WO2009097660A1 - Patch production - Google Patents
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- WO2009097660A1 WO2009097660A1 PCT/AU2009/000142 AU2009000142W WO2009097660A1 WO 2009097660 A1 WO2009097660 A1 WO 2009097660A1 AU 2009000142 W AU2009000142 W AU 2009000142W WO 2009097660 A1 WO2009097660 A1 WO 2009097660A1
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- WIPO (PCT)
- Prior art keywords
- projections
- passivant
- etching
- mask
- etchant
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B81—MICROSTRUCTURAL TECHNOLOGY
- B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
- B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
- B81C1/00015—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
- B81C1/00023—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems without movable or flexible elements
- B81C1/00111—Tips, pillars, i.e. raised structures
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J37/00—Discharge tubes with provision for introducing objects or material to be exposed to the discharge, e.g. for the purpose of examination or processing thereof
- H01J37/32—Gas-filled discharge tubes
- H01J37/32009—Arrangements for generation of plasma specially adapted for examination or treatment of objects, e.g. plasma sources
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J37/00—Discharge tubes with provision for introducing objects or material to be exposed to the discharge, e.g. for the purpose of examination or processing thereof
- H01J37/32—Gas-filled discharge tubes
- H01J37/32431—Constructional details of the reactor
- H01J37/3244—Gas supply means
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B81—MICROSTRUCTURAL TECHNOLOGY
- B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
- B81B2201/00—Specific applications of microelectromechanical systems
- B81B2201/05—Microfluidics
- B81B2201/055—Microneedles
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
- H01J2237/32—Processing objects by plasma generation
- H01J2237/33—Processing objects by plasma generation characterised by the type of processing
- H01J2237/334—Etching
Definitions
- the present invention relates to a method and apparatus for producing projections provided on a patch, and in particular to a method and apparatus for producing projections by etching a substrate.
- WO2005/072630 describes devices for delivering bioactive materials and other stimuli to living cells, methods of manufacture of the device and various uses of the device, including a number of medical applications.
- the device comprises a plurality of projections which can penetrate a body surface so as to deliver the bioactive material or stimulus to the required site.
- the projections are typically solid and the delivery end section of the projection is so dimensioned as to be capable of insertion into targeted cells to deliver the bioactive material or stimulus without appreciable damage to the targeted cells or specific sites therein.
- the projections typically need to have a sufficient length to pierce the stratum corneum.
- the projections include sub-millimetre and micron sized needles or blades that can be effective in delivering material through the skin.
- a number of different techniques have been proposed for forming patches of needles.
- US-6,334,856 and US-6,503,231 describes microneedle devices for transport of therapeutic and biological molecules across tissue barriers.
- an appropriate masking material e.g., metal
- the wafer is then subjected to plasma based on fluorine/oxygen chemistries to etch very deep, high aspect ratio trenches into the silicon.
- US-5,201,992 describes methods for forming tapered silicon structures, of interest for use in atomic force microscopes, in field-emission devices, and in solid state devices are made using silicon processing technology. Resulting tapered structures have, at their tip, a radius of curvature of 10 nanometres or less. Such preferred silicon structures are particularly suited as electron emitters in display devices.
- the projections produced using fluorine/oxygen based etching tend to have a concave profile, particularly when applied to projections having a length of less than 500 ⁇ m, resulting in a narrow tip, which is thin and liable to breakage. This limits the ability of such projections to adequately deliver stimulus or material to a subject, which in turn limits their effectiveness.
- Etching processes tend to lead to a bullseye effect, in which there are variations in the effectiveness of the etching process across a wafer being etched.
- some of the patches are unusable as they are inadequately or over etched.
- fluorine/oxygen etching process the bullseye effect tends to lead to a high percentage of unusable patches, such as about 40%. This high rate of inefficiency leads to high production costs due to the expense of the wafer material.
- US-6,551,849 describes an alternative technique that involves forming an array of microneedles by creating an array pattern on the upper surface of a silicon wafer and etching through openings in the pattern to define micro-needle sized cavities having a desired depth, to thereby form a mould.
- the mould thus formed may be filled with electrically conductive material, after which a desired fraction of the silicon wafer bulk is removed from the bottom- up by etching, to expose an array of projecting micro-needles.
- the present invention seeks to ameliorate any one or more of the disadvantages of the prior art.
- the present invention provides a method of producing projection on a patch, the method including: a) providing a mask on a substrate; and, b) etching the substrate using an etchant and a passivant to thereby control the etching process and form the projections, wherein the passivant does not include oxygen.
- the mask includes an organic photo-resist.
- the passivant is a gas including: a) at least one of: i) carbon; and, ii) silicon; and, b) at least one of: i) chlorine; and, ii) fluorine.
- the passivant is at least one of: a) a per-fluoride hydrocarbon; and, b) a fluorinated olefine; c) Octafiuorocyclobutane; d) Perfluoroisobutene; and, e) C 4 F 8 .
