Piezoelectric inkjet coating of injection moulded, reservoir-tipped microneedle arrays for transdermal delivery

Coated microneedles have significant potential for use in transdermal delivery applications. In this paper, we describe the fabrication of microneedle master templates using microstereolithography techniques and subsequently use a commercial injection moulding process to replicate these microneedles in biocompatible cyclic olefin polymer (COP) materials. Notably, the 475 μm-tall needle designs feature a shallow pit or reservoir at the tip, thereby providing both a target and holder for incoming droplets that are deposited using a piezoelectric inkjet printer. Using this design, no tilting or rotation of the needle array is required during the filling process. In the preliminary tests reported here, the reservoir is filled with a FITC-labelled dye that acts as a model drug, and ex vivo skin tests are used to verify skin penetration, the transfer of this model drug to the skin and to measure the reliability of the needles themselves. To our knowledge, this is the first time that such an inkjet-filled, reservoir-tipped microneedle has been demonstrated

Micro-injection moulded microneedles for drug delivery.

The emergence of microneedle (MN) technologies offers a route for a pain free, straightforward and efficient way of transdermal drug delivery, but technological barriers still exist which pose significant challenges for manufacture of MN systems with high volume outputs at low cost. The main aim of this research was to develop new ways for MN manufacture primarily using micro-injection moulding processes with high performance engineering thermoplastics. During the moulding process these polymeric melts will be subjected to extreme stress and temperature gradients and detailed material characterisation combined with in-line monitoring is desirable to optimise the moulding parameters and will help in achieving sharp microneedles with acceptable quality. Hence high shear rheology of these selected materials was performed at wall shear rates carried out in excess of 107 s-1 over a range of temperatures to predict the flow behaviour of polymer melts at such high shear strain rates. This information was fed into injection moulding simulation software tools (Moldflow) to assist the MN production process design. The optimal design was then used to produce a full 3D solid model of the injection mould and mould insert. Furthermore various design of experiments were conducted considering input parameters such as injection pressure, injection speed, melt temperature, filling time and mould cavity temperature. Response variables including product quality and data acquired from the cavity pressure and temperature transducers were used to optimise the manufacturing process. The moulded MNs were geometrically assessed using a range of characterisation techniques such as atomic force microscopy, confocal microscopy and scanning electron microscopy. An attempt to make hollow MNs was performed and encountered many challenges like partial cavity filling and part ejection during processing. Studies were carried out to understand the problem and identified the major problem was in tool design and improvements to the moulding tool design were recommended. Plasma treatment and mechanical abrasion were employed to increase the surface energy of the moulded polymer surfaces with the aim of enhancing protein adsorption. Sample surface structures before and after treatment were studied using AFM and surface energies have been obtained using contact angle measurement and calculated using Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness resulting in better adsorption and release of BSA. To assist design-optimisation and to assess performance, a greater understanding of MN penetration behaviour is required. Contact stiffness, failure strength and creep behaviour were measured during compression tests of MN against a steel surface, and in-vitro penetration of MNs into porcine skin. The MN penetration process into porcine skin was imaged using optical coherence tomography. Finally, a finite element model of skin was established to understand the effect of tip geometry on penetration. The output of findings from this research will provide proof of concept level development and understanding of mechanisms of MN penetration and failure, facilitating design improvements for micro-injection moulded polymeric MNs

Process Fingerprinting of Microneedle Manufacturing Using Conventional and Ultrasonic Micro-injection Moulding

This research work investigates the development and application of process fingerprinting for conventional micro-injection moulding and ultrasonic micro injection moulding manufacturing of microneedle arrays for drug delivery. The process fingerprinting method covers in-depth analysis, interrogation and selection of certain process data features and correlation of these features with product fingerprints which are defined by the geometrical outcomes of the microneedle arrays in micro scale. The method was developed using the data collected using extensive sensor technologies attached to the conventional and ultrasonic micromoulding machines. Moreover, a machine vision based microneedle product evaluation apparatus is presented. Micromachining capabilities of different processes is also assessed and presented where state-of-the-art laser machining was used for microneedle tool manufacturing in the work. By using process fingerprinting procedures, conventional and ultrasonic micromoulding processes has been characterised thoroughly and aspects of the process that is affecting the part quality was also addressed for microneedle manufacturing. It was found that polymer structure is of paramount importance in obtaining sufficient microneedle replication. An amorphous polymer have been found to be more suitable for conventional moulding whereas semi-crystalline materials performed better in ultrasonic micromoulding. In-line captured micromoulding process data for conventional and ultrasonic moulding provided detailed insight of machine dynamics and understanding. Linear correlations between process fingerprints and micro replication efficiency of the microneedles have been presented for both micromoulding technologies. The in-line process monitoring and product quality evaluation procedures presented in this work for micro-injection moulding techniques will pave ways for zero-defect micromanufacturing of miniature products towards Industry 4.0

