Below is our list of publications. If you would like a copy of any of these and can’t access them then please get in contact and we will send you a copy.
2022
Hazel Crichton Michael Crichton, Gregor Colville
Students’ Perceptions of Problem-Based Learning in Multidisciplinary Groups When Seeking to Solve an Engineering Grand Challenge Journal Article
In: Journal of Problem Based Learning in Higher Education, vol. in press, 2022, ISSN: 2246-0918.
@article{nokey,
title = {Students’ Perceptions of Problem-Based Learning in Multidisciplinary Groups When Seeking to Solve an Engineering Grand Challenge},
author = {Michael Crichton,
Hazel Crichton,
Gregor Colville},
url = {https://researchportal.hw.ac.uk/en/publications/afea56dd-ccdd-45a5-8fe2-4587288aeb77},
doi = {10.54337/ojs.jpblhe.v10i1.6823},
issn = {2246-0918},
year = {2022},
date = {2022-03-11},
journal = {Journal of Problem Based Learning in Higher Education},
volume = {in press},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Wei, Jonathan Cj; Cartmill, Ian D; Kendall, Mark Af; Crichton, Michael L
In: J Mech Behav Biomed Mater, vol. 130, pp. 105187, 2022, ISSN: 1878-0180.
@article{pmid35364362b,
title = {In vivo, in situ and ex vivo comparison of porcine skin for microprojection array penetration depth, delivery efficiency and elastic modulus assessment},
author = {Jonathan Cj Wei and Ian D Cartmill and Mark Af Kendall and Michael L Crichton},
doi = {10.1016/j.jmbbm.2022.105187},
issn = {1878-0180},
year = {2022},
date = {2022-01-01},
journal = {J Mech Behav Biomed Mater},
volume = {130},
pages = {105187},
abstract = {With the development of wearable technologies, the interfacial properties of skin and devices have become much more important. For research and development purposes, porcine skin is often used to evaluate device performance, but the differences between in vivo, in situ and ex vivo porcine skin mechanical properties can potentially misdirect investigators during the development of their technology. In this study, we investigated the significant changes to mechanical properties with and without perfusion (in vivo versus in vitro tissue). The device focus for this study was a skin-targeting Nanopatch vaccine microneedle device, employed to assess the variance to key skin engagement parameters - penetration depth and delivery efficiency - due to different tissue conditions. The patches were coated with fluorescent or C radiolabelled formulations for penetration depth and delivery efficiency quantification in vivo, and at time points up to 4 h post mortem. An immediate cessation of blood circulation saw mean microneedle penetration depth fell from ∼100 μm to ∼55 μm (∼45%). Stiffening of underlying tissues as a result of rigor mortis then augmented the penetration depths at the 4 h timepoint back to ∼100 μm, insignificantly different (p = 0.0595) when compared with in vivo. The highest delivery efficiency of formulation into the skin (dose measured in the skin excluding leftover dose on skin and patch surfaces) was also observed at this time point of ∼25%, up from ∼2% in vivo. Data obtained herein progresses medical device development, highlighting the need to consider the state and muscle tissues when evaluating prototypes on cadavers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
With the development of wearable technologies, the interfacial properties of skin and devices have become much more important. For research and development purposes, porcine skin is often used to evaluate device performance, but the differences between in vivo, in situ and ex vivo porcine skin mechanical properties can potentially misdirect investigators during the development of their technology. In this study, we investigated the significant changes to mechanical properties with and without perfusion (in vivo versus in vitro tissue). The device focus for this study was a skin-targeting Nanopatch vaccine microneedle device, employed to assess the variance to key skin engagement parameters - penetration depth and delivery efficiency - due to different tissue conditions. The patches were coated with fluorescent or C radiolabelled formulations for penetration depth and delivery efficiency quantification in vivo, and at time points up to 4 h post mortem. An immediate cessation of blood circulation saw mean microneedle penetration depth fell from ∼100 μm to ∼55 μm (∼45%). Stiffening of underlying tissues as a result of rigor mortis then augmented the penetration depths at the 4 h timepoint back to ∼100 μm, insignificantly different (p = 0.0595) when compared with in vivo. The highest delivery efficiency of formulation into the skin (dose measured in the skin excluding leftover dose on skin and patch surfaces) was also observed at this time point of ∼25%, up from ∼2% in vivo. Data obtained herein progresses medical device development, highlighting the need to consider the state and muscle tissues when evaluating prototypes on cadavers.
2019
Haridass, Isha N; Wei, Jonathan C J; Mohammed, Yousuf H; Crichton, Michael L; Anderson, Christopher D; Henricson, Joakim; Sanchez, Washington Y; Meliga, Stefano C; Grice, Jeffrey E; Benson, Heather A E; Kendall, Mark A F; Roberts, Michael S
Cellular metabolism and pore lifetime of human skin following microprojection array mediation Journal Article
In: J Control Release, vol. 306, pp. 59–68, 2019, ISSN: 1873-4995.
@article{pmid31121279,
title = {Cellular metabolism and pore lifetime of human skin following microprojection array mediation},
author = {Isha N Haridass and Jonathan C J Wei and Yousuf H Mohammed and Michael L Crichton and Christopher D Anderson and Joakim Henricson and Washington Y Sanchez and Stefano C Meliga and Jeffrey E Grice and Heather A E Benson and Mark A F Kendall and Michael S Roberts},
doi = {10.1016/j.jconrel.2019.05.024},
issn = {1873-4995},
year = {2019},
date = {2019-01-01},
journal = {J Control Release},
volume = {306},
pages = {59--68},
abstract = {Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch®). Pores induced by the microprojections were found to close by ~25% in diameter within the first 30 min, and almost completely close by ~6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of ~1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between ~518-583 ps. The ratio of free-bound NAD(P)H (α1/α2) in unaffected areas of the viable epidermis was ~2.5-3.0, whereas the ratio at puncture holes was almost double at ~4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch® treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch®, are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch®). Pores induced by the microprojections were found to close by ~25% in diameter within the first 30 min, and almost completely close by ~6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of ~1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between ~518-583 ps. The ratio of free-bound NAD(P)H (α1/α2) in unaffected areas of the viable epidermis was ~2.5-3.0, whereas the ratio at puncture holes was almost double at ~4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch® treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch®, are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.
van der Burg, Nicole M D; Depelsenaire, Alexandra C I; Crichton, Michael L; Kuo, Paula; Phipps, Simon; Kendall, Mark A F
A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin Journal Article
In: J Control Release, vol. 302, pp. 190–200, 2019, ISSN: 1873-4995.
