GB2600911A

GB2600911A - Apparatus for assessing touch sensitivity

Info

Publication number: GB2600911A
Application number: GB2014439.0A
Authority: GB
Inventors: Faithfull Sara; Cox David
Original assignee: University of Surrey
Current assignee: University of Surrey
Priority date: 2020-09-14
Filing date: 2020-09-14
Publication date: 2022-05-18
Also published as: GB202014439D0

Abstract

A method for manufacturing a substrate 9 for use in an apparatus for assessing the touch sensitivity of a subject such as assessing peripheral neuropathy. The method comprises the use of ion beam milling. The ion beam milling is used to create one or more recesses 12 in the surface of a material to produce a master template 11. The template 11 is used to create the substrate 9 wherein one or more protrusions 10 on the substrate correspond to one or more recesses 12 in the master template 11.

Description

APPARATUS FOR ASSESSING TOUCH SENSITIVITY

The present invention relates to an apparatus for assessing the touch sensitivity of an individual, in particular to an apparatus for use in assessing peripheral neuropathy.

Peripheral neuropathy is a condition that, amongst other things, affects the sensory nerves and can result in a reduced ability to sense touch. Typically, sufferers will experience tingling and numbness in their hands and feet which can mean that their sense of touch is impaired.

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common side-effect of cancer treatment that occurs with many chemotherapeutic agents; including platinum analogues, vinca alkaloids and taxanes. Adverse neurological effects after chemotherapy treatment significantly impacts people's quality of life. Symptoms include numbness, tingling and pain particularly in the hands and feet. This in turn impacts on people's ability to do daily activities, mobility, increases number of falls and reduces ability to return to work. Development of CIPN during treatment may lead to dose reductions in chemotherapy, decreased patient adherence and treatment interruptions thereby impacting on cancer outcomes. There is a critical need for early identification of people at higher risk and new clinical ways to objectively rate its occurrence and progression over treatment. While there are established clinical risk factors for CIPN (older age, increased BMI and neurotoxicity of drug) none has been shown to accurately predict the severity of CIPN. Genetic susceptibility through sub clinical neuropathy detected through touch tests and quantified sensory testing of the hands before treatment has been shown to be a strong predictor of severe CIPN and it has been confirmed using microscopy to relate to the number of active Meissner corpuscles in the skin. Decisions in relation to chemotherapy adherence and dose reductions need to be taken with consideration of the risk factors for severity of CIPN and potential personal disability so a tool that can be used clinically to aid decision making and used within remote follow-up to monitor symptoms would have value in cancer chemotherapy services The pathology of CIPN is different for different chemotherapy drugs. The longest axons are the first affected, myelinated fibres are damaged without altered myelin structure whereas unmyelinated fibres are mostly unaffected, slowing sensory nerve conduction velocity. Mitochondrial dysfunction and oxidative stress are also associated with the pathogeneses of CIPN highlighting the complexity of damage. Sensory nerve damage leads to symptoms of paraesthesia (pins and needles), dysesthesias (numbness of feet and hands), absence of deep tendon reflexes and muscle impairment that affect proprioception. Platinum compounds interfere with cancer cell proliferation resulting in damage to non-dividing post mitotic peripheral neural tissue. This damage may be associated with sensory neuropathy with anterograde axonal degeneration. In addition to chronic neuropathy, acute sensory loss is unique to oxaliplatin with cold induced dysesthesia thought to be related to the rapid generation of oxalate metabolites. Dose reductions in the later courses of chemotherapy are unlikely to change the pattern of damage from chemotherapy so prediction is essential to be able to modify treatment early and to prevent severe symptoms.

One way of determining the extent of this sensory impairment is by asking a subject to describe their symptoms and their severity. This is, however, a very subjective measure and results in inherent inaccuracies.

In order to provide a more accurate assessment, sensory tools exist which include a substrate, such as a smooth flat plate, with a plurality of objects on the substrate of varying sizes. The level of sensory impairment suffered by a subject will determine how many of the objects a subject can detect. This is then used to provide a much more accurate estimate of the severity of sensory impairment suffered by a subject.

Whilst the use of such sensory tools has greatly improved the ability to assess sensory touch impairment, they still suffer from various drawbacks. In particular, the substrate in existing tools is manufactured by hand filing or etching glass to produce a series of bumps on the surface of the substrate. Unfortunately, this method of manufacture is not reproducible or accurate, which means that different tools will produce different results, making it difficult to provide an accurate assessment of sensory impairment. In addition, the use of glass has many drawbacks, especially in a hospital setting, due to possible breakage. One such example of this sensory tool is disclosed in US8133189.

It is, therefore, an object of the present invention to seek to alleviate the above identified problems.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided a method for manufacturing a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions and wherein the method comprises ion beam milling.

Ion beam milling is a technique that has been used, for example, to fabricate aspherical microlenses. Further details regarding the technique can be found in Langridge et al (2014) "The fabrication of aspherical microlenses using focused ion-beam techniques" Micron 57, 56-66. Remarkably, the inventors of the present invention have found that ion beam milling can be used to mill recesses of different sizes in a silicon wafer and then use the milled silicon wafer as a master template for the production of a substrate with protrusions corresponding to the recesses milled in the surface of the silicon wafer.

