem in local-lag mechanism. This paper studied the effects of lag value (Oms-900ms) on task performance in a desktop CVE system. Experimental results indicate that the effect of lag value on task performance is not linear. The effect could be separated into four segments by three dividing points: 150ms, 300ms and 600ms. Lag has no effect on task performance while ranging from 0ms to 150ms. From 150ms to 300ms, lag slightly affects task performance. Lag deteriorates task performance seriously while ranging from 300ms to 600ms. When lag is longer than 600ms, the task cannot be accomplished sometimes.     

The fabrication and property of a novel coated out-of-plane microneedle arrays

The efficiency of transdermal drug delivery (TDD) is often undermined by stratum corneum of skin. In this paper, a novel design and fabricating process was developed to coat microneedles (MNs). Testing results of facture strength of the MNs demonstrated that the Ni coated microneedle can meet the mechanical requirement for practical TDD applications. Dip-coating experiment demonstrated that it was practical to load baicalin onto the surfaces of the MNs. The amount of loaded drug was increased simply by increasing times of dip-coating operation. It was also demonstrated that upon coated by HPMC or PVP, drug can be released from the MNs in a more sustainable manner. Coating solution had great impact on drug releasing rate, indicating that the required drug concentration can be achieved by proper coating solution.     

Controller design for time lag systems via a quadratic criterion

Theoretical results on the optimal control of linear time lag systems with respect to a quadratic criterion are shown to provide a practical feedback controller design procedure. A computational procedure is given for obtaining a stable linear feedback controller. A comprehensive illustration is given of the application of the quadratic criterion results to the design of a feedback controller for a chemical process having transport lag.     

Synthesis and performance of pH-sensitive hydrogel microspheres and in vitro evaluation as potential drug carriers

To accelerate the response rate of smart hydrogels to the environmental conditions, a novel pH-sensitive p(PEGMA-g-MAA) hydrogel microsphere with the controlled shapes and sizes were developed. Such monodispersed microspheres were synthesized via free radical polymerization under the protection of a multilayer stability system. The pH-responsibility of hydrogel microspheres was tested with the hydrogel bulk as a control. In vitro release studies were conducted in the simulated gastric fluid and intestinal juice with bovine serum albumin (BSA) as a model drug. The large specific surface areas endowed hydrogel microspheres a faster pH-responsibility than that of hydrogel bulk. In vitro release profiles showed that over 90 % BSA were released from hydrogel microspheres under the alkaline conditions (pH 7.4), which was faster than those from hydrogel bulks. In sum, the rapid pH-responsibility and ideal drug release profile could shorten the lag time to steady plasma-drug concentration, which was beneficial to increasing the therapeutic effect of the drugs.     

干旱对灌溉和雨养农田生态系统生产力的影响对比分析

灌溉是农作物应对干旱等极端气候条件的有效调节机制,在全球气候变化的背景下,未来干旱等极端气候事件发生的频率和严重程度预估会增加,定量分析灌溉和雨养条件下干旱对农田生态系统农作物生长的影响有助于更好地评估人类应对极端气候事件对生态系统的消极影响的能力,为制定合理有效的生态系统保护措施提供依据.以中国北方干旱区为研究区,基...     

煤矿瓦斯异常数据报警方法应用研究

对基于极差值、最小值、相关系数3种关联模型的煤矿瓦斯异常数据报警方法在应用中存在的2个传感器之间数据的延滞时间如何确定、传感器误差的影响、报警的准确率等问题进行了详细分析,提出应采用数据曲线比较法而不是距离风速计算法来确定延滞时间,同时发现巷道中瓦斯气团的运动速度低于风速的现象并对这一现象进行了初步解释;提出采用数理统计法消除传感器误差影响的方法;结合现场数据,对3种关联模型的准确率进行了验证,结果表明该报警方法完全可以在实际中有效应用。     

The effect of lead time variation on the performance of disassembly release mechanisms

A recoverable product environment, which includes strategies to extend product life, is an increasingly important method of waste prevention. A major part of this environment is the recoverable manufacturing system designed to remanufacture products. The recoverable manufacturing system has three distinct subsystems: disassembly, remanufacturing and reassembly. A key characteristic of this environment is the high degree of variability inherent in it. The impact of this variability as represented by highly variable lead times is examined for its effect on the control of parts release from the disassembly area to the remanufacturing area. Various disassembly release mechanisms for releasing the parts are examined. The choice is shown to be more critical for serial number specific parts. Lead time variation is shown to have a significant affect on the choice of disassembly release mechanism. Successful mechanisms for controlling the release of materials from the disassembly area are discussed and recommendations are made.     

