Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical Applications

Micro Electromechanical Systems (MEMS) based microfluidic devices have gained popularity in biomedicine field over the last few years. In this paper, a comprehensive overview of microfluidic devices such as micropumps and microneedles has been presented for biomedical applications. The aim of this paper is to present the major features and issues related to micropumps and microneedles, e.g., working principles, actuation methods, fabrication techniques, construction, performance parameters, failure analysis, testing, safety issues, applications, commercialization issues and future prospects. Based on the actuation mechanisms, the micropumps are classified into two main types, i.e., mechanical and non-mechanical micropumps. Microneedles can be categorized according to their structure, fabrication process, material, overall shape, tip shape, size, array density and application. The presented literature review on micropumps and microneedles will provide comprehensive information for researchers working on design and development of microfluidic devices for biomedical applications

Microneedles in advanced microfluidic systems: a systematic review throughout lab and organ-on-a-chip applications

Microneedles (MNs) have been widely used in biomedical applications for drug delivery and biomarker detection purposes. Furthermore, MNs can also be used as a stand-alone tool to be combined with microfluidic devices. For that purpose, lab- or organ-on-a-chip are being developed. This systematic review aims to summarize the most recent progress in these emerging systems, to identify their advantages and limitations, and discuss promising potential applications of MNs in microfluidics. Therefore, three databases were used to search papers of interest, and their selection was made following the guidelines for systematic reviews proposed by PRISMA. In the selected studies, the MNs type, fabrication strategy, materials, and function/application were evaluated. The literature reviewed showed that although the use of MNs for lab-on-a-chip has been more explored than for organ-on-a-chip, some recent studies have explored this applicability with great potential for the monitoring of organ models. Overall, it is shown that the presence of MNs in advanced microfluidic devices can simplify drug delivery and microinjection, as well as fluid extraction for biomarker detection by using integrated biosensors, which is a promising tool to precisely monitor, in real-time, different kinds of biomarkers in lab- and organ-on-a-chip platforms.This work was supported by the project EXPL/EMD-EMD/0650/2021, and partially supported by the project PTDC/EEI-EEE/2846/2021, through national funds (OE), within the scope of the Scientific Research and Technological Development Projects (IC&DT) program in all scientific domains (PTDC), through the Foundation for Science and Technology, I.P. (FCT, I.P). This project also received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 101032481. V.C. is grateful for her Ph.D. grant from Fundação para a Ciência e Tecnologia (FCT) with reference UI/BD/151028/2021 and Fulbright Grant for Research with the support of FCT, AY2022/2023. R.O.R. thanks FCT for her contract funding provided through 2020.03975.CEECIND. The authors also acknowledge the partial financial support within the R&D Unit Project Scope: UIDB/04436/2020, UIDB/04077/2020, UIDB/00532/2020, LA/P/0045/2020

Development of an automated design tool for FEM-based characterization of solid and hollow microneedles

Microneedle design for biomedical applications, such as transdermal drug delivery, vaccination and transdermal biosensing, has lately become a rapidly growing research field. In this sense, finite element analysis has been extendedly used by microneedle designers to determine the most suitable structural parameters for their prototypes, and also to predict their mechanical response and efficiency during the insertion process. Although many proposals include computer-aided tools to build geometrical models for mechanical analysis, there is a lack of software utilities intended to automate the design process encompassing geometrical modeling, simulation setup and postprocessing of results. This work proposes a novel MATLAB-based design tool for microneedle arrays that permits personalized selection of the basic characteristics of a mechanical model. The tool automatically exports the selected options to an ANSYS batch file, including instructions to run a static and a linear buckling analysis. Later, the subsequent simulation results can be retrieved for on-screen display and potential postprocessing. In addition, this work reviews recent proposals (2018-2022) about finite element model characterization of microneedles to establish the minimum set of features that any tool intended for automating a design process should provide.This research was funded by the Spanish “Consejería de Universidades, Igualdad, Cultura y Deporte del Gobierno de Cantabria” under the project VP47 Bloodless Antithrombotic Therapy Monitoring System (BATMS

A 3D-printed microfluidic-enabled hollow microneedle architecture for transdermal drug delivery.

Embedding microfluidic architectures with microneedles enables fluid management capabilities that present new degrees of freedom for transdermal drug delivery. To this end, fabrication schemes that can simultaneously create and integrate complex millimeter/centimeter-long microfluidic structures and micrometer-scale microneedle features are necessary. Accordingly, three-dimensional (3D) printing techniques are suitable candidates because they allow the rapid realization of customizable yet intricate microfluidic and microneedle features. However, previously reported 3D-printing approaches utilized costly instrumentation that lacked the desired versatility to print both features in a single step and the throughput to render components within distinct length-scales. Here, for the first time in literature, we devise a fabrication scheme to create hollow microneedles interfaced with microfluidic structures in a single step. Our method utilizes stereolithography 3D-printing and pushes its boundaries (achieving print resolutions below the full width half maximum laser spot size resolution) to create complex architectures with lower cost and higher print speed and throughput than previously reported methods. To demonstrate a potential application, a microfluidic-enabled microneedle architecture was printed to render hydrodynamic mixing and transdermal drug delivery within a single device. The presented architectures can be adopted in future biomedical devices to facilitate new modes of operations for transdermal drug delivery applications such as combinational therapy for preclinical testing of biologic treatments

