WO2014161036A1 - Stimulus responsive substrates - Google Patents

Abstract

The present disclosure relates to stimulus responsive substrates and uses of the substrates. Certain embodiments of the present disclosure provide a substrate comprising a stimulus responsive polymer attached to the substrate. Exemplary stimulus responsive polymers include those that are pH and thermoresponsive. Certain embodiments of the present disclosure are directed to substrates that include porous and non-porous particles, membranes and films. Uses for the substrates are directed to stimulus-responsive drug delivery devices, cell culture vessels, wound dressing or bandages and implantable articles.

Description

STIMULUS RESPONSIVE SUBSTRATES

PRIORITY CLAIM

[001] This application claims priorit to Australian provisional patent application number 20139031 128 filed on 2 April 2013, the contents of which are hereby incorporated by reference.

FIELD

[002] The present disclosure relates to stimulus responsive substrates and the use of stimulus responsive substrates.

BACKGROUND

[003] Materials that respond to changes in their environment have applications in many different fields. Such materials are often referred to as being "stimulus responsive". Considerable effort is being put into the developments of new materials with such properties.

[004] For example, materials that respond to changes in their environment often have utility in the fields of sensing and/or detection. Whilst such materials can be used for sensing generally, one emerging field is the development of materials that can be used for sensing in biological systems, such as for use in diagnosis or prognosis.

[005] Materials that respond to changes in their environment may also be used to modify that environment. Whilst there are a variety of applications, it has become apparent that such materials could, for example, be used to deliver agents under specific conditions. For example, materials that respond to changes in a biological setting could be used to deliver therapeutic agents under specific conditions.

[006] Wound management and/or treatment provide an example of the potential uses of materials that can respond to changes in the environment. Infection of wounds is a significant medical problem, and there is a significant need to enable early detection of infection and/or to determine whether treatment for infection is actually required. A variety of changes are produced in response to infection, such as changes in pH and/or temperature. Materials that have the ability to respond to such changes could be used to determine whether infection of a wound has occurred or not.

[007] in addition, such materials could also potentially be used to treat an infection, by assisting in the release of agents such as antibiotics in response to signals indicative of the presence of bacterial infection.

[008] The development of materials that have the capacity to respond to changes in their environment would therefore provide advantages in many fields of use, including in the fields of sensing and/or delivery of therapeutic agents. The present disclosure relates to the development of substrates that are stimulus responsive.

SUMMARY

[009] The present disclosure relates to substrates that are stimulus responsive and uses of such substrates.

[0010] Certain embodiments of the present disclosure provide a substrate comprising a stimulus responsive polymer attached to the substrate.

[001 1 ] Certain embodiments of the present disclosure provide a material comprising a substrate comprising a stimulus responsive polymer attached to the substrate.

[001 ] Certain embodiments of the present disclosure provide a sensor comprising a substrate comprising a stimulus responsive polymer attached to the substrate.

[0013] Certain embodiments of the present disclosure provide an optical fibre comprising a substrate comprising a stimulus responsive polymer attached to the substrate.

[0014] Certain embodiments of the present disclosure provide a cell culture vessel comprising a substrate comprising a stimulus responsive polymer attached to the substrate. [0015] Certain embodiments of the present disclosure provide a bandage comprising a substrate comprising a stimulus responsive polymer attached to the substrate.

[0016] Certain embodiments of the present disclosure provide a wound dressing or bandage comprising a substrate comprising a stimulus responsive polymer attached to the substrate.

[0017] Certain embodiments of the present disclosure provide an implantable article comprising a substrate comprismg a stimulus responsive polymer attached to the substrate.

[0018] Certain embodiments of the present disclosure provide a method of sensing a parameter, the method comprising using a substrate comprising a stimulus responsive polymer attached to the substrate to sense the parameter.

[0019] Certain embodiments of the present disclosure provide a method of delivering a releasable agent to a site, the method comprising:

providing to the site a substrate comprising a stimulus responsive polymer attached to the substrate and a releasable agent; and

releasing the releasable agent from the substrate in response to a stimulus, thereby delivering the releasable agent to the site.

