Evaluation of the clinical impact of repeat application of hydrogel-forming microneedle array patches

Abstract

Hydrogel-forming microneedle array patches (MAPs) have been proposed as viable clinical tools for patient monitoring purposes, providing an alternative to traditional methods of sample acquisition, such as venepuncture and intradermal sampling. They are also undergoing investigation in the management of non-melanoma skin cancers. In contrast to drug or vaccine delivery, when only a small number of MAP applications would be required, hydrogel MAPs utilised for sampling purposes or for tumour eradication would necessitate regular, repeat applications. Therefore, the current study was designed to address one of the key translational aspects of MAP development, namely patient safety. We demonstrate, for the first time in human volunteers, that repeat MAP application and wear does not lead to prolonged skin reactions or prolonged disruption of skin barrier function. Importantly, concentrations of specific systemic biomarkers of inflammation (C-reactive protein (CRP); tumour necrosis factor-α (TNF-α)); infection (interleukin-1β (IL-1β); allergy (immunoglobulin E (IgE)) and immunity (immunoglobulin G (IgG)) were all recorded over the course of this fixed study period. No biomarker concentrations above the normal, documented adult ranges were recorded over the course of the study, indicating that no systemic reactions had been initiated in volunteers. Building upon the results of this study, which serve to highlight the safety of our hydrogel MAP, we are actively working towards CE marking of our MAP technology as a medical device.

Keywords: Biomarkers; Clinical translation; Hydrogels; Microneedle array patches; Microneedles; Safety; Skin barrier.

Fig. 1

Schematic representations of hydrogel-forming MAP applications

Fig. 2

Hydrogel-forming microneedle array patch (MAP) design. Single microneedle array (A); microneedle array attached to the adhesive part of the TegadermTM dressing to form the MAP (B)

Fig. 3

Schematic representation of the study design

Fig. 4

Transepidermal water loss values measured before and after applying MAPs. First day (A), second day (B), third day (C), fourth day (D), fifth day (E). On all days, values increased significantly after MAP removal, but returned to baseline levels 18 h post-patch removal (means + SE, n = 11)

Fig. 5

Optical coherence tomography image of MAP immediately after insertion to the forearm of the researcher. It is clear that the MAP was able to create pores and penetrate into the skin upon manual application

Fig. 6

Digital images of MAPs after removal from volunteers’ upper arms. Microneedles and baseplates were flexible and rubbery (A). The array centres showed a higher degree of swelling compared with the baseplates (B). Microscope images of swollen MAPs after removal from a volunteer’s arm. MAPs became elastic as a result of imbibing interstitial fluid from the volunteers (C, D). All of the microneedles of every MAP were removed intact, without any deformation inside the skin (E)

Fig. 7

Microscope images of MAPs showing the dimensions of microneedle array (A) before and (B) after application to human volunteers. The area of the array was calculated by measuring the distance between the first and the last microneedle of the first line in the array in mm. Thus, the area was calculated in mm². The application time was 6 h

Fig. 8

Exemplar images of MAPs immediately upon application and after 6 h of wear. Signs of interstitial fluid absorption were noticed as swelling at the centre of the microneedle arrays in some volunteers. The Tegaderm™ adhesive dressing permitted the microneedles to stay in place over the time of wear

Fig. 9

Clinical photographs taken of the upper arm skin of randomly selected volunteers by a medical photographer on the first day of study. Photographs in the left hand column were taken before application of MAPs, while photographs in the right hand column were taken immediately after patch removal (6-h wear time). The area of patch application was marked with a pen

Fig. 10

Clinical photographs taken by medical photographer on the fifth day of study. Photographs in the left hand column were taken before application of MAPs, while photographs in the right hand column were taken immediately after patch removal. It is notable that erythema is directly centred to the site of microneedle insertion, rather than in the border area where the adhesive was

Fig. 11

Clinical photographs taken after 18 h of MAP removal. These images were taken on the fifth day of study (i.e. after four MAP applications; two to this approximate site). Erythema degree as assessed by the dermatologist is assigned to each image

Fig. 12

I: levels of plasma CRP at the beginning and the end of the study, as determined using ELISA (means ± SE, n = 11) (A) and individual volunteer values (B). II: levels of plasma IgG at the beginning and the end of the study, as determined using ELISA (means ± SE, n = 11) (A) and individual volunteer values (B). III: levels of plasma IgE at the beginning and the end of the study, as determined using ELISA (means ± SE, n = 11) (A) and individual volunteer values (B). IV: levels of plasma TNF-α at the beginning and the end of the study, as determined using ELISA (means ± SE, n = 11) (A) and individual volunteer values (B). ns, non-significant