Towards rapid 3D direct manufacture of biomechanical microstructures

The field of stereolithography has developed rapidly over the last 20 years, and commercially available systems currently have sufficient resolution for use in microengineering applications. However, they have not as yet been fully exploited in this field. This thesis investigates the possible microengineering applications of microstereolithography systems, specifically in the areas of active microfluidic devices and microneedles. The fields of micropumps and microvalves, stereolithography and microneedles are reviewed, and a variety of test builds were fabricated using the EnvisionTEC Perfactory Mini Multi-Lens stereolithography system in order to define its capabilities. A number of microneedle geometries were considered. This number was narrowed down using finite element modelling, before another simulation was used to optimise these structures. 9 × 9 arrays of 400 μm tall, 300 μm base diameter microneedles were subjected to mechanical testing. Per needle failure forces of 0.263 and 0.243 N were recorded for the selected geometries, stepped cone and inverted trumpet. The 90 μm needle tips were subjected to between 30 and 32 MPa of pressure at their failure point - more than 10 times the required pressure to puncture average human skin. A range of monolithic micropumps were produced with integrated 4 mm diameter single-layer 70 μm-thick membranes used as the basis for a reciprocating displacement operating principle. The membranes were tested using an oscillating pneumatic actuation, and were found reliable (>1,000,000 cycles) up to 2.0 PSIG. Pneumatic single-membrane nozzle/diffuser rectified devices produced flow rates of up to 1,000 μl/min with backpressures of up to 375 Pa. Another device rectified using active membrane valves was found to self-prime, and produced backpressures of up to 4.9 kPa. These devices and structures show great promise for inclusion in complex, fully integrated and active microfluidic systems fabricated using microstereolithography alone, with implications for both cost of manufacture and lead time

Fabrication of Silicon In-plane and Out-ofplane Microneedle Arrays for Transdermal Biological Fluid Extraction

This thesis presents research in the field of microelectromechanical systems and specifically in the area of microneedle-based transdermal skin fluid extraction and drug delivery. The objective of this thesis is to highlight the potential role of microneedles in achieving painless transdermal skin biofluid extraction and drug delivery of macromolecular drugs across the skin barrier. The work represents the design and fabrication of silicon out-of-plane and in-plane microneedles and an innovative double-side Deep Reactive Ion Etching (DRIE) approach was presented for producing hollow silicon microneedle arrays for transdermal biological fluid extraction. The solid silicon out-of-plane microneedles are fabricated from a single side polished wafer whereas the hollow out-of-plane microneedles are fabricated from a double side polished wafer to a shank height of 200-300 μm with 300 μm center-tocenter spacing. The single-step Bosch DRIE is performed for “in-plane” silicon microneedles to simultaneously etch the needle shaft (parallel to silicon substrate, etch through the wafer) and the narrow trenches as open capillary fluidic channels (partly etched into the wafer), taking advantage of the aspect-ratio dependent DRIE etching. Furthermore, the double-sided two stage DRIE is performed to etch the open trenches on the backside of wafer and then the needle shaft on the front side. The in-plane needles have the advantages of making long needles up to 2 mm. Moreover, the in vivo testing results are provided as well. In this thesis, different microfabrication techniques are investigated, developed, optimized, and applied in the fabrication process. The first chapter conveys an overview of nanotechnology, nano-/microfabrication and their role in medicine. The second chapter illustrates an introduction to transdermal drug delivery and extraction. Furthermore, the fundamental background of skin structure and interstitial fluid (ISF) is introduced as well. Device fabrication tools and techniques are shown in chapter three. The fourth chapter presents a detailed literature review of microneedles in terms of its general concepts, structures, materials and integrated fluidic system. Eventually, Chapter 5 introduces the details of our method to fabricate solid and hollow silicon microneedle arrays step by step. SEM images and in vivo testing results confirm that silicon microneedle both out-of-plane and in-plane arrays are not only sharp enough to penetrate the stratum corneum but also robust enough to extract ISF out of skin or to deliver drug

