WO2015198002A1 - Peau synthétique - Google Patents

Peau synthétique Download PDF

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Publication number
WO2015198002A1
WO2015198002A1 PCT/GB2015/000192 GB2015000192W WO2015198002A1 WO 2015198002 A1 WO2015198002 A1 WO 2015198002A1 GB 2015000192 W GB2015000192 W GB 2015000192W WO 2015198002 A1 WO2015198002 A1 WO 2015198002A1
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WO
WIPO (PCT)
Prior art keywords
skin
silicone
synthetic skin
roughened
grade
Prior art date
Application number
PCT/GB2015/000192
Other languages
English (en)
Inventor
Ehsan GAZI
David Clive Francis
Ian Michael SHORTMAN
Jayne Alexandra EDE
Original Assignee
The Secretary Of State For Defence
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Secretary Of State For Defence filed Critical The Secretary Of State For Defence
Priority to EP15732876.6A priority Critical patent/EP3158555A1/fr
Publication of WO2015198002A1 publication Critical patent/WO2015198002A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/04—Polysiloxanes

Definitions

  • the present invention relates to a synthetic skin, a method of production and use as a physical model, for evaluating the effect or behaviour of substances on skin, and processes for removing the substances from skin, such as in the development of cleaning agents or decontaminants.
  • the application of a substance to an animal skin surface covers a wide range of scenarios.
  • intentional application of a chemical, product or material to a skin surface includes use, by a person, of cosmetics (e.g. make-up, deodorant), topical treatments (e.g. antibiotics, moisturisers) and other skin care lotions, gels or creams.
  • cosmetics e.g. make-up, deodorant
  • topical treatments e.g. antibiotics, moisturisers
  • other skin care lotions, gels or creams e.g. antibiotics, moisturisers
  • the removal of substances from the skin surface can be achieved through a variety of processes, for example washing, using an absorbent material (e.g. wipes, cloths, tissues, powders), the application of a secondary cleaning substance (e.g. make-up remover), or a combination of such processes.
  • Assessing the effectiveness of a skin decontaminant or a skin decontamination procedure can be achieved using a biological skin sample as a testing surface.
  • the term 'biological skin' includes, but not exclusively, mammalian skin, in particular human skin or porcine skin.
  • Biological variance may be as a result of differences in stratum corneum thickness (the most superficial layer of biological skin and the rate-limiting step to penetration of exogenous substances), differences in biological skin hydration levels, and differences in dermal appendages (e.g. number of follicles and skin pores).
  • Biological skin needs to be maintained at physiological conditions to ensure representative in vivo absorption rates. Furthermore, compositional changes of excised biological skin occur over time and as a result of storage. Ideal conditions to preserve the ultrastructure of biological skin in long-term storage would be to flash- freeze the biological skin, to prevent ice crystal damage and to promote vitreous ice formation during the freezing process, and then to store the biological skin in liquid , nitrogen. However, there are practical limitations in storing biological skin at lower temperatures, for example at -20°C. Under these conditions in the longer-term, the biological skin may be unsuitable for penetration studies due to dehydration and ice crystal damage, particularly if the biological skin is exposed to several freeze-thaw cycles.
  • biological skin particularly human skin
  • biological skin is a limited source and not readily available.
  • Synthetic skin is widely used in the pharmaceutical industry as membranes to simulate skin barrier function for transdermal drug permeation studies or as a support to measure the release rate of a drug from a delivery system.
  • These synthetic membranes are sourced from the filter membrane industry and may be polymeric materials such as cellulose, silicone or polysulfone based materials.
  • the filter membranes can differ in pore size, order of their pore structure, chemical composition and hydrophobicity. Although this provides a range of parameters that can be exploited to simulate the permeability of human skin for a given substance, there are a number of additional physiochemical and practical requirements for a skin surrogate, especially to enable it to be used as a platform for the evaluation of personal decontaminants.
  • the surface of a synthetic skin should preferably be topographically representative of biological skin. This feature would help ensure, for example, that spread of a substance on the synthetic skin surface correlates with its spread on a biological skin surface and, furthermore, that the amount of substance absorbed into the synthetic skin correlates with that into biological skin. This ensures that the initial drop fraction available to the decontamination process reflects that for biological skin.
  • the synthetic skin should preferably be of sufficient thickness to prevent substance breakthrough. This is important for quantitative studies of residual contamination.
  • the synthetic skin should preferably enable solvent extraction of all of the absorbed substance from its bulk without introducing any interferents into the extraction medium that would confound analytical quantification.
  • the synthetic skin should preferably be suitable for attaching to an undulating or geometrically complex surface, for example a head-form.
  • the mechanical integrity of the synthetic skin should be preferably be maintained upon exposure to a substance or a decontamination procedure.
  • the synthetic skin should preferably not induce breakdown of the substance applied.
  • the synthetic skin should preferably be prepared so that there are no significant inter-batch variations in a surrogate's chemical and physical properties.
  • the aim of the present invention is to develop improved synthetic skins, and especially skins more topographically representative of biological skin, and methods for production of such skins.
  • a method for producing a synthetic skin comprising the steps of: depositing a curable polymer on a non-biological material having a rough surface, so that the curable polymer contacts the rough surface; curing the polymer such that the rough surface imprints on to the polymer; and removing the non-biological material from the cured polymer to provide the synthetic skin.