[0020] Certain embodiments of the present disclosure provide a therapeutic composition comprising a porous substrate comprising: (i) a stimulus responsive polymer attached to the porous substrate; and (ii) a therapeutic agent loaded onto the porous substrate.

[0021] Certain embodiments of the present disclosure provide a method of therapy, the method comprising exposing a subject to a therapeutic composition comprising a porous substrate comprising: (i) a stimulus responsive polymer attached to the porous substrate; and (ii) a therapeutic agent loaded onto the porous substrate.

[0022] Certain embodiments of the present disclosure provide use of a substrate comprising a stimulus responsive polymer in the preparation of a medicament. [0023] Certain embodiments of the present disclosure provide a method of producing a stimulus responsive material, the method comprising:

functionalising a surface of a substrate; and

forming a polymer on the functionalised surface, wherein the polymer comprises a stimulus responsive property.

[0024] Certain embodiments of the present disclosure provide an article for delivering a therapeutic agent and sensing a parameter, the article comprising a substrate comprising a stimulus responsive polymer attached to the substrate and a releasable therapeutic agent.

[0025] Certain embodiments of the present disclosure provide a drug delivery and sensing device, the device comprising a silicon substrate comprising a stimulus responsive polymer attached to the silicon substrate and a releasable drug.

[0026] Other embodiments are disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES

[0027] Certain embodiments are illustrated by the following figures. It is to be understood that the following description is for the purpose of describing particular embodiments only and is not intended to be limiting with respect to the description.

[0028] Figure 1 shows a schematic of poly(N-isopropylacrylamide) (pNIPAM) grafting onto a porous silicon (pSi) surface. Three different pathways were investigated. Path A: the porous silicon samples were thermally oxidised at 600°C for 1 h, followed by silanisation with 4% of 3-(2-biOmoisobutyi'amido)propyl(triethoxy)silane (BIBAPTES) in toluene and the surface initiated - atom transfer radical polymerisation (Si-ATRP) polymerisation process of NIP AM performed at 25°C for 10 mm. Path B: samples are oxidised by ozone for 30 min, the silanisation and the polymerisation process were identical to path A. Path C: hydrosilylation of the undecylenic alcohol for 3 h at 120 °C was performed on the freshly etched samples, then the surface was reacted with 2-bromoisobutyl bromide, followed by NIP AM polymerisation at 25 °C for 10 min. [0029] Figure 2 shows a schematic representation of a porous silicon substrate coated with a stimulus responsive polymer (top) and a photograph of the porous silicon substrate before and after coating with the polymer (bottom). The change in the colour of the porous silicon substrate indicates the surface has been covered with the polymer (> 100 nm).

[0030] Figure 3 shows a typical X-ray photoelectron spectroscopy (XPS) spectra of a porous silicon substrate coated with a 400 nm thick film of poly(2-diethylaminoethyl methacrylate) (pDEAEMA) by plasma polymerisation. The elements (oxygen, nitrogen, carbon) characteristic for the polymer are detected, whereas the underlying silicon substrate is not detected due to attenuation of the Si signal by the pDEAEMA film. This shows that the polymer was successfully coated onto the porous silicon substrate.

[0031] Figure 4 shows a side-on view of a porous silicon substrate coated with pDEAEMA by plasma polymerisation. The image was taken by scanning electron microscopy. The polymer thickness in this figure is 400 nm. It shows that the polymer is successfully coated over the porous silicon layer, which supports the XPS data.

[0032] Figure 5 shows a time-lapse graph demonstrating the change in the effective optical thickness (EOT) of porous silicon, coated with pDEAEMA, in response to changes in pH of 2.6 and 9.6. The pronounced and reproducible change in the EOT upon addition of low and high pll solutions clearly demonstrates the svvitchable nature of the sensor device.

[0033] Figure 6 shows time-lapse graph showing the change in the EOT of porous silicon, coated with pDEAEMA, in response to changes in pH from 6.0 to 2.6 as indicated in the graph. The results show the sensor has a detection limit as small as 0.2 pH units.