This method is far superior to the etching techniques used for frosted glass in the prior art and allows the provision of a substrate that not only has a smooth flat surface but on which are formed protrusions of the desired size and height. The size, height and position of the protrusions are carefully configured to test the touch sensitivity of a subject.

Importantly, ion beam milling is very accurate and reproducible. This means that the methods described herein can be used to produce a substrate with protrusions of exactly the desired size and location. This allows for a remarkable level of accuracy and reproducibility.

Preferably, the method comprises ion beam milling to create one or more recesses in the surface of a material to produce a master template.

It is to be understood that in the context of the invention, the "master template" is a template from which copies can be produced.

Preferably, the material is cleaned before milling.

Preferably, the material is cleaned with a solvent.

Preferably, the material is cleaned with acetone, methanol and/or isopropyl alcohol.

Preferably, the material is cleaned with an oxygen plasma clean.

Preferably, the recesses are milled at a beam current of between about 50pA and about 300pA.

Preferably, the recesses are milled at an accelerating voltage of between about 20 kV and about 40kV, preferably about 30kV.

Preferably, after milling the material is treated with hydrofluoric acid.

Preferably, the material is treated with hydrofluoric acid for between about 15 minutes and about 45 minutes, preferably for about 30 minutes.

Preferably, the material is treated with hydrofluoric acid at a concentration of between about 40% and about 60cYo, preferably, about 50%, most preferably about 48%.

Preferably, the material is treated with hydrofluoric acid at about room temperature.

Preferably, before treatment with hydrofluoric acid, the material (i) is washed, preferably in acetone and/or de-ionised water, and/or (ii) dried, preferably with nitrogen.

Preferably, after treatment with hydrofluoric acid, the material (i) is washed, preferably in de-ionised water, and/or (ii) dried, preferably with nitrogen.

Preferably, the material comprises silicon.

Preferably, the material comprises a sheet of silicon.

Preferably, the material comprises a silicon wafer.

The use of silicon is particularly advantageous because silicon is extremely pure and has an RMS surface roughness less than 4nm. It is also particularly well suited to ion beam milling and is highly reproducible in this regard.

Preferably, the method comprises use of the master template to create the substrate, wherein the substrate comprises one or more protrusions corresponding to the one or more recesses in the master template.

In this respect, it will be appreciated that the one or more recesses in the master template are a negative of the one or more protrusions in the substrate.

Alternatively, the method comprises (i) use of the master template to create an intermediate wherein the intermediate comprises one or more protrusions corresponding to the one or more recesses in the master template, (ii) use of the intermediate to create a mould, wherein the mould comprises one or more recesses corresponding to the one or more recesses formed in the surface of the material, and (Hi) use of the mould to create the substrate, wherein the substrate comprises one or more protrusions corresponding to the one or more recesses in the master template.

This is particularly advantageous because when a material such as a silicon wafer is used, the resultant master template can be brittle. The use of the brittle master template to create an intermediate means that a mould can be created from a more durable material such as soft silicone rubber.

Preferably, a releasing agent is applied to the master template before the master template is used to create the substrate or the intermediate.

Preferably, the releasing agent comprises (i) a thin metal coat metal, preferably of nickel or chromium, or (ii) a waxy material, preferably an alkane or isoalkane.

As will be appreciated, despite the use of the intermediate to create a mould, the one or more recesses in the master template are still a negative of the one or more protrusions in the substrate.

Preferably, the intermediate comprises a substantially rigid material.

Preferably, the intermediate comprises a polymeric material.

Preferably, the intermediate comprises a rubber-based material.

Preferably, the intermediate comprises rubber, preferably polydimethylsiloxane (PDMS).

Preferably, the intermediate can be released from the master template.

Preferably, the intermediate comprises a material that can be released from silicon.

Preferably, the intermediate comprises polystyrene dissolved in a solvent.

Preferably, the intermediate comprises polystyrene dissolved in toluene.

Preferably, the mould comprises a substantially flexible and/or resilient material.

Preferably, the mould comprises a polymeric material.

Preferably, the mould comprises a rubber-based material.

Preferably, the mould comprises silicone rubber, urethane rubber and/or latex rubber.

Preferably, the mould can be released from the intermediate.

Preferably, the mould can be released from the substrate.

Preferably, the substrate comprises a substantially rigid material.

Preferably, the substrate comprises a polymeric material.

Preferably, the substrate comprises a transparent material.

It will be appreciated that a transparent material is a material that a person can see through.

Preferably, the substrate comprises a plastics material.

Preferably, the substrate comprises a hard setting liquid polymer.

Preferably, the substrate comprises a liquid polymer to which a curing agent is added.

Preferably, the substrate comprises a liquid polymer comprising a solvent, wherein the polymer sets as the solvent evaporates.