Extracellular ph monitoring for use in closed-loop vagus nerve stimulation

Objective. Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices

Extracellular pH monitoring for use in closed-loop vagus nerve stimulation

Objective: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices

Development of on-farm diagnostic devices

The global population, currently 7.7 billion, is expected to grow to 9.7 billion by 2050. This is expected to lead to a 70% increase in demand for animal-based protein. Irish beef and dairy products account for over 50% of our agricultural output and DAFM’s Food Wise 2025 strategy aims to position Ireland as a world leader in sustainable agri-food production. However, the high percentage of livestock that are lost due to infectious diseases (20%), poses a challenge to achieving this sustainability, in addition to more sustainable use of antimicrobials, smarter livestock diagnostics and treatments are therefore required. The goal of this thesis was to develop a low-cost disposable biosensor that would permit point-of-care (POC) detection of diseases in bovines, through cost-effective, scalable microfabrication techniques. Such devices could enable real-time determination of the health status of animals on farm and contribute to more informed therapeutic interventions. Electrochemistry presents a viable option for POC devices in this regard and allows easy integration with portable electronics. Electrochemical Impedance Spectroscopy (EIS) is a surface sensitive technique that measures the resistive and capacitive behaviour of an electrochemical system. It lends itself to serological immunosensor development as it allows label-free detection. For the purposes of this research, silicon devices were fabricated with six microband working electrodes, gold counter, and platinum pseudo-reference electrodes. The microband working electrodes were modified with a biocompatible co-polymer. This co-polymer supported the cross-linking of a bioreceptor (e.g., anti-bovine IgG) to electrode surface, which selectively bound to the target biomolecule (bovine IgG) in serum. This EIS device could distinguish between seronegative and seropositive samples in 15 minutes making it suitable for POC applications. Additionally, the presence of six working electrodes allowed for testing of multiple samples at a time. Often, however, only a single test is required. As such, silicon presents an expensive option for disposable sensors. Hence, polymer replication methods were also investigated in this thesis. This process allowed a single silicon wafer to be repeatedly used to produce polymer structures. A microneedle format was chosen to eliminate the need for taking samples on-farm and provide a pain-free method of in vivo measurements in interstitial fluid in interstitial fluid. The fabrication method used a double-sided micro-moulding process to move towards mass manufacturing. COMSOL simulations were performed to explore the active layer on the microneedle tip surface, ensuring no diffusional overlap between electrodes and providing the most effective tip design. The microneedle structures also presented the opportunity for novel fabrication of nanoring arrays, by removing part of the protruding structure and exposing underlying nanorings. These have the potential to be highly sensitive electrochemical devices due to enhanced mass transport and high current densities, while maintaining the scalable cost-effective fabrication process of the microneedles. Devices produced steady-state CVs in a known redox molecule, with currents in the nA range

Minimally invasive clinical monitoring and data transference in cardiac patients

'Wet' electrodes used in electrocardiography (ECG), are applied to the surface of the skin to record cardiac activity. Over time, water-based electrolytic gels between the electrodes and skin dehydrate, reducing signal quality. Microneedle-electrodes negate the need for conductive gels and potentially improve signal fidelity by circumventing the stratum corneum and contacting the underlying conductive epidermal layers. This thesis aimed to assess the wearability and functionality of microneedle-electrodes in cardiac signal acquisition. Epoxy, 500μm-length microneedles were applied to excised skin models to assess insertion performance. Increasing downward application force increased microneedle penetration efficiency from 79%±8.20 (5N) to 87%±13.32 (15N). The microneedle application technique also had an impact on penetration efficiency, with impact insertion (93%±5.75) proving more effective than manual downward force (71%±22.01). Metallised versions of the epoxy microneedles were integrated into a commercial electrode and compared to conventional wet electrodes in human volunteers. Wet electrodes recorded higher quality signals than microneedle-electrodes in healthy human participants (1.6dB difference between the electrode types). This clinical data informed the development of an in vitro laboratory skin model to assess the influence of microneedle-electrode parameters on a simulated ECG signal. Increasing microneedle length from 500μm (25.2dB±3.25) to 600μm (24.3dB±2.31) did not result in a sustained improvement in signal quality (p>0.05). Bespoke second-generation microneedle-electrodes were manufactured allowing an improved signal quality to be maintained over the recording period (17.3dB±2.11 compared to 15.0dB±1.97 for wet electrodes; p>0.05) in the laboratory model. Human participant studies assessed their wearability and functionality. At rest, the metallised epoxy (23.2dB±5.79) and bespoke (22.5dB±7.57) microneedle-electrode performance was comparable to wet electrodes (24.9dB±6.44) (p>0.05). Under active conditions, the signal-to-noise ratio declined for all electrodes and ECG traces highlighted increased motion artifacts. Participants preferred wet electrodes and highlighted seven key wearability themes. Further optimisation of microneedle-electrodes for ECG monitoring is therefore, warranted