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.     

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]      

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.     

On-chip fabrication of magnetic alginate hydrogel microfibers by multilayered pneumatic microvalves

Alginate hydrogel has widespread applications in tissue engineering, cancer therapy, wound management and drug/cell/growth factor delivery due to its biocompatibility, hydrated environment and desirable viscoelastic properties. However, the lack of controllability is still an obstacle for utilizing it in the fabrication of 3D tissue constructs and accurate targeting in mass delivery. Here, we proposed a new method for achieving magnetic alginate hydrogel microfibers by dispersing magnetic nanoparticles in alginate solution and solidifying the magnetic alginate into hydrogel fiber inside microfluidic devices. The microfluidic devices have multilayered pneumatic microvalves with hemicylindrical channels to fully stop the fluids. In the experiments, the magnetic nanoparticles and the alginate solution were mixed and formed a uniform suspension. No aggregation of magnetic nanoparticles was found, which is crucial for flow control inside microfluidic devices. By regulating the flow rates of different solutions with the microvalves inside the microfluidic device, magnetic hydrogel fibers and nonmagnetic hydrogel fibers were fabricated with controlled sizes. The proposed method for fabricating magnetic hydrogel fiber holds great potential for engineering 3D tissue constructs with complex architectures and active drug release.     

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.     

Stamp-and-stick room-temperature bonding technique for microdevices

Multilayer MEMS and microfluidic designs using diverse materials demand separate fabrication of device components followed by assembly to make the final device. Structural and moving components, labile bio-molecules, fluids and temperature-sensitive materials place special restrictions on the bonding processes that can be used for assembly of MEMS devices. We describe a room temperature "stamp and stick (SAS)" transfer bonding technique for silicon, glass and nitride surfaces using a UV curable adhesive. Alternatively, poly(dimethylsiloxane) (PDMS) can also be used as the adhesive; this is particularly useful for bonding PDMS devices. A thin layer of adhesive is first spun on a flat wafer. This adhesive layer is then selectively transferred to the device chip from the wafer using a stamping process. The device chip can then be aligned and bonded to other chips/wafers. This bonding process is conformal and works even on surfaces with uneven topography. This aspect is especially relevant to microfluidics, where good sealing can be difficult to obtain with channels on uneven surfaces. Burst pressure tests suggest that wafer bonds using the UV curable adhesive could withstand pressures of 700 kPa (7 atmospheres); those with PDMS could withstand 200 to 700 kPa (2-7 atmospheres) depending on the geometry and configuration of the device.     

Multivariate regression modeling for monitoring quality of injection moulding components using cavity sensor technology: Application to the manufacturing of pharmaceutical device components

There is an increased demand within the moulding industry to improve the quality of moulded parts by maintaining consistent tolerances and overall dimensions. This interest is more important in areas of the moulding industry that are dedicated to pharmaceutical devices, where a quality by design approach is now expected to be adopted. A pharmaceutical device is an assembly of different plastic components which are manufactured by injection moulding; many have critical quality parameters which affect not only the device appearance but also more importantly its performance for drug delivery. Hence, the need of better understanding and control of injection moulding processes. This study presents the use of multivariate regression modeling approach to monitor the quality of the final product using cavity sensor technology (CST). The influence of the injection moulding process parameters on the quality of the final parts have been investigated using a design of experiment approach. The results demonstrate that the Partial Least Squares (PLS) regression model based on cavity pressure sensor data could be successfully used to monitor the quality (weight, dimensions) of the final product in plastic injection moulding.     

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.     

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.     

Development of Soft-Actuator-Based Wearable Tactile Display

As a major human sensory function, the implementation of the tactile sensation for the human-machine interface has been one of the core research interests for long time. In this paper, an innovative tactile display device based on the soft actuator technology is presented. Using electroactive polymer for the construction of the tactile display device, it can provide stimulation on the human skin without any additional electromechanical transmission. Softness and flexibility of the device structure, ease of fabrication, possibility for miniaturization, and low cost for mass production are the representative benefits of the presented device. Especially, the device application is open to many different purposes since the flexible structure offers the excellent adaptability to any contour of the human body. To prove its feasibility, a wearable device that can fit to the distal part of the human finger is presented and its performance is evaluated, experimentally.     

基于减速电机的微量药物输送系统的研制

介绍一种以直流电机为动力元件的驱动减速齿轮箱,实现微量药物输送的系统。采用单片机与光电传感器控制电机转动的圈数,实现药物的微量输注。阐述了系统的驱动机构和药量输送的控制方法。通过实验验证,输注精度为-2.3%～2.9%,满足临床应用要求,且稳定性高。此方法适于微型化,可为该类型微小尺寸装置的设计提供有意义的借鉴。     

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.     

A UML-based object-oriented approach for design and simulation of a drug delivery system

Given complexity of the design and manufacturing processes of microelectromechanical system (MEMS) products, we present a unified modeling language (UML) based design approach for multi-domain products or systems like MEMS to designing and evaluating possible solutions at the early design stage to shorten their development time. Specifically, the proposed approach is used to model and analyze a novel drug delivery system combining MEMS devices and integrated circuit (IC) units. This drug delivery system aims to be used for safer and more effective therapy of the diabetics. Two design models about the whole drug delivery system and its micropump subsystem are established using UML diagrams; in particular a composition diagram with components and ports describes the topology of the system. Through design and simulation on the micropump subsystem, it is found that the variations of geometrical dimension and excitation voltage affect the characterization of the micropump. The simulation results demonstrate and validate the proposed approach, and can be used as a significant reference for the designer to design the optimal micropump.     