  • the present invention relates to an improved synthetic skin, in particular wherein the surface of the synthetic skin simulant is topographically modified so that the spread of an agent on its surface is representative of its spread on biological skin, a method of production of the improved synthetic skin and its use as a physical model, for evaluating the effect or behaviour of substances on skin, and processes for removing the substances from skin, such as in the development of cleaning agents or decontaminants.
  • the present invention is a suitable platform for assessing the efficacy of personal decontamination products and procedures, in the event of potential skin contamination by agents such as chemical agents, in particular chemical warfare agents or associated simulants.
  • 'agent' for the purpose of the present invention is known to the person skilled in the art and includes, but not exclusively, a chemical or biological agent, in particular a chemical agent, for example a chemical agent in a solid, liquid or gaseous phase, in particular a liquid chemical agent.
  • a chemical agent for example a chemical agent in a solid, liquid or gaseous phase, in particular a liquid chemical agent.
  • the term 'agent' also includes chemical warfare agents or associated simulants.
  • improved synthetic skin for purposes such as those outlined above may provide benefits that include: higher experimental throughput due to ease of use; greater availability, thus providing improved statistical power to resolve efficacy of decontamination products and/or procedures; enabling standardised methods, for example testing the efficacy of decontamination processes on skin, which is particularly advantageous for those countries that are restricted or limited in their use of biological skin; and correlating the spread of simulant on synthetic skin with the spread of live chemical agent (e.g. chemical warfare agent) the simulant represents on biological skin, thus providing a non-super toxic model to perform realistic decontamination protocols that do not require specialist facilities or resources.
  • live chemical agent e.g. chemical warfare agent
  • 'depositing' includes, but not exclusively, using an applicator to uniformly draw a curable polymer over a non-biological rough surface, preferably at a slow and steady speed over the non-biological rough surface.
  • the non-biological rough surface is preferably maintained in a substantially horizontal plane to ensure the curable polymer remains uniformly deposited on the non-biological rough surface.
  • 'depositing' may include pjacing a non-biological rough surface down onto a curable polymer such that the non-biological rough surface is progressively rolled over the curable polymer and allowed to rest before polymer curing.
  • the term 'curable polymer' is known to a person skilled in the art and includes, but not exclusively, a synthetic and/or natural substance comprising repeating monomer subunits, that can be stored at suitable environmental conditions and duration to facilitate its hardening into a solid form.
  • the term 'curable polymer includes silicone, which includes, but not exclusively, polymers comprising silicon, for example polymers containing silicon and additional elements such as carbon, hydrogen and/or oxygen.
  • silicone includes polymerised siloxanes ('polysiloxanes'), comprising an inorganic-organic compound of chemical formula [R 2 SiO] n , structured as a silicon-oxygen backbone with additional organic groups bound to the silicon atoms.
  • the term 'rough surface' includes, but not exclusively, any non-biological material surface, for example an artificial or man-made surface, that displays a non-smooth, textured or undulating surface.
  • the rough surface includes strands of naturally-occurring or synthetic hair protruding from the surface, so that the hair strands become embedded in the curable polymer following depositing the curable polymer on a non-biological material having a rough surface.
  • the term 'curing' includes, but not exclusively, storing the curable polymer at suitable environmental conditions and duration to facilitate its hardening into a solid form.
  • the term 'curing' in relation to silicone includes, but not exclusively, storing silicone in a liquid form at suitable environment conditions and duration to facilitate its hardening into a solid form. Suitable environmental conditions and duration for curing silicone are known to those skilled in the art, for example at room temperature e.g. approximately 23°C and a duration of up to or greater than 1 hour.
  • this method is a simple and reproducible means of providing a synthetic skin with a topographically-modified surface that enables an agent to spread on its surface in a manner representative of said agent's spread oh biological skin.
  • the Applicant has surprisingly found that using a non-biological material having a rough surface, as an embedding surface, facilitates the production of a synthetic skin with a topographically-modified surface that enables an agent to spread on its surface in a manner representative of said agent's spread on biological skin.
  • the Applicants have demonstrated that the drop spread of methyl salicylate (MS), a sulphur mustard (HD) simulant, on the roughened synthetic skin surface statistically matches MS drop spread on porcine skin. Furthermore, the present invention overcomes the need to modify the surface chemistry of the synthetic skin, or for the availability of biological skin as a casting surface for the synthetic skin.
  • MS methyl salicylate
  • HD sulphur mustard
  • the curable polymer of the present invention comprises silicone.
  • the curable polymer of the present invention is a commercially-available silicone, for example Dragon Skin FX Pro. This characteristic is advantageous as it aids the production of standardised methods for use by different laboratories to compare, for example, the efficacy of decontamination processes on skin. Silicone also has the advantageous properties of mechanical robustness, for example to decontamination procedures, and the ability to be produced in sufficient lateral sizes to cover body-forms. As shown by the Applicant, the synthetic skin of the present invention was demonstrated to be capable of being attached to a head-form and was mechanically stable during a decontamination drill wherein a General Service Respirator was donned and doffed during the decontamination procedure.
  • silicone enables high percentages of solvent extraction of the absorbed substance from its bulk.
