A comparison of flow- and pressure-controlled infusion strategies for microneedle-based transdermal drug delivery

Microneedle-based transdermal drug delivery is considered an attractive alternative to conventional injections using hypodermic needles due to its minimally invasive and painless nature; this has the potential to improve patient adherence to medication regimens. Hollow microneedles (MNs) are sharp, sub-millimeter protrusions with a channel that serves as a fluidic interface with the skin. This technology could be coupled with micro-pumps, embedded sensors, actuators and electronics to create Micro Transdermal Interface Platforms - smart, wearable infusion systems capable of delivering precise microdoses over a prolonged period. Using 500 µm tall hollow microneedles, ex-vivo human skin and a customized application/retraction device, this work focuses on comparing two infusion control strategies, namely ‘set pressure’ (SP) and ‘set flow’ (SF) infusion. It was found that flow-controlled infusion was capable of delivering higher volumes than pressure-driven delivery, and a mean volume of 3.8 mL was delivered using a set flowrate of 50 µL/minute. This suggests that flow driven delivery is a better control strategy and confirms that MN array retraction is beneficial for transdermal MN infusion

Towards micropump- and microneedle-based drug delivery using Micro Transdermal Interface Platforms (MicroTIPs)

Micro Transdermal Interface Platforms (MicroTIPs) will combine minimally invasive microneedle arrays with highly miniaturized sensors, actuators, control electronics, wireless communications and artificial intelligence. These patch-like devices will be capable of autonomous physiological monitoring and transdermal drug delivery, resulting in increased patient adherence and devolved healthcare. In this paper, we experimentally demonstrate the feasibility of controlled transdermal drug delivery using a combination of 500 μm tall silicon microneedles, a commercial micropump, pressure and flow sensors, and bespoke electronics. Using ex-vivo human skin samples and a customized application/retraction system, leak-free delivery of volumes ranging from 0.7-1.1 mL has been achieved in under one hour. Clinical Relevance — This work experimentally confirms the feasibility of combining micropumps with microneedle arrays for applications in transdermal drug delivery

Cell-cell signalling in capillary stabilisation : implications for therapeutic angiogenesis

Homotypic and heterotypic cell interactions are critical in the assembly and maturation of blood vessels. The aim of this study was to determine the role of Angiopoietin-1 in controlling interaction between endothelial cells and mural cells, and define the classes of molecules involved in mediating this interaction. The influence of heterotypic cell interaction on expression of activin receptor-like kinase 1 (ALK-1) was examined in order to gain insight into the mechanisms of mural cell control of endothelial phenotype. In addition, to begin to explore cell-cell interaction in vessel assembly in vivo attempts were made to establish a non-invasive model for inducing neovessel formation.;Angiopoietin-1 was found to stimulate adhesion between endothelial cells and smooth muscle cells by more than two-fold. This adhesion was calcium-dependent and inclusion RGD-peptides decreased adhesion by 70%, and decreased the effect of Angiopoietin-1 by 66%. Blockade of neural-cadherin (N-cadherin) with cyclic-HAV peptides decreased heterotypic adhesion between endothelial cells and mural cells by 30%. N-cad was found to localise strongly to junctions between smooth muscle cells and homotypic adhesion between these cells was inhibited by inclusion of N-cad-blocking peptides. Previous work suggested ALK-1 expression was modulated by endothelial cell-mural cell contact. No evidence was found for contact-induced changes in expression of ALK-1 under the conditions of this study. An in vivo model for augmenting microvessel number was established in patients with peripheral vascular disease by local application of subcontractile electrical stimulation.;These studies define a direct role for Angiopoietin-1 in control of heterotypic interaction between cells of the vessel wall and show involvement of both integrins and N-cadherin in this interaction. The non-invasive model for increasing neovessel density could be useful for examining capillary stabilisation in vivo in future studies

High-Frequency Electroporation and Chemotherapy for the Treatment of Cutaneous Malignancies: Evaluation of Early Clinical Response

High-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local anaesthesia. This proof-of-concept study investigated the efficacy and tolerability of HF-EP protocols on a variety of cutaneous malignancies. A total of 97 lesions of five different histological subtypes were treated across 25 patients. At 12 weeks post-treatment, a 91.3% overall lesion response rate was observed (complete response: 79%; partial response: 12.3%), with excellent intraprocedural patient tolerability under local anaesthetic. HF-EP with chemotherapy shows promising results regarding tumour response rates for cutaneous malignancies of varying histological subtypes when compared to traditional ECT protocols. Improved patient tolerability is important, increasing the possibility of treatment delivery under local anaesthesia and potentially broadening the treatment envelope for patients with cutaneous malignancies

Embedded sensors for Micro Transdermal Interface Platforms (MicroTIPs)

Wearable 'smart patches' of the future will incorporate microneedle technologies that painlessly interact with the body, using closed-loop theranostic systems to continuously monitor the physiological status of the body and deliver appropriate therapeutic agents when needed. Among other components, these Micro Transdermal Interface Platforms (MicroTIPs) will require embedded sensors to verify that the patch is operating as intende

Health-related quality of life trajectories in melanoma patients after electrochemotherapy: real-world insights from the InspECT register

Background: Electrochemotherapy (ECT) effectively controls skin metastases from cutaneous melanoma. Objectives: This study aimed to evaluate health-related quality of life (HRQoL) in melanoma patients pre-/post-ECT and its effect on treatment outcome. Methods: The analysis included prospective data from the International Network for Sharing Practices of ECT register. Following the Standard Operating Procedures, patients received intravenous or intratumoural bleomycin (15,000 IU/m2; 1000 IU mL/cm3) followed by 100-microsecond, 1000-V/cm electric pulses. Endpoints included response (RECIST v3.0), local progression-free survival (LPFS), toxicity (CTCAE v5.0), and patient-reported HRQoL at baseline, one, two, four and ten months (EuroQol [EQ-5D-3L], including 5-item utility score [EQ-5D] and visual analogue scale for self-reported health state [EQ-VAS]). Comparisons within/between subgroups were made for statistical and minimal important differences (MID). HRQoL scores and clinical covariates were analysed to identify predictors of response in multivariate analysis. Results: Median tumour size was 2 cm. Complete response rate, G3 toxicity and one-year LPFS in 378 patients (76% of the melanoma cohort) were 47%, 5%, and 78%. At baseline, age-paired HRQoL did not differ from the general European population. Following ECT, both EQ-5D and EQ-VAS scores remained within MID boundaries, particularly among complete responders. A subanalysis of the EQ-5D items revealed a statistically significant deterioration in pain/discomfort and mobility (restored within four months), and self-care and usual activities (throughout the follow-up) domains. Concomitant checkpoint inhibition correlated with better EQ-5D and EQ-VAS trajectories. Baseline EQ-5D was the exclusive independent predictor for complete response (RR 14.76, p=0.001). Conclusions: HRQoL of ECT melanoma patients parallels the general population and is preserved in complete responders. Transient deterioration in pain/discomfort and mobility and persistent decline in self-care and usual activities may warrant targeted support interventions. Combination with checkpoint inhibitors is associated with better QoL outcomes. Baseline HRQoL provides predictive information which can help identify patients most likely to respond

Recommendations for improving the quality of reporting clinical electrochemotherapy studies based on qualitative systematic review

Electrochemotherapy is becoming a well-established treatment for malignancies of skin and non-skin origin and its use is widening across Europe. The technique was developed and optimized from solid experimental and clinical evidence. A consensus document is now warranted to formalize reporting results, which should strengthen evidence-based practice recommendations. This consensus should be derived from high quality clinical data collection, clinical expertise and summarizing patient feedback. The first step, which is addressed in this paper, aims to critically analyze the quality of published studies and to provide the recommendations for reporting clinical trials on electrochemotherapy

Recommendations for improving the quality of reporting clinical electrochemotherapy studies based on qualitative systematic review

BACKGROUND: Electrochemotherapy is becoming a well-established treatment for malignancies of skin and non-skin origin and its use is widening across Europe. The technique was developed and optimized from solid experimental and clinical evidence. A consensus document is now warranted to formalize reporting results, which should strengthen evidence-based practice recommendations. This consensus should be derived from high quality clinical data collection, clinical expertise and summarizing patient feedback. The first step, which is addressed in this paper, aims to critically analyze the quality of published studies and to provide the recommendations for reporting clinical trials on electrochemotherapy. METHODS: The quality of reporting in published studies on electrochemotherapy was analyzed in order to produce procedure specific reporting recommendations. A comprehensive literature search of studies published from 2006 to 2015 was performed followed by qualitative analysis of manuscripts assessing for 47 quality criteria grouped into four major clusters: (1) trial design, (2) description of patient population, (3) description of treatment delivery and patient outcome, (4) analysis of results and their interpretation. The summary measure during literature assessment was the proportion of studies fulfilling each manuscript quality criteria. RESULTS: A total of 56 studies were screened, from the period 2006 to 2015, of which 33 were included in the qualitative analysis, with a total of 1215 patients. Overall, the quality of reporting was highly variable. Twenty-four reports (73%) were single-center, non-comparative studies, and only 15 (45%) were prospective in nature (only 2 of them were entered into a clinical trials registry). Electrochemotherapy technique was consistently reported, with most studies (31/33) adhering closely to published standard operating procedures. The quality of reporting the patient population was variable among the analyzed studies, with only between 45% and 100% achieving dedicated quality criteria. Reporting of treatment delivery and patient outcome was also highly variable with studies only fulfilling between 3% and 100%. Finally, reporting study results critically varied, fulfilling from 27% to 100% of the quality criteria. Based on the critical issues emerging from this analysis, recommendations and minimal requirements for reporting clinical data on electrochemotherapy were prepared and summarized into a checklist. CONCLUSIONS: There is an increasing body of published clinical data on electrochemotherapy, but more high quality clinical data are needed. Published papers often lack accurate description of study population, treatment delivery as well as patient outcome. Our recommendations, provided in the form of a summary checklist, are intended to ameliorate data reporting in future studies on electrochemotherapy and help researchers to provide a solid evidence basis for clinical practice