@article{pmid30940498,
title = {A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin},
author = {Nicole M D van der Burg and Alexandra C I Depelsenaire and Michael L Crichton and Paula Kuo and Simon Phipps and Mark A F Kendall},
doi = {10.1016/j.jconrel.2019.03.027},
issn = {1873-4995},
year = {2019},
date = {2019-01-01},
journal = {J Control Release},
volume = {302},
pages = {190--200},
abstract = {In a low inflammatory skin environment, Langerhans cells (LCs) - but not dermal dendritic cells (dDCs) - contribute to the pivotal process of tolerance induction. Thus LCs are a target for specific-tolerance therapies. LCs reside just below the stratum corneum, within the skin's viable epidermis. One way to precisely deliver immunotherapies to LCs while remaining minimally invasive is with a skin delivery device such as a microprojection arrays (MPA). Today's MPAs currently achieve rapid delivery (e.g. within minutes of application), but are focussed primarily at delivery of therapeutics to the dermis, deeper within the skin. Indeed, no MPA currently delivers specifically to the epidermal LCs of mouse skin. Without any convenient, pre-clinical device available, advancement of LC-targeted therapies has been limited. In this study, we designed and tested a novel MPA that delivers ovalbumin to the mouse epidermis (eMPA) while maintaining a low, local inflammatory response (as defined by low erythema after 24 h). In comparison to available dermal-targeted MPAs (dMPA), only eMPAs with larger projection tip surface areas achieved shallow epidermal penetration at a low application energy. The eMPA characterised here induced significantly less erythema after 24 h (p = 0.0004), less epidermal swelling after 72 h (p < 0.0001) and 52% less epidermal cell death than the dMPA. Despite these differences in skin inflammation, the eMPA and dMPA promoted similar levels of LC migration out of the skin. However, only the eMPA promoted LCs to migrate with a low MHC II expression and in the absence of dDC migration. Implementing this more mouse-appropriate and low-inflammatory eMPA device to deliver potential immunotherapeutics could improve the practicality and cell-specific targeting of such therapeutics in the pre-clinical stage. Leading to more opportunities for LC-targeted therapeutics such as for allergy immunotherapy and asthma.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In a low inflammatory skin environment, Langerhans cells (LCs) - but not dermal dendritic cells (dDCs) - contribute to the pivotal process of tolerance induction. Thus LCs are a target for specific-tolerance therapies. LCs reside just below the stratum corneum, within the skin's viable epidermis. One way to precisely deliver immunotherapies to LCs while remaining minimally invasive is with a skin delivery device such as a microprojection arrays (MPA). Today's MPAs currently achieve rapid delivery (e.g. within minutes of application), but are focussed primarily at delivery of therapeutics to the dermis, deeper within the skin. Indeed, no MPA currently delivers specifically to the epidermal LCs of mouse skin. Without any convenient, pre-clinical device available, advancement of LC-targeted therapies has been limited. In this study, we designed and tested a novel MPA that delivers ovalbumin to the mouse epidermis (eMPA) while maintaining a low, local inflammatory response (as defined by low erythema after 24 h). In comparison to available dermal-targeted MPAs (dMPA), only eMPAs with larger projection tip surface areas achieved shallow epidermal penetration at a low application energy. The eMPA characterised here induced significantly less erythema after 24 h (p = 0.0004), less epidermal swelling after 72 h (p < 0.0001) and 52% less epidermal cell death than the dMPA. Despite these differences in skin inflammation, the eMPA and dMPA promoted similar levels of LC migration out of the skin. However, only the eMPA promoted LCs to migrate with a low MHC II expression and in the absence of dDC migration. Implementing this more mouse-appropriate and low-inflammatory eMPA device to deliver potential immunotherapeutics could improve the practicality and cell-specific targeting of such therapeutics in the pre-clinical stage. Leading to more opportunities for LC-targeted therapeutics such as for allergy immunotherapy and asthma.
2018
Wei, Jonathan C J; Haridass, Isha N; Crichton, Michael L; Mohammed, Yousuf H; Meliga, Stefano C; Sanchez, Washington Y; Grice, Jeffrey E; Benson, Heather A E; Roberts, Michael S; Kendall, Mark A F
Space- and time-resolved investigation on diffusion kinetics of human skin following macromolecule delivery by microneedle arrays Journal Article
In: Sci Rep, vol. 8, no. 1, pp. 17759, 2018, ISSN: 2045-2322.
@article{pmid30531828,
title = {Space- and time-resolved investigation on diffusion kinetics of human skin following macromolecule delivery by microneedle arrays},
author = {Jonathan C J Wei and Isha N Haridass and Michael L Crichton and Yousuf H Mohammed and Stefano C Meliga and Washington Y Sanchez and Jeffrey E Grice and Heather A E Benson and Michael S Roberts and Mark A F Kendall},
doi = {10.1038/s41598-018-36009-8},
issn = {2045-2322},
year = {2018},
date = {2018-01-01},
journal = {Sci Rep},
volume = {8},
number = {1},
pages = {17759},
abstract = {Microscale medical devices are being developed for targeted skin delivery of vaccines and the extraction of biomarkers, with the potential to revolutionise healthcare in both developing and developed countries. The effective clinical development of these devices is dependent on understanding the macro-molecular diffusion properties of skin. We hypothesised that diffusion varied according to specific skin layers. Using three different molecular weights of rhodamine dextran (RD) (MW of 70, 500 and 2000 kDa) relevant to the vaccine and therapeutic scales, we deposited molecules to a range of depths (0-300 µm) in ex vivo human skin using the Nanopatch device. We observed significant dissipation of RD as diffusion with 70 and 500 kDa within the 30 min timeframe, which varied with MW and skin layer. Using multiphoton microscopy, image analysis and a Fick's law analysis with 2D cartesian and axisymmetric cylindrical coordinates, we reported experimental trends of epidermal and dermal diffusivity values ranging from 1-8 µm s to 1-20 µm s respectively, with a significant decrease in the dermal-epidermal junction of 0.7-3 µm s. In breaching the stratum corneum (SC) and dermal-epidermal junction barriers, we have demonstrated practical application, delivery and targeting of macromolecules to both epidermal and dermal antigen presenting cells, providing a sound knowledge base for future development of skin-targeting clinical technologies in humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Microscale medical devices are being developed for targeted skin delivery of vaccines and the extraction of biomarkers, with the potential to revolutionise healthcare in both developing and developed countries. The effective clinical development of these devices is dependent on understanding the macro-molecular diffusion properties of skin. We hypothesised that diffusion varied according to specific skin layers. Using three different molecular weights of rhodamine dextran (RD) (MW of 70, 500 and 2000 kDa) relevant to the vaccine and therapeutic scales, we deposited molecules to a range of depths (0-300 µm) in ex vivo human skin using the Nanopatch device. We observed significant dissipation of RD as diffusion with 70 and 500 kDa within the 30 min timeframe, which varied with MW and skin layer. Using multiphoton microscopy, image analysis and a Fick's law analysis with 2D cartesian and axisymmetric cylindrical coordinates, we reported experimental trends of epidermal and dermal diffusivity values ranging from 1-8 µm s to 1-20 µm s respectively, with a significant decrease in the dermal-epidermal junction of 0.7-3 µm s. In breaching the stratum corneum (SC) and dermal-epidermal junction barriers, we have demonstrated practical application, delivery and targeting of macromolecules to both epidermal and dermal antigen presenting cells, providing a sound knowledge base for future development of skin-targeting clinical technologies in humans.
2017
Wei, Jonathan C J; Edwards, Grant A; Martin, Darren J; Huang, Han; Crichton, Michael L; Kendall, Mark A F
In: Sci Rep, vol. 7, no. 1, pp. 15885, 2017, ISSN: 2045-2322.
@article{pmid29162871,
title = {Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans},
author = {Jonathan C J Wei and Grant A Edwards and Darren J Martin and Han Huang and Michael L Crichton and Mark A F Kendall},
doi = {10.1038/s41598-017-15830-7},
issn = {2045-2322},
year = {2017},
date = {2017-11-01},
journal = {Sci Rep},
volume = {7},
number = {1},
pages = {15885},
abstract = {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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
Meliga, Stefano C; Coffey, Jacob W; Crichton, Michael L; Flaim, Christopher; Veidt, Martin; Kendall, Mark A F
The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model Journal Article
In: Acta Biomater, vol. 48, pp. 341–356, 2017, ISSN: 1878-7568.
