ADDITIVE MANUFACTURING OF HOLLOW MICRONEEDLES FOR INSULIN DELIVERY

Microneedles (MN) are miniature devices capable of perforating painlessly stratum corneum and delivering active ingredients in the inner epidermal layers. Hollow microneedles (HMNs) are highly detailed objects due to their internal microchannels and thus, their fabrication with Additive Manufacturing (AM) is a challenging task. Vat polymerization techniques provide a sufficient accuracy for such microstructures. Differentiated from other approaches where stereolithography and 2-photon polymerization were adopted, this paper presents the 3D-printing of HMNs purposed for insulin delivery, using the more economic Liquid Crystal Display (LCD) method. First, different geometries (hexagon, square pyramid, beveled) were 3D printed with constant height and varying curing time, printing angle and layer resolution. Quality features in each case were captured with optical and scanning electron microscopy (SEM). The most promising geometry was found to be the beveled one due to the more refined tip area and the feasibility of non-clogged microchannel formation. Among printing parameters, printing angle proved to be the most influential, as it affects resin flow phenomenon during printing process. Lastly, optimized HMN geometry was the beveled configuration, where the average height was measured 900μm, 3D printing angle was set at -45°, the curing time was 10s per layer and the optimal layer height was 30μm.

Producing Hollow Polymer Microneedles Using Laser Ablated Molds in an Injection Molding Process

Microneedle arrays contain needle-like microscopic structures which facilitate drug or vaccine delivery in a minimally invasive way. However, producing hollow microneedles is currently limited by expensive, time consuming and complex microfabrication techniques. In this paper, a novel method to produce hollow polymer microneedles is presented. This method utilizes a femtosecond laser to create hollow microneedle cavities in a mold insert. This mold insert is used in an injection molding process, to replicate polymethyl methacrylate microneedles. The combined effect of the mold temperature, volumetric injection rate and melt temperature on the replication fidelity was evaluated. It was found that the combination of high injection molding parameters facilitated the replication. Furthermore, the functionality of the manufactured hollow microneedles was successfully tested by injecting a controlled flow of colored water into an agarose matrix. The developed methodology enables the production of low-cost, high-volume microneedle devices, which could be a key asset for large scale vaccination campaigns.

One-Shot Fabrication of Polymeric Hollow Microneedles by Standard Photolithography

Microneedles (MNs) are an emerging technology in pharmaceutics and biomedicine, and are ready to be commercialized in the world market. However, solid microneedles only allow small doses and time-limited administration rates. Moreover, some well-known and already approved drugs need to be re-formulated when supplied by MNs. Instead, hollow microneedles (HMNs) allow for rapid, painless self-administrable microinjection of drugs in their standard formulation. Furthermore, body fluids can be easily extracted for analysis by a reverse use of HMNs, thus making them perfect for sensing issues and theranostics applications. The fabrication of HMNs usually requires several many-step processes, increasing the costs and consequently decreasing the commercial interest. Photolithography is a well-known fabrication technique in microelectronics and microfluidics that fabricates MNs. In this paper, authors show a proof of concept of a patented, easy and one-shot fabrication of two kinds of HMNs: (1) Symmetric HMNs with a “volcano” shape, made by using a photolithographic mask with an array of transparent symmetric rings; and (2) asymmetric HMNs with an oblique aperture, like standard hypodermic steel needles, made by using an array of transparent asymmetric rings, defined by two circles, which centers are slightly mismatched. Simulation of light propagation, fabrication process, and preliminary results on ink microinjection are presented.

Development of Microneedle Devices for Drug Delivery

There are numerous modes of therapeutic administration, of which oral delivery is the most convenient and conventional as it involves administration of therapeutics in the form of liquids or solid capsules and tablets. However, this mode encounters several challenges, such as chemical processes within the gastrointestinal track and first pass metabolism which subsequently reduce the efficacy of the therapeutic drugs. To overcome these issues, transdermal drug administration in the form of hypodermic needles, topical creams, and transdermal patches have been employed. However, the effect of transdermal administration is limited due the stratum corneum layer of the skin, which acts as a lipophilic and hydrophobic barrier preventing external molecules from entering the skin. Therefore, hypodermic needles are used due to their sharp tip facilitating penetration through the stratum corneum to deposit the drug formulation into the skin, subcutaneous fat, or muscles layers. However, these needles induce needle-phobia and reduce patient compliance due to the complexity with administration and pain associated with injection. Microneedle devices have been developed to avoid these issues and provide enhanced transdermal therapeutic drug delivery in a minimally invasive manner to eliminate the first-pass metabolism and provide a sustained release. Unlike hypodermic needles injection, they do not cause pain and related fear or phobia in individuals, thereby improving compliance to the prescribed dosage regime. Till now different types of microneedles have been fabricated. These include, solid, coated, hollow and dissolvable, where each type has its own advantages and unique properties and designs. In this thesis, two novel methods utilising silicon etching processes, for the fabrication of both out-of-plane and in-plane silicon microneedles are presented. Hollow out-of-plane microneedles are manufactured through deep reactive-ion etching (DRIE) technology. The patented three-step process flow has been developed to produce multiple arrays of sharp bevelled tipped, hollow microneedles which facilitate easy insertion and controlled fluid injection into excised skin samples. The in-plane microneedles have been fabricated from simultaneous wet KOH etching of the front and reverse of (100) orientated silicon wafers. The characteristic 54.7˚ sidewall etch angle was utilised to form a sharp six-sided microneedle tip and hexagonal shaped shaft. Employing this method allowed fabrication of both solid and hollow microneedles with different geometries i.e., widths and heights of several µm, to determine the optimal MN height and width for effective penetration and transdermal drug delivery. All microneedles fabricated during the PhD studentship tenure have been characterised through histology, fluorescent studies, and delivery into ex-vivo porcine and human skin tissue (research ethics committee reference 08/WSE03/55) to demonstrate effective microneedle based transdermal therapeutic drug delivery. The transdermal delivery of insulin and hyaluronic acid has been successfully demonstrated by employing a simple poke and patch application technique, presenting a clinical improvement over traditional application such as creams and ointments.