Preferably, the substrate comprises an epoxy resin or a polyurethane resin, preferably a polyurethane resin.

Preferably, the substrate comprises epoxy casting resin.

Preferably, the substrate comprises polyurethane casting resin.

Preferably, the substrate and/or the intermediate comprises a plurality of protrusions.

Preferably, the substrate and/or the intermediate comprises protrusions of different dimensions.

Preferably, the substrate and/or the intermediate comprises a first protrusion of a first dimension and a second protrusion of a second dimension, wherein the first protrusion having the first dimension would be expected to be felt by all subjects, except for those with a very severely impaired sense of touch, and the second protrusion having the second dimension would be expected to only be felt by those with a normal sense of touch.

Preferably, the substrate and/or the intermediate comprises at least 3 protrusions of different dimensions, preferably at least about 4, preferably at least about 5, preferably at least about 6, preferably at least about 7, preferably at least about 8 protrusions of different dimensions.

Preferably, the substrate and/or the intermediate comprises between about 4 and about 15 protrusions of different dimensions, preferably, between about 6 and about 12, preferably, between about 7 and about 11, preferably about Sand about 10 protrusions of different dimensions.

Preferably, the substrate and/or the intermediate comprises about 8 or about 10 protrusions of different dimensions.

Preferably, each different dimension corresponds to a different level of sensory touch.

In this respect, reference to "level of sensory touch" refers to the ability of a protrusion to be felt by a subject suffering from sensory touch impairment.

Preferably, the substrate and/or the intermediate comprises a first protrusion corresponding to a first level of sensory touch and a second protrusion corresponding to a second level of sensory touch, wherein the first protrusion will only be felt by a subject with a normal sense of touch and the second protrusion will be felt by all subjects, except for those with a very severely impaired sense of touch.

Put another way, it is preferred that the substrate and/or the intermediate comprises a plurality of protrusions, wherein each protrusion can be felt to a different degree by a user.

By providing protrusions of different levels of sensory touch, it is possible to test a subject suffering from, or suspected of suffering from, sensory touch impairment to determine their lowest level of sensory touch, corresponding to the smallest protrusion that they are able to feel.

In addition, the provision of protrusions of different levels of sensory touch means it is possible to identify not only the smallest protrusion the subject can identify, but also whether the subject can identify the next largest protrusion, thus ensuring that the threshold of sensory touch impairment is accurately determined.

Preferably, the substrate and/or the intermediate comprises: (a) a first protrusion corresponding to a first level of sensory touch and a second protrusion corresponding to a second level of sensory touch, wherein the first protrusion will only be felt by a subject with a normal sense of touch and the second protrusion will be felt by all subjects, except for those with a very severely impaired sense of touch, and (b) one or more protrusions comprising a level of sensory touch between the level of sensory touch of the first protrusion and the level of sensory touch of the second protrusion.

Preferably, reference to "a very severely impaired sense of touch" means a high level of CIPN.

Preferably, the one or more protrusions comprising a level of sensory touch between the level of sensory touch of the first protrusion and the level of sensory touch of the second protrusion each have a different level of sensory touch.

By providing protrusions corresponding to different levels of sensory touch between the first and second protrusions, the sense of touch of a subject can be accurately assessed.

Preferably, each protrusion corresponds to a different level of sensory touch.

Preferably, the substrate and/or the intermediate comprises protrusions of any one or more of different heights and/or diameters and/or shapes.

As will be appreciated, the recesses formed in the material and the mould correspond to the protrusions formed in the substrate and/or the intermediate. That is, the recesses are a mirror of the protrusions.

Preferably, the master template and/or the mould comprises a plurality of recesses.

Preferably, the master template and/or the mould comprises recesses of different dimensions.

Preferably, the master template and/or the mould comprises a first recess of a first dimension and a second recess of a second dimension, wherein the first recess having the first dimension will produce a protrusion in the substrate which would be expected to be felt by all subjects, except for those with a very severely impaired sense of touch, and the second recess having the second dimension will produce a protrusion in the substrate which would be expected to only be felt by those with a normal sense of touch.

Preferably, the master template and/or the mould comprises at least 3 recesses of different dimensions, preferably at least about 4, preferably at least about 5, preferably at least about 6, preferably at least about 7, preferably at least about 8 recesses of different dimensions.

Preferably, the master template and/or the mould comprises between about 4 and about 15 recesses of different dimensions, preferably, between about 6 and about 12, preferably, between about 7 and about 11, preferably about 8 and about 10 recesses of different dimensions.

Preferably, the master template and/or the mould comprises about 8 or about 10 recesses of different dimensions.

Preferably, each different dimension corresponds to a recess which will produce a protrusion of a different level of sensory touch.

Preferably, the master template and/or the mould comprises a first recess which will produce a first protrusion in the substrate corresponding to a first level of sensory touch and a second recess which will produce a second protrusion in the substrate corresponding to a second level of sensory touch, wherein the first protrusion will only be felt by a subject with a normal sense of touch and the second protrusion will be felt by all subjects, except for those with a very severely impaired sense of touch.

Put another way, it is preferred that the master template and/or the mould comprises a plurality of recesses to produce a plurality of protrusions in the substrate, wherein each protrusion can be felt to a different degree by a user.

Preferably, the master template and/or the mould comprises: (a) a first recess which will produce a first protrusion in the substrate corresponding to a first level of sensory touch and a second recess which will produce a second protrusion in the substrate corresponding to a second level of sensory touch, wherein the first protrusion will only be felt by a subject with a normal sense of touch and the second protrusion will be felt by all subjects, except for those with a very severely impaired sense of touch, and (b) one or more recesses which will produce protrusions in the substrate comprising a level of sensory touch between the level of sensory touch of the first protrusion and the level of sensory touch of the second protrusion.

Preferably, the one or more recesses will produce one or more protrusions comprising a level of sensory touch between the level of sensory touch of the first protrusion and the level of sensory touch of the second protrusion each have a different level of sensory touch.

Preferably, each recess corresponds to a different level of sensory touch.

Preferably, the master template and/or the mould comprises recesses of any one or more of different depths and/or diameters and/or shapes.

Preferably, the substrate comprises a plurality of areas, wherein each area comprises a protrusion.

Preferably, the areas are visible to a subject.

Preferably, the areas are printed onto the substrate.

Preferably, the protrusions are provided on a front surface of the substrate and the areas are provided on a rear surface of the substrate.

Preferably, the areas are provided on a backing positioned on a rear surface of the substrate.

Preferably, the backing comprises a sheet.

Preferably, the backing comprises a printed sheet. Preferably, the areas are printed on the backing. Preferably, the backing comprises paper or card. Preferably, the backing is a backing disc.

Preferably, the substrate comprises a plurality of areas and each area contains a protrusion of a different size, preferably of a different height.

Preferably, one or more of the areas comprises a shape, preferably a circle or a hexagon.

Preferably, the maximum diameter of the one or more areas is between about 20mm and about 30mm, preferably between about 22mm and about 28mm, preferably about 25mm.

Preferably, one or more of the areas comprises a plurality of segments.

Preferably, the segments are visible defined segments.

Preferably, one or more of said areas comprises between about 4 and about 8 segments, preferably between about 5 and about 8 segments, preferably about 6 segments.

Preferably, one or more segments in each area comprises one or more protrusions.

Preferably, a single segment in each area comprises a protrusion.

Preferably, each area comprises a protrusion of a different size when compared with the protrusions in the other areas.

Preferably, each area comprises a protrusion of a different height when compared with the protrusions in the other areas.

Preferably, the substrate comprises at least 3 areas, preferably at least about 4, preferably at least about 5, preferably at least about 6, preferably at least about 7, preferably at least about 8 areas.

Preferably, the substrate comprises between about 4 and about 15 areas, preferably, between about 6 and about 12, preferably, between about 7 and about 11, preferably about 8 and about 10 areas.

Preferably, the substrate comprises about 8 or about 10 areas.

Preferably, the protrusions comprise one or more bumps.

In the context of this invention, a "bump" is understood to mean a protrusion from a level surface.

Preferably, the protrusions comprise one or more domes.

Preferably, the one or more domes are parabolic domes.

Preferably, the one or more domes comprise a parabolic cross-sectional profile.

Preferably, the one or more protrusions comprise a transverse cross-section that is substantially circular. Put another way, the one or more protrusions are preferably circular in plan view.

Preferably, the protrusions are annular.

Preferably, the protrusions comprise one or more rings. That is, they are ring-shaped in plan view.

This is particularly advantageous because the provision of an annulus, for example a ring, means a smaller volume needs to be milled which has been found to be nearly five times faster to mill than for a dome-shaped protrusion. In addition, the ridge of the annulus adds texture to the protrusion. A small-scale study suggested that this was more easily detected than a similar sized (height and outer diameter) circular protrusion.

Preferably, the one or more protrusions are between about 2pm and about 50pm in height, preferably between about 2pm and about 30pm in height, preferably between about 2pm and about 25pm in height, preferably between about 2pm and about 20pm in height, preferably between about 2.5pm and about 18pm in height.

Preferably, the substrate comprises protrusions of different height with the smallest protrusion having a height of about 2pm and the largest protrusion having a height of about 50pm.

Preferably, the smallest protrusion has a height of about 2.5pm.

Preferably, the largest protrusion has a height of about 50pm, preferably about 30pm, preferably about 25pm, preferably about 20pm, preferably about 18pm.

In this respect, a protrusion with a height of 18pm would be expected to be felt by all subjects, except for those with a very severely impaired sense of touch, and a protrusion with a height of 2.5pm would only be felt by those with a normal or uninhibited sense of touch.

Preferably, the largest protrusion is associated with a visible marker. This allows the largest protrusion to be more easily seen by a subject.

Preferably, the visible marker is a dot or circle.

Preferably, the visible marker is printed onto the substrate, preferably a rear surface of the substrate.

Preferably, each protrusion covers a part of the surface of substrate and said part of the surface has a maximum dimension of between about 100pm and about 500pm, preferably between about 150pm and about 400pm, preferably, between about 200pm and about 300pm, preferably between about 225pm and about 275pm, preferably about 250pm.

Preferably, each protrusion has a maximum dimension of between about 100pm and about 500pm, preferably between about 150pm and about 400pm, preferably, between about 200pm and about 300pm, preferably between about 225pm and about 275pm, preferably about 250pm.

Preferably, the maximum dimension is the longest distance from one edge of the part of the surface covered by the protrusion to another edge of the part of the surface covered by the protrusion.

Preferably, each protrusion has a maximum diameter of between about 100pm and about 500pm, preferably between about 150pm and about 400pm, preferably, between about 200pm and about 300pm, preferably between about 225pm and about 275pm, preferably about 250pm.

Preferably, the substrate comprises at least 3 protrusions of different heights, preferably between about 4 and about 15 protrusions of different heights, preferably, between about 6 and about 12, preferably, between about 7 and about 11, preferably between about 8 and about 10, most preferably about 8 or about 10 protrusions of different heights.

By providing protrusions of maximum and minimum heights and one or more protrusions of differing heights therebetween, the sense of touch of a subject can be accurately assessed.

In this respect, it will be appreciated that reference to "height" is with reference to how far a protrusion projects away from the upper (front) surface of the substrate.

Preferably, the maximum diameter of the substrate is between about 100mm and about 200mm, preferably between about 125mm and about 175mm.

Preferably, the maximum diameter of the substrate is about 150mm.

According to another aspect of the present invention, there is provided a substrate produced by a method as described herein for use in an apparatus for assessing the touch sensitivity of a subject.

According to another aspect of the present invention, there is provided a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions and has been produced by a method which comprises the use of ion beam milling.

According to another aspect of the present invention, there is provided a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate has been manufactured from (i) an ion beam milled mould, or (ii) a copy of an ion beam milled template.

According to another aspect of the present invention, there is provided a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions and is a relief from (i) an ion beam milled mould, or (ii) a copy of an ion beam milled template.

According to another aspect of the present invention, there is provided a master template as described herein.

Preferably, the master template comprises one or more recesses in the surface of a material.

According to another aspect of the present invention, there is provided a mould as described herein.

Preferably, the mould comprises one or more recesses.

According to another aspect of the present invention, there is provided a substrate as described herein.

According to another aspect of the present invention, there is provided a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions, wherein said one or more protrusions comprise a ring shape in plan-view.

According to another aspect of the present invention, there is provided an apparatus for assessing the touch sensitivity of a subject, wherein the apparatus comprises a substrate as described herein.

Preferably, the apparatus comprises a substrate as described herein and a backing, wherein the protrusions are provided on a front surface of the substrate and the backing is positioned on a rear surface of the substrate, wherein the backing comprises a plurality of areas, wherein the position of each area corresponds to the position of a protrusion.

Preferably, the backing comprises a sheet.

Preferably, the backing comprises a printed sheet.

Preferably, the areas are printed on the backing.

Preferably, the backing comprises paper or card.

Preferably, the backing is a backing disc.

Preferably, the backing comprises a plurality of areas and the position of each area corresponds to a protrusion of a different size, preferably of a different height.

Preferably, one or more of the areas comprises a circle or a hexagon.

Preferably, one or more of the areas comprises a plurality of segments.

Preferably, the segments are visible defined segments.

Preferably, the position of one or more segments in each area corresponds to the position of one or more protrusions.

Preferably, a single segment in each area corresponds to the position of a protrusion.

Preferably, the position of each area corresponds to a protrusion of a different size when compared with the protrusions in the other areas.

Preferably, the position of each area corresponds to a protrusion of a different height when compared with the protrusions in the other areas.

Preferably, the backing comprises at least 3 areas, preferably at least about 4, preferably at least about 5, preferably at least about 6, preferably at least about 7, preferably at least about 8 areas.

Preferably, the backing comprises between about 4 and about 15 areas, preferably, between about 6 and about 12, preferably, between about 7 and about 11, preferably about 8 and about 10 areas.

Preferably, the backing comprises about 8 or about 10 areas.

Preferably, the backing comprises a visible marker to show the position of the largest protrusion.

Preferably, the visible marker is a dot or circle.

Preferably, the apparatus comprises a base.

Preferably, the base is a base plate, preferably a base disc.

Preferably, the backing is sandwiched between the substrate and the base.

Within this specification embodiments have been described in a way which enables a clear and concise specification to be written, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the invention. For example, it will be appreciated that all preferred features described herein are applicable to all aspects of the invention described herein and vice versa.

Within this specification, the term "about" means plus or minus 20%, more preferably plus or minus 100/0, even more preferably plus or minus 5%, most preferably plus or minus 20/0.

Within this specification, reference to "smooth" preferably means having an RMS surface roughness of less than about lpm.

Preferably, the substrate has an RMS surface roughness of less than about 1 pm.

Preferably, reference to RMS surface roughness means the root mean square deviation of the surface profile measured using atomic force microscopy (AFM).

Preferably, reference to ion beam milling means focussed ion beam milling.

Preferably, reference to a subject with a very severely impaired sense of touch means a subject with grade 4 peripheral neuropathy as determined by the World Health Organization (WHO) Common Toxicity Criteria for Peripheral Neuropathy.

It will be appreciated that reference to "one or more" includes reference to "a plurality".

DETAILED DESCRIPTION

Example embodiments of the present invention will now be described with reference to the accompanying Figures, in which Figure 1 shows an apparatus as described herein; Figure 2 shows a schematic enlargement of a small part of the segment of a hexagon showing a view from above of a protrusion; Figure 3A shows a schematic side view of an example of a recess milled in the surface of a silicon wafer; Figure 3B shows a schematic side view of an example of a silicon master template and an intermediate; Figure 3C shows a schematic side view of an example of an intermediate and a silicone rubber mould; Figure 3D shows a schematic side view of an example of a silicone rubber mould and a substrate; Figure 4A shows schematic examples of protrusions with different cross-sections; Figure 4B shows schematic examples of protrusions with different plan views; and Figure 5 shows an example of a ring-shaped protrusion.

The present invention relates to an apparatus for assessing the touch sensitivity of a subject, in particular for assessing peripheral neuropathy in a subject.

With reference to Figure 1, an apparatus according to the present invention is shown.

The apparatus 1 comprises a substrate 2 upon which a plurality of protrusions 3 (not visible in Figure 1) are provided. In the example shown there are ten protrusions 3 each of a different height from the upper (front) planar surface of the substrate 2.

The smallest protrusion is 2.5pm in height and the largest protrusion is 50pm in height. In the example shown, the other protrusions are 3.5 pm, 5pm, 6.5pm, 8pm, 10pm, 12pm, 14pm and 18pm in height. The base of each protrusion 3 is 250pm in diameter and each protrusion has a domed cross-section. When viewed from above, each protrusion is circular, although it will be appreciated that the protrusions could be provided in other shapes, for example an annular shape. Examples of possible protrusion cross-sectional shapes are shown in Figure 4A and these include (i) domed and (ii) parabolic. Examples of possible protrusion plan views are shown in Figure 4B and these include (i) circular and (H) annular.

As discussed in further detail below, the substrate 2 is a disc of polyurethane casting resin which has been cast from a soft silicone rubber mould. The silicone rubber mould includes ten recesses which form the protrusions 3 in the substrate.

Whilst a disc is shown in the example, it will be appreciated that the substrate could take any shape, for example rectangular.

As noted above, each protrusion 3 is of a different height corresponding to a different touch sensitivity. In essence, the largest protrusion can be felt by all subjects, unless they are suffering from a very severe loss of touch sensation. The protrusions then gradually decrease in height to the smallest protrusion, which can only be felt by those with a normal sense of touch.

As shown in Figure 1, the apparatus includes ten hexagons 4. In the example shown, the substrate 2 is transparent and the hexagons 4 are printed on a disc of card 5 which is sandwiched between the substrate 2 and a base plate 13. However, it will be appreciated that the hexagons could be provided in different ways. For example, they could be printed directed on to the substrate, either on the front (upper) face or rear (lower) face thereof.

The protrusions 3 and hexagons 4 are lined up so that a single protrusion 3 is positioned within each hexagon 4. More specifically, each hexagon 4 includes a protrusion in one of its six segments 6. The segment containing a protrusion varies between the hexagons so that a subject being tested is unaware within which segment the protrusion is located. This means that it is very difficult for a subject to correctly guess which segment contains a protrusion, thus providing an accurate test when using the apparatus.

The largest protrusion, at 50pm, is visible to the naked eye, allowing a user to see how to use the device. The other protrusions are not visible to the naked eye. Coupled with the differing locations of the protrusions in each hexagon, this also means that the test is very accurate. In order to increase visibility of the largest protrusion, this could be provided on a visible dot, for example provided on the card 5.

Figure 2 shows a schematic enlargement of a small part (A) in one of the segments 6 of a hexagon 4 on the substrate showing the presence of a protrusion 3.

In order to identify the hexagons 4, each hexagon is labelled A to J. In addition, each segment 6 within each hexagon is provided in a different colour to the remaining segments of that hexagon. This makes it easy for a subject being tested to identify and record in which segments 6 they can feel a protrusion 3. In fact, this makes the apparatus so straightforward that a subject can be tested at home without the need for a medical practitioner to be present. For example, the apparatus 1 could be sent in the post for use by a subject, with the subject then independently recording and reporting back to a medical practitioner their results. For example, by recording a protrusion sensed in a red segment of hexagon A, blue segment of hexagon B, green segment of hexagon C, etc. It will also be appreciated that, instead of or in addition to colour, a different way of differentiating between each segment 6 could be used. For example, a numbering system could be used, labelling the segments 6 in each hexagon 1 to 6, and/or the use of braille could be used. The test results could then be reported as a protrusion sensed in A2, B6, C3 etc. Test results could be recorded in written form or verbally.