@article{pmid27746361,
title = {The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model},
author = {Stefano C Meliga and Jacob W Coffey and Michael L Crichton and Christopher Flaim and Martin Veidt and Mark A F Kendall},
doi = {10.1016/j.actbio.2016.10.021},
issn = {1878-7568},
year = {2017},
date = {2017-01-01},
journal = {Acta Biomater},
volume = {48},
pages = {341--356},
abstract = {In-depth understanding of skin elastic and rupture behavior is fundamental to enable next-generation biomedical devices to directly access areas rich in cells and biomolecules. However, the paucity of skin mechanical characterization and lack of established fracture models limits their rational design. We present an experimental and numerical study of skin mechanics during dynamic interaction with individual and arrays of micro-penetrators. Initially, micro-indentation of individual skin strata revealed hyperelastic moduli were dramatically rate-dependent, enabling extrapolation of stiffness properties at high velocity regimes (>1ms). A layered finite-element model satisfactorily predicted the penetration of micro-penetrators using characteristic fracture energies (∼10pJμm) significantly lower than previously reported (≫100pJμm). Interestingly, with our standard application conditions (∼2ms, 35gpistonmass), ∼95% of the application kinetic energy was transferred to the backing support rather than the skin ∼5% (murine ear model). At higher velocities (∼10ms) strain energy accumulated in the top skin layers, initiating fracture before stress waves transmitted deformation to the backing material, increasing energy transfer efficiency to 55%. Thus, the tools developed provide guidelines to rationally engineer skin penetrators to increase depth targeting consistency and payload delivery across patients whilst minimizing penetration energy to control skin inflammation, tolerability and acceptability.
STATEMENT OF SIGNIFICANCE: The mechanics of skin penetration by dynamically-applied microscopic tips is investigated using a combined experimental-computational approach. A FE model of skin is parameterized using indentation tests and a ductile-failure implementation validated against penetration assays. The simulations shed light on skin elastic and fracture properties, and elucidate the interaction with microprojection arrays for vaccine delivery allowing rational design of next-generation devices.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In-depth understanding of skin elastic and rupture behavior is fundamental to enable next-generation biomedical devices to directly access areas rich in cells and biomolecules. However, the paucity of skin mechanical characterization and lack of established fracture models limits their rational design. We present an experimental and numerical study of skin mechanics during dynamic interaction with individual and arrays of micro-penetrators. Initially, micro-indentation of individual skin strata revealed hyperelastic moduli were dramatically rate-dependent, enabling extrapolation of stiffness properties at high velocity regimes (>1ms). A layered finite-element model satisfactorily predicted the penetration of micro-penetrators using characteristic fracture energies (∼10pJμm) significantly lower than previously reported (≫100pJμm). Interestingly, with our standard application conditions (∼2ms, 35gpistonmass), ∼95% of the application kinetic energy was transferred to the backing support rather than the skin ∼5% (murine ear model). At higher velocities (∼10ms) strain energy accumulated in the top skin layers, initiating fracture before stress waves transmitted deformation to the backing material, increasing energy transfer efficiency to 55%. Thus, the tools developed provide guidelines to rationally engineer skin penetrators to increase depth targeting consistency and payload delivery across patients whilst minimizing penetration energy to control skin inflammation, tolerability and acceptability.
STATEMENT OF SIGNIFICANCE: The mechanics of skin penetration by dynamically-applied microscopic tips is investigated using a combined experimental-computational approach. A FE model of skin is parameterized using indentation tests and a ductile-failure implementation validated against penetration assays. The simulations shed light on skin elastic and fracture properties, and elucidate the interaction with microprojection arrays for vaccine delivery allowing rational design of next-generation devices.
STATEMENT OF SIGNIFICANCE: The mechanics of skin penetration by dynamically-applied microscopic tips is investigated using a combined experimental-computational approach. A FE model of skin is parameterized using indentation tests and a ductile-failure implementation validated against penetration assays. The simulations shed light on skin elastic and fracture properties, and elucidate the interaction with microprojection arrays for vaccine delivery allowing rational design of next-generation devices.
2016
Raphael, Anthony P; Crichton, Michael L; Falconer, Robert J; Meliga, Stefano; Chen, Xianfeng; Fernando, Germain J P; Huang, Han; Kendall, Mark A F
Formulations for microprojection/microneedle vaccine delivery: Structure, strength and release profiles Journal Article
In: J Control Release, vol. 225, pp. 40–52, 2016, ISSN: 1873-4995.
@article{pmid26795684,
title = {Formulations for microprojection/microneedle vaccine delivery: Structure, strength and release profiles},
author = {Anthony P Raphael and Michael L Crichton and Robert J Falconer and Stefano Meliga and Xianfeng Chen and Germain J P Fernando and Han Huang and Mark A F Kendall},
doi = {10.1016/j.jconrel.2016.01.027},
issn = {1873-4995},
year = {2016},
date = {2016-03-01},
journal = {J Control Release},
volume = {225},
pages = {40--52},
abstract = {To develop novel methods for vaccine delivery, the skin is viewed as a high potential target, due to the abundance of immune cells that reside therein. One method, the use of dissolving microneedle technologies, has the potential to achieve this, with a range of formulations now being employed. Within this paper we assemble a range of methods (including FT-FIR using synchrotron radiation, nanoindentation and skin delivery assays) to systematically examine the effect of key bulking agents/excipients - sugars/polyols - on the material form, structure, strength, failure properties, diffusion and dissolution for dissolving microdevices. We investigated concentrations of mannitol, sucrose, trehalose and sorbitol from 1:1 to 30:1 with carboxymethylcellulose (CMC), although mannitol did not form our micro-structures so was discounted early in the study. The other formulations showed a variety of crystalline (sorbitol) and amorphous (sucrose, trehalose) structures, when investigated using Fourier transform far infra-red (FT-FIR) with synchrotron radiation. The crystalline structures had a higher elastic modulus than the amorphous formulations (8-12GPa compared to 0.05-11GPa), with sorbitol formulations showing a bimodal distribution of results including both amorphous and crystalline behaviour. In skin, diffusion properties were similar among all formulations with dissolution occurring within 5s for our small projection array structures (~100μm in length). Overall, slight variations in formulation can significantly change the ability of our projections to perform their required function, making the choice of bulking/vaccine stabilising agents of great importance for these devices. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
To develop novel methods for vaccine delivery, the skin is viewed as a high potential target, due to the abundance of immune cells that reside therein. One method, the use of dissolving microneedle technologies, has the potential to achieve this, with a range of formulations now being employed. Within this paper we assemble a range of methods (including FT-FIR using synchrotron radiation, nanoindentation and skin delivery assays) to systematically examine the effect of key bulking agents/excipients - sugars/polyols - on the material form, structure, strength, failure properties, diffusion and dissolution for dissolving microdevices. We investigated concentrations of mannitol, sucrose, trehalose and sorbitol from 1:1 to 30:1 with carboxymethylcellulose (CMC), although mannitol did not form our micro-structures so was discounted early in the study. The other formulations showed a variety of crystalline (sorbitol) and amorphous (sucrose, trehalose) structures, when investigated using Fourier transform far infra-red (FT-FIR) with synchrotron radiation. The crystalline structures had a higher elastic modulus than the amorphous formulations (8-12GPa compared to 0.05-11GPa), with sorbitol formulations showing a bimodal distribution of results including both amorphous and crystalline behaviour. In skin, diffusion properties were similar among all formulations with dissolution occurring within 5s for our small projection array structures (~100μm in length). Overall, slight variations in formulation can significantly change the ability of our projections to perform their required function, making the choice of bulking/vaccine stabilising agents of great importance for these devices.
Muller, David A; Pearson, Frances E; Fernando, Germain J P; Agyei-Yeboah, Christiana; Owens, Nick S; Corrie, Simon R; Crichton, Michael L; Wei, Jonathan C J; Weldon, William C; Oberste, M Steven; Young, Paul R; Kendall, Mark A F
In: Sci Rep, vol. 6, pp. 22094, 2016, ISSN: 2045-2322.
