Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

STPA-SafeSec: Safety and Security Analysis for Cyber-Physical Systems

Cyber-physical systems tightly integrate physical processes and information and communication technologies. As today’s critical infrastructures, e.g., the power grid or water distribution networks, are complex cyber-physical systems, ensuring their safety and security becomes of paramount importance. Traditional safety analysis methods, such as HAZOP, are ill-suited to assess these systems. Furthermore, cybersecurity vulnerabilities are often not considered critical, because their effects on the physical processes are not fully understood. In this work, we present STPA-SafeSec, a novel analysis methodology for both safety and security. Its results show the dependencies between cybersecurity vulnerabilities and system safety. Using this information, the most effective mitigation strategies to ensure safety and security of the system can be readily identified. We apply STPA-SafeSec to a use case in the power grid domain, and highlight its benefits.

Evaluating Train Protection Systems

This paper arose from the work carried out for the Cullen/Uff Joint Inquiry into Train Protection Systems. It is concerned with the problem of evaluating the benefits of safety enhancements in order to avoid rare, but catastrophic accidents, and the role of Operations Research in the process. The problems include both input values and representation of outcomes. A key input is the value of life. This paper briefly discusses why the value of life might vary from incident to incident and reviews alternative estimates before producing a 'best estimate' for rail. When the occurrence of an event is uncertain, the normal method is to apply a single 'expected' value. This paper argues that a more effective method of representing such situations is through Monte-Carlo simulation and demonstrates the use of the methodology on a case study of the decision as to whether or not advanced train protection (ATP) should have been installed on a route to the west of London. This paper suggests that the output is more informative than traditional cost-benefit appraisals or engineering event tree approaches. It also shows that, unlike the results from utilizing the traditional approach, the value of ATP on this route would be positive over 50% of the time.

Better together: Interprofessional Education in Medication Safety

Background: The importance of actively working with other professionals, as part of a single team, is well embedded in discussions relating to effective healthcare. The need for effective teamwork specifically in relation to patient safety is also widely acknowledged; however healthcare has traditionally been poor at building teams and professional groups tend to function semi-autonomously and autocratically.1
Objective: This study aims to gain the views and experiences of students from nursing, pharmacy and medicine involved in an interprofessional workshop in medication safety.
Setting and methods: Interprofessional workshops involving students from nursing, pharmacy and medicine were delivered using case studies involving medication incidents. Focus groups were used to investigate participant’s views and experiences of the workshop.
Results: Focus groups were completed with 22 students. Five main themes were identified from the focus group data relating to medication safety; these were increasing confidence, insight into roles, improving skills, culture of responsibility and application to future practice.
Conclusions: This study represents a model for delivery of training that has demonstrated improvement in the students’ attitudes towards team working and is a first step towards introducing team working into the medication safety program. The programme continues to run using live and virtual workshops.

1. Leape LL. A systems analysis approach to medical error. J Clin Eval Clin Pract. 1997. 3, 3, 213-222.

Development of a Bridge Weigh-in-Motion Sensor: Performance comparison using fibre optic and electric resistance strain sensor systems

This paper addresses the problems of effective in situ measurement of the real-time strain for bridge weigh in motion in reinforced concrete bridge structures through the use of optical fiber sensor systems. By undertaking a series of tests, coupled with dynamic loading, the performance of fiber Bragg grating-based sensor systems with various amplification techniques were investigated. In recent years, structural health monitoring (SHM) systems have been developed to monitor bridge deterioration, to assess load levels and hence extend bridge life and safety. Conventional SHM systems, based on measuring strain, can be used to improve knowledge of the bridge's capacity to resist loads but generally give no information on the causes of any increase in stresses. Therefore, it is necessary to find accurate sensors capable of capturing peak strains under dynamic load and suitable methods for attaching these strain sensors to existing and new bridge structures. Additionally, it is important to ensure accurate strain transfer between concrete and steel, adhesives layer, and strain sensor. The results show the benefits in the use of optical fiber networks under these circumstances and their ability to deliver data when conventional sensors cannot capture accurate strains and/or peak strains.

Patient safety and beyond: what should we expect from microneedle arrays in the transdermal delivery arena?

Research based upon microneedle (MN) arrays has intensified recently. While the initial focus was on biomolecules, the field has expanded to include delivery of conventional small-molecule drugs whose water solubility currently precludes transdermal administration. Much success has been achieved, with peptides, proteins, vaccines, antibodies and even particulates delivered by MN in therapeutic/prophylactic doses. Recent innovations have focused on enhanced formulation design, scalable manufacture and extension of exploitation to minimally invasive patient monitoring, ocular delivery and enhanced administration of cosmeceuticals. Only two MN-based drug/vaccine delivery products are currently marketed, partially due to limitations with older MN designs based upon silicon and metal. Even the more promising polymeric MN have raised a number of regulatory and manufacturability queries that the field must address. MN arrays have tremendous potential to yield real benefits for patients and industry and, through diligence, innovation and collaboration, this will begin to be realised over the next 3-5 years.

Novel Delivery Systems for Transdermal and Intradermal Drug Delivery

This research book covers the major aspects relating to the use of novel delivery systems in enhancing both transdermal and intradermal drug delivery. It provides a review of transdermal and intradermal drug delivery, including the history of the field and the various methods employed to produce delivery systems from different materials such as device design, construction and evaluation, so as to provide a sound background to the use of novel systems in enhanced delivery applications.

Furthermore, it presents in-depth analyses of recent developments in this exponentially growing field, with a focus on microneedle arrays, needle-free injections, nanoparticulate systems and peptide-carrier-type systems. It also covers conventional physical enhancement strategies, such as tape-stripping, sonophoresis, iontophoresis, electroporation and thermal/suction/laser ablation Discussions about the penetration of the stratum corneum by the various novel strategies highlight the importance of the application method. Comprehensive and critical reviews of transdermal and intradermal delivery research using such systems focus on the outcomes of in vivoanimal and human studies. The book includes laboratory, clinical and commercial case studies featuring safety and patient acceptability studies carried out to date, and depicts a growing area for use of these novel systems is in intradermal vaccine delivery. The final chapters review recent patents in this field and describe the work ongoing in industry.

Realist synthesis: Critical care rapid response systems.

Background Rapid Response Systems (RRS) consist of four interrelated and interdependent components; an event detection and trigger mechanism, a response strategy, a governance structure and process improvement system. These multiple components of the RRS pose problems in evaluation as the intervention is complex and cannot be evaluated using a traditional systematic review. Complex interventions in healthcare aimed at changing service delivery and related behaviour of health professionals require a different approach to summarising the evidence. Realist synthesis is such an approach to reviewing research evidence on complex interventions to provide an explanatory analysis of how and why an intervention works or doesn’t work in practice. The core principle is to make explicit the underlying assumptions about how an intervention is suppose to work (ie programme theory) and then use this theory to guide evaluation. Methods A realist synthesis process was used to explain those factors that enable or constrain the success of RRS programmes. Results The findings from the review include the articulation of the RRS programme theories, evaluation of whether these theories are supported or refuted by the research evidence and an evaluation of evidence to explain the underlying reasons why RRS works or doesn’t work in practice. Rival conjectured RRS programme theories were identified to explain the constraining factors regarding implementation of RRS in practice. These programme theories are presented using a logic model to highlight all the components which impact or influence the delivery of RRS programmes in the practice setting. The evidence from the realist synthesis provided the foundation for the development of hypothesis to test and refine the theories in the subsequent stages of the Realist Evaluation PhD study [1]. This information will be useful in providing evidence and direction for strategic and service planning of acute care to improve patient safety in hospital. References: McGaughey J, Blackwood B, O’Halloran P, Trinder T. J. & Porter S. (2010) Realistic Evaluation of Early Warning Systems and the Acute Life-threatening Events – Recognition and Treatment training course for early recognition and management of deteriorating ward-based patients: research protocol. Journal of Advanced Nursing 66 (4), 923-932.

Early warning systems: problems, pragmatics and potential

Symposium Chair: Dr Jennifer McGaughey

Title: Early Warning Systems: problems, pragmatics and potential

Early Warning Systems (EWS) provide a mechanism for staff to recognise, refer and manage deteriorating patients on general hospital wards. Implementation of EWS in practice has required considerable change in the delivery of critical care across hospitals. Drawing their experience of these changes the authors will demonstrate the problems and potential of using EWS to improve patient outcomes.