In the example shown, the apparatus is 150mm in diameter and approximately 5mm thick. The substrate 2 is approximately 2mm thick and the base disc 13 is approximately 3mm thick. In the example shown, the base disc 13 is also formed from a transparent hard epoxy resin; however, it will be appreciated that any suitable material could be used.

A method for manufacturing the substrate 2 is as follows.

Referring to Figures 3A, 3B, 3C and 3D, in a first step, focussed ion beam milling is used to mill ten recesses 7 in the surface of a silicon wafer 8. Each recess 7 is of a different depth. A schematic example of a recess 7 which has been milled in the surface of a silicon wafer 8 is shown in Figure 3A. The resultant silicon wafer provides a master template 8 with the position and size of the recesses 7 corresponding to the desired final position and size of the protrusions 3 on the substrate 2.

As noted above, ion beam milling is a technique that has been used, for example, to fabricate aspherical microlenses. Further details regarding the technique in this regard can be found in Langridge et al (2014) "The fabrication of aspherical microlenses using focused ion-beam techniques" Micron 57, 56-66. Remarkably, the inventors have found that ion beam milling can be used to mill recesses of different sizes in a silicon wafer and then use the milled silicon wafer as a master template for the production of a substrate with different sized protrusions corresponding to the recesses milled in the surface of the silicon wafer.

This method is far superior to the glass etching used in the prior art and allows the provision of a substrate that not only has a smooth flat surface but on which are formed protrusions of the desired size and height.

Importantly, ion beam milling is very accurate and reproducible. This means that the methods described herein can be used to produce a substrate with protrusions of exactly the desired size. This allows for reproducibility in relation to the apparatus of the invention.

Focussed ion beam milling can be used to produce different shaped protrusions, for example spherical or parabolic shaped protrusions.

In focused ion-beam milling, the depth milled in any region is controlled by the dose of ions to which an area is exposed. Due to a linear relationship between depth and dose in silicon, any region exposed to a controlled dose will sputter to a known depth. This also gives the advantage that the depth for multiple patterns milled in the same place will be a summation of the individual pattern depths.

The dose is controlled by the dwell time, beam current and number of passes the beam makes over an area. Increasing the dwell time in a single-pass pattern results in a non-linear increase in depth for long dwell times, caused by the increasing difficulty of removing material from deeper structures. By increasing the number of passes made, the total dwell time of all passes can be the same as a long dwell time, but the depth of the structure increases linearly. By better re-distributing the redeposited material, a higher number of passes also creates a much smoother recess.

This method allows for the milling of any footprint as a set of concentric shapes, such as circles or n-sided polygons. Increasing the depth starting with the smallest entity in the pattern achieves an approximately parabolic profile. In theory this leaves a step edge, creating areas where the surface is either above or below the parabolic shape required. However, due to an edge effect whilst milling, the sharp peak of the corners will be eroded more quickly than the surrounding area. Some of the sputtered material caused by milling will redeposit, filling in the corners which dip below the parabolic function. Only a small number of circles are necessary in the pattern to create a smooth profile, from 10-30 circles for 1-10pm recesses.

As the dose is calculated by a combination of the ion-beam current (which is intrinsically linked to the beam spot size) and the dwell of the spot, the choice of beam current controls the speed of milling for a certain shape. The recesses herein can be milled at a beam current of 50-300pA, at an accelerating voltage of 30kV, optimizing the beam spot size for smoothness of the recess, whilst keeping milling times to a minimum.

It is also possible to mill spherical, elliptical, hyperbolic or other profiles by using the relevant equation for the doses. With the correctly calibrated doses applied, the pattern is then ready to run.

Before milling the silicon wafer, the silicon is prepared by cleaning it in acetone, methanol and isopropyl alcohol (IPA), finishing with an oxygen-plasma clean. The silicon is then milled in an FEZ -Nova dual-beam, controlled by a Nabity Pattern Generation System (NPGS) to handle the provided CAD-drawn pattern which determines the milling pattern. The recesses produced in this way are highly polished and free of debris.

In order to improve the surface of the milled recesses and improve release of either the substrate or the intermediate, the surface can optionally be treated with hydrofluoric acid. Whilst this step is not required, it can improve the characteristics of the substrate. It will also be appreciated that other techniques could be used, for example the use of a releasing agent such as a thin metal coat of nickel or chromium, or a waxy material such as an alkane or isoalkane.

Before treatment with hydrofluoric acid, the milled silicon wafer is washed in acetone, and de-ionised water, before drying with nitrogen. This is done to remove silver electrodag used to attach the sample to its SEM (Scanning Electron Microscope) stub during milling.

Samples are then placed in 48% concentration hydrofluoric acid (HF) for 30 minutes, at room temperature. When removed, they are washed in de-ionised water and dried with nitrogen.

Whilst the master template 8 could be used to directly produce the substrate 2, silicon wafers are fragile and so this could cause problems during large scale manufacture of the substrate 2.

In order to solve this problem, the master template 8 is used to create an intermediate 9 with a plurality of protrusions 10 corresponding to the position of the recesses in the master template 8 and the desired final position and size of the protrusions 3 on the substrate 2. In the examples shown, the intermediate 9 is formed from polydimethylsiloxane (PDMS), a hard rubber. This is shown in Figure 3B.

The PDMS intermediate 9 is then used to make a soft silicone rubber mould 11 with ten recesses 12 corresponding to the desired final position and size of the protrusions 3 on the substrate 2. This is shown in Figure 3C. As will be appreciated, the mould 11 is a copy of the ion milled silicon master template 7.

The soft silicone rubber mould 11 is used to cast the hard epoxy resin substrate disc 2 with ten protrusions 3 in the desired location. This is shown in Figure 3D. The soft silicone rubber mould 11 is much more robust that the silicon master template 8 and so can be used to mass produce the substrate 2.

Once the substrate 2 has been created, a card 5 with the hexagons printed thereon is positioned on the rear surface of the substrate 2. In this respect, it will be appreciated that the front surface is the surface upon which the protrusions 3 are formed. A base disc 13 is then secured to the substrate 2, sandwiching the card therebetween. As will be appreciated, the card 5 can be glued to the substrate 2 and the base disc 13 can be glued to the card 5. Alternatively, the card could be provided so that it does not cover the entire rear surface of the substrate 2, allowing the base disc 13 to be secured directly to the substrate 2, for example by an adhesive.

Whilst the example described above used circular recesses to produce circular protrusions, it will be appreciated that other shaped protrusions could be used. In particular, as discussed above, the use of ring-shaped protrusions has been found to be particularly effective. An example of a ring-shaped protrusion is shown in Figure 5.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications are covered by the appended claims.

The content of all references cited herein is incorporated by reference in its entirety.

Claims

CLAIMS1. A method for manufacturing a substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions and wherein the method comprises ion beam milling.
2. A method according to claim 1, wherein the method comprises ion beam milling to create one or more recesses in the surface of a material to produce a master template.
3. A method according to claim 2, wherein the material comprises silicon.
4. A method according to claim 2 or 3, wherein the method comprises use of the master template to create the substrate, wherein the substrate comprises one or more protrusions corresponding to the one or more recesses in the master template.
5. A method according to claim 2 or 3, wherein the method comprises (i) use of the master template to create an intermediate wherein the intermediate comprises one or more protrusions corresponding to the one or more recesses in the master template, (ii) use of the intermediate to create a mould, wherein the mould comprises one or more recesses corresponding to the one or more recesses formed in the surface of the material, and (iii) use of the mould to create the substrate.
6. A method according to claim 5, wherein the intermediate comprises a substantially rigid material.
7. A method according to claim 5 or 6, wherein the mould comprises a substantially flexible and/or resilient material.
8. A method according to any preceding claim, wherein the substrate comprises a substantially rigid material.
9. A method according to any preceding claim, wherein substrate comprises a plastics material.
10. A method according to any preceding claim, wherein the substrate comprises a plurality of protrusions.
11. A method according to any preceding claim, wherein the substrate comprises protrusions of different dimensions.
12. A method according to any preceding claim, wherein the substrate comprises a first protrusion of a first dimension and a second protrusion of a second dimension, wherein the first protrusion having the first dimension would be expected to be felt by all subjects, except for those with a very severely impaired sense of touch, and the second protrusion having the second dimension would be expect to only be felt by those with a normal sense of touch.
13. A method according to any preceding claim, wherein the substrate comprises at least 3 protrusions of different dimensions.
14. A method according to claim 13, wherein each different dimension corresponds to a different level of sensory touch.
15. A method according to any preceding claim, wherein the substrate comprises a plurality of areas, wherein each area comprises a protrusion.
16. A method according to claim 15, wherein the areas are visible to a subject.
17. A method according to claim 15 or 16, wherein one or more of the areas comprises a plurality of segments.
18. A method according to any of claims 15 to 17, wherein each area contains a protrusion of a different size when compared with the protrusions in the other areas.
19. A method according to any preceding claim, wherein the protrusions are annular.
20. A substrate produced by a method according to any preceding claim for use in an apparatus for assessing the touch sensitivity of a subject.
21. A substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein (a) the substrate comprises one or more protrusions and has been produced by a method which comprises the use of ion beam milling, or (b) the substrate has been manufactured from (i) an ion beam milled mould, or (ii) a copy of an ion beam milled template, or (c) the substrate comprises one or more protrusions and is a relief from ( ) an ion beam milled mould, or (ii) a copy of an ion beam milled template.
22. A substrate for use in an apparatus for assessing the touch sensitivity of a subject, wherein the substrate comprises one or more protrusions, wherein said one or more protrusions comprise a ring shape in plan-view.
23. An apparatus for assessing the touch sensitivity of a subject, wherein the apparatus comprises a substrate as described herein.
24. A master template as described in claim 2 or 3.
25. A mould as described in claim 5 or 7.