  • absorbed MS can be solvent extracted from cured silicone with recoveries of 98% +/- 15% (95% CI).
  • the applicant has found that a synthetic skin comprising silicone can be stored for approximately one month at ambient temperature (e.g. 21 °C) and air conditions.
  • the act of depositing the curable polymer on the non-biological material having a rough surface at a slow and steady speed overcomes the problem of air bubbles becoming trapped in the synthetic skin.
  • the curing process also results in any remaining air bubbles rising out of the curable polymer, leaving a uniform polymer sheet at the end of the curing process.
  • Air bubbles may damage the uniformity of the material, for example by producing regions on the synthetic skin that are void of roughened surface and/or thinner than the average thickness of the synthetic skin, the later characteristic conferring mechanical weakness which may resulting in rips and holes in the synthetic skin when being removed from the rough surface.
  • a method for producing a synthetic skin wherein the rough surface is an abrasive surface.
  • the term 'abrasive surface' includes, but not exclusively, a surface comprising grains or a similar hard substance, each of a size ranging from, for example, millimetre to submicrometre, adhered to a surface, particularly a flexible surface, such as paper, cloth, metal or plastic.
  • Abrasive surfaces include those provided by, for example, coated abrasive surfaces such as sandpaper, emery cloths and other associated variants that provide a rough surface with abrasive qualities.
  • the term 'abrasive surface' also includes surfaces that are moulded or prepared such that their surface is comparable in texture to coated abrasive surfaces.
  • a method for producing a synthetic skin wherein the abrasive surface comprises grains of average particle diameter 50 - 450 ⁇ .
  • the non-biological material comprises grit (i.e. grains) of standardised grit designation as defined, for example, by the European Federation of European Producers of Abrasives (FEPA), ISO 6344 (coated abrasives, size and tests) and/or the United States Coated Abrasive Manufacturers Institute (CAMI), said grit comprising coarse-grade grit, for example coarse-grade 40 (e.g. ISO/FEPA grit designation P40; CAM!
  • FEPA European Federation of European Producers of Abrasives
  • ISO 6344 coated abrasives, size and tests
  • CAMI United States Coated Abrasive Manufacturers Institute
  • grit designation 40 average particle diameter 425 ⁇ ; coarse-grade particle range 336-425 ⁇
  • medium-grade grit for example medium-grade 70 (or similar e.g. ISO/FEPA grit designation P60, average particle diameter 269 ⁇ ; CAMI grit designation 60; average particle diameter 265 ⁇ ; medium-grade particle range 190 - 265 ⁇ )
  • fine- grade grit for example fine-grade 120 (ISO/FEPA grit designation P120, average particle diameter 125 ⁇ ; CAMI grit designation 120; average particle diameter 1 15 ⁇ ; fine-grade particle range 1 15 - 162 im) or very fine-grade grit, for example fine- grade 150 (ISO/FEPA grit designation P150, average particle diameter 100 ⁇ ; CAMI grit designation 150; average particle diameter 92 m; very fine-grade particle range 68-100 ⁇ ).
  • the grit is a combination of coarse-grade, medium- grade, fine-grade and very fine-grade grit.
  • the non-biological material comprises grit of coarse-grade 40 or medium-grade 70.
  • the non-biological material comprises grit of coarse-grade 40.
  • a method for producing a synthetic skin wherein the non-biological material is sandpaper.
  • abrasive surfaces are recognised as readily available, cost effective and easy-to-use, thus providing a simplistic and reliable means of permanently imprinting a roughened surface onto a curable polymer, to provide a synthetic skin with a topographically-modified surface that enables an agent to spread on its surface in a manner representative of said agent's spread on biological skin.
  • abrasive surfaces such as sandpaper comprising different grit grade (for example coarse-grade, medium-grade or very fine-grade), can be varied according to the agent to be tested.
  • the appropriate grit grade of the rough surface for use as an embedding surface to produce a synthetic skin, can be determined by testing of a given agent's spread on the surface of the resultant synthetic skin, and its corresponding agent spread on biological skin.
  • a method for producing a synthetic skin wherein the rough surface of the non- biological material is pre-coated with a non-stick substance.
  • non-stick substance' includes, but not exclusively, nano-particulate or liquid constitutions providing durability, smoothness and/or conferring the rough surface with an ability to repel foreign substances (i.e. 'super-phobic') such as oil, water, chemicals and soiling agents, prior to depositing the curable polymer on to the rough surface.
  • 'super-phobic' i.e. oil, water, chemicals and soiling agents
  • the non-stick substance comprises silicone dioxide (S1O2) liquid glass, one or more fluorine- containing chemical(s), manganese oxide polystyrene or zinc oxide polystyrene.
  • the pre-coating substance is a silicon dioxide liquid glass super-phobic coating ('nanoglass'), for example Radaglass® liquid glass.
  • a method for producing a synthetic skin wherein non-bonded siloxane components are extracted from the cured polymer, the method comprising the steps of: immersing the cured polymer in an organic solvent; removing the cured polymer from the organic solvent; draining the cured polymer to remove non-bonded siloxane components; and air-drying the cured polymer.
  • Organic solvent' is known to the person skilled in the art and includes carbon-containing compounds, in particular liquid compounds, used to extract soluble compounds from other substances.