@article{pmid26911254,
title = {Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses},
author = {David A Muller and Frances E Pearson and Germain J P Fernando and Christiana Agyei-Yeboah and Nick S Owens and Simon R Corrie and Michael L Crichton and Jonathan C J Wei and William C Weldon and M Steven Oberste and Paul R Young and Mark A F Kendall},
doi = {10.1038/srep22094},
issn = {2045-2322},
year = {2016},
date = {2016-02-01},
journal = {Sci Rep},
volume = {6},
pages = {22094},
abstract = {Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns.
Crichton, Michael Lawrence; Muller, David Alexander; Depelsenaire, Alexandra Christina Isabelle; Pearson, Frances Elizabeth; Wei, Jonathan; Coffey, Jacob; Zhang, Jin; Fernando, Germain J P; Kendall, Mark Anthony Fernance
The changing shape of vaccination: improving immune responses through geometrical variations of a microdevice for immunization Journal Article
In: Sci Rep, vol. 6, pp. 27217, 2016, ISSN: 2045-2322.
@article{pmid27251567,
title = {The changing shape of vaccination: improving immune responses through geometrical variations of a microdevice for immunization},
author = {Michael Lawrence Crichton and David Alexander Muller and Alexandra Christina Isabelle Depelsenaire and Frances Elizabeth Pearson and Jonathan Wei and Jacob Coffey and Jin Zhang and Germain J P Fernando and Mark Anthony Fernance Kendall},
doi = {10.1038/srep27217},
issn = {2045-2322},
year = {2016},
date = {2016-01-01},
journal = {Sci Rep},
volume = {6},
pages = {27217},
abstract = {Micro-device use for vaccination has grown in the past decade, with the promise of ease-of-use, painless application, stable solid formulations and greater immune response generation. However, the designs of the highly immunogenic devices (e.g. the gene gun, Nanopatch or laser adjuvantation) require significant energy to enter the skin (30-90 mJ). Within this study, we explore a way to more effectively use energy for skin penetration and vaccination. These modifications change the Nanopatch projections from cylindrical/conical shapes with a density of 20,000 per cm(2) to flat-shaped protrusions at 8,000 per cm(2), whilst maintaining the surface area and volume that is placed within the skin. We show that this design results in more efficient surface crack initiations, allowing the energy to be more efficiently be deployed through the projections into the skin, with a significant overall increase in penetration depth (50%). Furthermore, we measured a significant increase in localized skin cell death (>2 fold), and resultant infiltrate of cells (monocytes and neutrophils). Using a commercial seasonal trivalent human influenza vaccine (Fluvax 2014), our new patch design resulted in an immune response equivalent to intramuscular injection with approximately 1000 fold less dose, while also being a practical device conceptually suited to widespread vaccination.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Micro-device use for vaccination has grown in the past decade, with the promise of ease-of-use, painless application, stable solid formulations and greater immune response generation. However, the designs of the highly immunogenic devices (e.g. the gene gun, Nanopatch or laser adjuvantation) require significant energy to enter the skin (30-90 mJ). Within this study, we explore a way to more effectively use energy for skin penetration and vaccination. These modifications change the Nanopatch projections from cylindrical/conical shapes with a density of 20,000 per cm(2) to flat-shaped protrusions at 8,000 per cm(2), whilst maintaining the surface area and volume that is placed within the skin. We show that this design results in more efficient surface crack initiations, allowing the energy to be more efficiently be deployed through the projections into the skin, with a significant overall increase in penetration depth (50%). Furthermore, we measured a significant increase in localized skin cell death (>2 fold), and resultant infiltrate of cells (monocytes and neutrophils). Using a commercial seasonal trivalent human influenza vaccine (Fluvax 2014), our new patch design resulted in an immune response equivalent to intramuscular injection with approximately 1000 fold less dose, while also being a practical device conceptually suited to widespread vaccination.
Crichton, Michael L; Archer-Jones, Cameron; Meliga, Stefano; Edwards, Grant; Martin, Darren; Huang, Han; Kendall, Mark A F
Characterising the material properties at the interface between skin and a skin vaccination microprojection device Journal Article
In: Acta Biomater, vol. 36, pp. 186–194, 2016, ISSN: 1878-7568.
@article{pmid26956913,
title = {Characterising the material properties at the interface between skin and a skin vaccination microprojection device},
author = {Michael L Crichton and Cameron Archer-Jones and Stefano Meliga and Grant Edwards and Darren Martin and Han Huang and Mark A F Kendall},
doi = {10.1016/j.actbio.2016.02.039},
issn = {1878-7568},
year = {2016},
date = {2016-01-01},
journal = {Acta Biomater},
volume = {36},
pages = {186--194},
abstract = {The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure. First, we used custom fabricated nanoindentation micro-probes to puncture skin at the micrometre scale, and show that puncture forces are ∼0.25-1.75mN for fresh mouse skin, in agreement with finite element simulations for our device. Then, we used two methods to perform strength tests of Nanopatch projections with varied aspect ratios. The first method used a nanoindenter to apply a force directly on the top or on the side of individual silicon projections (110μm in length, 10μm base radius), to measure the force of fracture. Our second method used an Instron to fracture full rows of projections and characterise a range of projection designs (with the method verified against previous nanoindentation experiments). Finally, we used Cryo-Scanning Electron Microscopy to visualise projections in situ in the skin to confirm the behaviour we quantified, qualitatively.
STATEMENT OF SIGNIFICANCE: Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro-scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi-implantable devices, which will require clear understanding of tissue behaviour and material characterisation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure. First, we used custom fabricated nanoindentation micro-probes to puncture skin at the micrometre scale, and show that puncture forces are ∼0.25-1.75mN for fresh mouse skin, in agreement with finite element simulations for our device. Then, we used two methods to perform strength tests of Nanopatch projections with varied aspect ratios. The first method used a nanoindenter to apply a force directly on the top or on the side of individual silicon projections (110μm in length, 10μm base radius), to measure the force of fracture. Our second method used an Instron to fracture full rows of projections and characterise a range of projection designs (with the method verified against previous nanoindentation experiments). Finally, we used Cryo-Scanning Electron Microscopy to visualise projections in situ in the skin to confirm the behaviour we quantified, qualitatively.
STATEMENT OF SIGNIFICANCE: Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro-scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi-implantable devices, which will require clear understanding of tissue behaviour and material characterisation.
STATEMENT OF SIGNIFICANCE: Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro-scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi-implantable devices, which will require clear understanding of tissue behaviour and material characterisation.
2014
McNeilly, Celia L; Crichton, Michael L; Primiero, Clare A; Frazer, Ian H; Roberts, Michael S; Kendall, Mark A F
Microprojection arrays to immunise at mucosal surfaces Journal Article
In: J Control Release, vol. 196, pp. 252–260, 2014, ISSN: 1873-4995.