A novel packaging approach for RF MEMS switching functions on alumina substrate

This paper reports the design of a hermetic-compatible wafer-scale package for RF MEMS based components. The presented packaging concept consists in encapsulating the whole RF device or subsystem instead of encapsulating each MEMS component separately, which will reduce the device size and cost. This approach is based on the MEMS fabrication technology on ceramic substrate and the use of laser drilled vias hole techniques to realize full metallized vias in alumina substrates. These vias holes will allow a low loss RF signal transmission inside the package without breaking its hermeticity. Hence, several packaged switching networks prototypes, based on ohmic contact MEMS switches, have been designed following this approach and the packaging electromagnetic impact on these components has been especially studied to result on good performance devices.     

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.     

Optofluidic sensor system with Ge PIN photodetector for CMOS-compatible sensing

Vertical optofluidic biosensors based on refractive index sensing promise highest sensitivities at smallest area footprint. Nevertheless, when it comes to large-scale fabrication and application of such sensors, cheap and robust platforms for sample preparation and supply are needed—not to mention the expected ease of use in application. We present an optofluidic sensor system using a cyclic olefin copolymer microfluidic chip as carrier and feeding supply for a complementary metal–oxide–semiconductor compatibly fabricated Ge PIN photodetector. Whereas typically only passive components of a sensor are located within the microfluidic channel, here the active device is directly exposed to the fluid, enabling top-illumination. The capability for detecting different refractive indices was verified by different fluids with subsequent recording of the optical responsivity. All components excel in their capability to be transferred to large-scale fabrication and further integration of microfluidic and sensing systems. The photodetector itself is intended to serve as a platform for further sophisticated collinear sensing approaches.     

Characterizing fruit fly flight behavior using a microforce sensor with a new comb-drive configuration

This paper reports a MEMS microforce sensor with a novel configuration of bulk micromachined differential triplate comb drives that overcomes the difficulty of electrically isolating the two stationary capacitor comb sets in bulk micromachining. A high-yield fabrication process using deep-reactive ion etching (DRIE) on silicon-on-insulator (SOI) wafers and only three lithographic masks was utilized to construct the high aspect ratio devices. The process features dry release of both suspended structures and the entire device in order to protect fragile components. The sensor has a high sensitivity (1.35 mV//spl mu/N), good linearity (<4%), and a large bandwidth (7.8 kHz), and is therefore well suited for characterizing flight behavior of fruit flies (Drosophila melanogaster). The technique allows for the instantaneous measurement of flight forces, which result from a combination of aerodynamic forces and inertial forces generated by the wings, and demonstrates a novel experimental paradigm for exploring flight biomechanics in the fruit fly. The average lift force is determined to be 9.3 /spl mu/N (/spl plusmn/2.3 /spl mu/N), which is in the range of typical body weights of fruit flies. The potential impact of this research extends beyond gathering flight data on Drosophila melanogaster by demonstrating how MEMS technology can be used to provide valuable tools for biomechanical investigations.     

Highly integrated polymeric microliquid flow controller for droplet microfluidics

Microfluidic applications demand accurate control and measurement of small fluid flows and volumes, and the majority of approaches found in the literature involve materials and fabrication methods not suitable for a monolithic integration of different microcomponents needed to make a complex Lab-on-a-Chip (LoC) system. The present work leads to a design and manufacturing approach for problem-free monolithic integration of components on thermoplastics, allowing the production of excellent quality devices either as stand-alone components or combined in a complex structures. In particular, a polymeric liquid flow controlling system (LFCS) at microscale is presented, which is composed of a pneumatic microvalve and an on-chip microflow sensor. It enables flow regulation between 30 and 230 μl/min with excellent reproducibility and accuracy (error lower than 5%). The device is made of a single Cyclic Olefin Polymer (COP) piece, where the channels and cavities are hot-embossed, sealed with a single COP membrane by solvent bonding and metalized, after sealing, to render a fully functional microfluidic control system that features on-chip flow sensing. In contrast with commercially available flow control systems, the device can be used for high-quality flow modulation in disposable LoC devices, since the microfluidic chip is low cost and replaceable from the external electronic and pneumatic actuators box. Functionality of the LFCS is tested by connecting it to a microfluidic droplet generator, rendering highly stable flow rates and allowing generation of monodisperse droplets over a wide range of flow rates. The results indicate the successful performance of the LFCS with significant improvements over existing LFCS devices, facing the possibility of using the system for biological applications such as generating distinct perfusion modes in cell culture, novel digital microfluidics. Moreover, the integration capabilities and the reproducible fabrication method enable straightforward transition from prototype to product in a way that is lean, cost-effective and with reduced risk.     

Electronic Mosquito: designing a semi-invasive Microsystem for blood sampling, analysis and drug delivery applications

In this study we present an innovative design idea for a semi-invasive blood sampling, analysis and drug delivery device called “Electronic Mosquito” (“e-Mosquito”). The major building blocks of the device are discussed. The principle of operation is described and its feasibility is demonstrated. The integration of the microsystem is outlined and its practical implementation proposed.