The first paper (Dr Jennifer McGaughey: Early Warning Systems: what works?) reviews the research evidence regarding the factors that support or constrain the implementation of Early Warning System (EWS) in practice. These findings explain those processes which impact on the successful achievement of patient outcomes. In order to improve detection and standardise practice National EWS have been implemented in the United Kingdom. The second paper (Catherine Plowright: The implementation of the National EWS in a District General Hospital) focuses on the process of implementing and auditing a National EWS. This process improvement is essential to contribute to future collaborative research and collection of robust datasets to improve patient safety as recommended by the Royal College of Physicians (RCP 2012). To successfully implement NEWS in practice requires strategic planning and staff education. The practical issues of training staff is discussed in the third paper. This paper (Collette Laws-Chapman: Simulation as a modality to embed the use of Early Warning Systems) focuses on using simulation and structured debrief to enhance learning in the early recognition and management of deteriorating patients. This session emphasises the importance of cognitive and social skills developed alongside practical skills in the simulated setting.

A Novel Approach for Axle Detection in Bridge Weigh-In-Motion Systems

Bridge weigh-in-motion (B-WIM), a system that uses strain sensors to calculate the weights of trucks passing on bridges overhead, requires accurate axle location and speed information for effective performance. The success of a B-WIM system is dependent upon the accuracy of the axle detection method. It is widely recognised that any form of axle detector on the road surface is not ideal for B-WIM applications as it can cause disruption to the traffic (Ojio & Yamada 2002; Zhao et al. 2005; Chatterjee et al. 2006). Sensors under the bridge, that is Nothing-on-Road (NOR) B-WIM, can perform axle detection via data acquisition systems which can detect a peak in strain as the axle passes. The method is often successful, although not all bridges are suitable for NOR B-WIM due to limitations of the system. Significant research has been carried out to further develop the method and the NOR algorithms, but beam-and-slab bridges with deep beams still present a challenge. With these bridges, the slabs are used for axle detection, but peaks in the slab strains are sensitive to the transverse position of wheels on the beam. This next generation B-WIM research project extends the current B-WIM algorithm to the problem of axle detection and safety, thus overcoming the existing limitations in current state-of–the-art technology. Finite Element Analysis was used to determine the critical locations for axle detecting sensors and the findings were then tested in the field. In this paper, alternative strategies for axle detection were determined using Finite Element analysis and the findings were then tested in the field. The site selected for testing was in Loughbrickland, Northern Ireland, along the A1 corridor connecting the two cities of Belfast and Dublin. The structure is on a central route through the island of Ireland and has a high traffic volume which made it an optimum location for the study. Another huge benefit of the chosen location was its close proximity to a nearby self-operated weigh station. To determine the accuracy of the proposed B-WIM system and develop a knowledge base of the traffic load on the structure, a pavement WIM system was also installed on the northbound lane on the approach to the structure. The bridge structure selected for this B-WIM research comprised of 27 pre-cast prestressed concrete Y4-beams, and a cast in-situ concrete deck. The structure, a newly constructed integral bridge, spans 19 m and has an angle of skew of 22.7°.

Field Testing and Development of Novel SHM systems at Queen’s University Belfast

Ageing and deterioration of infrastructure is a challenge facing transport authorities. In
particular, there is a need for increased bridge monitoring in order to provide adequate
maintenance and to guarantee acceptable levels of transport safety. The Intelligent
Infrastructure group at Queens University Belfast (QUB) are working on a number of aspects
of infrastructure monitoring and this paper presents summarised results from three distinct
monitoring projects carried out by this group. Firstly the findings from a project on next
generation Bridge Weight in Motion (B-WIM) are reported, this includes full scale field testing
using fibre optic strain sensors. Secondly, results from early phase testing of a computer
vision system for bridge deflection monitoring are reported on. This research seeks to exploit
recent advances in image processing technology with a view to developing contactless
bridge monitoring approaches. Considering the logistical difficulty of installing sensors on a
‘live’ bridge, contactless monitoring has some inherent advantages over conventional
contact based sensing systems. Finally the last section of the paper presents some recent
findings on drive by bridge monitoring. In practice a drive-by monitoring system will likely
require GPS to allow the response of a given bridge to be identified; this study looks at the
feasibility of using low-cost GPS sensors for this purpose, via field trials. The three topics
outlined above cover a spectrum of SHM approaches namely, wired monitoring, contactless
monitoring and drive by monitoring