@article{pmid25285611,
title = {Microprojection arrays to immunise at mucosal surfaces},
author = {Celia L McNeilly and Michael L Crichton and Clare A Primiero and Ian H Frazer and Michael S Roberts and Mark A F Kendall},
doi = {10.1016/j.jconrel.2014.09.028},
issn = {1873-4995},
year = {2014},
date = {2014-12-01},
journal = {J Control Release},
volume = {196},
pages = {252--260},
abstract = {The buccal mucosa (inner cheek) is an attractive site for delivery of immunotherapeutics, due to its ease of access and rich antigen presenting cell (APC) distribution. However, to date, most delivery methods to the buccal mucosa have only been topical-with the challenges of: 1) an environment where significant biomolecule degradation may occur; 2) inability to reach the APCs that are located deep in the epithelium and lamina propria; and 3) salivary flow and mucous secretion that may result in removal of the therapeutic agent before absorption has taken place. To overcome these challenges and achieve consistent, repeatable targeted delivery of immunotherapeutics to within the buccal mucosa (not merely on to the surface), we utilised microprojection arrays (Nanopatches-110 μm length projections, 3364 projections, 16 mm2 surface area) with a purpose built clip applicator. The mechanical application of Nanopatches bearing a dry-coated vaccine (commercial influenza vaccine, as a test case immunotherapeutic) released the vaccine to a depth of 47.8±14.8 μm (mean±SD, n=4), in the mouse buccal mucosa (measured using fluorescent delivered dyes and CryoSEM). This location is in the direct vicinity of APCs, facilitating antigenic uptake. Resultant systemic immune responses were similar to systemic immunization methods, and superior to comparative orally immunised mice. This confirms the Nanopatch administered vaccine was delivered into the buccal mucosa and not ingested. This study demonstrates a minimally-invasive delivery device with rapid (2 min of application time), accurate and consistent release of immunotherapeutics in to the buccal mucosa-that conceptually can be extended in to human use for broad and practical utility.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The buccal mucosa (inner cheek) is an attractive site for delivery of immunotherapeutics, due to its ease of access and rich antigen presenting cell (APC) distribution. However, to date, most delivery methods to the buccal mucosa have only been topical-with the challenges of: 1) an environment where significant biomolecule degradation may occur; 2) inability to reach the APCs that are located deep in the epithelium and lamina propria; and 3) salivary flow and mucous secretion that may result in removal of the therapeutic agent before absorption has taken place. To overcome these challenges and achieve consistent, repeatable targeted delivery of immunotherapeutics to within the buccal mucosa (not merely on to the surface), we utilised microprojection arrays (Nanopatches-110 μm length projections, 3364 projections, 16 mm2 surface area) with a purpose built clip applicator. The mechanical application of Nanopatches bearing a dry-coated vaccine (commercial influenza vaccine, as a test case immunotherapeutic) released the vaccine to a depth of 47.8±14.8 μm (mean±SD, n=4), in the mouse buccal mucosa (measured using fluorescent delivered dyes and CryoSEM). This location is in the direct vicinity of APCs, facilitating antigenic uptake. Resultant systemic immune responses were similar to systemic immunization methods, and superior to comparative orally immunised mice. This confirms the Nanopatch administered vaccine was delivered into the buccal mucosa and not ingested. This study demonstrates a minimally-invasive delivery device with rapid (2 min of application time), accurate and consistent release of immunotherapeutics in to the buccal mucosa-that conceptually can be extended in to human use for broad and practical utility.
2013
Crichton, Michael L; Chen, Xianfeng; Huang, Han; Kendall, Mark A F
Elastic modulus and viscoelastic properties of full thickness skin characterised at micro scales Journal Article
In: Biomaterials, vol. 34, no. 8, pp. 2087–2097, 2013, ISSN: 1878-5905.
@article{pmid23261214,
title = {Elastic modulus and viscoelastic properties of full thickness skin characterised at micro scales},
author = {Michael L Crichton and Xianfeng Chen and Han Huang and Mark A F Kendall},
doi = {10.1016/j.biomaterials.2012.11.035},
issn = {1878-5905},
year = {2013},
date = {2013-03-01},
journal = {Biomaterials},
volume = {34},
number = {8},
pages = {2087--2097},
abstract = {The recent emergence of micro-devices for vaccine delivery into upper layers of the skin holds potential for increased immune responses using physical means to target abundant immune cell populations. A challenge in doing this has been a limited understanding of the skin elastic properties at the micro scale (i.e. on the order of a cell diameter; ~10 μm). Here, we quantify skin's elastic properties at a micro-scale by fabricating customised probes of scales from sub- to super-cellular (0.5 μm-20 μm radius). We then probe full thickness skin; first with force-relaxation experiments and subsequently by elastic indentations. We find that skin's viscoelastic response is scale-independent: consistently a ~40% decrease in normalised force over the first second, followed by further 10% reduction over 10 s. Using Prony series and Hertzian contact analyses, we determined the strain-rate independent elastic moduli of the skin. A high scale dependency was found: the smallest probe encountered the highest elastic modulus (~30 MPa), whereas the 20 μm radius probe was lowest (below 1 MPa). We propose that this may be a result of the load distribution in skin facilitated by the hard corneocytes in the outermost skin layers, and softer living cell layers below.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The recent emergence of micro-devices for vaccine delivery into upper layers of the skin holds potential for increased immune responses using physical means to target abundant immune cell populations. A challenge in doing this has been a limited understanding of the skin elastic properties at the micro scale (i.e. on the order of a cell diameter; ~10 μm). Here, we quantify skin's elastic properties at a micro-scale by fabricating customised probes of scales from sub- to super-cellular (0.5 μm-20 μm radius). We then probe full thickness skin; first with force-relaxation experiments and subsequently by elastic indentations. We find that skin's viscoelastic response is scale-independent: consistently a ~40% decrease in normalised force over the first second, followed by further 10% reduction over 10 s. Using Prony series and Hertzian contact analyses, we determined the strain-rate independent elastic moduli of the skin. A high scale dependency was found: the smallest probe encountered the highest elastic modulus (~30 MPa), whereas the 20 μm radius probe was lowest (below 1 MPa). We propose that this may be a result of the load distribution in skin facilitated by the hard corneocytes in the outermost skin layers, and softer living cell layers below.
Pearson, Frances E; McNeilly, Celia L; Crichton, Michael L; Primiero, Clare A; Yukiko, Sally R; Fernando, Germain J P; Chen, Xianfeng; Gilbert, Sarah C; Hill, Adrian V S; Kendall, Mark A F
In: PLoS One, vol. 8, no. 7, pp. e67888, 2013, ISSN: 1932-6203.
@article{pmid23874462,
title = {Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice},
author = {Frances E Pearson and Celia L McNeilly and Michael L Crichton and Clare A Primiero and Sally R Yukiko and Germain J P Fernando and Xianfeng Chen and Sarah C Gilbert and Adrian V S Hill and Mark A F Kendall},
doi = {10.1371/journal.pone.0067888},
issn = {1932-6203},
year = {2013},
date = {2013-01-01},
journal = {PLoS One},
volume = {8},
number = {7},
pages = {e67888},
abstract = {The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent. These attributes make these technologies particularly suitable for delivery of vaccines against diseases such as malaria, which exerts its worst effects in countries with poorly-resourced healthcare systems. Live viral vectors including adenoviruses and poxviruses encoding exogenous antigens have shown significant clinical promise as vaccines, due to their ability to generate high numbers of antigen-specific T cells. Here, the simian adenovirus serotype 63 and the poxvirus modified vaccinia Ankara--two vectors under evaluation for the delivery of malaria antigens to humans--were formulated for coating onto Nanopatch microprojections and applied to murine skin. Co-formulation with the stabilising disaccharides trehalose and sucrose protected virions during the dry-coating process. Transgene-specific CD8(+) T cell responses following Nanopatch delivery of both vectors were similar to intradermal injection controls after a single immunisation (despite a much lower delivered dose), though MVA boosting of pre-primed responses with Nanopatch was found to be less effective than the ID route. Importantly, disaccharide-stabilised ChAd63 could be stored for 10 weeks at 37°C with less than 1 log10 loss of viability, and retained single-dose immunogenicity after storage. These data support the further development of microprojection patches for the deployment of live vaccines in hot climates.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent. These attributes make these technologies particularly suitable for delivery of vaccines against diseases such as malaria, which exerts its worst effects in countries with poorly-resourced healthcare systems. Live viral vectors including adenoviruses and poxviruses encoding exogenous antigens have shown significant clinical promise as vaccines, due to their ability to generate high numbers of antigen-specific T cells. Here, the simian adenovirus serotype 63 and the poxvirus modified vaccinia Ankara--two vectors under evaluation for the delivery of malaria antigens to humans--were formulated for coating onto Nanopatch microprojections and applied to murine skin. Co-formulation with the stabilising disaccharides trehalose and sucrose protected virions during the dry-coating process. Transgene-specific CD8(+) T cell responses following Nanopatch delivery of both vectors were similar to intradermal injection controls after a single immunisation (despite a much lower delivered dose), though MVA boosting of pre-primed responses with Nanopatch was found to be less effective than the ID route. Importantly, disaccharide-stabilised ChAd63 could be stored for 10 weeks at 37°C with less than 1 log10 loss of viability, and retained single-dose immunogenicity after storage. These data support the further development of microprojection patches for the deployment of live vaccines in hot climates.