- the etchant is a gas or plasma.
- the etchant is sulphur hexa-fluoride.
- the method includes, controlling the etching process by varying etching parameters including at least one of: a) a ratio of the etchant to the passivant; b) a gas flow for at least one of the etchant and the passivant; and, c) a pressure for at least one of the etchant and the passivant.
- the ratio is in the range of 0.25 to 0.60.
- the pressure of at least one of the etchant and the passivant is in the range of 0 to 26.7 Pa (0 to 200 mT).
- the pressure of at least one of the etchant and the passivant is in the range of 0.67 to 8.0 Pa (5 to 60 mT).
- the etchant is supplied at a flow rate in the range of at least one of: a) 0 to 200 seem; and, b) 40 to 120 seem.
- the passivant is supplied at a flow rate in the range of at least one of: a) 0 to 200 seem; and, b) 10 to 80 seem.
- the method includes: a) applying a mask material to the substrate; and, b) selectively exposing the mask material to radiation to thereby form the mask.
- the mask material is at least one of: a) an organic photo-resist; b) a polymer mask; and, c) a crosslinked epoxy resin.
- the mask material is Su-8.
- the method includes, performing post-etch processing.
- the method includes, chemically sharpening the projections.
- the method includes, sharpening the projections by: a) forming a silicon dioxide layer on the projections; and, b) removing the silicon dioxide layer.
- the method includes forming a silicon dioxide layer on the projections by heating the projections in an oxygen rich environment.
- the method includes heating the projections to a temperature of greater than 1000 0 C.
- the method includes removing the silicon dioxide using 10%HF.
- the method includes, applying a coating to the projections.
- the coating is a metallic coating.
- the method includes using sputter deposition to deposit: a) an adhesion layer; and, b) a metallic layer on the adhesion layer.
- the adhesion layer includes chromium.
- the metal layer includes gold.
- the method further includes coating the projections with a material.
- the material is a therapeutic agent.
- the patch has a surface area of approximately 0.4 cm 2 .
- the projections have a density of between 1,000-30,000 projections/cm 2 .
- the projections have a density of 20,000 projections/cm 2
- the projections have a length of between 10 to 200 ⁇ m.
- the projections have a length of 90 ⁇ m
- the projections have a radius of curvature of greater than 1 ⁇ m.
- the projections have a radius of curvature greater than 5 ⁇ m.
- the projections include a support section and a targeting section.
- the targeting section has a diameter of less than at least one of: a) 1 ⁇ m; and, b) 0.5 ⁇ m.
- a length for the targeting section is at least: a) less than 0.5 ⁇ m; and, b) less than 1.0 ⁇ m; and, c) less than 2.0 ⁇ m.
- a length for the support section is at least one of: a) for epidermal delivery ⁇ 200 ⁇ m; b) for dermal cell delivery ⁇ 1000 ⁇ m; c) for delivery to basal cells in the epithelium of the mucosa 600-800 ⁇ m; and, d) for lung delivery of the order of 100 ⁇ m in this case.
- the present invention provides a method of producing projection on a patch, the method including: a) providing a mask on a substrate, the mask including an organic photo-resist material; and, b) etching the substrate using an etchant and a passivant to thereby control the etching process and form the projections.
- the present invention provides a method of controlling an etching process to thereby produce projections on a patch, the method including: a) etching the substrate using an etchant; and, b) using a passivant other than oxygen to control the etching.
- the present invention provides a method of producing projection on a patch, the method including: a) providing a mask on a substrate; and, b) etching the substrate using an etchant and a passivant to thereby control the etching process and form the projections, wherein the passivant includes at least one of: i) a per-fluoride hydrocarbon; and, ii) a fluorinated olefine; iii) Octafluorocyclobutane; iv) Perfluoroisobutene; and, v) C 4 F 8 .
