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.     

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.     

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.     

Numerical modeling of a novel degradable drug delivery system with microholes

Based on UV-LIGA technology, a novel drug delivery microsystem is proposed to eliminate the time lag in initial drug release. With proper microholes in bonding membrane, the drug release rate can be controlled at a stable level in the whole release process. This microsystem is fabricated by degradable polymer and suitable for subcutaneous implants. As a significant parameter, the demarcation time of polymer absorption/erosion is estimated by comparing the experimental results of polymer erosion and in vitro release. By considering diffusion, swelling and erosion mechanisms simultaneously, a numerical drug releasing model is developed to investigate the effect of microholes on drug release and impact factors of linear drug releasing. The simulation results show that the microholes are beneficial to eliminate the time lag, and furthermore, the area of microholes and the initial drug loading have great impact on the release time and the linear drug release rate.     

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.     

Numerical simulation of drug release from collagen matrices by enzymatic degradation

Biodegradable collagen matrices have become a promising alternative to synthetic polymers as drug delivery systems for sustained release. Previously, a mathematical model describing water penetration, matrix swelling and drug release by diffusion from dense collagen matrices was introduced and tested (cf. Radu et al. in J. Pharm. Sci. 91:964–972, 2002). However, enzymatic matrix degradation influences the drug release as well. Based on experimental studies (cf. Metzmacher in Enzymatic degradation and drug release behavior of dense collagen implants. Ph.D. thesis, LMU University of Munich, 2005), a mathematical model is presented here that describes drug release by collagenolytic matrix degradation. Existence and uniqueness of a solution of the model equations is reviewed. A mixed Raviart–Thomas finite element discretization for solving the coupled system of partial and ordinary differential equations is proposed and analyzed theoretically. The model is verified by a comparison of numerically calculated and experimentally measured data and, in particular, investigated by a parameter sensitivity study. For illustration, some concentration profiles of a two-dimensional simulation are shown.     

Rapidly in situ forming biodegradable hydrogels by combining alginate and hydroxyapatite nanocrystal

The in situ forming biodegradable polymer scaffolds are important biomaterials for tissue engineering and drug delivery.Hydrogels derived from natural proteins and polysaccharides are ideal tissue engineering scaffolds since they resemble the extracellular matrices of the tissue comprising various amino acids and sugar based macromolecules.This work presented an injectable system from partially oxidized alginate and hydroxyapatite(HAP) nanocrystal for tissue engineering and drug delivery applications.In sit...     

Simulation of the USP drug delivery problem using CFD: experimental,numerical and mathematical aspects

The numerical simulation of the dissolution of drug-containing compacts in a stirred reactive medium is presented. This is of interest to the design of drug delivery systems in which the goal is to design compacts which release the drug according to certain desired release profiles. A moving boundary finite element approach is adopted to simulate dissolution of layered compacts made up of a number of layers of different acids which dissolve at different rates. The simulation results are compared to experimental measurements. Although a number of idealisations have been adopted in the numerical model, good agreement with experiment is achieved. A semi-analytic solution is also developed which leads to an expression for the mass flux from a dissolving cylinder. Results for this model are compared with the numerical and experimental data.     

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.     

APPLICATION OF ARTIFICIAL NEURAL NETWORKS IN CONTROLLED DRUG DELIVERY SYSTEMS

Estimation of release profiles of drugs normally requires time-consuming trial-and-error experiments. Feed-forward neural networks including multilayer perceptron (MLP), radial basis function network (RBFN), and generalized regression neural network (GRNN) are used to predict the release profile of betamethasone (BTM) and betamethasone acetate (BTMA) where in situ forming systems consist of poly (lactide-co-glycolide), N-methyl-1-2-pyrolidon, and ethyl heptanoat as a polymer, solvent, and additive, respectively. The input vectors of the artificial neural networks (ANNs) include drug concentration, gamma irradiation, additive substance, and type of drug. As the outputs of the ANNs, three features are extracted using the nonlinear principal component analysis technique. Leave-one-out cross-validation approach is used to train each ANN. We show that for estimation of BTM and BTMA release profiles, MLP outperforms GRNN and RBF networks in terms of reliability and efficiency.     

