Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or ...provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600® (MicronJet hereafter) device was used to deliver reporter plasmids (pCMVβ and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50μL bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMVβ reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery.
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Summary
Background
Translation of cell therapies to the clinic is accompanied by numerous challenges, including controlled and targeted delivery of the cells to their site of action, without ...compromising cell viability and functionality.
Objectives
To explore the use of hollow microneedle devices (to date only used for the delivery of drugs and vaccines into the skin and for the extraction of biological fluids) to deliver cells into skin in a minimally invasive, user‐friendly and targeted fashion.
Methods
Melanocyte, keratinocyte and mixed epidermal cell suspensions were passed through various types of microneedles and subsequently delivered into the skin.
Results
Cell viability and functionality are maintained after injection through hollow microneedles with a bore size ≥ 75 μm. Healthy cells are delivered into the skin at clinically relevant depths.
Conclusions
Hollow microneedles provide an innovative and minimally invasive method for delivering functional cells into the skin. Microneedle cell delivery represents a potential new treatment option for cell therapy approaches including skin repigmentation, wound repair, scar and burn remodelling, immune therapies and cancer vaccines.
What's already known about this topic?
Cutaneous cell therapy is currently perceived as a promising new way of treating skin damage, depigmentation and genetic disorders, and has many possible cosmetic applications.
What does this study add?
In this study we explore, for the first time, the potential of microneedle delivery systems as a novel, minimally invasive delivery tool for facilitating cell therapy in skin.
What is the translational message?
A microneedle delivery platform would offer a less invasive, more controlled and targeted system for the delivery of cell therapy to skin and is thus likely to be welcomed by patients, clinicians and regulatory bodies.
Linked Comment: Boniface et al. Br J Dermatol 2018; 178:588–589
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Botulinum toxin A (BT) is used therapeutically for the treatment of primary focal hyperhidrosis, a chronic debilitating condition characterised by over-activity of the eccrine sweat glands. Systemic ...toxicity concerns require BT to be administered by local injection, which in the case of hyperhidrosis means multiple painful intradermal injections by a skilled clinician at 6-monthly intervals. This study investigates the potential of a liquid-loaded pocketed microneedle device to deliver botulinum toxin A into the human dermis with the aim of reducing patient pain, improving therapeutic targeting and simplifying the administration procedure. Initially, β-galactosidase was employed as a detectable model for BT to (i) visualise liquid loading of the microneedles, (ii) determine residence time of a liquid formulation on the device and (iii) quantify loaded doses. An array of five stainless steel pocketed microneedles was shown to possess sufficient capacity to deliver therapeutic doses of the potent BT protein. Microneedle-mediated intradermal delivery of β-galactosidase and formaldehyde-inactivated botulinum toxoid revealed effective deposition and subsequent diffusion within the dermis. This study is the first to characterise pocketed microneedle delivery of a liquid formulation into human skin and illustrates the potential of such systems for the cutaneous administration of potent proteins such as BT. A clinically appropriate microneedle delivery system for BT could have a significant impact in both the medical and cosmetic industries.
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The stratum corneum (SC) represents a significant barrier to the delivery of gene therapy formulations. In order to realise the potential of therapeutic cutaneous gene transfer, delivery strategies ...are required to overcome this exclusion effect. This study investigates the ability of microfabricated silicon microneedle arrays to create micron-sized channels through the SC of ex vivo human skin and the resulting ability of the conduits to facilitate localised delivery of charged macromolecules and plasmid DNA (pDNA). Microscopic studies of microneedle-treated human epidermal membrane revealed the presence of microconduits (10-20 microm diameter). The delivery of a macromolecule, beta-galactosidase, and of a 'non-viral gene vector mimicking' charged fluorescent nanoparticle to the viable epidermis of microneedle-treated tissue was demonstrated using light and fluorescent microscopy. Track etched permeation profiles, generated using 'Franz-type' diffusion cell methodology and a model synthetic membrane showed that >50% of a colloidal particle suspension permeated through membrane pores in approximately 2 hours. On the basis of these results, it is probable that microneedle treatment of the skin surface would facilitate the cutaneous delivery of lipid:polycation:pDNA (LPD) gene vectors, and other related vectors, to the viable epidermis. Preliminary gene expression studies confirmed that naked pDNA can be expressed in excised human skin following microneedle disruption of the SC barrier. The presence of a limited number of microchannels, positive for gene expression, indicates that further studies to optimise the microneedle device morphology, its method of application and the pDNA formulation are warranted to facilitate more reproducible cutaneous gene delivery.
The current literature on undergraduate interprofessional education (IPE) for pharmacy and medical students highlights a range of positive outcomes, although to date IPE has focused predominantly on ...student views and experiences of IPE sessions with these opinions being sought at the end of the sessions. This study aimed to evaluate medical students' experiences of therapeutics and prescribing IPE, with pharmacy students, 1 year following the session.
Following ethics committee approval, 3rd year medical students at Cardiff University were invited to participate using non-probability sampling. Topic guide development was informed by the literature and research team discussions, including a review of the materials used in the IPE session. Semi-structured one-to-one interviews explored experiences, prior to, during, and after the IPE session. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically.
Eighteen medical students were interviewed; 11 were females. Seven themes were identified, namely 1) refinement of pre-session preparation, 2) session value, 3) learning with a pharmacy student, 4) learning about a pharmacist, 5) learning from a pharmacy student, 6) importance and application of what was learnt into practice, and 7) suggestions for change.
This study provides a valuable insight into medical students' experiences of a therapeutics and prescribing IPE session and emphasizes the value they placed on interaction with pharmacy students. Medical students were able to recall clear learning experiences from the IPE session that had taken place 12 months earlier, which itself is an indicator of the impact of the session on the students. Furthermore, they were able to describe how knowledge and skills learnt had been applied to subsequent learning activities. Those developing IPE sessions should consider the following: clarify professional roles in the session content, incorporate IPE as a series of activities, and use small groups of students to optimize student-student interaction and active learning.
Achievement goal theory helps us understand what motivates students to participate in educational activities. However, measuring achievement goals in a precise manner is problematic. Elliot and ...McGregor's Achievement Goal Questionnaire (AGQ) and Elliot and Murayama's revised Achievement Goal Questionnaire (AGQ-R) are widely used to assess students' achievement goals. Both instruments were developed and validated using undergraduate psychology students in the USA.
In this study, our aims were to first of all, assess the construct validity of both questionnaires using a cohort of Australian pharmacy students and, subsequently, to test the generalizability and replicability of these tools more widely in schools of pharmacy in other English-speaking countries. The AGQ and the AGQ-R were administered during tutorial class time. Confirmatory factor analysis procedures, using AMOS 19 software, were performed to determine model fit.
In contrast to the scale developers' findings, confirmatory factor analysis supported a superior model fit for the AGQ compared with the AGQ-R, in all countries under study.
Validating measures of achievement goal motivation for use in pharmacy education is necessary and has implications for future research. Based on these results, the AGQ will be used to conduct future cross-sectional and longitudinal analyses of the achievement goals of undergraduate pharmacy students from these countries.
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