- Figures IA and IB are schematic side and plan views of an example of device for delivery of material to targets within a body;
- Figure 1C is a schematic diagram of an example of the device of Figure IA in use;
- Figures ID to IF are schematic diagrams of examples of projections used in the device of
- Figure 2 is an example of a secondary electron image of a concave profiled projection
- Figure 3 is an example of a secondary electron image of a straight profiled projection
- Figure 4 is an example of a secondary electron image of a projection having a gold coating
- Figures 5 A to 5C are schematic diagrams of an example of the steps in etching projections in a substrate
- Figures 6 A to 6C are examples of secondary electron images of projections produced using different etching times
- Figure 7 is a graph illustrating an example of the effect of mask dots size and array pitch on etch depth
- Figures 8A to 8C are graphs illustrating examples of the variation in vertical etch rates depending on C 4 F 8 : SF 6 ratios, gas flow rates and gas pressures respectively;
- Figure 9 is a graph illustrating an example of the effect of gas flow rates on projection tip angle
- Figure 10 is a graph illustrating an example of the effect of system pressure on lateral etch rates
- Figure 11 is a graph illustrating an example of the effect of system pressure on etch uniformity
- Figure 12 is a graph illustrating an example of the effect of C 4 F 8 - 1 SF 6 ratio on projection length
- Figures 13A to 13C are examples of secondary electron images of projections following an
- Figures 14A to 14C are secondary electron images of example patches including projections having lengths of 60, 100 and 150 ⁇ m, respectively;
- Figure 14D is a secondary electron image of a projection patch after insertion into a subject
- Figures 15A and 15B are examples of secondary electron images of projections obtained using a high rate Oerlikon etching system
- Figures 16A and 16B are examples of secondary electron images of projections obtained using a high rate STS etching system
- Figure 17 is an example of a secondary electron images of projections obtained using a lower system pressure and power
- Figures 18 A to 18E are secondary electron images of examples of projections having a conical straight edge profile
- Figures 19A and 19B are secondary electron images of examples of projections having a conical convex edge profile
- Figures 2OA to 2OE are secondary electron images of examples of projections having a stepped profile
- Figure 21 is a secondary electron image of examples of projections having a hyper sharp tip
- Figure 22 is a secondary electron image of examples of projections having a conical convex edge generated using a ramped etch process
- Figures 23 A and 23B are secondary electron images of examples of projection arrays having coated and uncoated projections respectively;
- Figures 24A and 24B are examples of CryoSEM images illustrating the penetration of skin by the projections on a patch
- Figures 25A and 25B are examples of CryoSEM images illustrating the penetration of skin by the projections on a patch
- Figures 26A and 26B are secondary electron images of a patch after application to mouse ear skin.
- the device is in the form of patch 100 having a number of projections 110 provided on a surface 121 of a substrate 120.
- the projections 110 and substrate 120 may be formed from any suitable material, but in one example, are formed from a silicon type material.
- the projections may be solid, non-porous and non-hollow, although this is not essential.
- the patch has a width W and a breadth B with the projections 110 being separated by spacing S.
- the patch 100 is positioned against a surface of a subject, allowing the projections to enter the surface and provide material to targets therein. An example of this is shown in Figure 1C.
- the patch 100 is urged against a subject's skin shown generally at 150, so that the projections 110 pierce the Stratum Corneum 160, and enter the Viable Epidermis 170 to reach targets of interest, shown generally at 180.
- this is not essential and the patch can be used to deliver material to any part or region in the subject.
- projections can have a variety of shapes, and examples of suitable projection shapes are shown in more detail in Figures ID, IE and IF.
- the projection includes a targeting section 111, intended to deliver the material or stimulus to targets within the body, and a support section 112 for supporting the targeting section 111.
- a targeting section 111 intended to deliver the material or stimulus to targets within the body
- a support section 112 for supporting the targeting section 111.
- this is not essential, and a single element may be used.
- the projection is formed from a conically shaped member, which tapers gradually along its entire length.
- the targeting section 111 is therefore defined to be the part of the projection having a diameter of less than fife.
- the structure of the projection may vary along its length to provide a defined targeting section 111 with a designed structure.
- the targeting section 111 is in the form of a substantially cylindrical shape, such that the diameter di is approximately equal to the diameter ⁇ % 2 , with a tapered support section, such that the diameter d ⁇ is smaller than the diameter d ⁇ .
- the targeting section 111 is in the form of taper such that the diameter dj is smaller than the diameter d 2 , with a cylindrical support section, such that the diameter d2 is substantially equal to the diameter d ⁇ .
- the support section 112 has a length a, whilst the targeting section 111 has a length /.
- the diameter of the tip is indicated by di, whilst the diameter of the support section base is given by d$.
- the device can be used to deliver material to specific targets within the body or more generally to the blood supply, or tissue within the body and the configuration of the device will tend to depend on its intended use.
- the device can be provided with a particular configuration of patch parameters to ensure specific targeting.
- the patch parameters can include the number of projections N, the spacing S between projections, and the projection size and shape. This is described in more detail in co-pending application USSN-11/496053.
- a patch having a surface area of approximately 0.16 cm 2 has projections provided at a density of between 1,000-30,000 projections/cm 2 , and typically at a density of approximately 20,000 projections/cm 2 .
- alternative dimensions can be used.
- a patch for an animal such as a mouse may have a surface area of 0.32 to 0.48 cm
- a patch for a human may have a surface area of approximately 1 cm .
- a variety of surface areas can be achieved by mounting a suitable number and arrangement of patches on a common substrate.
- the projections typically have a length of between 10 to 200 ⁇ m and typically 90 ⁇ m with a radius of curvature of greater than 1 ⁇ m and more typically greater than 5 ⁇ m. However, it will be appreciated that other dimensions may be used.
- the targeting section typically has a diameter of less than 1 ⁇ m and more typically less than 0.5 ⁇ m.
- the length of the targeting section is typically less than 100 ⁇ m, less than 10 ⁇ m and typically less than 5 ⁇ m.
- the length of the support section typically varies depending on the location of the target within the subject. Example lengths include less than 200 ⁇ m for epidermal delivery, less than 1000 ⁇ m for dermal cell delivery, 600-800 ⁇ m for delivery to basal cells in the epithelium of the mucosa and approximately 100 ⁇ m for lung delivery.
- the process includes providing a mask on a substrate and etching the substrate using an etchant and a passivant to thereby control the etching process and form the projections.
- the etchant is typically a compound formed from a group 16 element and a halide.
- the etchant contains sulphur and fluorine, and may therefore include sulphur hex- fluoride (SF 6 ) or the like.
- the passivant is typically a gas other than oxygen, and in particular typically includes a group 14 element and a halide.
- the passivant is a per-fluoride hydrocarbon such as octafluorocyclobutane (C 4 Fs).
- etchants and passivants other than oxygen allows for a high degree of control to be provided over the etching process.
- adjusting etch parameters such as the passivant to etchant ratio, the gas flow and the system pressure, this allows etching rates to be controlled.
- etching rates to be controlled.
- degree to which the process is isotropic or anisoptropic to be adjusted.
- this allows the shape of the resulting projections to be carefully controlled.
- the mask may be provided on the substrate using any one of a suitable number of techniques. However, in one example, this is achieved by applying a mask material to the substrate and then selectively exposing the mask material to radiation to thereby form the mask.
- the mask material can be formed from an organic photo-resist, such as a crosslinked epoxy resin based polymer.
- an organic photo-resist such as a crosslinked epoxy resin based polymer.
- Su-8 2000 supplied by MicroChem Corp, although other similar related materials can be used.
- Polymer masks are generally significantly easier to create and use, resulting in the process being significantly cheaper than when a hard mask, such as a metal mask is used.
- the above described technique allows for the production of silicon projections to be completed using a combination of optical lithography and deep silicon etching. This allows the profile of the projections to be carefully controlled, thereby allowing projections suitable for use in a range of applications to be created.
- Prior art techniques utilising fluorine/oxygen chemistry provide only extremely limited control over the etching process. This is in part due to the formation of a SiliconOxyFluoride layer on the surface of the wafer as part of the passivation process. Formation of the layer occurs rapidly and is difficult to control. Furthermore, the hardness of the layer means that it tends to interfere with the remainder of the etch process. As a result, it is generally only possible to produce projections having a concaved profile, which in turn results in a narrow tip that is thin and liable to breakage.
- a secondary electron image of an example of a concave profiled projection is shown in Figure 2.
- this avoids the formation of a SiliconOxyFluoride layer, which in turn allows a greater control over projection shape to be achieved.
- this can be used to allow for a more straight profiled conical shape to be produced, an example of which is shown in Figure 3.
- the thicker tip shape this provides for more robust projections which are more capable of delivery of material or stimulus to a desired target within a subject.
- Other shapes can also be provided for, as will be described in more detail below.
- the use of the above described passivants and etchants allows an organic based photo-resists to be used as masks, instead of the metal required by the prior art.
- the organic based photo-resist masks are easier and cheaper to produce. Additionally, these can be of a reduced height as compared to the metal masks required in fluorine/oxygen based etching processes, which in turn provides further control over the resulting patch geometry.
- one or more post-etch processing steps may be performed.
- the projections undergo a chemical sharpening process.
- Chemical sharpening is performed so as to reduce the roughness of the projections, which can in turn enhance the ability of the projections to deliver material or stimulus to targets within the subject.
- Sharpening may be achieved in any one of a number of manners, but in one example, is achieved by forming a silicon dioxide layer on the projections and then subsequently removing the silicon dioxide layer. This process will be described in more detail below.
- a further post-etch process that may be performed is to coat the projections.
- Any suitable coating may be used, and this can include coating the projections with a material to be delivered to the subject, as described for example in co-pending application AU- 2007907092.
- the projection may be coated with a metallic material such as gold. This can assist binding of other material to the projection, and can also improve surface properties to assist in material delivery to the subject.
- An example of a gold coated projection is shown in Figure 4.
- the first step is to produce a plasma etch mask.
- a suitable mask material such as Su-8, which is a photoreactive polymer, is applied to a substrate 500, which in one example is 4 inch, 500 ⁇ m thick 100 silicon wafer.
- the substrate 500 is then spun at an appropriate speed to distribute polymer in a layer 510 over a surface 501 of the substrate 500.
- the spin speed is selected to control the thickness of the mask layer 510.
- the mask layer 510 has a thickness in the region of 7-8 ⁇ m. It will be appreciated that a thicker mask, such as up to 30 ⁇ m may be used.
- the substrate 500 and mask layer 510 are optionally treated. This may be performed, for example to remove any excess solvent, which can be achieved by soft baking the substrate 500 and layer 510 for five minutes at 95 0 C.
- the mask layer 510 can be selectively exposed with radiation 520 to cause the exposed mask material to harden. In one example, this is achieved using a suitable photo-mask 530 and radiation source.
- exposure of the Su-8 film can be performed using chromium on quartz photo-mask and a Carl Suss MA6 mask aligner set to supply lOmJ/second UV light.
- complete cross-linking of the Su-8 polymer occurs after 1.8 seconds of exposure for l ⁇ m of Su-8 thickness, although longer exposure of up to 30 seconds can be used to ensure complete cross-linking of mask layers.
- the substrate 500 and mask layer 510 may again be optionally treated, for example by baking for one minute at 95 0 C. This can be used to promote the formation and release of a Lewis Acids which aids the cross-linking process and formation of a straight sidewall profile for the mask.
- the unexposed mask material can be removed using a suitable solvent.
- the uncross-linked Su-8 can be removed by developing in EC solvent (PGMEA) for two minutes.
- the complete removal of uncross-linked Su-8 can be confirmed by washing the wafer with IPA. If a white precipitated is observed (indicating uncompleted development) the wafer is replaced in the EC solvent for further 30 seconds. Development is completed until no white precipitated is observed upon washing with IPA.
- the excess IPA can be removed by blow drying with dry nitrogen gas.
- the mask layer 510 includes a number of dots 511, as shown in Figure 5B.
- the next stage in the process is the formation of projections by etching. In one example, this is achieved using plasma etching, which can be completed on an STS (Surface Technology Systems) ASE (Advanced Silicon Etch) system. In one example, this is achieved using SF 6 as the etch gas and C 4 F 8 as the passivation gas, although as described above, other gases can be used.
- Controlled continuous isotropic plasma etch process was complete with a plasma gas mixture of SF 6 :C 4 Fg typically in the ratio range of 0.25 to 0.60.
- Vertical, horizontal and projection tip angle can be controlled to provide required projection profiles. This is achieved by ramping or varying the plasma gas condition throughout the etch process, by changing the rate of gas flow, pressure and SF 6 : C 4 F 8 ratios.
- projection profiles of concave to convex shapes can be achieved, as shown at 550, 551, 552 in Figure 5C.
- Example projection profiles obtained in performing etching under similar conditions, but for different time periods are shown in Figures 6A to 6C, which show the result of etching for 40 mins, 45 mins and 50 mins respectively.
- the images highlight how the longer etching time results in a narrower taller projection, as would be expected by the increased amount of etching.
- etching can be performed in multiple stages to provide additional control.
- a continuous etch is performed for approximately 30-60 minutes, with a subsequent etch being performed for a further 15-30 minutes. This allows a projection 560 having a column shaped supporting section 561 and a conical tip 562 to be produced, as shown in Figure 5C.
- the profile of the projection can be formed by altering etching parameters, such as the SF 6 : C 4 F 8 ratio, pressures, or the like, between the different etch steps.
- the wafer 500 can be removed from the ASE system, allowing the wafer and/or passivant to react with the ambient atmosphere. This can alter the effect of the passivant, thereby altering the profiles that can be produced.
- the ability to pause the etching process allows further control over the etching process. For example, the etching can be performed to near completion, with the process then being halted to allow the wafer or patches to be examined to determine the amount of etching required to complete the process. The process can then be resumed and completed.
- Pausing the etching process can be performed as the passivant binds only relatively weakly to the silicon surface. Consequently, even when the passivant has reacted with the ambient air outside the etching system, the passivant can still be removed when etching recommences.
- the passivant in fluorine/oxygen based etching techniques, the passivant binds strongly to the silicon surface through covalent bonding. Consequently, when the wafer is removed from the etching system an oxide layer is formed which cannot be controllably etched. This prevents fluorine/oxygen based etching process from being halted or paused to allow examination of the wafer, which in turn limits the degree of control that can be achieved.
- the achievable height of the projections is dependent on a number of factors, such as the size and pitch (separation) of mask dots.
- An example of the effect of mask dots size and array pitch on etch depth is shown in Figure 7.
- the dots are typically formed with a diameter in the region of 7-8 ⁇ m. This is a smaller dot size than is typically required in a fluorine/oxygen based plasma etching technique.
- plasma conditions effect projection profile control such that vertical silicon etch rates decrease with increasing C 4 F 8 : SF 6 ratios, lower gas flow rates and low gas pressures as shown in Figures 8 A to 8C.
- FIG. 9 is a graph illustrating an example of the effect of system pressure on etch uniformity. This illustrates that in general a lower pressure of below 1.3 Pa (10 mT) is preferred to ensure good etch uniformity.
- Figure 12 is a graph of the effect of C 4 Fs:SF 6 ratio on projection length for etching performed using a 50 ⁇ m dot 70 ⁇ m pitch mask, at 0.3 Pa (2.5 mT), total flow rate 100 seem and power 800 watts. This illustrates that as the C 4 Fg:SF 6 ratio increases, so does the projection length that can be achieved.
- etchant is supplied at a flow rate in the range of 0 to 200 seem (standard centimetre cube per minute), and more typically in the range of 40 to 120 seem.
- Passivant may be supplied at a flow rate in the range of 0 to 200 seem, and more typically in the range of 10 to 80 seem.
- etch parameters such as the passivant to etchant ratio, the gas flow and the system pressure
- this allows projection heights and profiles to be well defined.
- etch parameters such as the passivant to etchant ratio, the gas flow and the system pressure
- a conventional switched BORSH process can be performed. However, this is not essential and may depend on the system being used to perform the etching process.
- the etch mask can be removed and the silicon wafer chemical cleaned. This can be performed using an oxygen plasma and washing of silicon wafer in micro-strip (concentrated H 2 SO 4 peroxide mixture).
- Sharpening of the projections can be achieved via the formation of a silicon dioxide layer on the projections by heating the projections in an oxygen rich environment.
- a 1-2 ⁇ m thick layer of thermal silicon dioxide is formed by heating at 1050 °C under oxygen for 24-48 hours. The oxide is subsequently removed using 10% HF and washing in distilled water.
- Further optional treatment can be performed such as baking the wafer at 100 0 C for 10 minutes to remove residual water.
- gold coating can optionally be preformed using a DC sputter coating system. To achieve this, it is typical to clean the wafer surface using Argon gas sputtering before the depositing 50 nm of Chromium to act as an adhesion layer, followed by 100 nm of Gold.
- a further benefit of the provision of a gold coating is to enhance the physical properties of the projections. Silicon tends to be brittle and as a result can fracture in use due to crack growth. However, the gold provide a soft ductile coating, which tends to absorb unwanted forces and impacts, thereby enhancing the resilience of the projections and reducing their failure rate in use.
- the final wafer may be further cleaned using Argon gas sputtering.
- FIGS 14A to 14C Examples of patches including 60, 100 and 150 ⁇ m length projections are shown in Figures 14A to 14C.
- FIG 14D An example of a projection patch after insertion into a subject is shown in Figure 14D. It can be seen that the projections remain unbroken, highlighting that the projections are strong enough to remain intact after insertion into the subject.
- a suitable passivation gas such as C 4 F 8 allows the direct use of an organic photo-resist (for example Su-8).
- Su-8 is a high aspect ratio negative resist with good plasma etching properties (i.e. selectivity).
- a greatly increased selectivity of mask to silicon etching is found when using a passivant other than oxygen, such as C 4 F 8 . This allows for a simplification in manufacturing by reducing the number of process steps. Firstly the need for deposition of a hard etch mask is removed (no deposition of metals or dielectric required), secondly etching of the hard mask not required and thirdly removal photo-resist not necessary.
- Su-8 is suitable for use in both anisotropic and isotropic etching. Using Su-8 as an etch mask provides a considerable reducing in production costs and time compared to prior art processes.
- a passivation gas such as C 4 F 8 allows a greater control over projection tip profiles to be provided.
- cryo ICP systems are generally expensive to operate and maintain, thereby making this technique unsuitable for use on a mass scale.
- C 4 F 8 as a passivation gas projections with profiles of concave, flat and convex form can be produced.
- the use of parameter ramping allows a high degree of tip profile control to be maintained.
- etching can be paused, allowing additional control over the etching process. This can be used to allow a range of different projection profiles to be produced, as well as to control termination of the etching process more accurately.
- fluorocarbons such as C 4 F 8 also reduces the impact of the bullseye effect, thereby increasing the amount of useable patches resulting from the etching process.
- Chemical sha ⁇ ening and surface morphology changes to silicon projection tips Chemical sharpening to ⁇ 10 nm tip diameter can be achieved, allowing for easier penetration of the stratum corneum with less pressure being required.
- Wet and dry oxidation sharpening methods can be used. Morphological differences have been observed between wet and dry oxidation conditions consequently smooth or porous surface structure can be produced respectively. Porosity can also be further increased using electrochemical methods.
- Gold can be used as an adhesion layer for delivery of DNA and biological materials with using the projections. This can also enhance the physical properties of the projections, thereby reducing their failure rate.
- the above described process provides for the more efficient and cost effective manufacture of projections by plasma etching, as well as enabling greater control over the etching process, to allow specific projection profiles to be created.
- FIG. 15A, 15B, 16A, and 16B A number of example projection shapes are shown in Figures 15A, 15B, 16A, and 16B.
- etching is performed as a two step process, using a SF 6 :C 4 F 8 ratio 2.5 for the first step and a SF 6 :C 4 F 8 ratio 1.2 for the second step. Both steps are performed at 2000 watts, 200 seem total gas flow and 26.6 Pa (200 mT) pressure, using an Oerlikon etching system, which typically can etch at higher rates that the STS ASE system discussed above. In these examples a grainy structure is present at the top of the projections due to excess HF in the chamber.
- Figures 16A and 16B show similar results are obtained for a high rate STS etch.
- the projections have a length of 120 ⁇ m.
- the creation of a grainy structure can be reduced either by using a lower system power and pressure, which results in the smooth shaped projections shown in Figure 17.
- the reduced pressure and power results in a shorter projection having a length of 80 ⁇ m, for similar etching parameters.
- Example patch configuration produced using the above described etching techniques will now be described with reference to Figures 18 to 22.
- the etching parameters are broadly as set out below, resulting in projections having a length of approximately 50-70 ⁇ m depth, sub-micron sharp, 3-to-l base to length aspect ratio, with a straight edge profile: Etch mask 30 ⁇ m dot with 70 ⁇ m pitch; Resist: Su8-5 spun to give 10 ⁇ m thickness Etch: 36 seem C 4 F 8 passivant, 64sccm SF 6 etchant, pressure 0.3 Pa (2.5 mT), power 800 watts coil, 20 watts platen time 50 minutes.
- a similar single stage etching process can be used with different etching parameters to produce projections have dimensions of 30 ⁇ m length, 70 ⁇ m spacing; 50 ⁇ m length, 70 ⁇ m spacing; and 70 ⁇ m length, 100 ⁇ m spacing, as shown in Figures 18C to 18E, respectively. It will be appreciated from this that a range of different conical projections can be produced and that these are for the purpose of example only.
- a single stage etching process is used to produce projections having a conical shape, with a convex profile edge.
- the projections typically have a length of approximately 150 ⁇ m, sub-micron sharp, 5-to-l base to length aspect ratio, with a convex profile:
- a two stage etching process is used to produce stepped projections having a cylindrical base and conical shaped tip.
- etching parameters are broadly as set out below, resulting in projections having a length of approximately 150 ⁇ m depth, hyper sharp, 5-to-l base to length aspect ratio:
- the etching parameters are broadly as set out below, resulting in projections having a length of approximately 80-90 ⁇ m depth, hyper sharp, 5-to-l base to length aspect ratio:
- etching parameters are broadly as set out below.
- a ramped etch is performed to result in a convex edge profile on projections having a length of approximately 60-70 ⁇ m:
- etching parameters described above are for the purpose of example only and are not intended to be limiting.
- the parameters will typically be etching system specific, so that if similar dimensioned projections are to be produced using different etching equipment, appropriate modification of the parameters will be required.
- the projection patches used for this study were designed to give a high probability of Langerhans cell-antigen interaction.
- the patches are fabricated using the etching techniques outlined above in a two step process, to thereby produce projections having a stepped configuration including a conical tip and cylindrical base.
- the projections have a length of 65 ⁇ m and a 50 ⁇ m conical section, atop a 15 ⁇ m cylindrical base.
- the projections have a density of 20,000/cm 2 , with 4mm x 4mm projection area on a 5mm x 5mm silicon base.
- the delivery system for this experiment is a solid coating on the surface of the projections. This coating dissolves once wetted in the skin for the vaccine delivery.
- Vybrant ® DiD a lipophilic fluorescent dye, Molecular Probes Inc., Eugene, Oregon
- Methylcellulose was coated on the array using a nitrogen jet method described in copending application number PCT/AU2008/001903. The dye is used to provide projection penetration tracks when the dye is released from the projections. Concentrations in solution were titrated for minimal diffusion following insertion.
- the skin is prepared for confocal section dye measurement.
- the skin is fixed in 2% Paraformaldehyde in 0.1 M Phosphate buffer, preceding cryo- preservation. Once frozen, 10 ⁇ m thick sections of skin were cut on a cryostat before imaging on a Zeiss LSM510 Meta confocal Multi-Photon Microscope (Carl Zeiss, Inc., Germany).
- Dye delivery highlighting projection tracks were measured in length from the point where the stratum corneum was breached at the edge of the hole, to the lowest dye point in the skin.
- An example of the sections used are shown in Figure 24 A and 24B. Projection holes with significant stratum corneum deflection, obscuring the viable epidermis, were neglected as they represent incomplete penetration.
- FIG. 26A shows the entire patch after application to mouse ear skin
- Figure 26B shows a close- up of nine projections.
- the images show that the patch has large areas covered by corneocytes which have been frozen with liquid nitrogen showing their profiles.
- the frozen corneocytes reveal penetration profiles and show the bulk behaviour of the outermost layer of skin. It is clear that for the case shown , the step in conical projection geometry is acting to restrain entrance to the skin. This is also evident in the Figure 18C where there are circular impressions around projection holes at higher velocities indicative of the step reaching the skin. Projection progression appears to have been restricted by this.
- the quantitative measurement of penetration performance of our MNP patch is from raw data such as the typical histological section shown in Figures 24 A and 24B. This shows a section of mouse ear skin and the corresponding dye delivered. This can be used to measure delivery depth of dye payload, showing successful delivery beyond the stratum corneum. These data show that this device is capable of delivering molecules into the skin.
- the ability to perform a two step etch, and hence produce a stepped projection profile allows the depth of projection penetration to be controlled in use, which can in turn be used to deliver payloads to specific cells or layers of cells in the skin.
- the viable epidermis, and Langerhans cells therein can be targeted directly using a stepped projection profile of appropriate length.
- the projections may be used for delivery not only through the skin but through other body surfaces, including mucosal surfaces, to cellular sites below the outer layer or layers of such surfaces.
- the device is suitable for intracellular delivery.
- the device is suitable for delivery to specific organelles within cells.
- organelles to which the device can be applied include a cell nucleus, or endoplasmic reticulum, for example.
- the device having a needle support section, that is to say the projections comprise a suitable support section, of sufficient length to reach the desired site and a (needle) delivery end section having a length no greater than 20 microns and a maximum width no greater than 5 microns, preferably no greater than 2 microns.
- the maximum width of the delivery end section is no greater than 1000 nm, even more preferably the maximum width of the delivery end section is no greater than 500 nm.
- the device is for mucosal delivery.
- This device may have a needle support section, that is to say the projections comprise a suitable support section, of sufficient length to reach the desired site, such as of length at least 100 microns and a (needle) delivery end section having a length no greater than 20 microns and a maximum width no greater than 5 microns, preferably no greater than 2 microns.
- the device of the invention is for delivery to lung, eye, cornea, sclera or other internal organ or tissue.
- the device is for in-vitro delivery to tissue, cell cultures, cell lines, organs, artificial tissues and tissue engineered products.
- This device typically has a needle support section, that is to say the projections comprise a suitable support section, of length at least 5 microns and a needle delivery end section having a length no greater than 20 microns and a maximum width no greater than 5 microns, preferably no greater than 2 microns.
- the device comprises projections in which the (needle) delivery end section and support length, that is to say the "needle support section”, is coated with a bioactive material across the whole or part of its length, as described in further detail in the copending application AU- 2007907092.
- the (needle) delivery end section and support length may be coated on selective areas thereof. This may depend upon the bioactive material being used or the target selected for example.
- a bioactive material is releasably incorporated into the material of which the needle, or projection, is composed. All, or part of the projection may be constructed of a biocompatible, biodegradable polymer (such as Poly Lactic Acid (PLA), PolyGlycolic Acid (PGA) or PGLA or Poly Glucleic Acid), which is formulated with the bioactive material of choice.
- PHA Poly Lactic Acid
- PGA PolyGlycolic Acid
- PGLA Poly Glucleic Acid
- the device is provided in the form of a patch containing a plurality of needles (projections) for application to a body surface.
- a multiplicity of projections can allow multiple cells and organelles to be targeted and provided with a material at the same time.
- the patch may be of any suitable shape, such as square or round for example.
- the overall number of projections per patch depends upon the particular application in which the device is to be used.
- the patch has at least 10 needles per mm, and more preferably at least 100 needles per mm . Considerations and specific examples of such a patch are provided in more detail below.
- any suitable biocompatible material may be provided as a coating, such as Titanium, Silver, Silicon, or the like. This may be the entire device, or altematively it may only be the projections or the delivery end section of the projections which are made from the biocompatible materials.
- the device may be for a single use or may be used and then recoated with the same or a different bioactive material or other stimulus, for example.
- the device comprises projections which are of differing lengths and/or diameters (or thicknesses depending on the shape of the projections) to allow targeting of different targets within the same use of the device.
Abstract
Description
Claims
Priority Applications (7)
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Also Published As
Publication number | Publication date |
---|---|
US8883015B2 (en) | 2014-11-11 |
US20150224294A1 (en) | 2015-08-13 |
AU2009212106A1 (en) | 2009-08-13 |
CA2749347C (en) | 2018-03-27 |
US20110223542A1 (en) | 2011-09-15 |
US20160220803A1 (en) | 2016-08-04 |
AU2009212106B2 (en) | 2014-05-01 |
CA2749347A1 (en) | 2009-08-13 |
EP2247527A1 (en) | 2010-11-10 |
AU2009212106B9 (en) | 2014-05-22 |
EP2247527A4 (en) | 2014-10-29 |
CN102007066B (en) | 2013-06-26 |
US9283365B2 (en) | 2016-03-15 |
CN102007066A (en) | 2011-04-06 |
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