2011
Crichton, Michael L; Donose, Bogdan C; Chen, Xianfeng; Raphael, Anthony P; Huang, Han; Kendall, Mark A F
The viscoelastic, hyperelastic and scale dependent behaviour of freshly excised individual skin layers Journal Article
In: Biomaterials, vol. 32, no. 20, pp. 4670–4681, 2011, ISSN: 1878-5905.
@article{pmid21458062,
title = {The viscoelastic, hyperelastic and scale dependent behaviour of freshly excised individual skin layers},
author = {Michael L Crichton and Bogdan C Donose and Xianfeng Chen and Anthony P Raphael and Han Huang and Mark A F Kendall},
doi = {10.1016/j.biomaterials.2011.03.012},
issn = {1878-5905},
year = {2011},
date = {2011-07-01},
journal = {Biomaterials},
volume = {32},
number = {20},
pages = {4670--4681},
abstract = {Micro-devices using mechanical means to target skin for improved drug and vaccine delivery have great promise for improved clinical healthcare. Fully realizing this promise requires a greater understanding of key micro-biomechanical properties for each of the different skin layers - that are both the mechanical barriers and biological targets of these devices. Here, we performed atomic force microscopy indentation on a micro-nano scale to quantify separately, in fresh mouse skin, the viscous and elastic behaviour of the stratum corneum, viable epidermis and dermis. By accessing each layer directly, we examined the response to nanoindentation at sub-cellular and bulk-cellular scale. We found that the dermis showed greatest mechanical stiffness (elastic moduli of 7.33-13.48 MPa for 6.62 μm and 1.90 μm diameter spherical probes respectively). In comparison, the stratum corneum and viable epidermis were weaker at 0.75-1.62 MPa and 0.49-1.51 MPa respectively (again with the lower values resulting from indentations with the large probe 6.62 μm). The living cell layer of the epidermis (viable epidermis) showed greatest viscoelasticity - almost fully relaxing from shallow indentation - whilst the other layers reached a plateau after relaxing by around 40%. With small scale (sub-micron) AFM indentation, we directly determined the effects of different layer constituents - in particular, the dermis showed that some indents contacted collagen fibrils and others contacted ground substance/cellular areas. This work has far reaching implications for the design of micro-devices using mechanical means to deliver drugs or vaccines into the skin; providing key characterized mechanical property values for each constituent of the target delivery material.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Micro-devices using mechanical means to target skin for improved drug and vaccine delivery have great promise for improved clinical healthcare. Fully realizing this promise requires a greater understanding of key micro-biomechanical properties for each of the different skin layers - that are both the mechanical barriers and biological targets of these devices. Here, we performed atomic force microscopy indentation on a micro-nano scale to quantify separately, in fresh mouse skin, the viscous and elastic behaviour of the stratum corneum, viable epidermis and dermis. By accessing each layer directly, we examined the response to nanoindentation at sub-cellular and bulk-cellular scale. We found that the dermis showed greatest mechanical stiffness (elastic moduli of 7.33-13.48 MPa for 6.62 μm and 1.90 μm diameter spherical probes respectively). In comparison, the stratum corneum and viable epidermis were weaker at 0.75-1.62 MPa and 0.49-1.51 MPa respectively (again with the lower values resulting from indentations with the large probe 6.62 μm). The living cell layer of the epidermis (viable epidermis) showed greatest viscoelasticity - almost fully relaxing from shallow indentation - whilst the other layers reached a plateau after relaxing by around 40%. With small scale (sub-micron) AFM indentation, we directly determined the effects of different layer constituents - in particular, the dermis showed that some indents contacted collagen fibrils and others contacted ground substance/cellular areas. This work has far reaching implications for the design of micro-devices using mechanical means to deliver drugs or vaccines into the skin; providing key characterized mechanical property values for each constituent of the target delivery material.
Chen, Xianfeng; Fernando, Germain J P; Crichton, Michael L; Flaim, Christopher; Yukiko, Sally R; Fairmaid, Emily J; Corbett, Holly J; Primiero, Clare A; Ansaldo, Alexander B; Frazer, Ian H; Brown, Lorena E; Kendall, Mark A F
Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization Journal Article
In: J Control Release, vol. 152, no. 3, pp. 349–355, 2011, ISSN: 1873-4995.
@article{pmid21371510,
title = {Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization},
author = {Xianfeng Chen and Germain J P Fernando and Michael L Crichton and Christopher Flaim and Sally R Yukiko and Emily J Fairmaid and Holly J Corbett and Clare A Primiero and Alexander B Ansaldo and Ian H Frazer and Lorena E Brown and Mark A F Kendall},
doi = {10.1016/j.jconrel.2011.02.026},
issn = {1873-4995},
year = {2011},
date = {2011-06-01},
journal = {J Control Release},
volume = {152},
number = {3},
pages = {349--355},
abstract = {Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23°C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23°C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport.
2010
Chen, Xianfeng; Kask, Angela Shaulov; Crichton, Michael L; McNeilly, Celia; Yukiko, Sally; Dong, Lichun; Marshak, Joshua O; Jarrahian, Courtney; Fernando, Germain J P; Chen, Dexiang; Koelle, David M; Kendall, Mark A F
Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays Journal Article
In: J Control Release, vol. 148, no. 3, pp. 327–333, 2010, ISSN: 1873-4995.
@article{pmid20850487,
title = {Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays},
author = {Xianfeng Chen and Angela Shaulov Kask and Michael L Crichton and Celia McNeilly and Sally Yukiko and Lichun Dong and Joshua O Marshak and Courtney Jarrahian and Germain J P Fernando and Dexiang Chen and David M Koelle and Mark A F Kendall},
doi = {10.1016/j.jconrel.2010.09.001},
issn = {1873-4995},
year = {2010},
date = {2010-12-01},
journal = {J Control Release},
volume = {148},
number = {3},
pages = {327--333},
abstract = {HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 ± 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer. Associated with this efficient delivery of the vaccine into the vicinity of the professional antigen presenting cells, we achieved superior antibody responses and statistically equal protection rate against an HSV-2 virus challenge, when compared with the mice immunized with intramuscular injection using needle and syringe, but with less than 1/10th of the delivered antigen.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 ± 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer. Associated with this efficient delivery of the vaccine into the vicinity of the professional antigen presenting cells, we achieved superior antibody responses and statistically equal protection rate against an HSV-2 virus challenge, when compared with the mice immunized with intramuscular injection using needle and syringe, but with less than 1/10th of the delivered antigen.
Corrie, Simon R; Fernando, Germain J P; Crichton, Michael L; Brunck, Marion E G; Anderson, Chris D; Kendall, Mark A F
Surface-modified microprojection arrays for intradermal biomarker capture, with low non-specific protein binding Journal Article
In: Lab Chip, vol. 10, no. 20, pp. 2655–2658, 2010, ISSN: 1473-0197.