基于T-S模糊模型的离散混沌系统变结构控制

研究了离散混沌系统模糊变结构控制问题.采用T-S模糊模型描述离散混沌系统,将离散混沌系统模糊化为局部线性模型.依据Lyapunov稳定性定理和线性系统变结构控制趋近律设计方法,设计了一种新型的离散变结构控制器,该控制器不仅能保证局部线性模型渐近稳定,而且能确保模糊动态模型全局渐近稳定.利用Matlab对确定Henon系统和不确定Henon系统进行数值仿真,结果表明所设计的控制器不但有效,而且具备很强的鲁棒性.     

A hybrid push/pull system in assemble-to-order manufacturing environment

A hybrid push/pull system of an assemble-to-order manufacturing environment is investigated in this paper. In this environment, raw material can be transformed into common semi-finished products at a point where next downstream operations are triggered by customer orders. The production of the earlier upstream stations is controlled by push-type production, while the production of the later downstream stations is controlled by pull-type production. The hybrid system often compromises the conflicting performance characteristics of the push and the pull environments. In the push type, high inventory cost is anticipated in the return of low delivery leadtime. On the contrary, in the pull type, high delivery leadtime is expected in the return of low inventory cost. The objective function for the presented hybrid model is to minimize the sum of inventory holding cost and delivery leadtime cost, which is the cost of the time period since customers have placed an order until it is fulfilled. The model is applied to solve the inventory and late delivery problems in an assemble-to-order manufacturer. A genetic algorithm (GA) is used. A discrete event simulation model is used to evaluate the objective function for each chromosome in the GA. The pure push and pull systems are also simulated in order to compare their performance with the hybrid system. Sensitivity analysis on the coefficient of variation (CV) of time between actual customer order arrivals and on various cost ratios of delivery leadtime and inventory are carried out. In most cases, the hybrid performs the best. Results show that the hybrid production system would save the company significantly compared to the pure push or pure pull production systems.     

Study on a piezoelectric micropump for the controlled drug delivery system

We present the design of a new controlled drug delivery system potential for in vitro injection of diabetics. The system incorporates some integrated circuit units and microelectromechanical system devices, such as micropump, microneedle array and microsensor. Its goal is to achieve safer and more effective drug delivery. Moreover, a valveless micropump excited by the piezoelectric actuator is designed for the drug delivery system, and a simple fabrication process is proposed. A dynamic model is developed for the valveless micropump based upon the mass conservation. To characterize the micropump, a complete electro-solid-fluid coupling model, including the diffuser/nozzle element and the piezoelectric actuator, is built using the ANSYS software. The simulation results show that the performance of micropump is in direct proportion to the stroke volume of the pump membrane and there is an optimal thickness of the piezoelectric membrane under the 500 V/mm electric field. Based on this simulation model, the effects of several important parameters such as excitation voltage, excitation frequency, pump membrane dimension, piezoelectric membrane dimension and mechanical properties on the characteristics of valveless micropump have been investigated.     

MIMO regulation control design for magnetic steering of a ferromagnetic particle inside a fluidic environment

As an important development of medical instrumentation, minimally invasive therapeutic operations have been recently introduced. The foremost element of minimally invasive techniques is navigating a micro-device through human body, especially inside blood vessels. A remote actuation over the micro-device is normally provided by electromagnetic actuators. In most applications, a control scheme is also required to initiate the actuation force, the magnetic propulsion, such that at every time step, the micro-device moves towards or along a given path. This paper contributes in development of the electromagnetic system model mostly used in magnetic navigation systems to be representable in control affine form. Next, a multi-input multi-output (MIMO) trajectory tracking controller is designed to conduct the auto-navigation of the device along a given path. This method is a generalised version of a ‘semi-global nonlinear output regulation’ introduced for single-input single-output (SISO) systems. Finally, the proposed scheme is examined for an iron particle moving in a fluidic environment. The simulation results show fast decay in deviation of the particle position from the reference path under some assumptions. This shows that the proposed scheme can be offered for medical applications.     