[0034] Figure 7 shows time-lapse EOT measurements of porous silicon functionalised with pDEAEMA under different pll solutions. The results show a pronounced change in EOT between buffers of pH 7.0-5.0, pH 7.0-4.0 and pH 7.0-6.0. The magnitude of change in the EOT was dependant on the pH demonstrating that quantitative detection of pH changes is possible. [0035] Figure 8 shows the increase in EOT in response to change in pll from pH 7.0 to 4.0. or pH 7.0 to 5.0 or pH 7.0 to 6.0. Porous silicon samples were coated with pDEAEMA by plasma polymerisation at 2 W to a thickness of 100 or 400 nm in Panel A and at 2 W or 5 W to a thickness of 100 nm in Panel B. The results show that a range of plasma polymerisation conditions can be used for the preparation of the pH sensor for quantitative sensing.

[0036] Figure 9 shows the results of a pH sensing experiment on flat silicon. The sensor device in this experiment consists of flat silicon coated with pDEAEMA. The coating gives an interference pattern, which can be monitored interference reflectance spectroscopy. The graph shows that the wavelength of the interference pattern rcproducibly increases or decreases as the pH of the solution is increased or decreased. This type of sensor can also be used to measure quantifiable changes in pH of the solution ( or other types of environment).

[0037] Figure 10 shows a pH sensor embedded in a wound dressing scaffold. A photograph of a porous silicon substrate connected to a porous PCL scaffold, by thermally annealing the two materials together at 55°C, is shown at the top. The porous nature of the scaffold makes it possible to still use the sensor to measure quantifiable changes in pH of the solution (or other types of environment ).

[0038] Figure 11 shows the results of a pH sensing experiment on a porous silicon substrate coated with a plasma polymerised film of acrylic acid. The data shows that acrylic acid plasma, polymer coatings on porous silicon can be used to measure quantifiable changes in pH and in a reproducible fashion (left graph— buffer only) and the readout signal (i.e. increase or decrease in the EOT) is not affected by fouling proteins (fetal bovine serum, FBS) in the solution (right graph (Buffer + 10% (v/v/) FBS). This shows that a variety of polymers can be applied to make the sensor device enabling the fabrication of sensors with different sensitivities to pH; and that the sensors can be used in environments containing a complex mixture of organic materials and proteins such as wound fluid.

[0039] Figure 12 shows qualitative detection of pH changes on flat silicon coated with plasma polymerised pDEAEMA. Photographs of the pH sensor were taken in air and after subjecting the same sensor device to pll 7.0 and pH 4.0 solutions. The figure shows that obvious changes in colour can be detected on the sensor in response to changes in pH of the solution (or other types of environment).

[0040] Figure 13 shows qualitative detection of pH changes on flat silicon coated with plasma polymerised pDEAEMA. Photographs of the pH sensor were taken after spotting solutions of pH 4 and pH 7 over the sensor and after removing the excess solutions off the surface of the sensor device. This shows that the sensor can be used to map the pH of the environment (e.g. a wound bed) and can be used as a "dip-stick'^' or point-of-care sensor.

[0041] Figure 14 shows an example of a dip-stick type pH sensor fabricated by coating flat silicon with a plasma polymerised film of pDEAEMA. Solutions of pH 3.0 to 8.0, as indicated in the figure, were spotted onto the sensor device and were subsequently allowed to air dry. The figure shows that the contrast of the spots (in comparison to the background polymer coating) decreased as the pH was increased. This type of sensor could be used as a point of care device or for mapping the pH of the wound environment.

[0042] Figure 15 show the stimulus responsive polymers can be used to coal a wide range of materials such as a) polystyrene sheets for tissue culture or b) bandages for wound dressings. The porous silicon particles coated with the stimulus responsive polymers can be embedded into wound dressings such as polycaprolactone (PCL) scaffolds for sensing or drug delivery as shown in c) or d) porous silicon or flat silicon substrates can also be connected to (PCL) wound dressings for sensing/drug delivery.

[0043] Figure 16 shows a schematic representation showing the fabrication process of the porous silicon drug delivery device, which can also be used concurrently for sensing pH.

