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Title: Quantifying the mechanical properties of skin in vivo and ex vivo to optimise microneedle device design
Author: Groves, Rachel
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2012
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The transdermal delivery of therapeutics is limited to only a few molecules due to the outermost layer of skin, the stratum corneum, which acts as a barrier against the ingress of substances into the body. Microneedle arrays, which are commonly between 70μm and 900μm in length, have been developed as a method of promoting drug and vaccine delivery by creating microperforations in the stratum corneum to increase transport into the skin. The design of microneedle devices has significantly developed over recent years to allow for the delivery of numerous compounds into in vivo and ex vivo skin. Microneedle devices are now beginning to be taken away from the laboratory and towards clinical use but to achieve this it is desirable that all microneedles within the device penetrate skin in vivo to a sufficient depth. As microneedle devices have been extensively tested in cadaver tissue, a greater understanding of the mechanical properties of skin in vivo and ex vivo is required and to hypothesise whether animal models such as murine skin ex vivo serves as an appropriate model for human skin ex vivo. Measurements were performed on human skin in vivo by applying small cylindrical and spherical indenters to the volar aspect of the forearm on 7 volunteers. The average Young’s Modulus of the skin was 39.64kPa and 65.86kPa when applying the spherical and cylindrical indenters respectively. In a series of tensile measurements performed at three load axis orientations using ex vivo samples from human and murine donors, it was found that the key variation was attributed to the deformation experienced at initial low loads. This was shown to be significantly longer for human skin with an average of 5.10mm, when compared with murine skin which had an average of 1.61mm (p<0.05). Histological examination showed that human skin was far thicker, with an increased volume of dermal tissue, compared with murine skin, and this anatomical variation may have been the main reason why human and murine skin exhibited different mechanical properties. Finite element models (FEMs) were established of skin indentation in vivo, which incorporated the epidermis, dermis and hypodermis, and of human and murine skin in tension. Appropriate boundary conditions and mesh densities were implemented and the geometries were taken from real life measurements where possible. The Ogden material model of hyperelasticity was chosen to represent the skin layers for the FEM of skin indentation and an anisotropic material was used to describe human and murine skin in tension by adapting the Weiss et al model of transverse isotropy. Inverse finite element analysis was then used to match the FEMs with the experimental measurements. The multilayered FEM of skin was correlated against the in vivo indentation tests where model and experimental fit gave average root mean squared errors (R2 ave) of between 0.00103 and 0.0488 for the 7 volunteers. The optimal material parameters showed correlations with experimental measurements, where volunteers 1, 6 and 7 were shown to have the stiffest skin through Young’s Modulus calculations, which was reflected in the increased nonlinearity of the parameters extracted for the hypodermal layer. A stronger agreement between model and experiment for the anisotropic model of human and murine skin in tension was shown where the R2 ave was between 0.0038 and 0.0163. Again, model and experimental observations were shown to correlate where there was a significant difference (p<0.05) between 6 of the 14 average material parameters (C2, C3,1, λ1, C3,2, C3,3, λ3) when comparing human to murine skin. The multilayered FEM of human skin in vivo was further validated by modelling the application of a single microneedle to skin, prior to penetration. The model was then correlated against in vivo measurements performed on one of the volunteers and it was found that the model provided a good approximation for the experimental measurements. Using the multilayered FEM of human skin indentation, it was possible to model the deflection of the skin during the application of a pressure load comparable to microneedle array application. This allowed for the development of several curved microneedle arrays which aimed to distribute the load over all microneedles to potentially create uniform skin penetration by all those within the array. The microneedles were manufactured simply and quickly using wire cutting technologies from stainless steel and tested in human skin in vivo and in ex vivo samples of human and murine skin, where methylene blue was applied to identify any microchannels created by the microneedles. Preliminary measurements taken from murine skin ex vivo were discounted as microchannel staining was not possible. Analyses performed on human skin ex vivo showed penetration at high loads (4-5N) for all four microneedle array designs and the microneedle array with the smallest curvature (0.95mm) had the most consistent puncture for all microneedles, however puncture in vivo was difficult to characterise using approach developed. Therefore further work is required to assess more volunteers and donors. This study has highlighted the great differences in the mechanical properties of human and murine skin, suggesting that murine skin is not an appropriate model to assess microneedle puncture. It has also shown that the underlying tissues and hypodermis play a pivotal role in microneedle insertion mechanics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General) ; TJ Mechanical engineering and machinery