PIDIC

Ondertitel:Platform for Intradermal Injections in Children: medisch-technisch onderzoek naar intradermale injectie bij kinderen en adolescenten

This doctoral thesis aimed to investigate anatomical and physiological characteristics of the skin in children and adolescents to develop an intradermal injection device for this population. To meet regulatory requirements, the different clinical investigations were first performed in adults and subsequently in children. To allow determining the maximum penetration depth and needle characteristics in adults and children, the skin thickness at the proximal ventral and dorsal forearm, deltoid and the lateral part of the upper leg (only in 8 weeks to 2 year-olds) was assessed and compared in an age and gender stratified sample using high-frequency ultrasound as highly accurate imaging. Both in adults and children, the overall mean skin thickness increased from the proximal ventral and dorsal forearm, the lateral part of the upper leg, to the deltoid region. A significant association between gender and adult skin thickness was shown in this thesis., whereas the skin thickness increases significantly with age in children and adolescents (8 weeks to 18 years) over the different body sites. An increase in BMI was associated with an increase in skin thickness at all investigated body sites for all ages, except for the lateral part of the upper leg. To guarantee accurate intradermal delivery, which includes no leakage to the hypodermal layer nor to the body surface, the stratification of the population to design different dimensions is not of interest, in case of emergencies, such as pandemics, where single solutions, meaning a device that is configured to be suited for the entire population independent of age, gender or other confounding factors, are preferred. Therefore, the smallest skin thickness found at the different investigated body sites drove the development of the accurate drug delivery system VAX-ID®. Based on the data in this doctoral thesis and according to the ease of use of the forearm (as done with the Mantoux technique), the proximal dorsal forearm is proposed as the designated injection site for an intradermal injection device in children and adults. A needle length of 1.0mm is the best option for adults and 0.7 mm is advised to guarantee intradermal injection in children (8 weeks to 18 years). It’s undeniable that a 1 size fits all is of more interest. Accordingly, an intradermal injection device having a maximum penetration depth of 0.65mm is advised to use in the entire population. VAX-ID®, designed by Novosanis, fits this purpose and has been designed, also based on this thesis, to allow for use with 27G, 32G or 33G needle. To evaluate device and needle characteristics, different verification studies have been performed. Firstly, skin thickness of different animal species was mapped using histology and high-frequency ultrasound, resulting in pigs, piglets and lamas as most suitable verification models for intradermal injections with VAX-ID®. Through various injection studies it was shown that VAX-ID® facilitates in a proper injection into dermal layer of the skin of the used animal models. Secondly, technical verification tests were performed to evaluate the dose sparing potentiality (e.g. reducing the per injection-cost, by minimizing the overfill and correct amount of injected fluid), the impact of injection forces and shear stress, and biological safety. The developed intradermal injection device, VAX-ID®, was validated on the following aspects: 1) functionality, 2) performance, 3) usability, and 4) clinical evaluation. An evaluation in healthy adults was performed twice. Firstly, an evaluation was performed on the acceptability and usability of the device. The new VAX-ID® device was shown to have a high degree of acceptability as well as usability. Secondly the device was evaluated on its efficacy (e.g. correct delivery of the fluid into the dermal layer by triggering an immunogenic reaction) and safety with a commercially available vaccine. VAX-ID® has been compared to the Mantoux technique and intramuscular injection in a booster vaccination study with recombinant hepatitis B vaccine. A dose of 10µg/1.0ml was injected intramuscularly, whereas a dose of 4µg/0.1ml was injected intradermally, meaning that the ID dose was in fact 2.5 times less compared to the IM dose. Higher anti-HBs levels were recorded for the intradermal groups compared to the intramuscular group, nevertheless those results were not statistically significant. The reported adverse events were similar to other trials. The frequency of local adverse events reported in the intradermal group was significantly higher, but they were rather mild. Building upon the successful performance results in adults, the acceptability and efficacy of utilising VAX-ID®, having a 33G needle, in children around 6 - 12 years of age is to be assessed. The injection of 0.1ml of sterile, pyrogen free 0.9% NaCl solution will be visualised using high-frequency ultrasound and the pain perception will be measured using the Wong-Baker Scale. Additionally, the participants are required to complete a diary for 5 days to report potential adverse events. VAX-ID® device can bring an added value to intradermal drug delivery, as the dose-sparing effect of the device will result in a reduction of healthcare costs (especially in developing countries) and offers a solution for vaccine shortages. Additionally, an innovative solution for intradermal injection will offer the following benefits: 1) reduced cold-chain volumes; 2) decreased number of failed injections and loss of dose by increased usability and user-independent administration; 3) potential for self-administration. Furthermore, a painless injection could convince hesitant parents to vaccinate their children. Finally, an “invisible” needle provides additional benefits for people with needle-phobia. This doctoral thesis has been accomplished by the interdisciplinary conjunction of engineering, medical sciences, mathematics and product development. This thesis reflects on the pre-commercial trajectory of a new medical device. Despite the absence of validation data in children, the results are beneficial for the further expansion of the device platform VAX-ID®.

Jaar van publicatie:2019

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed