Field of the Invention

The invention relates to a micro moulding process for forming structures with a functional surface, and in particular to a method of forming a functional surface by electrostatic spraying of functional materials and a resulting structure comprising a functional surface .

Background

Functional surfaces have applications in a large and diverse range of fields. The addition of a functionalised material to a structure can allow the tuning of the properties of the structure, or create entirely new effects. Of particular interest are functionalised micro- or nano-scale structures, which can be used for example in micro-optic, microfluidic or medical applications. Arrays of microneedles functionalised with vaccines or drugs have been shown to have promise for medical device use. The traditional vaccine delivery route of the needle suffers from storage, distribution and disposal issues, as well as discouraging uptake of vaccines. Needle-free transdermal patches are effective for only the small range of drugs with low enough molecular weights to pass through the skin.

Microneedles offer a hybrid solution to vaccination. A microneedle array disposed on a flexible substrate can be applied as a patch to the skin. The microneedles can penetrate the skin, delivering the vaccine or drug that they are functionalised with. Arrays of other functionalised micro-proj ections may be of use in other applications. For example, arrays of functionalised nanorods may be used for gas sensing applications (Kim et al., Reference 1).

Such arrays of micro-proj ections may be formed by micro moulding. A mould consisting of micro-scale cavities is provided, and the cavities are filled with a moulding material to form an array of micro-projections. The micro-projections may be subsequently coated with a functional material to produce the desired effect. Coating may be achieved by processes such as dip coating (WO2006/138719, Reference 2), rolling (WO2002/074173, Reference 3) or brushing (WO2008139648, Reference 4) . These liquid based methods are limited by significant surface tension and viscous effects at micrometre scales, which can prevent effective production of a uniform or controlled functional layer on the micro-projections. Other previous approaches have used spray coating to functionalise arrays of micro- proj ections. WO2009/081 125 (Reference 5) for example discloses a spray coating technique that requires elevated temperatures and heated aerosols. This technique is, however, not suitable for coating of heat-sensitive functional materials, for example live entities such as viruses used for vaccination.

US2013/03 10665 (Reference 6) discloses a method of spray coating that aims to overcome problems associated with surface temperature and heating. A microneedle- forming composition is sprayed into a microneedle mould, and allowed to dry at ambient temperature . The composition may include the functional material, so that functionalising the array of microneedles occurs during the process of forming the microneedles. This method may, however, not be suitable for some applications. In order to achieve a desired concentration of functional material at the surface of the microneedle, a much larger amount of the functional material may have to be dispersed in the micro-needle forming composition than if the functional material was only covering the surface of the microneedle . In cases where the functional material is expensive or difficult to produce, it may therefore not be feasible to waste excess material in the forming of the microneedle just so that a required concentration can be obtained at the needle tips. The above methods also do not offer control of the placement and arrangement of the functional material within the micro-proj ection, which may be necessary for some applications. For vaccine and drug delivery, for example, it is particularly beneficial to concentrate the functional material at the tip of a microneedle, from where it can most rapidly be delivered.

It is an obj ect of the invention to address one or more of the above mentioned problems. Summary of the Invention

In accordance with a first aspect of the invention there is provided a method of forming a structure with a functional surface, the method comprising the steps of: providing a mould comprising an array of cavities across a first upper surface of the mould;

depositing a functional material within the cavities by electrostatic spraying of the functional material across the upper surface of the mould;

filling the cavities with a curable polymer; and

removing the cured polymer from the mould, resulting in a structure formed of the cured polymer having the functional material bonded to the surface.

An advantage of the invention is that the process of electrospraying, i.e . spraying the functional material in the form of charged particles, allows a greater degree of control over where the particles are deposited in the mould. This is due to the need to apply an opposite electrical charge to the mould to attract the charged particles, which will vary across the mould and increase within the cavities. The electrosprayed particles will as a result tend to concentrate within the cavities, and in particular towards the base of each cavity, resulting in the functional material being preferentially provided at the tips of the resulting proj ections formed of the cured polymer.

The cavities may be filled with a curable polymer composite with the curable polymer forming the matrix of the polymer composite, for example a curable polymer with a mineral filling agent such as silica. One particular example is a UV curable epoxy with a silica filler, the silica serving to increase the hardness of the resulting composite material. One suitable example is Master Bond UV22, a reactive UV curable epoxy based system comprising a nanoscale silica filler.

The array of cavities is configured to produce an array of projections formed of the cured polymer or polymer composite. The structure formed in this way may comprise an array of micro-projections, which may be microneedles.

In some embodiments, the mould is a bilayer mould, which comprises a cured layer formed of a moulding compound and an underling electrically conductive substrate layer. The conductive substrate allows the opposite charge to be applied to the mould for attracting the electrosprayed particles and/or droplets, and will tend to result in concentrations of charged particles and/or droplets towards the bottom of each cavity, particularly when the mould in which the cavities are formed has a relatively low electrical conductivity to that of the conductive substrate layer. The conductive substrate may be porous and/or flexible . A flexible substrate is beneficial in allowing the moulded structure to be more easily removed from the mould. The conductive substrate layer may be impregnated with the moulding compound to facilitate bonding between the conductive substrate layer and the cured moulding compound layer. The conductive substrate may be formed of an electrically conductive mesh such as an ultrafine metal wire mesh, a metallised plastic mesh, a conductive textile or a non-porous bulk conductive material with a porous surface.

In some embodiments, the process of electrostatic spraying of the functional material may involve a nano-electrospray, electrostatically charged inkj et, electrochemical or charged aerosol deposition process. The material source for the nano-electrospray process may be a single source or may be multiple sources. The electrically charged deposition may comprise multi-chamber multi -material deposition.

The functional material may be a vaccine or a pharmaceutical compound, intended for delivery into a patient. .The pharmaceutical compound may for example be a vaccine, a small molecule drug, a macro molecule drug or a nanoparticle-drug combination. The functional material may be in the form of solid particles, liquid droplets or combinations which form core-shell particles. The physical size of the charged functional material may range between around lnm 10 μιη.

The method of filling the cavities with the curable polymer or polymer composite may comprise a vacuum fill technique to minimise the entrapment of air bubbles. Air bubbles create voids in the structure, and so undermine structural integrity. In some embodiments, filling the cavities further comprises over-filling the cavities with a UV curable polymer and curing the UV curable polymer with a UV source, such that a single thicker layer of cured polymer is deposited, which serves to provide structural support for the array of moulded projections. In some embodiments, an adhesive tape, which may be pressure sensitive, is applied to the cured polymer to provide a backing that allows the moulded proj ections to be removed from the mould. In other embodiments, only the cavities are filled with the UV curable polymer or polymer composite, without a layer of the polymer forming to j oin the cavities, and cured with a UV source. In one embodiment, pressure sensitive tape is applied to the cured polymer. In an alternative embodiment, a UV cured or thermal cured polymer composite is applied to the cured polymer.

In accordance with an aspect of the invention there is provided a structure comprising an array of proj ections with a functional surface formed by a method according to the above . The array of projections may be an array of micro-projections, which may be microneedles, i.e . having a maximum linear dimension of less than 100 μιη and optionally a minimum linear dimension of greater than 1 μιη.

In accordance with a further aspect of the invention there is provided a structure comprising an array of projections, each projection having a concentration of functional particles embedded within a tip region thereof. Having the functional particles concentrated within the tip region of each proj ection allows for a more efficient use of such particles, allowing less functional material to be used to achieve the same effect.

Detailed Description

The invention is described in further detail below by way of example and with reference to the accompanying drawings, in which:

figure 1 is a schematic cross-sectional diagram of an exemplary mould for use in forming a structure with a functional surface;

figure 2 is a schematic diagram of the mould of figure 1 with particles of a functional material within the mould cavities;

figure 3a is a schematic diagram of particles of a functional material within a cured polymer or polymer composite formed within a cavity of the mould of figure 1 ; figure 3b is a schematic diagram of a combination of functional materials within a cured polymer formed within a cavity of the mould of figure 1 ;

figure 3c is a schematic diagram of an alternative combination of functional materials within a cured polymer formed within a cavity of the mould of figure 1 ; figure 4a is a schematic diagram of a structure with a functional surface as formed in the mould of figure 1 ; figure 4b is a schematic diagram of a formed structure having a functional surface;

figure 5a is a schematic diagram of an alternative structure with a functional surface as formed in the mould of figure 1 ;

figure 5b is a schematic diagram of the formed alternative structure of figure

5a with a functional surface after removal from the mould;

figure 6a is a schematic diagram of an alternative structure with a functional surface as formed in the mould of figure 1 ;

figure 6b is a schematic diagram of the formed alternative structure of figure 6a with a functional surface after removal from the mould;

figure 7a is a schematic diagram of an alternative structure with a functional surface as formed in the mould of figure 1 ;

figure 7b is a schematic diagram of the formed alternative structure with a functional surface after removal from the mould;

figure 8 is a schematic diagram of a master mould used to form a mould of the type shown in figure 1 ; and

figure 9 is a flow diagram illustrating an example method for forming a structure with a functional surface Figure 1 is a schematic cross-sectional diagram of a mould 10 used to form a structure with a functional surface according to an aspect of the invention. The mould 10 comprises an array of cavities 1 1 across a first upper surface 12. The cavities 1 1 are configured to form an array of projections across the structure 12. The array of cavities 1 1 may be arranged such that the cavities 1 1 are equidistant from each other in a regular array. Alternatively the cavities 1 1 may be arranged in any other order. The cavities 1 1 are an inverse of the projections they are intended to form. In some embodiments, the cavities may be inverted micro-projections for producing an array of micro-projections on the formed structure. In the illustrated embodiment, the cavities 1 1 are inverted conical shape microneedles for producing an array of microneedles on the formed structure. Typical dimensions of the cavities are of the order of 20 to 3000 μιη deep and 5 to 1000 μιη across at the opening 15.

The mould 10 may be attached to an underlying electrically conductive substrate 13 forming a second layer 17, while the cavities are formed in a first layer 16. The first layer 16 may be formed of a material that is relatively electrically insulating, compared with the substrate 13. The substrate 13 may be also be flexible, for example sufficiently flexible to allow the substrate to be pulled over surfaces with a radius of curvature as low as 1mm. The substrate may be porous. Suitable materials for forming the substrate 13 include an ultrafine metal wire mesh, for example with a wire diameter as small as 1 μιη and a gap between adjacent wires as low as 2 μιη, a metallised plastic mesh, electrically conductive textiles or a non-porous metal foil with one or both surfaces being porous to assist with mechanical bonding to an adj acent layer..

Referring to figure 2, particles 14 of a functional material are electrosprayed over the upper surface 12 of the mould 10. The particles 14 are initially electrostatically charged and will therefore tend to be deposited at oppositely charged surfaces, thereby allowing the deposition pattern to be controlled by applying an opposing potential to the substrate 13.

Electrostatic spraying, or electrospraying, may involve directing a beam of charged particles 14 using an external electric or magnetic field. However, in preferred embodiments the conductive substrate 13 of the mould 10 is electrically charged to attract the charged particles 14. The charged particles 14 attracted to the conductive substrate 13 will tend to collect at sites in the mould 10 as close to the conductive substrate 13 as possible - i.e. in this case at the lowest point of the cavities 1 1. In the example illustrated in figure 2, the particles 14 collect in the tip regions 18 of the inverted microneedle cavities 1 1. This arrangement is particularly suitable for vaccine and drug delivery applications, where concentrating the particles 14 of the vaccine or drug at the tip of a microneedle allows the quantity of vaccine or drug to be minimised as well as positioning the particles where they can be easily and rapidly delivered to their target, typically the subdermal tissue. The process of electrostatic spraying may compromise using at least one of a nano- electrospray, electrostatically charged inkj et, electrochemical or charged aerosol deposition process. The material source for the nano-electrospray process may be single source or may comprise multiple sources. Nano-electrospray deposition may comprise multi-chamber deposition. The choice of process may be determined by the requirements of the functional material to be deposited. The particles 14 may be sprayed as liquid droplets that subsequently dry within the cavities 1 1 of the mould. Each particle 14 may contain one or more solid particle suspended in a liquid droplet, with the liquid evaporating during or after deposition within the cavities 1 1. A multi-material combination may be defined by intermixing different deposition processes and deposited functional materials. Figures 3a-c schematically illustrate different combinations and arrangements of particles within an exemplary inverted microneedle cavity 1 1. In figure 3a, the deposited particles 14 are composed of a single species of functional material. Deposition by electrostatic spraying deposits the particles 14 at the tip region 18 of the cavity 1 1.

In the alternative embodiment illustrated in figure 3b, multiple functional materials are deposited. Particles 14a, 14b and 14c are particles of different functional materials. The particles 14a, 14b and 14c may be deposited using the same deposition method, or different deposition methods. In the illustrated embodiment, the particles

14a, 14b, 14c are deposited such that layers of the same particle material are formed.

For example, particles 14a may be deposited first, followed by the deposition of particles 14b and finally the deposition of particles 14c. In an alternative embodiment, all different types of particle 14a, 14b, 14c may be deposited simultaneously, to create a random arrangement of particles within the cavity 1 1.

Figure 3c is a schematic diagram of an alternative combination of different functional materials. In this embodiment, particles 14a of a first species of functional material are first deposited such that they line the outside of the tip region 18 of the cavity 1 1. Particles 14b of a different functional material are then deposited within the cavity formed by particles 14a, such that the particles 14a of the first species form an outer layer surrounding the particles 14b of the second species. This type of arrangement may be useful in applications where a delayed action is required for one particular species, as the second species will have further to diffuse to reach the target region.

Following deposition of the functional material, the cavities 1 1 are filled with a liquid curable polymer. Figure 3a illustrates schematically a curable polymer 3 1 filling the cavity 1 1. The curable polymer 3 1 wicks through the microporous deposit of particles 14, resulting in the particles 14 becoming embedded within the polymer 3 1. The curable polymer is subsequently cured, resulting in a solid structure in the shape of the cavity. Particles 14 are thus embedded within the tip region 18 of the structure formed by the cured polymer 3 1.

The curable polymer 3 1 may be an ultraviolet light (UV) curable polymer or polymer composite. Curing the UV curable polymer or polymer composite comprises providing a suitable UV source which matches the UV cross-linking photoinitiator in the UV curable polymer, and exposing the UV curable polymer to the UV source. For polymer composites which consist of nanoparticle fillers, the optical properties of filler aid the transmission of UV light deeper into polymer composite and increase the hardness of the resulting cured moulding material.

After curing, the mould 10 may be pulled away from the cured structure. The mould may then be reused.

The cavities 1 1 may be filled with the curable polymer or polymer composite 3 1 using a vacuum fill technique in order to minimise entrapment of air bubbles within the polymer, i.e. by introducing the liquid curable polymer or polymer composite under vacuum. This is because any trapped air bubbles will tend to undermine the structural integrity of the array. This is particularly a problem, for example, when the structure is a microneedle for vaccine delivery, where the microneedle must be strong enough to pierce the outer layers of skin. Figures 4-7 illustrate four different alternative embodiments of a structure formed by electrospraying followed by back-filling of the cavities with a curable polymer.

In figure 4a, the array of cavities 1 1 are over-filled with a curable polymer or polymer composite 3 1 such that a layer 41 of curable polymer extends over the upper surface 12 of mould 10 between the cavities 1 1. The structure 40 thus formed after removal of the mould from the cured polymer or polymer composite 3 1 , illustrated schematically in figure 4b, comprises a monolithic layer 3 1 of curable polymer or polymer composite with projections 42 containing the particles 14 at the tip of each of the proj ections 42. Figures 5a and 5b illustrate schematically an alternative embodiment of a moulded structure formed by electrospraying followed by back-filling of the cavities with a curable polymer or polymer composite . In this embodiment, the cavities 1 1 are filled with curable polymer or polymer composite 3 1 up to the upper surface 12 of mould 10, such that no layer of the polymer 3 1 is formed between the cavities. A polymer composite layer 5 1 may then be deposited across the upper surface 12 of the mould 10 to form a backing layer. The polymer composite backing layer 5 1 may comprise a UV or thermally curable polymer matrix and a reinforcement material, for example in the form of a fabric or mesh material that allows the resulting structure to have strength and flexibility. This arrangement allows the polymer material forming the proj ections 52 to be a more rigid material that will serve better for use as transdermal needles, while the material forming the backing layer 5 1 can be chosen more for flexibility.

After the composite has been cured, the mould 10 may be pulled away, leaving the moulded structure 50 illustrated in figure 5b. The structure 50 consists of a substrate 5 1 of the cured polymer composite, with projections 52 of the cured polymer or polymer composite 3 1 extending from a surface of the substrate 5 1 , the projections 52 having particles/regions 14 of a functional material embedded within the tip region of each proj ection.

In a general aspect therefore, the cured polymer forming the proj ections 52 may have a higher mechanical stiffness than that of the backing layer 5 1 , thereby allowing for more flexibility in the resulting array while retaining a required rigidity of each of the proj ections 52.

Figure 6a and 6b illustrate schematically a further embodiment of the moulded structure . The cavities 1 1 are filled with curable polymer or polymer composite 3 1 as in the embodiment illustrated in figure 5a, such that the curable polymer or polymer composite 3 1 fills only the cavities 1 1. A flexible tape 61 having an adhesive layer 62 is applied across the upper surface 12 of mould 10. The adhesive layer 62 bonds to the cured polymer 3 1 , but preferably has a poorer adhesion to the material of the mould 10. The mould 10 may be removed from the structure 60, leaving the structure 60 as illustrated in figure 6b, consisting of projections 62 of cured polymer or polymer composite 3 1 adhered to the flexible tape 61 , each projection 62 containing embedded particles 14 at a tip region. Figures 7a and 7b illustrate schematically a further embodiment of the moulded structure . In this embodiment, the cavities are over-filled with curable polymer or polymer composite 3 1 , as in the embodiment illustrated in figure 4a, to form a thick layer of curable polymer or polymer composite 3 1 connecting the projections 72 formed in the cavities 1 1. A flexible tape 61 having an adhesive layer 62 is applied across the thick cured polymer or polymer composite layer 3 1. The mould 10 may be removed, leaving the structure 70 illustrated in figure 7b. The structure 70 comprises a single thick layer of curable polymer 3 1 with adhesive tape 61 on a first surface, and proj ections 72 containing embedded particles 14 at their tip regions on an opposing second surface of the layer 3 1.

In the embodiments illustrated in figures 4-7, the deposited particles 14 of functional material have been described as being of a single type of particle 14 embedded in the tip of the proj ections -i.e. the arrangement illustrated in figure 3a. It is to be understood that any other arrangement of particles may be included in the embodiments of figures 4-7. For example, the particles may be of several types, and organised in many different ways, as illustrated in figures 3b and 3c. Figure 8 illustrates schematically a process of forming a mould 10 for use in forming the above mentioned structures. A master mould 81 is first fabricated, the master mould 81 having an array of proj ections 82 across a first upper surface 83. The array of proj ections 82 match the dimensions of the projections on the structure intended to be formed by the mould 10. A curable moulding compound 84 is deposited across the upper surface 83 of the master mould 81. Suitable moulding compounds may include Struers Repliset, or ACC Silicones MM730FG (MM230FG) addition cure moulding rubber.

A conductive substrate 13 is attached to the upper surface 85 of the curable moulding compound 84 before curing of the moulding compound 84 is complete . The conductive substrate may be porous and flexible . Porosity of the substrate 13 allows for a mechanical bond to be formed with the moulding compound 84, while flexibility allows for easier removal from the mould. The conductive substrate 13 may be impregnated with moulding compound to facilitate bonding between the conductive substrate 13 and the layer of curable moulding compound 84. After curing, the conductive substrate 13 may be bonded to the layer of moulding compound 84 by physical and/or chemical bonds.

After curing, the mould 10 may be removed from the master mould 81. The master mould 81 may then be used again to form other moulds 10.

The master mould 81 may be produced using any suitable production technique. Suitable techniques may include precision milling, turning, cutting, powder blasting, erosion, plasma etching, moulding, laser ablation, silicon microfabrication based on photolithography followed by etching, and greyscale photolithography. The master mould may be formed of any suitable material, including silicon, glass, quartz, wood, and plastic.

In a preferred embodiment, greyscale photolithography is used to produce a silicon master mould 81. The lithography may be a conventional mask based lithography technique, or may be a mask-less technique, for example by using a system provided by Intelligent Micro Patterning, LLC (www.intelligentmp.com). In such a process, photoresist deposited on a silicon substrate is exposed to light, and a modified deep silicon plasma etching process used to pattern sloped profiles into the silicon substrate.

In an alternative embodiment, potassium hydroxide etching may be used to selectively etch preferred crystal planes in silicon. Further details of this process are provided in US2013/03 10665. Both greyscale lithography and potassium hydroxide etching allow master mould 81 to be formed with sub-micron tolerances.

Figure 9 is a flow diagram illustrating an example method for forming a structure with a functional surface. In a first step 901 , a mould comprising an array of cavities across a first upper surface is provided. In a second step 902, a functional material is deposited within the mould cavities by electrostatic spraying of a functional material across the upper surface of the mould. In a third step 903, the cavities are filled with a curable polymer. In a final fourth step, the cured polymer is removed from the mould, resulting in a structure formed of the cured polymer having the functional material bonded to, or embedded within, the surface of the cured polymer.

Other embodiments are intentionally within the scope of the invention as defined by the appended claims.

References

1. Hyunsu Kim et al, "Enhanced gas sensing properties of p-type Te0 ₂ Nanorods functionalized with Pd", Nano 06, 455 (201 1).

2. WO2006/138719

3. WO2002/074173

4. WO2008139648

5. WO2009/081 125

6. US2013/03 10665