Self-learning speaker identification for enhanced speech recognition

A novel approach for joint speaker identification and speech recognition is presented in this article. Unsupervised speaker tracking and automatic adaptation of the human-computer interface is achieved by the interaction of speaker identification, speech recognition and speaker adaptation for a limited number of recurring users. Together with a technique for efficient information retrieval a compact modeling of speech and speaker characteristics is presented. Applying speaker specific profiles allows speech recognition to take individual speech characteristics into consideration to achieve higher recognition rates. Speaker profiles are initialized and continuously adapted by a balanced strategy of short-term and long-term speaker adaptation combined with robust speaker identification. Different users can be tracked by the resulting self-learning speech controlled system. Only a very short enrollment of each speaker is required. Subsequent utterances are used for unsupervised adaptation resulting in continuously improved speech recognition rates. Additionally, the detection of unknown speakers is examined under the objective to avoid the requirement to train new speaker profiles explicitly. The speech controlled system presented here is suitable for in-car applications, e.g. speech controlled navigation, hands-free telephony or infotainment systems, on embedded devices. Results are presented for a subset of the SPEECON database. The results validate the benefit of the speaker adaptation scheme and the unified modeling in terms of speaker identification and speech recognition rates.     

Biodegradable submicrometric sieves in PLLA fabricated by soft lithography

Sieves are membranes with a regular array of uniform pores that present low flow resistance. Because of such characteristics they are promising devices for filtration, separation of particles by size and drug delivery control systems. In this paper, we propose and demonstrated the use of a soft lithography process for fabrication of biodegradable sieves in PLLA (poly-l-lactide) with pores in the scale of hundred of nanometers. The fabrication process is suitable for mass production and submicrometric pore diameters can be fabricated with homogeneity of about 15%. The PLLA self sustained sieve can be integrated to PLLA capsules, compounding a drug delivery systems or implants.     

基于电化学原理的消化道释药电子胶囊研究

基于电化学原理,提出了一种可用于消化道药物释放的微型电子胶囊。该电子胶囊采用电化学反应作为驱动单元的物理模型,它可采用无线遥控方式或定时方式控制药物的定时、定量释放。当胶囊系统接收到控制指令后(如定时时间已到或接收到遥控指令),接通电化学反应电路,产生氢气,该气体驱动活塞机构运动,实现药物释放。释放药量可由控制电路导通时间的长短来决定。     

非线性多变量零阶接近有界系统的多模型自适应控制

针对一类多变量非线性离散时间系统,提出一种新的基于神经网络的多模型自适应控制方法.为了将非线性系统的高阶非线性项的限制条件放宽到零阶接近有界,该方法引入了一种新的非线性模型.该模型在传统线性回归模型基础上增加了非线性补偿项,使模型的估计误差有界.一个神经网络模型与非线性模型同时被用来对系统进行辨识.基于性能指标的切换机构选择性能较好的模型对应的控制器 对系统进行控制. 理论分析证明了零阶接近有界多模型自适应控制系统的有界输 入和有界输出稳定性. 仿真实验说明了提出的多模型自适应控制方法的有效性.     

Microfluidics assisted fabrication of microspheres by poly(2–hydroxyethyl methacrylate)-block-poly(l-histidine) hybrid materials and their utilization as potential drug encapsulants

A new series of synthetic polymer bioconjugate hybrid materials consisting of poly(2-hydroxyethyl methacrylate)[p(HEMA)]as a synthetic polymer block and poly(l-histidine) [p(His)] as a polypeptide block were synthesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl-N-carboxy-l-histidine anhydride. The resulting biocompatible p(HEMA)₂₅-b-p(His)_n (n = 15, 25, 35, and 45) hybrid polymers were investigated for their use as pH-sensitive drug delivery system. Highly uniform microspheres were fabricated by using the microfluidics assisted self-assembly of these block polymers and utilized them as carriers for a chemotherapeutic agent doxorubicin and a beta-lactam antibiotic ampicillin for the evaluation of the drug-loading and release behaviors according to pH, demonstrating the release is sensitive to pH. The capability of the new p(HEMA)-b-p(His) hybrid materials to self-assemble in microenvironments and to effectively encapsulate drug molecules serves as suitable carriers for the delivery of drug molecules with varying physiochemical properties.     

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．