Karen Mooney

Microneedle-Mediated Minimally Invasive Patient Monitoring

Background: The emerging field of microneedle-based minimally invasive patient monitoring and diagnosis is reviewed. Microneedle arrays consist of rows of micron-scale projections attached to a solid support. They have been widely investigated for transdermal drug and vaccine delivery applications since the late 1990s. However, researchers and clinicians have recently realized the great potential of microneedles for extraction of skin interstitial fluid and, less commonly, blood, for enhanced monitoring of patient health. Methods: We reviewed the journal and patent literature, and summarized the findings and provided technical insights and critical analysis. Results: We describe the basic concepts in detail and extensively review the work performed to date. Conclusions: It is our view that microneedles will have an important role to play in clinical management of patients and will ultimately improve therapeutic outcomes for people worldwide.

Children's views on microneedle use as an alternative to blood sampling for patient monitoring

To explore childrens views on microneedle use for this population, particularly as an alternative approach to blood sampling, in monitoring applications, and so, examine the acceptability of this approach to children.

Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring.

We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.

Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87 μg/mL in rats at 24 h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.

Hydrogel-Forming Microneedles Increase in Volume During Swelling in Skin, but Skin Barrier Function Recovery is Unaffected

We describe, for the first time, quantification of in-skin swelling and fluid uptake by hydrogel-forming microneedle (MN) arrays and skin barrier recovery in human volunteers. Such MN arrays, prepared from aqueous blends of hydrolyzed poly(methylvinylether/maleic anhydride) (15%, w/w) and the cross-linker poly(ethyleneglycol) 10,000 Da (7.5%, w/w), were inserted into the skin of human volunteers (n = 15) to depths of approximately 300 μm by gentle hand pressure. The MN arrays swelled in skin, taking up skin interstitial fluid, such that their mass had increased by approximately 30% after 6 h in skin. Importantly, however, skin barrier function recovered within 24 h after MN removal, regardless of how long the MN had been in skin or how much their volume had increased with swelling. Further research on closure of MN-induced micropores is required because transepidermal water loss measurements suggested micropore closure, whereas optical coherence tomography indicated that MN-induced micropores had not closed over, even 24 h after MN had been removed. There were no complaints of skin reactions, adverse events, or strong views against MN use by any of the volunteers. Only some minor erythema was noted after patch removal, although this always resolved within 48 h, and no adverse events were present on follow-up.

Initial studies on the occurrence of cyanobacteria and microcystins in Irish lakes.

We report the results of a synoptic survey at 14 sites across the north of Ireland undertaken to determine the occurrence of cyanobacteria and their constituent microcystin cyanotoxins. Seven microcystin toxins were tested for, and five of which were found, with MC‐LR, MC‐RR, and MC‐YR being the most prevalent. Gomphosphaeria spp and Microcystis aeruginosa were the most dominant cyanobacterial species encountered. Together with Aphanizomenon flos‐aquae, these were the cyanobacteria associated with the highest microcystin concentrations. The occurrence of several microcystin toxins indicates that there may potentially be more than one cyanobacteria species producing microcystins at many sites. Total microcystin concentrations varied over three orders of magnitude dividing the sites into two groups of high (>1000 ngMC/μgChla, six sites) or low toxicity (<200 ngMC/μgChla, eight sites).

Fabrication of Microneedles

Delivery of active pharmaceutical ingredients through transdermal route has been limited due to the excellent barrier properties of the stratum corneum (SC) of the skin. Only drugs with very specific physicochemical properties (molecular weight < 500 daltons, adequate lipophilicity and low melting point) can be successfully administered transdermally. Disrupting the barrier properties of the SC is one of the techniques utilised in enhancing transdermal drug delivery. With this intention, microneedle/s (MN/MNs) have been developed that can painlessly penetrate the SC and create micropores through which drug molecules can readily permeate to the dermal microcirculation for absorption. MNs consist of a plurality of micron-sized needles, generally ranging from 25 to 2000 μm in height, of a variety of different shapes and composition (e.g. silicon, metal, sugars and biodegradable polymers). Even though the concept of MNs was first conceived in 1976, it was not possible to make such micron-sized medical devices until the first exploitation of microelectromechanical systems (MEMS) for this purpose in 1998. MEMS utilise a variety of techniques and highly sophisticated tools to allow fabrication of MNs from different materials with varying designs. Now, due to the MEMS, MNs are considered as one of the few third-generation enhancement strategies that will have a significant impact on medicine. Therefore, this chapter will focus on recent progress on MN technology that includes discussion on the fabrication techniques of MNs using MEMS, the design and material consideration of MNs and the application of MNs in drug delivery and monitoring biological fluids.

Hierarchical structuring of genetic variation at differing geographic scales in the cultivated sugar kelp Saccharina latissima

The cultivation of macroalgae for biofuels, food and fertilisers has increased dramatically in recent years. The demand for such algal-derived products means that large scale cultivation in coastal waters will become necessary to provide sufficient algal biomass. As part of the process of establishing new macroalgal farms, the potential for gene flow between cultivated specimens and natural populations needs to be taken into consideration. Consequently, in the present study we have used a combined population genetic and hydrodynamic modelling approach to determine potential levels and patterns of gene flow in the kelp Saccharina latissima. Microsatellite analysis of 14 populations sampled across the northern part of the Irish Sea indicated four distinct genetic clusters. These were consistent with dispersal patterns indicated by the particle tracking model and show a combination of isolation by distance and genetic structuring due to local hydrodynamic conditions. At smaller scales (less than a few 10s of km), gene flow appears to be fairly extensive, with evidence of local population connectivity due to local currents. At larger scales, however, factors such as freshwater efflux and open water would appear to represent barriers to gene flow. Together, these patterns suggest that factors other than simple geographical distance and proximity need to be taken into account when planning the siting of kelp farms with the aim of minimizing gene flow to and from natural populations.

ePS03.5 Adherence monitoring in cystic fibrosis centres: Current practice and pharmacists’ perspectives

Objectives Cystic Fibrosis (CF) management requires complex treatment regimens but adherence to treatment is poor. Various methods exist to measure adherence, but little is known about the extent of their use in CF centres. The aims of this work were to determine adherence monitoring practices in CF centres and to establish CF pharmacists’ views on these. Methods A questionnaire was designed, piloted and subsequently reviewed to survey pharmacists’ from the UK and Ireland Cystic Fibrosis Pharmacists’ Groups at their annual meeting (2014). The questionnaire explored (i) inhaled antibiotic supply to CF patients, (ii) adherence monitoring within CF centres, and (iii) demographics. Closed question responses were analysed using descriptive statistics. Open questions were analysed using thematic analysis. Results Twenty-one respondents were included in the analysis (Response rate: 84%). Adherence was most commonly described to be measured at ‘every clinic visit’ (29%) and ‘occasionally’ (29%). Patient self-reported adherence was the most commonly used method of measuring adherence in practice (90%). The availability of electronic monitoring did not guarantee its use. Seventy-six percent of pharmacists deemed current adherence monitoring as inadequate and linked this to the absence of appropriate pharmacist involvement in CF. Many suggested that greater specialist pharmacist involvement could facilitate better adherence monitoring and improve care. Conclusion Current adherence knowledge is largely based on self-report. Further work is required to improve the recording of adherence and the impact of an adherence advocate, on that adherence.