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

Three-Dimensional (3D) Printed Microneedles for Microencapsulated Cell Extrusion

Cell-hydrogel based therapies offer great promise for wound healing. The specific aim of this study was to assess the viability of human hepatocellular carcinoma (HepG2) cells immobilized in atomized alginate capsules (3.5% (w/v) alginate, d = 225 µm ± 24.5 µm) post-extrusion through a three-dimensional (3D) printed methacrylate-based custom hollow microneedle assembly (circular array of 13 conical frusta) fabricated using stereolithography. With a jetting reliability of 80%, the solvent-sterilized device with a root mean square roughness of 158 nm at the extrusion nozzle tip (d = 325 μm) was operated at a flowrate of 12 mL/min. There was no significant difference between the viability of the sheared and control samples for extrusion times of 2 h (p = 0.14, α = 0.05) and 24 h (p = 0.5, α = 0.05) post-atomization. Factoring the increase in extrusion yield from 21.2% to 56.4% attributed to hydrogel bioerosion quantifiable by a loss in resilience from 5470 (J/m3) to 3250 (J/m3), there was no significant difference in percentage relative payload (p = 0.2628, α = 0.05) when extrusion occurred 24 h (12.2 ± 4.9%) when compared to 2 h (9.9 ± 2.8%) post-atomization. Results from this paper highlight the feasibility of encapsulated cell extrusion, specifically protection from shear, through a hollow microneedle assembly reported for the first time in literature

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

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

Creation and Optimisation of Plasma Etch Processes for the Manufacture of Silicon Microstructures

Microneedles are an area of growing interest for applications in transdermal delivery. Small, minimally invasive medical or cosmetic devices, microneedles are intended to penetrate the skin’s outer protective layer (stratum corneum) to facilitate delivery of active formulations into the skin. Delivery of solution via microneedles has the benefits associated with hypodermic injection, i.e. avoiding the first-pass metabolism systems, with the added advantages of painless delivery and dose sparing from the reduced solution volumes required.Advancements in semiconductor processing technologies and equipment have enabled the creation of devices and structures that could not have been fabricated in the past. This is also true for the fabrication of microneedles, where previous manufacturing methods have relied on hazardous chemicals such as Hydrofluoric Acid and Potassium Hydroxide to create the sharp tip of the needle, required to reduce insertion force.In this thesis, the realisation of a hollow bevelled silicon microneedle fabricated using only plasma processing techniques is presented, providing a route to scalable manufacture of high-performance, sharp-tipped microneedles. The microneedle fabrication process consists of three main etch steps in the process flow to create hollow structures. For each of the Bevel, Bore, and Shaft processes the development and optimisation is detailed. Throughout the process development, several unexpected processing issues were encountered, including depth non-uniformity, “notching”, and “silicon grass”. Investigations have been performed to determine the root cause of each issue and fine-tune processes to optimise the final devices. A discussion of the process hardware is also presented, with reference to the benefits for each specific application process.Following development and optimisation of each individual process, the Bevel, Bore, and Shaft processes were integrated in the manufacturing flow to create the final hollow silicon microneedle device. Issues arising from the combination of the three processes have been investigated, resolved, and optimised. This includes the conception and execution of a novel process for the plasma smoothing of an angled silicon surface, which improved the quality of lithography on the non-planar bevel surface and minimised grass formation.Preliminary testing, undertaken to assess the suitability of these devices for transdermal use, included mechanical fracture force, skin penetration, and injection testing. The microneedles were found to be strong enough to remain intact during insertion, and demonstrate successful penetration and injection through the stratum corneum and into the deeper skin layers

