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

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

Optimization of square microneedle arrays for increasing drug permeability in skin

Microneedles array is a new transdermal drug delivery technique designed to create holes in the epidermis and penetrate the stratum corneum, thus avoiding the high resistance of this barrier. Microneedles have been shown to increase the skin permeability of drugs with no or little pain. However, the skin permeability of epidermis while using microneedle arrays has yet to be fully studied. In some cases, microneedle and microneedle array designs which were developed based on certain criteria (e.g., material of the microneedles) have to be related to other criteria (e.g., drug permeability in skin, skin thickness, etc.). Therefore, in order to determine the optimum design of the microneedle arrays, the effect of different factors (e.g., number of the microneedle, surface area of the patch, etc.) along with skin permeability by using microneedles should be determined accurately. In this work, an optimization framework for transdermal delivery of high molecular weight drug from microneedle is presented. The outputs of this framework have allowed us to identify the optimum design of various microneedles. Data from this optimization algorithm is then used to predict skin permeability of high molecular weight injected into the skin from a microneedle system. The effect of the optimized microneedles on blood drug concentration has been determined. The outcome of this study is useful to propose an optimum design based on different measurement (e.g., variation of skin thickness) for transdermal delivery of drugs

A nanostructured porous silicon based drug delivery device

Targeted and controlled delivery of therapeutic agents on demand is pivotal in realising the efficacy of many pharmaceuticals. The design and fabrication of a novel, electrically-addressable, porous structure-based drug delivery device for the controlled release of therapeutic proteins and peptides, are described in this thesis. The initial prototype microdevice design incorporates a porous polysilicon (PPSi) structure as a drug reservoir. Two alternative methods were investigated to fabricate the PPSi structure: i) the chemical stain etching method; ii) a reactive ion etching (RIE) method through a masking template. Random pores, with irregular pore shape and size in the micro- to mesoporous regime (< 50 nm), were obtained using the stain etching method but this method suffered from poor reproducibility and non-uniformity. Two novel RIE approaches were investigated to fabricate ordered PPSi structures; two different masking templates were investigated – a porous anodic alumina (PAA) and a metal mask with hexagonally arranged holes produced by a novel nanosphere lithography (NSL) technique. A quasi-ordered PAA template with pore diameters in the region of 50 nm was fabricated but was not suitable for the subsequent proposed RIE process. By using the NSL technique, quasi-ordered PPSi structures with tapered pore profiles, were obtained. This is the first demonstration of the fabrication of PPSi with ordered pores of sizes in the macropore range of ~ 370 nm.A revised silicon-based prototype microdevice was designed and fabricated. The microdevice incorporates a nanostructured, quasi-ordered porous silicon (PSi) as a drug reservoir and an integrated heater and temperature sensor as an active control mechanism. The PSi structure was fabricated using a modified NSL technique and a Bosch-based RIE process. Hexagonally arranged cylindrical pores with diameters between ~75 nm and ~120 nm, and depths in the range of ~330 nm and 500 nm, were obtained. The novel fabrication techniques investigated here are simple and versatile; both p-type and n-type PSi structures have been successfully fabricated. Proof-of-concept studies, using the revised prototype drug delivery microdevices, suggested that the nanostructured PSi would be suitable for the passive release of an intermediate-sized (~23,000 Dalton) model protein. It is envisaged that the microdevice has the potential to deliver osteoinductive growth factors, on demand, to the site of fracture, in a controlled and sustainable manner, as a first step to an intelligent therapeutic system for skeletal regeneration

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

Design and Fabrication of Microneedles for Drug Delivery

Ph.DDOCTOR OF PHILOSOPH

An overview of microneedle applications, materials, and fabrication methods

Microneedle-based microdevices promise to expand the scope for delivery of vaccines and therapeutic agents through the skin and withdrawing biofluids for point-of-care diagnostics - so-called theranostics. Unskilled and painless applications of microneedle patches for blood collection or drug delivery are two of the advantages of microneedle arrays over hypodermic needles. Developing the necessary microneedle fabrication processes has the potential to dramatically impact the health care delivery system by changing the landscape of fluid sampling and subcutaneous drug delivery. Microneedle designs which range from sub-micron to millimetre feature sizes are fabricated using the tools of the microelectronics industry from metals, silicon, and polymers. Various types of subtractive and additive manufacturing processes have been used to manufacture microneedles, but the development of microneedle-based systems using conventional subtractive methods has been constrained by the limitations and high cost of microfabrication technology. Additive manufacturing processes such as 3D printing and two-photon polymerization fabrication are promising transformative technologies developed in recent years. The present article provides an overview of microneedle systems applications, designs, material selection, and manufacturing methods

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