@article{pmid20820632,
title = {Surface-modified microprojection arrays for intradermal biomarker capture, with low non-specific protein binding},
author = {Simon R Corrie and Germain J P Fernando and Michael L Crichton and Marion E G Brunck and Chris D Anderson and Mark A F Kendall},
doi = {10.1039/c0lc00068j},
issn = {1473-0197},
year = {2010},
date = {2010-10-01},
journal = {Lab Chip},
volume = {10},
number = {20},
pages = {2655--2658},
abstract = {Minimally invasive biosensors are of great interest for rapid detection of disease biomarkers for diagnostic screening at the point-of-care. Here we introduce a device which extracts disease-specific biomarkers directly from the upper dermis, without the needle and syringe or resource-intensive blood processing. Using antigen-specific antibodies raised in mice as a model system, we confirm the analytical specificity and sensitivity of the antibody capture and extraction in comparison to the conventional methods based on needle/syringe blood draw followed by processing and antigen-specific ELISAs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Minimally invasive biosensors are of great interest for rapid detection of disease biomarkers for diagnostic screening at the point-of-care. Here we introduce a device which extracts disease-specific biomarkers directly from the upper dermis, without the needle and syringe or resource-intensive blood processing. Using antigen-specific antibodies raised in mice as a model system, we confirm the analytical specificity and sensitivity of the antibody capture and extraction in comparison to the conventional methods based on needle/syringe blood draw followed by processing and antigen-specific ELISAs.
Prow, Tarl W; Chen, Xianfeng; Prow, Natalie A; Fernando, Germain J P; Tan, Cindy S E; Raphael, Anthony P; Chang, David; Ruutu, Merja P; Jenkins, Derek W K; Pyke, Alyssa; Crichton, Michael L; Raphaelli, Kristin; Goh, Lucas Y H; Frazer, Ian H; Roberts, Michael S; Gardner, Joy; Khromykh, Alexander A; Suhrbier, Andreas; Hall, Roy A; Kendall, Mark A F
Nanopatch-targeted skin vaccination against West Nile Virus and Chikungunya virus in mice Journal Article
In: Small, vol. 6, no. 16, pp. 1776–1784, 2010, ISSN: 1613-6829.
@article{pmid20665754,
title = {Nanopatch-targeted skin vaccination against West Nile Virus and Chikungunya virus in mice},
author = {Tarl W Prow and Xianfeng Chen and Natalie A Prow and Germain J P Fernando and Cindy S E Tan and Anthony P Raphael and David Chang and Merja P Ruutu and Derek W K Jenkins and Alyssa Pyke and Michael L Crichton and Kristin Raphaelli and Lucas Y H Goh and Ian H Frazer and Michael S Roberts and Joy Gardner and Alexander A Khromykh and Andreas Suhrbier and Roy A Hall and Mark A F Kendall},
doi = {10.1002/smll.201000331},
issn = {1613-6829},
year = {2010},
date = {2010-08-01},
journal = {Small},
volume = {6},
number = {16},
pages = {1776--1784},
abstract = {The 'Nanopatch' (NP) comprises arrays of densely packed projections with a defined geometry and distribution designed to physically target vaccines directly to thousands of epidermal and dermal antigen presenting cells (APCs). These miniaturized arrays are two orders of magnitude smaller than standard needles-which deliver most vaccines-and are also much smaller than current microneedle arrays. The NP is dry-coated with antigen, adjuvant, and/or DNA payloads. After the NP was pressed onto mouse skin, a protein payload co-localized with 91.4 + or - 4.1 APC mm(-2) (or 2925 in total) representing 52% of the delivery sites within the NP contact area, agreeing well with a probability-based model used to guide the device design; it then substantially increases as the antigen diffuses in the skin to many more cells. APC co-localizing with protein payloads rapidly disappears from the application area, suggesting APC migration. The NP also delivers DNA payloads leading to cutaneous expression of encoded proteins within 24 h. The efficiency of NP immunization is demonstrated using an inactivated whole chikungunya virus vaccine and a DNA-delivered attenuated West Nile virus vaccine. The NP thus offers a needle-free, versatile, highly effective vaccine delivery system that is potentially inexpensive and simple to use.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The 'Nanopatch' (NP) comprises arrays of densely packed projections with a defined geometry and distribution designed to physically target vaccines directly to thousands of epidermal and dermal antigen presenting cells (APCs). These miniaturized arrays are two orders of magnitude smaller than standard needles-which deliver most vaccines-and are also much smaller than current microneedle arrays. The NP is dry-coated with antigen, adjuvant, and/or DNA payloads. After the NP was pressed onto mouse skin, a protein payload co-localized with 91.4 + or - 4.1 APC mm(-2) (or 2925 in total) representing 52% of the delivery sites within the NP contact area, agreeing well with a probability-based model used to guide the device design; it then substantially increases as the antigen diffuses in the skin to many more cells. APC co-localizing with protein payloads rapidly disappears from the application area, suggesting APC migration. The NP also delivers DNA payloads leading to cutaneous expression of encoded proteins within 24 h. The efficiency of NP immunization is demonstrated using an inactivated whole chikungunya virus vaccine and a DNA-delivered attenuated West Nile virus vaccine. The NP thus offers a needle-free, versatile, highly effective vaccine delivery system that is potentially inexpensive and simple to use.
Raphael, Anthony P; Prow, Tarl W; Crichton, Michael L; Chen, Xianfeng; Fernando, Germain J P; Kendall, Mark A F
Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays Journal Article
In: Small, vol. 6, no. 16, pp. 1785–1793, 2010, ISSN: 1613-6829.
@article{pmid20665628,
title = {Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays},
author = {Anthony P Raphael and Tarl W Prow and Michael L Crichton and Xianfeng Chen and Germain J P Fernando and Mark A F Kendall},
doi = {10.1002/smll.201000326},
issn = {1613-6829},
year = {2010},
date = {2010-08-01},
journal = {Small},
volume = {6},
number = {16},
pages = {1785--1793},
abstract = {Targeting of vaccines to abundant immune cell populations within our outer thin skin layers using miniaturized devices-much thinner than a needle and syringe, could improve the efficacy of vaccines (and other immunotherapies). To meet this goal, a densely packed dissolving microprojection array (dissolving Nanopatch) is designed, achieving functional miniaturization by 1) formulating small microneedles (two orders of magnitude smaller than a standard needle and syringe) and 2) multiple layering of the payload within microprojections with tight tolerances (of the order of a micrometer). The formulation method is suitable to many vaccines because it is without harsh or complex chemical processes, and it is performed at low temperatures and at a neutral pH. When the formulated dNPs are applied to skin, consistent and robust penetration is achieved, rapidly targeting the skin strata of interest (<5 min; significantly faster than larger dissolving microneedles that have been previously reported). Resultant diffusion is significantly enhanced within the dermis compared with the epidermis. Using two different antigens (ovalbumin and a commercial trivalent influenza vaccine [Fluvax2008]), the administration of these dissolving patches generate robust systemic immune responses in a mouse model. To the authors' knowledge, this is the first report of successful vaccination with any form of dissolving microneedles. The patches made by this method therefore have the potential for pain-free, needle-free, and effective vaccination in humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Targeting of vaccines to abundant immune cell populations within our outer thin skin layers using miniaturized devices-much thinner than a needle and syringe, could improve the efficacy of vaccines (and other immunotherapies). To meet this goal, a densely packed dissolving microprojection array (dissolving Nanopatch) is designed, achieving functional miniaturization by 1) formulating small microneedles (two orders of magnitude smaller than a standard needle and syringe) and 2) multiple layering of the payload within microprojections with tight tolerances (of the order of a micrometer). The formulation method is suitable to many vaccines because it is without harsh or complex chemical processes, and it is performed at low temperatures and at a neutral pH. When the formulated dNPs are applied to skin, consistent and robust penetration is achieved, rapidly targeting the skin strata of interest (<5 min; significantly faster than larger dissolving microneedles that have been previously reported). Resultant diffusion is significantly enhanced within the dermis compared with the epidermis. Using two different antigens (ovalbumin and a commercial trivalent influenza vaccine [Fluvax2008]), the administration of these dissolving patches generate robust systemic immune responses in a mouse model. To the authors' knowledge, this is the first report of successful vaccination with any form of dissolving microneedles. The patches made by this method therefore have the potential for pain-free, needle-free, and effective vaccination in humans.