  • Organic solvent' includes compounds such as isopropanol, ethanol and ethyl acetate.
  • this embodiment is advantageous as this extracting step removes the presence of components, in particular non-bonded siloxane components, which may interfere with post-decontamination quantification of residual chemical or simulant, for example during gas chromatography analysis.
  • the embodiment is performed at least once, preferably three times, to ensure removal of non-bonded siloxane components.
  • this embodiment includes a final quality control step comprising removing a section of the synthetic skin for subsequent analysis, for example gas chromatography analysis, to confirm the absence of interfering components.
  • the organic solvent is isopropanol.
  • a method for producing a synthetic skin wherein hair is embedded into the synthetic skin.
  • the embodiment could be achieved by initially incorporating the hair onto the rough surface of the non-biological material, said hair in turn becoming incorporated into the curable polymer upon deposition of the curable polymer on the non- biological material having a rough surface.
  • hair is firstly applied to the pre-coated, non-biological material having a rough surface by inserting each hair into a fabricated root appendage or hair bulb.
  • the rough surface is in contact with the curable polymer and the hair or, as required, root appendage, also embeds into the curable polymer.
  • a synthetic skin wherein the average thickness of the synthetic skin is greater than 0.35 mm. In a further embodiment, the average thickness of the synthetic skin is 1.11 mm ⁇ 0.23 mm.
  • a synthetic skin as a physical model, wherein the synthetic skin is prepared according to the above- mentioned methods.
  • the agent for testing using the synthetic skin as a physical model is a chemical agent.
  • the agent for testing using the synthetic skin as a physical model is a liquid chemical agent.
  • Methyl salicylate (MS) and tributyl phosphate (TBP) were purchased from Sigma- Aldrich (UK). RadaglassTM fibre protect S2 was purchased from Radal Technology (UK). PL red 515 (Petroleum Logistics, UK) was used to ' dye MS. Close-clipped porcine skin from the abdominal area of 3 healthy pigs (Sus scrofa, Oxford Landrace strain; weight range 15-20 kg) was dermatomed to a nominal 500 pm thickness using a ZimmerTM air dermatome (Zimmer LTD, Dover Ohio, USA). Skin specimens were stored flat and wrapped in tin foil on cardboard within a freezer (- 20°C) prior to use. The use of animals was conducted in accordance with the Animals (Scientific Procedures) Act 1986.
  • Nitrile and neoprene (polychloropene) polymer sheets were purchased from PAR Group Ltd.
  • Translucent silicone and pigmented silicone (red) polymer sheets were purchased from SAMCO Ltd.
  • Smooth-on Dragon skin FX Pro, Dragon Skin Medium 10, Dragon Skin Body Double brush-on silicones were purchased from Bentley Advanced Materials (UK).
  • Coarse-grade (40) and medium-grade (70) sandpaper was purchased from Wickes, UK.
  • Grade P150 emery cloth was purchased from Radio-spares, UK.
  • the commercial off-the-shelf silicone (Dragon Skin FX Pro (DSFXP)) was prepared in accordance to manufacturers instructions: liquid rubber Part B (polyorganosilioxanes, amorphous silica) was mixed thoroughly into Part A (polyorganosilioxanes, amorphous silica, platinum-siloxane complex) using a 1 :1 ( ⁇ / ⁇ ratio.
  • the liquid silicone was deposited onto nano-glass (RadaglassTM fibre protect S2) pre-coated sandpaper (Wickes, UK), which was attached to a flat metal surface using tape along its periphery.
  • Sandpaper coarse-grade 40, medium-grade 70 or very fine-grade 150 was pre- coated by spraying nanoglass over its surface and drying at ambient conditions prior to roughened silicone preparation.
  • the liquid silicone was slowly drawn over the sandpaper using a 30 mm width film applicator (Sheen Instruments, UK) set to 2.2 mm using adjustable micrometers. The slow motion ensured the mixture was not moved so fast that it 'pulled' creating excessive air bubbles.
  • the silicone sheet was cured at 23°C for a minimum of 1 hr, during which the sandpaper acted as a mould to form a roughened topography, on to the surface of the silicone sheet. Any air bubbles in the silicone rose out of the silicone as it cured leaving a uniform sheet of silicone at the end of the process.
  • the roughened DSFXP silicone required further treatment so that it could be used for the post-decontamination quantification of residual simulant. This was due to non- bonded siloxane components that were extracted from the roughened silicone in I PA and which overlapped with the MS retention time in the gas chromatogram. This necessitated their extraction from the roughened silicone by immersion in isopropanol (1 ml/cm 2 isopropanol to silicone) and then air-drying under ambient conditions for 24 hrs prior to its use in experiments. This pre-conditioning typically required 3 consecutive extractions over 3 days in isopropanol, where the silicone sheet was drained as well as possible between extractions.
  • a 25 cm 2 section of the silicone was removed and placed into 10 ml isopropanol for 12 hrs and then sampled for gas chromatography (GC) analysis (i.e. the final extraction was performed in the same or smaller volume of solvent that would be used to extract the silicone in the decontamination experiment).
  • GC gas chromatography
  • the thickness of the roughened DSFXP silicone following the above processes was measured using a digital calliper as 1.11 mm ⁇ 0.23 mm.
