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

Integrated Lithographic Molding for Microneedle-Based Devices

This paper presents a new fabrication method consisting of lithographically defining multiple layers of high aspect-ratio photoresist onto preprocessed silicon substrates and release of the polymer by the lost mold or sacrificial layer technique, coined by us as lithographic molding. The process methodology was demonstrated fabricating out-of-plane polymeric hollow microneedles. First, the fabrication of needle tips was demonstrated for polymeric microneedles with an outer diameter of 250 mum, through-hole capillaries of 75-mum diameter and a needle shaft length of 430 mum by lithographic processing of SU-8 onto simple v-grooves. Second, the technique was extended to gain more freedom in tip shape design, needle shaft length and use of filling materials. A novel combination of silicon dry and wet etching is introduced that allows highly accurate and repetitive lithographic molding of a complex shape. Both techniques consent to the lithographic integration of microfluidic back plates forming a patch-type device. These microneedle-integrated patches offer a feasible solution for medical applications that demand an easy to use point-of-care sample collector, for example, in blood diagnostics for lithium therapy. Although microchip capillary electrophoresis glass devices were addressed earlier, here, we show for the first time the complete diagnostic method based on microneedles made from SU-8

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

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

Fabrication of Hollow Silicon Microneedle Arrays for Transdermal Biological Fluid Extraction

This thesis presents the research in the field of microelectromechanical systems with the specific aim of investigating a microneedle based transdermal skin fluid extraction concept. This work presents an innovative double-side Deep Reactive Ion Etching (DRIE) approach for producing hollow silicon microneedle arrays for transdermal biological fluid extraction. The microneedles are fabricated from a double side polished wafer to a shank height of 200-300 μm with 300 μm center-to-center spacing. Moreover, the in vivo testing results are provided as well. In this thesis, several microfabrication techniques are investigated, developed and applied in the fabrication process. The first chapter brings an overview of nano-/microfabrication and MEMS for biomedical applications (drug delivery and biofluid extraction). Furthermore, the fundamental background of skin structure and interstitial fluid (ISF) is introduced as well. The second chapter clearly illustrates three key techniques specifically employed in the microneedle fabrication process which are photolithography, wet etching and dry etching. The third chapter presents a detailed literature review of microneedles in terms of its general concepts, structures, materials and integrated fluidic system. Eventually, Chapter 4 introduces the details of our method to fabricate hollow silicon microneedle arrays step by step. SEM images and in vivo testing results confirm that hollow silicon microneedle arrays are not only sharp enough to penetrate the stratum corneum but also robust enough to extract ISF out of skin. Ongoing work will focus on the optimization of the assemble extraction apparatus and the capillary filling of the holes

Fabrication of Silicon Microneedles for Dermal Interstitial Fluid Extraction in Human Subjects

The goal of this project is to design and develop a fabrication process for silicon microneedle arrays to extract dermal interstitial fluid (ISF) from human skin. ISF is a cell- free, living tissue medium that is known to contain many of the same, clinical biomarkers of general health, stress response and immune status as in blood. However, a significant barrier to adoption of ISF as a diagnostic matrix is the lack of a rapid, minimally invasive method of access and collection for analysis. Microfabricated chips containing arrays of microneedles that can rapidly and painlessly access and collect dermal ISF for bioassay could greatly facilitate point-of-care diagnosis and health monitoring, especially in times of crisis or in austere environments, where drawing venous blood poses an unnecessary infection or biohazard risk. Two different fabrication methods were explored. The first method borrows from a previously reported dicing saw process, where a series of parallel and perpendicular cuts of partial depth are made into a thicker silicon wafer, creating arrays of square columns, which are subsequently sharpened into needles. The second method uses a new, entirely-DRIE process to create the arrays of columns. The columns are sharpened into needles using an isotropic wet etch method (HNA etch) which preferentially enhances etching at the tips and diminishes etching at the base, creating remarkably sharp, conical shaped needles capable of piercing skin. The needles contain holes that pass through the wafer to the opposite side, where they connect to a series of microfluidic channels that lead to a reservoir. The back of the wafer is bonded to glass, providing a hydrophilic cap to the channels, as well as a way to see into the device to detect whether the channels are filling with liquid. The fabrication procedures for both methods are presented, along with 2D- and 3D-rendered schematics for the final devices. Needle geometric shape is crucial to their ability to extract ISF. To determine the appropriate pre-sharpened etched shape, needle columns with a variety of different shapes were designed, produced, sharpened, and examined under a scanning electron microscope. The most promising shapes were selected for further processing and testing. Resulting chips were first bench tested to ensure capillary filling capability, and then tested for ISF collection from human skin. Microneedle arrays which were successfully demonstrated to extract ISF are presented, and the unsuccessful shapes are also shown in the interest of completion. Potential means for improving performance and future research directions are discussed

Application prospects for wearable body surface microfluidic system in sports

The wearable body surface microfluidic system has great application potential in the field of sports. The use of the wearable body surface microfluidic system to monitor the physiological state of athletes can solve problems faced such as long inspection cycle in sports monitoring, difficulties in continuous monitoring, dependence on laboratory platforms, athlete resistance and other problems faced in technological integration to promote the development of the sports field. In recent years, the development of key technologies such as microfluidic chips and microneedle delivery provides an ideal solution for real-time monitoring and even immediate intervention of physiological states during exercise. This paper summarizes the latest research progress of wearable body surface microfluidic systems and focuses on eight wearable body surface microfluidic systems that may be applied in the field of sports, with their application prospects in sports analyzed and discussed. Finally, the application direction of the wearable body surface microfluidic system that may achieve breakthroughs is illustrated with the prospect demonstration of the future research and development direction of wearable sports equipment. This paper aims to focus on technical problems in the development of the sports field, provide multi-disciplinary solutions and advocate technology integration as well as provide scientific and technological assistance for the development of the sports field

Mini-Review: Assessing the Potential Impact of Microneedle Technologies on Home Healthcare Applications

The increasing devolution of healthcare towards community care has meant that the management of many conditions is conducted within the home either by community nurses or by the patients themselves. The administration of medicines within home healthcare scenarios can however be problematic—especially when considering the delivery of medicines through injection. The possibility of needlestick injury (NSI) has become an ever-present hazard within healthcare settings, with a significant proportion of percutaneous injuries occurring during the handling and disposal of the needle. The emergence of transdermal microneedle systems, however, offers a potentially revolutionary advance and could dramatically improve safety—particularly within home healthcare where there are mounting concerns over the use and disposal of sharps. A mini-review of the advantages proffered by microneedle drug delivery technologies is presented and the potential impact on delivery of medicines within the home is critically appraised

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