Optimization of control parameters in micro hot embossing

The key control parameters in hot embossing (such as the imprint pressure, the imprint temperature, the holding time and the demolding temperature) can significantly impact on the pattern quality. The finite element method was used to analyze the embossing, cooling and demolding step to acquire the optimized process parameters. The simulation results show that the polymer flow has a reference to the imprint pressure, the imprint temperature and the holding time. While the adhesion force between the polymer and the mold can significantly influence the replication accuracy. Because of polymer flow, non-uniform pressure distribution can be observed and this results in the pattern height difference. The hydraulic pressure system was designed to acquire uniform pressure. Thermal stress caused by the difference of the thermal expansion coefficients between the mold and the polymer can induce stress concentration at the corner. If the demolding direction is not vertical to horizon, another stress concentration will appear. Excessive stress results in defects and causes fracture at the base part of the pattern during the demolding step. To eliminate the defects, cooling to a relative high temperature was introduced to reduce the stress concentration and an auto-demolding device was used to insure no additional stress was imported at the demolding step. The following experiment showed the successful fabrication of fine patterns with the optimized parameters.     

Competing or coordinating: IT R&;D investment decision making subject to information time lag

In this paper, we apply a dynamic option-game framework to examine the impact of information time lag on Research and Development (R&D) investment in innovative information technology (IT) industry. We focus on incentives of competition and coordination in R&D. Our results show that shorter information time lag may induce firms to coordinate their investments and avoid over-investment. The threshold of information time lag developed in this paper can facilitate managerial decisions on whether to compete or coordinate R&D investments.     

机载雷达跟踪方法研究与仿真

研究机载雷达跟踪运动物体的准确性问题.针对当物体运动的速度较快时,在机载雷达跟踪过程中需要完成光机扫描、图像合成、图像处理、信息传输等一系列综合处理过程,产生时间滞后,一旦被跟踪的物体运动速度较大,两者速度不匹配,就会造成跟踪高速运动目标识别不准确的问题.为了解决上述问题,提出基于滞后时间补偿的机载雷达跟踪方法.通过建立被跟踪的目标的运动模型,估计出跟踪物体下一刻运动位置,提前消除时间滞后,克服传统方法的缺点.实验结果表明,运用改进方法可以很好的消除时间上的滞后延迟,完成机载雷达对高速运动物体的跟踪,大幅提高跟踪的准确性.     

A novel spark erosion technique for the fabrication of high aspect ratio micro-grooves

Micro groove is an important geometrical feature of components used in microsystem technology (MST). Straight micro grooves are the predominant features in microsystem components such as micro heat exchangers and diffraction gratings. Micro Electrical Discharge Machining (micro EDM) is a complementary microfabrication technique adopted from the conventional EDM machining process for the purpose of micro machining. Using micro EDM it is possible to machine all electrically conductive materials irrespective of their hardness. High aspect ratio microgroove machining for length as high as 20 mm is a formidable task for the conventional micro EDM. In the present work, a novel spark erosion technique has been described wherein a graphite foil has been used instead of the traditional pin shaped tool electrode, for the purpose of making straight grooves. In a single setup microgroove of 20 mm length and an aspect ratio of about 2.3 has been achieved on hardened tool steel by this technique. This process is further refined by using the gravitational effect for the effective debris removal, which has improved the aspect ratio to about 8.Accepted: September 2003     

密封元器件水汽含量时效变化研究

聚合物材料作为一种芯片粘接材料,被广泛使用在各类元器件中,具有操作过程简单,不依赖表面金属化等优点,适用于多芯片、小尺寸、绝缘等复杂环境。但聚合物粘接剂具有缓慢释放气氛的性质,长时间使用下的密封腔体内部气氛变化与控制是行业内研究的重点。研究高温贮存环境和温度循环环境中,不同时间变量下,聚合物粘接芯片的密封电路内部气氛变化情况,并与在常温环境长时间静置电路气氛测量结果进行对比分析,得到加速条件与常规静置条件之间的换算关系参考值,为后续聚合物粘接可靠性的研究提供依据。     

Reduction of mechanical stress in micromachined components caused by humidity-induced volume expansion of polymer layers

 Polymer layers frequently used in microsystem technology tend to absorb water from ambient humid air which typically results in swelling of the polymer layers. Depending on the specific component design, this volume expansion may cause changes in the mechanical stress, or even displacement of device structures. In most applications, these effects limit performance and reliability, and should therefore be minimized. The present paper describes an approach for the investigation of swelling phenomena in thin polymer layers. Polyimide PI2540 was chosen as a model polymer. After extensive characterization of the polymer layer properties, static and dynamic sorption behavior was investigated by different means. Based on our experimental results, we have developed linearized models to accurately describe the swelling behavior. Several polymers were characterized. Although the micro-physical mechanisms responsible for the humidity-induced swelling are still poorly understood, we are – based on our data – able to effectively reduce humidity induced stress by selecting suitable polymers and optimizing processing procedures. Received: 25 August 1997/Accepted: 19 December 1997