  • a high-throughput screen was developed to initially select the most suitable surrogates for downstream testing.
  • the porcine skin or skin surrogate (25 cm 2 surface area) was placed onto an 11 ⁇ im pore Whatman Grade 1 filter paper laid flat against a glass plane.
  • a 4 ⁇ MS or TBP drop (dyed with 1 % PL Red 515 dye) was deposited onto the surface of the porcine skin/skin surrogate using a positive- displacement Eppendorf Multipipette.
  • a glass block 25 cm 2 , 87.7g ⁇ 0.23g was then placed onto the drop to provide an applied pressure of 0.35 kPa. The lateral spread area photographed through the glass weight was recorded at 15 minutes post- application of the glass weight.
  • the area was measured using these photographs following scale-setting and freehand selection by Image J v.1 .40g software.
  • the glass weight was then carefully removed to observe whether unabsorbed simulant remained on the porcine skin/skin surrogate surface.
  • the porcine skin/skin surrogate was removed to observe whether simulant had broken-through onto the filter paper or was on the underside of the skin sample.
  • porcine skin 500 ⁇ dermatome
  • porcine skin 500 ⁇ dermatome
  • 50 % ethanol in water 50:50 v/v
  • Rubber polymers were washed in isopropanol (3 x 3 s swirls) and then dried overnight prior to performing the test.
  • This test was designed to obtain quantitative information on the mass of liquid CW simulant absorbed into silicone or porcine skin following contact with an absorbent or non-absorbent contact medium.
  • the porcine skin/skin surrogate was placed onto a (lower) glass block and a 2 ⁇ drop of MS was deposited using a positive-displacement Eppendorf Multipipette.
  • a low-force Thermo Finnipippete was used to dispense a 2 ⁇ drop carefully onto the surface.
  • the MS mass was calculated from its density upon weighing the dispensed drop on the silicone surface.
  • the initial contamination mass for drops deposited onto porcine skin was determined through an independent experiment where the operator mean mass dispensed was calculated from several drops deposited onto roughened silicone.
  • the contaminated silicone / porcine skin was contacted with either: an absorbent clean room wipe (CRW; VWR, UK) applied to the drop at 2.35 kPa (using one glass block weighing 87.7 g and a 500 g brass weight over a 25 cm 2 surface) for 3 seconds; or a non-absorbent glass block applied to the drop at 2.35 kPa (using one glass block weighing 87.7 g and a 500 g brass weight over a 25 cm 2 surface) for 3 seconds.
  • an absorbent clean room wipe (CRW; VWR, UK) applied to the drop at 2.35 kPa (using one glass block weighing 87.7 g and a 500 g brass weight over a 25 cm 2 surface) for 3 seconds
  • a non-absorbent glass block applied to the drop at 2.35 kPa (using one glass block weighing 87.7 g and a 500 g brass weight over a 25 cm 2 surface) for 3 seconds.
  • MS absorbed into porcine skin/skin surrogate were extracted using consecutive 24 h extractions, where the first extraction was in 10 ml propan-2-ol (IPA) and second or third extracts were in 11 .13 ml IPA until no MS was detected in the final extract by GC.
  • the silicone was washed under 20 ml IPA flow (10 ml IPA on each side) to prevent MS carry-over between extraction vessels.
  • the upper and lower glass blocks were placed into a jar and washed under a flow of propan-2-ol (10 ml). All extracts and washes were sampled and quantified by GC.
  • medium an absorbent clean room wipe CRW; WVR, UK
  • the MS in CRW was extracted in 20 ml IPA and washed with 10 ml IPA (each side) between extractions.
  • ANOVA analysis-of-variance
  • Quantification of MS in extracts and washes was performed using an Agilent Technologies 6890N Network GC System. Quantification of MS solutions was performed using an Agilent Technologies 6890 GC System. An autoinjector was used to introduce liquid samples into the capillary using on-column injection (2.5 ⁇ volume, 50 °G). Samples were eluted from the capillary column (Agilent DB-WAX 30 m length x 0.530 mm megabore x 0.5 pm film thickness) using He carrier gas (10 ml min "1 flow, 6.82 psi, 66 cm/s).
  • a temperature program method was utilised: the oven was initially held at 50°C (2 min), followed by a 50°C/min ramp, and finally held at 150°C (8 min). Eluent was analysed using a flame ionisation detector (FID, 250°C).
  • FID flame ionisation detector
  • This test was designed to observe the spreading behaviour of drops deposited onto the porcine skin or skin surrogate surface at an incline.
  • a glass block was placed onto a weighted stand at a 51 ° incline.
  • a video camera was used to capture temporal drop spread over a ca. 1 min.
  • the porcine skin (500 pm dermatome) was thawed and conditioned in 50 % ethanol in water (50:50 v/V) at 32°C for 1 h; it was then removed and excess fluid from the skin surfaces was blotted-off prior to performing the screen test. Rubber polymers were washed in isopropanol (3 x 3 s swirls) and then dried overnight prior to performing the test. Roughened Silicon Application to Mannequin Head-Form
  • the roughened silicone was fixed to a metal head-form for immediate decontamination experiments.
  • An undercoat of Dragon Skin FX Pro (DSFXP) silicone mix (Part A:B, 1 :1 ⁇ / ⁇ was applied to the underside of the roughened silicone.