Fabrication of Nano-Injection Needles for Neural Pathway Study in Mice

The potential of micro-needles to provide an interconnection between the microscopic and the macroscopic worlds makes it one of the most revolutionary fields in health care, allowing for precise transdermal drug delivery of highly targeted small doses of the active compound. Current micro electro mechanical systems (MEMS) technologies, originally designed for the micro-electronics industry, have been utilized in the fabrication of different micro-needle designs and their integration with various micro-fabricated micro-fluidics devices. The target of this thesis is to achieve a micro-needle injection system to deliver several strains of pico-liter volumes of a fluid combination of transgenic virus and luminescent compound, to be injected into the visual cortex of mice in order to study the structure and function of the neural networks of the brain. Micro-needles having a body dimension of 10 mm x 10 mm and a shaft 1 mm wide and 3 mm long have been constructed from silicon wafers, using technologies originally developed for integrated circuit (IC) fabrication. Silicon wafers have also been used in the fabrication of the needle channels having a width of 4 μm and a total depth of 60 μm with a 20 μm deep channel at the base of the 40 μm trench. Both wet and dry bulk micromachining techniques have been used to create the needle bodies and channels. The optimum fabrication method has been found to be the deep reactive ion etching (DRIE) and SiO2 deposition using the plasma enhanced chemical vapor deposition (PECVD) has been used to seal the channels

An Electrically Active Microneedle Electroporation Array for Intracellular Delivery of Biomolecules

The objective of this research is the development of an electrically active microneedle array that can deliver biomolecules such as DNA and drugs to epidermal cells by means of electroporation. Properly metallized microneedles could serve as microelectrodes essential for electroporation. Furthermore, the close needle-to-needle spacing of microneedle electrodes provides the advantage of utilizing reduced voltage, which is essential for safety as well as portable applications, while maintaining the large electric fields required for electroporation. Therefore, microneedle arrays can potentially be used as part of a minimally invasive, highly-localized electroporation system for cells in the epidermis layer of the skin. This research consists of three parts: development of the 3-D microfabrication technology to create the microneedle array, fabrication and characterization of the microneedle array, and the electroporation studies performed with the microneedle array. A 3-D fabrication process was developed to produce a microneedle array using an inclined UV exposure technique combined with micromolding technology, potentially enabling low cost mass-manufacture. The developed technology is also capable of fabricating 3-D microstructures of various heights using a single mask. The fabricated microneedle array was then tested to demonstrate its feasibility for through-skin electrical and mechanical functionality using a skin insertion test. It was found that the microneedles were able to penetrate skin without breakage. To study the electrical properties of the array, a finite element simulation was performed to examine the electric field distribution. From these simulation results, a predictive model was constructed to estimate the effective volume for electroporation. Finally, studies to determine hemoglobin release from bovine red blood cells (RBC) and the delivery of molecules such as calcein and bovine serum albumin (BSA) into human prostate cancer cells were used to verify the electrical functionality of this device. This work established that this device can be used to lyse RBC and to deliver molecules, e.g. calcein, into cells, thus supporting our contention that this metallized microneedle array can be used to perform electroporation at reduced voltage. Further studies to show efficacy in skin should now be performed.Ph.D.Committee Chair: Mark G. Allen; Committee Member: Mark R. Prausnitz; Committee Member: Oliver Brand; Committee Member: Pamela Bhatti; Committee Member: Shyh-Chiang She

Recent advances in micro-electro-mechanical devices for controlled drug release applications

In recent years, controlled release of drugs has posed numerous challenges with the aim of optimizing parameters such as the release of the suitable quantity of drugs in the right site at the right time with the least invasiveness and the greatest possible automation. Some of the factors that challenge conventional drug release include long-term treatments, narrow therapeutic windows, complex dosing schedules, combined therapies, individual dosing regimens, and labile active substance administration. In this sense, the emergence of micro-devices that combine mechanical and electrical components, so called micro-electro-mechanical systems (MEMS) can offer solutions to these drawbacks. These devices can be fabricated using biocompatible materials, with great uniformity and reproducibility, similar to integrated circuits. They can be aseptically manufactured and hermetically sealed, while having mobile components that enable physical or analytical functions together with electrical components. In this review we present recent advances in the generation of MEMS drug delivery devices, in which various micro and nanometric structures such as contacts, connections, channels, reservoirs, pumps, valves, needles, and/or membranes can be included in their design and manufacture. Implantable single and multiple reservoir-based and transdermal-based MEMS devices are discussed in terms of fundamental mechanisms, fabrication, performance, and drug release applications.Fil: Villarruel Mendoza, Luis A.. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; ArgentinaFil: Scilletta, Natalia Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; ArgentinaFil: Bellino, Martin Gonzalo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Constituyentes | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Constituyentes.; ArgentinaFil: Desimone, Martín Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Catalano, Paolo Nicolás. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

Microfluidics for Advanced Drug Delivery Systems.

Considerable efforts have been devoted towards developing effective drug delivery methods. Microfluidic systems, with their capability for precise handling and transport of small liquid quantities, have emerged as a promising platform for designing advanced drug delivery systems. Thus, microfluidic systems have been increasingly used for fabrication of drug carriers or direct drug delivery to a targeted tissue. In this review, the recent advances in these areas are critically reviewed and the shortcomings and opportunities are discussed. In addition, we highlight the efforts towards developing smart drug delivery platforms with integrated sensing and drug delivery components