Dissolving microneedles for cutaneous drug and vaccine delivery

Currently, biopharmaceuticals including vaccines, proteins, and DNA are delivered almost exclusively through the parenteral route using hypodermic needles. However, injection by hypodermic needles generates pain and causes bleeding. Disposal of these needles also produces biohazardous sharp waste. An alternative delivery tool called microneedles may solve these issues. Microneedles are micron-size needles that deliver drugs or biopharmaceuticals into skin by creating tiny channels in the skin. This thesis focuses on dissolving microneedles in which the needle tips dissolve and release the encapsulated drug or vaccine upon insertion. The project aimed to (i) design and optimize dissolving microneedles for efficient drug and vaccine delivery to the skin, (ii) maintain vaccine stability over long-term storage, and (iii) immunize animals using vaccine encapsulated microneedles. The results showed that influenza vaccine encapsulated in microneedles was more thermally stable than unprocessed vaccine solution over prolonged periods of storage time. In addition, mice immunized with microneedles containing influenza vaccine offered full protection against lethal influenza virus infection. As a result, we envision the newly developed dissolving microneedle system can be a safe, patient compliant, easy to-use and self-administered method for rapid drug and vaccine delivery to the skin.Ph.D.Committee Chair: Prausnitz, Mark; Committee Member: Compans, Richard; Committee Member: Milam, Valeria; Committee Member: Murthy, Niren; Committee Member: Weniger, Bruc

Potential of biodegradable microneedles as a transdermal delivery vehicle for lidocaine

There has been an increasing interest in applying biotechnology in formulating and characterising new and innovative drug delivery methods, e.g., drug-loaded biodegradable microneedles within the area of transdermal delivery technology. Recently, microneedles have been proposed for use in pain management, e.g., post-operative pain management through delivery of a local anaesthetic, namely, lidocaine. Lidocaine is a fairly common, marketed prescription-based, local anaesthetic pharmaceutical, applied for relieving localised pain and lidocaineloaded microneedles have been explored. The purpose of this review is to evaluate the properties of biodegradable polymers that may allow the preparation of microneedle systems, methods of preparing them and pharmacokinetic conditions in considering the potential use of lidocaine for delivery through the skin

Biopolymer based microneedles patch by laser technology for biomedical applications

One of the most important issues in creating new drug delivery methods is improving drug permeation into the skin. Therefore, many techniques have been proposed, such as oral administration, intradermal vaccines, transdermal patches, among others, but all of them present several limitations. In the past few years, a new effective, innovative and safe drug delivery system was proposed. This technology is named as microneedles (MNs) and it is a hybrid combination of hypodermic injections and transdermal drug delivery systems, which consists in micro-scale needles that can pierce the skin by a simple, minimally invasive and painless route, enabling to transport drugs and macromolecules into the human body. This dissertation reports the development of a biopolymer-based microneedle patch, using biodegradable and biocompatible polymers, polylactic acid (PLA) and poly(hydroxybutyrate-co-hydroxyvalerate) (P(HB-co-HV)), through a low-cost and maskless laser technology. The laser technology was used to engrave specific patterns on a substrate that served as mold for the MNs production. The best results were obtained with a laser power of 30 W at 0.15 m/s, with the spiral model as pattern. The respective MNs had a length of 0.69 mm and a diameter of 0.33 mm, ideal for painless penetration of skin. Moreover, P(HB-co-HV) demonstrated a higher mechanical stability than commercial PLA, confirming its promising use as MNs biomaterial

A compendium of current developments on polysaccharide and protein-based microneedles

Microneedles (MNs), i.e. minimally invasive three-dimensional microstructures that penetrate the stratum corneum inducing relatively little or no pain, have been studied as appealing therapeutic vehicles for transdermal drug delivery. Over the last years, the fabrication of MNs using biopolymers, such as polysaccharides and proteins, has sparked the imagination of scientists due to their recognized biocompatibility, biodegradability, ease of fabrication and sustainable character. Owing to their wide range of functional groups, polysaccharides and proteins enable the design and preparation of materials with tunable properties and functionalities. Therefore, these biopolymer-based MNs take a revolutionary step offering great potential not only in drug administration, but also in sensing and response to physiological stimuli. In this review, a critical and comprehensive overview of the polysaccharides and proteins employed in the design and engineering of MNs will be given. The strategies adopted for their preparation, their advantages and disadvantages will be also detailed. In addition, the potential and challenges of using these matrices to deliver drugs, vaccines and other molecules will be discussed. Finally, this appraisal ends with a perspective on the possibilities and challenges in research and development of polysaccharide and protein MNs, envisioning the future advances and clinical translation of these platforms as the next generation of drug delivery systems.publishe

Microneedles for drug delivery: trends and progress

In recent years there has been a surge in the research and development of microneedles, a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable microneedles have been researched in the literature and have several advantages compared to solid or hollow microneedles, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in microneedle research and shows the rapidly growing numbers of research papers and patent publications since the first invention of microneedles (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field