  • the roughened silicone was then attached to the head-form using cable ties and goggles. This ensured the silicone maintained contact with the head surface and facial contours (particularly around the eye sockets, nose) as the "silicone-glue" undercoat dried overnight.
  • the cable-ties and goggles were removed following the -drying process for Immediate Decontamination experiments.
  • the roughened silicone was firstly overlaid on to the head-form and areas around the eyes, lower part of the nose and the left and right side of the mouth were cut away.
  • the roughened silicone was then fixed to a metal head-form using a spray COTS adhesive that was pre-screened to ensure absence of interfering chromatographic peaks that would affect MS quantification by GC.
  • Spray mount (3M) was applied to the underside of the roughened silicone and swiftly transferred to the head-form, where it was fastened using the procedure outlined in the above section. This was necessitated by the adhesive quickly becoming brittle and foam-like due to latent heat during its application. Following drying of the adhesive and release of the silicone from the cable ties, tape was used at the edges of the silicone to further secure it to the head-form.
  • the head-form was fitted with a GSR by Respirator Technicians at Dstl's Chamber Facility.
  • the respirator size was 3 and the oro-nasal silicone rubber was size 3.
  • the following strap adjustments were made: crown straps: position 8; side straps: position 15; and adjustable jaw straps: position 34.
  • the GSR was applied to the head -form by inserting the mannequin chin into the yoke and then fitting the straps using the settings above.
  • the GSR was applied to the head-form by inserting the mannequin chin into the yoke and then fitting the straps.
  • a vacuum pump drew air from the inlet of the drinking straw, which was situated within the oro-nasal (inside) area of the GSR. This air was drawn through a series Of Tenax tubes that were attached, but-to-but, to the end of the drinking straw. This method de-risked the loss of analyte vapour to vacuum pump.
  • the air flow was set to 15 L / min using a flow meter.
  • the system was checked for leaks by closing the value to the straw, which was located outside the GSR, and ensuring the flow dropped to 0 L / min *1 . Sample tubes were analysed using different analytical approaches depending on the expected amounts of MS vapour evaporating from the roughened silicone surface, pre and post decontamination.
  • Unilateral nuclear magnetic resonance was used to obtain proton depth- profiles of pre-conditioned DSFXP silicone to measure impregnation of roughness.
  • the instrumental parameters used to obtain the measurement are as follows. Depth profiles were obtained using a PM2 Profile NMR-MOUSE (Act Mobile NMR Solutions, Aachen, Germany). The NMR data was collected using an 8 mm x 8 mm (x-y dimensions) x 10 m (z direction) sensitive volume.
  • the T1 (spin-lattice relaxation time) of the roughened silicone was used to inform the time required between repetitions of the basic sequence in the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence and to achieve the maximum sensitivity per unit time; a repetition time (Rj) of 1 .5 * T1 (630 ms) was used.
  • the sensitive volume was positioned within the roughened silicone to measure the raw probe amplitude, which was used as the normalisation value (188 A.U), for each depth profile.
  • the Fourier transform of 32 CPMG scans was averaged and used to obtain the signal amplitude at each depth, with a 10 ⁇ step size, and measurements repeated by resampling a minimum of 3 times. Thickness was determined to be the z-axis range within which a signal above that of noise was detected.
  • a high-throughput screen was developed to initially select suitable surrogates for downstream testing.
  • the test provided information on the following parameters that were used to compare with skin response:
  • MS methyl salicylate
  • TBP tributyl phosphate
  • PTFE polytetraflurorethylene
  • WTP hydrophobic and inert polytetraflurorethylene
  • WTP hydrophobic and inert polytetraflurorethylene
  • WTP hydrophobic and inert polytetraflurorethylene
  • WTP hydrophobic and inert polytetraflurorethylene
  • WTP hydrophobic and inert polytetraflurorethylene
  • WTP hydrophobic and inertetraflurorethylene
  • DSFXP silicone was further investigated as a potential synthetic skin surrogate due to: (a) absence of simulant breakthrough at high pressures (10 kPa) and (b) a droplet contact angle is formed upon its deposition onto the DSFXP surface. Additional benefits of DSFXP silicone were: translucent when cured, which broadens its application in experiments, particularly in the use of dyed simulants to determine contamination spread; can be procured as liquid silicone for easy application to body-forms; fast cure time (ca. 1 hr at 23°C); MS absorbed into DSFXP can be solvent extracted; and MS absorption into DSFXP is comparable with its absorption into porcine skin.
  • a head-form was brush-coated with DSFXP silicone mix (Part A:B, 1 :1 v/v) and cured at 23°C for 3 hrs.
  • the silicone was within 1 mm thick across all areas of the head, which is suitable for ensuring quantification of post-decontamination residual MS by extraction.
  • the surface charge on the roughened silicone could be sustained due to its well-known properties as an electrical insulator.
  • the electric field resulting from a surface charge can be enhanced by surface roughness. Repulsion between charged liquids deposited onto charged surfaces can cause liquid droplets to expel microdroplets upon contact. Thus, methods were pursued to minimise this surface charge.
  • Antistatic gun projects a stream of positive and negatively charged particles towards the substrate when a trigger is pressed.
  • the antistatic gun was fired at the skin surrogate from a distance of approximately 15 cm to neutralise surface charge.
