The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model

Meliga, Stefano C.; Coffey, Jacob W.; Crichton, Michael L.; Flaim, C.; Veidt, Martin; Kendall, M. A. F.

doi:10.1016/j.actbio.2016.10.021

Cited by 39 publications

(37 citation statements)

References 101 publications

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“…To examine how mechanical application of stress/energy to the skin is transmitted and how it is linked with skin cell death, we applied a skin deformation and fracture model 17 to estimate the consequences of static or dynamic application of flat plate, pillar or cylindrical–conical microprojection array (Supplementary Figs 2 and 3). Using choices of energy and penetration data from previous work, we compared the spatial distribution of stress calculated by simulation with experimentally measured cell death in mouse ear skin.…”

Section: Resultsmentioning

confidence: 99%

“…Dynamic application requires an applicator to fire the array at a constant energy (3500, 5800 or 11,200 J/m 2 ) and the arrays are rested on the skin for 2 min, similar to the transcutaneous immunisation. The stress distributions were computed using the finite element model of the skin developed in Meliga et al 17 and were solved using Abaqus (Abaqus 6.11; Dassault Systemes Simulia, Corp., Providence, RI, USA). Specifically, the mouse ear was represented as a seven-layer material constituted by a 70 μm-thick cartilage layer sandwiched between the ventral and dorsal skin tissues having the following geometry: a 5 μm-thick stratum corneum (SC), a 15 μm-thick VE and a 60 μm-thick Dermis (D).…”

Section: Methodsmentioning

confidence: 99%

“…For example, the 11,200 J/m 2 microprojection application was simulated using respectively the following Young’s moduli and stretch exponents: 187 MPa and 5.77 for the SC, 2.7 MPa and 162 for the VE, 401 MPa and 15.5 for the D, 0.02 MPa and 115 for the Cartilage. The complete set of rate and size-dependent moduli and exponents is summarised in Meliga et al 17 Similar to that in our previous work, 17 we used the following properties for SC, VE, D and Cartilage: mass densities were 1.3, 1.1, 1.27 and 1.3 g cm −3 , respectively. Poisson’s ratio was set to 0.45.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Tuong

Fernando

et al. 2019

npj Vaccines

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Chemical adjuvants are typically used to improve immune responses induced by immunisation with protein antigens. Here we demonstrate an approach to enhance immune responses that does not require chemical adjuvants. We applied microprojection arrays to the skin, producing a range of controlled mechanical energy to invoke localised inflammation, while administering influenza split virus protein antigen. We used validated computational modelling methods to identify links between mechanical stress and energy generated within the skin strata and resultant cell death. We compared induced immune responses to those induced by needle-based intradermal antigen delivery and used a systems biology approach to examine the nature of the induced inflammatory response, and correlated this with markers of cell stress and death. Increasing the microprojection array application energy and the addition of QS-21 adjuvant were each associated with enhanced antibody response to delivered antigen and with induction of gene transcriptions associated with TNF and NF-κB signalling pathways. We concluded that microprojection intradermal antigen delivery inducing controlled local cell death could potentially replace chemical adjuvants to enhance the immune response to protein antigen.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Tuong

Fernando

et al. 2019

npj Vaccines

Self Cite

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show abstract

“…Other more complex skin modelling approaches utilise finite element analysis (e.g. 51 ) which is time consuming and expensive. For many purposes, this model serves as an engineering tool that can provide estimates of the skin’s mechanical properties.…”

Section: Discussionmentioning

confidence: 99%

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans

Wei

Edwards

Martin

et al. 2017

Sci Rep

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213

124

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Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin’s stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species’ body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.

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“…Each Nanopatch™ was delivered using a custom applicator, PoP4 (Proof of Principle 4). PoP4 pushed the patches onto the site at a high speed (∼15 m/s) to ensure full engagement of the Nanopatch™ surface with the skin [40], [41]. For Nanopatch™ delivery studies, the PoP4 applicator is first attached to the Nanopatch™ with holder, the Nanopatch™ is removed from the holder, placed against the skin, and the plunger activated to administer the Nanopatch™ to the skin.…”

Section: Methodsmentioning

confidence: 99%

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment

Meyer¹,

Kendall

Williams³

et al. 2019

Vaccine: X

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The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM). The aim of this study was to determine preclinically whether intradermal (ID) vaccination with an unadjuvanted 9-valent recombinant HPV vaccine using a first-generation ID delivery device, the Nanopatch™, could enhance vaccine immunogenicity compared with the traditional ID route (Mantoux technique). IM injection of HPV VLPs formulated with Merck & Co., Inc., Kenilworth, NJ, USA Alum Adjuvant (MAA) were included in the rhesus study for comparison. The Nanopatch™ prototype contains a high-density array comprised of 10,000 microprojections/cm 2 , each 250 µm long. It was hypothesized the higher density array with shallower ID delivery may be superior to the Mantoux technique. To test this hypothesis, HPV VLPs without adjuvant were coated on the Nanopatch™, stability of the Nanopatch™ with unadjuvanted HPV VLPs were evaluated under accelerated conditions, skin delivery was verified using radiolabelled VLPs or FluoSpheres®, and the immune response and skin site reaction with the Nanopatch™ was evaluated in rhesus macaques. The immune response induced by Nanopatch™ administration, measured as HPV-specific binding antibodies, was similar to that induced using the Mantoux technique. It was also observed that a lower dose of unadjuvanted HPV VLPs delivered with the first-generation Nanopatch™ and applicator or Mantoux technique resulted in an immune response that was significantly lower compared to a higher-dose of alum adjuvanted HPV VLPs delivered IM in rhesus macaques. The study also indicated unadjuvanted HPV VLPs could be delivered with the first-generation Nanopatch™ and applicator to the skin in 15 s with a transfer efficiency of approximately 20%. This study is the first demonstration of patch administration in non-human primates with a vaccine composed of HPV VLPs.

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The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model

Cited by 39 publications

References 101 publications

Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment

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