Crichton, Michael L; Ansaldo, Alexander; Chen, Xianfeng; Prow, Tarl W; Fernando, Germain J P; Kendall, Mark A F
The effect of strain rate on the precision of penetration of short densely-packed microprojection array patches coated with vaccine Journal Article
In: Biomaterials, vol. 31, no. 16, pp. 4562–4572, 2010, ISSN: 1878-5905.
@article{pmid20226519,
title = {The effect of strain rate on the precision of penetration of short densely-packed microprojection array patches coated with vaccine},
author = {Michael L Crichton and Alexander Ansaldo and Xianfeng Chen and Tarl W Prow and Germain J P Fernando and Mark A F Kendall},
doi = {10.1016/j.biomaterials.2010.02.022},
issn = {1878-5905},
year = {2010},
date = {2010-06-01},
journal = {Biomaterials},
volume = {31},
number = {16},
pages = {4562--4572},
abstract = {If skin's non-linear viscoelastic properties are mechanically exploited for precise antigen placement, there is tremendous promise for improved vaccines. To achieve this, we designed a Nanopatch-densely packed micro-nanoprojections (>20,000/cm(2)) to directly deposit antigen to large numbers of epidermal Langerhans cells and dermal dendritic cells. Here, we controllably applied our Nanopatches with discrete conditions between peak strain rates of approximately 100 s(-1)-7000 s(-1) and quantified resulting penetration depths, delivery payloads and skin mechanics. Increasing the strain rate of application, we overcame key skin variability, achieving increases in both projection penetration depth (by over 50% length) and area coverage of a full array (from 50% to 100%). This delivery depth precision opens the way for more fully utilizing the skin's immune function. Furthermore, we yielded new insights on mechanical behaviour of skin, including: 1) internal skin property changes that could affect/facilitate penetration; 2) projection design to dictate penetration depth; 3) puncture mechanics of skin in this strain rate range. Indeed, we show delivery of a model vaccine using our tested range of strain rates achieved functionally relevant tunable systemic antibody generation in mice. These findings could be of great utility in extending skin strata vaccine targeting approaches to human use.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
If skin's non-linear viscoelastic properties are mechanically exploited for precise antigen placement, there is tremendous promise for improved vaccines. To achieve this, we designed a Nanopatch-densely packed micro-nanoprojections (>20,000/cm(2)) to directly deposit antigen to large numbers of epidermal Langerhans cells and dermal dendritic cells. Here, we controllably applied our Nanopatches with discrete conditions between peak strain rates of approximately 100 s(-1)-7000 s(-1) and quantified resulting penetration depths, delivery payloads and skin mechanics. Increasing the strain rate of application, we overcame key skin variability, achieving increases in both projection penetration depth (by over 50% length) and area coverage of a full array (from 50% to 100%). This delivery depth precision opens the way for more fully utilizing the skin's immune function. Furthermore, we yielded new insights on mechanical behaviour of skin, including: 1) internal skin property changes that could affect/facilitate penetration; 2) projection design to dictate penetration depth; 3) puncture mechanics of skin in this strain rate range. Indeed, we show delivery of a model vaccine using our tested range of strain rates achieved functionally relevant tunable systemic antibody generation in mice. These findings could be of great utility in extending skin strata vaccine targeting approaches to human use.
Fernando, Germain J P; Chen, Xianfeng; Prow, Tarl W; Crichton, Michael L; Fairmaid, Emily J; Roberts, Michael S; Frazer, Ian H; Brown, Lorena E; Kendall, Mark A F
Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model Journal Article
In: PLoS One, vol. 5, no. 4, pp. e10266, 2010, ISSN: 1932-6203.
@article{pmid20422002,
title = {Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model},
author = {Germain J P Fernando and Xianfeng Chen and Tarl W Prow and Michael L Crichton and Emily J Fairmaid and Michael S Roberts and Ian H Frazer and Lorena E Brown and Mark A F Kendall},
doi = {10.1371/journal.pone.0010266},
issn = {1932-6203},
year = {2010},
date = {2010-04-01},
journal = {PLoS One},
volume = {5},
number = {4},
pages = {e10266},
abstract = {BACKGROUND: Over 14 million people die each year from infectious diseases despite extensive vaccine use [1]. The needle and syringe--first invented in 1853--is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe.
METHODOLOGY/PRINCIPAL FINDINGS: To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch, which contains an array of densely packed projections (21025/cm(2)) invisible to the human eye (110 microm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe--but with less than 1/100(th) of the delivered antigen.
CONCLUSIONS/SIGNIFICANCE: Our results represent a marked improvement--an order of magnitude greater than reported by others--for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies--and we speculate that successful translation of these findings into humans could uniquely assist with problems of vaccine shortages and distribution--together with alleviating fear of the needle and the need for trained practitioners to administer vaccine, e.g., during an influenza pandemic.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Over 14 million people die each year from infectious diseases despite extensive vaccine use [1]. The needle and syringe--first invented in 1853--is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe.
METHODOLOGY/PRINCIPAL FINDINGS: To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch, which contains an array of densely packed projections (21025/cm(2)) invisible to the human eye (110 microm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe--but with less than 1/100(th) of the delivered antigen.
CONCLUSIONS/SIGNIFICANCE: Our results represent a marked improvement--an order of magnitude greater than reported by others--for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies--and we speculate that successful translation of these findings into humans could uniquely assist with problems of vaccine shortages and distribution--together with alleviating fear of the needle and the need for trained practitioners to administer vaccine, e.g., during an influenza pandemic.
METHODOLOGY/PRINCIPAL FINDINGS: To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch, which contains an array of densely packed projections (21025/cm(2)) invisible to the human eye (110 microm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe--but with less than 1/100(th) of the delivered antigen.
CONCLUSIONS/SIGNIFICANCE: Our results represent a marked improvement--an order of magnitude greater than reported by others--for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies--and we speculate that successful translation of these findings into humans could uniquely assist with problems of vaccine shortages and distribution--together with alleviating fear of the needle and the need for trained practitioners to administer vaccine, e.g., during an influenza pandemic.
2009
Chen, Xianfeng; Prow, Tarl W; Crichton, Michael L; Jenkins, Derek W K; Roberts, Michael S; Frazer, Ian H; Fernando, Germain J P; Kendall, Mark A F
Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin Journal Article
In: J Control Release, vol. 139, no. 3, pp. 212–220, 2009, ISSN: 1873-4995.
@article{pmid19577597,
title = {Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin},
author = {Xianfeng Chen and Tarl W Prow and Michael L Crichton and Derek W K Jenkins and Michael S Roberts and Ian H Frazer and Germain J P Fernando and Mark A F Kendall},
doi = {10.1016/j.jconrel.2009.06.029},
issn = {1873-4995},
year = {2009},
date = {2009-11-01},
journal = {J Control Release},
volume = {139},
number = {3},
pages = {212--220},
abstract = {Dry-coated microprojections (MPs) deliver vaccine to abundant immunogenic cells within the skin to induce immune responses. Success in this targeted vaccine delivery relies on overcoming the challenges of dry-coating the vaccine onto the very small (
pubstate = {published},
tppubtype = {article}
}
Dry-coated microprojections (MPs) deliver vaccine to abundant immunogenic cells within the skin to induce immune responses. Success in this targeted vaccine delivery relies on overcoming the challenges of dry-coating the vaccine onto the very small (
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