  • Anti-static bar The anti-static bar generates an electrical field that causes air molecules in the vicinity of the bar to break down into positive and negative ions.
  • the bar was operated at its optimum distance from the roughened silicone surface (40 - 100 mm). Charge neutralisation of the silicone took place under the following conditions:-
  • Tap water contains many ions, which may neutralise surface charge.
  • the roughened DSFXP sample was immersed in a tap water bath for 10 s before drying on filter paper.
  • Aqueous sodium hydroxide wash The roughened silicone was immersed in a 1 M NaOH bath for 10 s before drying on filter paper. An additional pre-treatment was performed in the same manner as methods 3 and 4 using isopropanol (IPA) solvent. Although IPA is a non-ionic solution, it was used during the preconditioning of the roughened silicone to enable quantitative measurement of post-decon residual MS in this study.
  • IPA isopropanol
  • Nano-glass is a silicon dioxide (Si0 2 ) liquid glass super-phobic coating.
  • Unilateral nuclear magnetic resonance (NMR) proton density depth-profiling was used to determine the depth at which the roughness was impregnated into the DSFXP silicone bulk. A gradual increase in proton density from the surface of the silicone into its bulk over 250 pm was observed; this is indicative of the thickness of the surface roughness. Beyond this region the silicone had a constant proton density. The mechanical stability of the roughened silicone significantly reduced when the silicone was less than ca. 350 pm, i.e. thicknesses that approached or impinged on the impregnated roughness.
  • the contact test was repeated but without the absorbent CRW so that the contact medium was a non-absorbent glass block.
  • the post-contact mass distribution using these contact parameters also showed little difference in the mass distribution of MS measured with roughened silicone with that measured using porcine skin. This was supported by 2-way ANOVA of this dataset.
  • the post-contact residual MS on the roughened silicone surface better represented the mass-distribution of MS on porcine skin compared with smooth silicone. Residual droplets of dyed MS were observed on the glass contact medium following contact with porcine skin or roughened silicone dosed with a MS drop (at 0.4 kPa for 15 min); in contrast, trace contamination was observed on the glass post-contact with a MS drop on smooth silicone under the same contact conditions.
  • the blot-bang-rub procedure was carried out as directed by the printed instructions on the DKP 1-MK1 packaging.
  • the contamination spread area, on the FE (Fullers Earth) pad was measured following the above procedure using Image J software to provide an approximation of the spread on the silicone.
  • the experiment was conducted on porcine skin (pre-conditioned in 50% ethanol in water at 32 °C for 1 hr before patted dry using filter paper), which was secured to the head form at the same location as for the silicone experiment (above left eyebrow, the experiment was also conducted with 4 ⁇ TBP on porcine skin and roughened silicone but at a different location (right cheek).
  • Table 3 compares the dyed simulant spread areas on the DKP 1 -MK 1 pad following the above decontamination experiments.
  • the spread area for each MS drop could be measured directly on the silicone due to an improved visibility of the spread drop.
  • Earlier experiments administered blot-bang- rub directly onto a single contamination site resulting in significant FE deposition and masking the spread drop.
  • blot-bang-rub was administered over a larger area and multiple contamination sites, which ultimately deposited less FE per unit area.
  • the greatest spread of dyed MS coincided with contamination sites that were in-line with the GSR seals; these drops had been under contact pressure.
  • the MS (dyed) spread data determined the contamination sites and guidelines for excising silicone sections from the head-form without under-sampling the post-decon residual contamination. Each excision was made around the contamination site within a 16 cm 2 area.
  • the preconditioning process removed interferents from the silicone that leached into the extraction fluid and interfered with subsequent GC quantification of post-decon residual MS. Therefore, it was not possible to use the DSFXP silicone as an adhesive to attach the pre-conditioned roughened silicone to the head-form, since this would re-introduce the interferents.
  • Alternative adhesives were investigated to attach the roughened silicone to the metal head-form (3M Spray Mount; Wickes PVA; Wickes High Strength; UHU Twist & Glue; Staples Liquid Glue Pen; Monett Black Witch).
  • the range of Commercial-Off-The-Shelf adhesives had different bonding strengths, viscosities, application methods and drying times.
  • Each adhesive was tested to ensure absence of interfering peaks for GC quantification of MS (data not shown).
  • the experiment was performed by depositing approximately 0.1 cm 3 of the adhesive into a glass vial, which was left open to the air (at ambient conditions) to allow the adhesive to cure over 12 hours. Following this period, the cured adhesive was exposed to 10 ml IPA (the same volume used to extract MS from silicone sections) and then sampled for GC analysis at 12 hours post-exposure. PVA was the only adhesive that produced an interfering chromatographic peak and was not taken forward to further experiments. The strength of the adhesive to bond the roughened silicone to the head-form was assessed.
  • the force required to peel the sections off the head-form was made by a single operator and scored between 0 and 4 (in order of increasing adhesive strength).
  • the neoprene Black Witch adhesive provided the highest bonding strength and stability during the blot-bang-rub drill, it was supplied as a viscous liquid in a small volume. This makes it problematic to sufficiently cover roughened silicone of an area to fit the face of the head-form.
  • the adhesive on the underside of the roughened silicone may potentially affect the efficiency for extracting bulk MS by solvent extraction.
  • the extraction efficiency of MS from adhesive-backed silicone was measured following a contact test (Table 4).
  • Samples of preconditioned roughened silicone (5 cm x 5 cm) were coated with an under layer of 3M Spray Mount adhesive. The samples were left to cure for 12 hours prior to performing the contact test. A 2 ⁇ MS drop was deposited onto the adhesive- backed roughened silicone and then contacted with a glass block at 6 kPa applied pressure for 15 min. Following this period, the silicone was solvent extracted in 3 x IPA baths (first extract in 10 ml IPA, second or third extracts in 11. 3 ml IPA), where no simulant was detected in the final extract. Note, each side of the silicone was washed in 10 ml IPA to remove MS carry-over as it was transferred between extraction vessels.
  • the mean total recovery was 97.5% ⁇ 14.7% ( ⁇ 95 % CI) upon summing the amounts recovered from washing the non-absorbent contact medium (upper glass block) and the amount on/in silicone.
  • the GSR was doffed and the head- form decontaminated using a controlled blot-bang-rub procedure with one DKP 1-MK 1 pad. This entailed blotting each contamination site once (knuckle-to knuckle method), banging each contamination site once to release FE (using opposite fresh side of the pad) and rubbing each contamination site once. Note the rubbing procedure involved rubbing the FE away from the head-form. The time taken to administer the blot-bang-rub procedure using the above parameters was 38 seconds.
  • the controlled method used to apply the blot-bang-rub process ensured that each contamination site was contacted with each step of the process using the minimum number of touches (x1). This provided a well-controlled baseline to determine the relative efficacies of any future modifications to the processes.
  • the inside of the GSR was then decontaminated using the same DKP 1-MK 1 pad as was used for the head-form.
  • the peripheral seal was banged to release the FE and this action was continued on all parts of the GSR working inwards.
  • the visor area was wiped as well as the flaps of each seal.
  • the GSR was then fitted onto the head-form and a second series of three Tenax tubes was immediately attached to the end of the drinking straw.
  • the pump was started and the post-decontamination residual simulant vapour was sampled from inside the GSR for 5 minutes.
  • the GSR was doffed after vapour sampling and the roughened silicone carefully excised.

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Abstract

La présente invention concerne une peau synthétique, et son procédé de production et d'utilisation en tant que modèle physique, pour l'évaluation de processus sur la peau.
PCT/GB2015/000192 2014-06-23 2015-06-23 Peau synthétique WO2015198002A1 (fr)

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EP15732876.6A EP3158555A1 (fr) 2014-06-23 2015-06-23 Peau synthétique

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GB1411131.4A GB2527513B (en) 2014-06-23 2014-06-23 Synthetic skin
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107941984A (zh) * 2017-11-14 2018-04-20 北京工业大学 一种检测管道中颗粒物浓度的离子色谱方法
WO2019083904A1 (fr) 2017-10-23 2019-05-02 Chan Zuckerberg Biohub, Inc. Mesure de glycanes fc d'igg afucosylés et procédés de traitement associés
CN113574584A (zh) * 2018-08-30 2021-10-29 诺曼底勒阿弗尔大学 非生物性皮肤模型

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US4937030A (en) * 1986-07-21 1990-06-26 Mitusboshi Belting Ltd. Method of fabricating a slush mold and skin made therefrom
JPH03165772A (ja) * 1989-11-24 1991-07-17 Aderans Co Ltd 人工皮膚及びこれを利用した脱毛教習用ベース
US20070288186A1 (en) * 2006-02-10 2007-12-13 Saswati Datta Methods of use of substrate having properties of keratinous tissue

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US5211894A (en) * 1990-10-09 1993-05-18 Amway Corporation Skin replication technique
WO2007021844A2 (fr) * 2005-08-12 2007-02-22 The Procter & Gamble Company Substrat revêtu des propriétés d'un tissu kératinique
US10144204B2 (en) * 2007-01-08 2018-12-04 The Procter & Gamble Company Substrate having properties of mammalian skin
EP2527817B1 (fr) * 2008-06-13 2015-07-01 Shiseido Company, Ltd. Membrane de substitution cutanée, moule métallique, et procédé d' évaluation d'un agent pour une application externe sur la peau

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Publication number Priority date Publication date Assignee Title
US4937030A (en) * 1986-07-21 1990-06-26 Mitusboshi Belting Ltd. Method of fabricating a slush mold and skin made therefrom
JPH03165772A (ja) * 1989-11-24 1991-07-17 Aderans Co Ltd 人工皮膚及びこれを利用した脱毛教習用ベース
US20070288186A1 (en) * 2006-02-10 2007-12-13 Saswati Datta Methods of use of substrate having properties of keratinous tissue

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Title
See also references of EP3158555A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019083904A1 (fr) 2017-10-23 2019-05-02 Chan Zuckerberg Biohub, Inc. Mesure de glycanes fc d'igg afucosylés et procédés de traitement associés
CN107941984A (zh) * 2017-11-14 2018-04-20 北京工业大学 一种检测管道中颗粒物浓度的离子色谱方法
CN113574584A (zh) * 2018-08-30 2021-10-29 诺曼底勒阿弗尔大学 非生物性皮肤模型

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