[0044] Figure 17 shows the demonstration for the delivery of a biologically active horseradish peroxidase enzyme (left graph) and a glycosaminoglycan (right graph) from porous silicon and from porous silicon coated with a pH responsive plasma polymer film, enabling the sustained release of biomolecules. The plasma coating process does not damage/remove the sensitive enzyme when it is loaded into porous silicon. The drug delivery functionality can be directly incorporated into the sensor device without deterioration of the sensor's sensitivity. The hybrid drug delivery/sensor devices can be incorporated into wound bandage dressings.

[0045] Figure 18 shows a porous silicon-polymer surface preparation using a silanisation approach and ATRP to graft the polymer from the surface.

[0046] Figure 19 shows changes in EOT of the pNIPAM grafted surface on temperature switching between 25 and 50 °C, as a function of crosslinker concentration. The polymer used here was pNTPAM and crosslinker was methylene bisacrylamide and polymerisation was carried out using the silanisation route. The EOT changes indicate a switch in behaviour of the polymer from individual (EOT>0) chains to bulk hydrogel (EOT<0) as the crosslinker concentration increases.

[0047] Figure 20 shows aspirin release from A) a non-crosslinked and B) a crosslinked (1% crosslinker) porous silicon-pNIPAM surface prepared using the silanisation approach and 10 min of ATRP polymerisation. From the data it can be inferred that the responsive release characteristics of the drug is dependent on the crosslinking density offering additional control over the release.

[0048] Figure 21 shows a schematic showing fabrication of polymer cap on porous silicon using a dual hydrosilylation approach.

[0049] Figure 22 shows levofloxacin release from porous silicon pNIPAM surface prepared using dual hydrosilylation; A) 30 and B) 60 mins of polymerisation (ATRP) with 1% crosslinker (methylene bisacrylamide).

[0050] Figure 23 shows the effect of the thickness of the plasma polymerised 1,7 - octadiene on levofloxacin release from pSi.

[0051] Figure 24 shows the effect of plasma power during 1 ,7 - octadiene deposition on levofloxacin release from pSi.

[0052] Figure 25 shows the drug release from oxidised pSi at pH 3 and pH 7. [0053] Figure 26 shows drug release from pSi modified with 500 nm of acrylic acid plasma polymer.

[0054] Figure 27 shows drug release from pSi modified with octadiene followed by acrylic acid.

[0055] Figure 28 shows cell count data, demonstrating that functional heparin and heparin + FGF-2 can be released from the porous silicon pH sensor (coated with 400 nm thick film of pDEAEMA) to stimulate cell proliferation after 120 h of incubation.

[0056] Figure 29A shows a schematic of polymer templated from colloidal crystal array of 200 nm diameter polystyrene spheres. Figure 29B shows a schematic of photonic polymer formation. A typical optical reflectance is shown in Figure 29C.

[0057] Figure 30 shows a photograph of the photonic polymer at low (pH 5.56) and high pH (pH 7.41).

[0058] Figure 31A shows measurements of reflected photonic spectra at different pH from the photonic polymer incorporated into Smith & Nephew transparent bandage. Figure 3 IB shows the shift in photonic peak with changing pH.

[0059] Figures 32A and B show the photonic polymer integrated into a 3M bandage. In this case the polymer is sealed between two dressings to demonstrate the observable colour of the polymer. Figure 32C, D and E shows the photonic polymer integrated into wound dressing, applied to healthy skin (C) and two chronic wounds (D, E).

[0060] Figure 33A shows a SEM image of an optical fibre coupled to a porous membrane to form a dip sensor. Figure 33B shows a schematic of the optical setup of the dip sensor for the analysis of interferometry the porous silicon. DETAILED DESCRIPTION

[0061 ] The present disclosure relates to substrates that are stimulus responsive and uses of such substrates.

[0062] Certain disclosed embodiments have one or more combinations of advantages. For example, some of the advantages of the embodiments disclosed herein include one or more of the following: a substrate that is responsive to temperature and/or pH; a substrate that provides a visual output of temperature and/or pH; a substrate that provides the ability to measure changes in temperature; a substrate that provides the ability to measure changes in pH; a substrate that can be used to both detect changes in temperature and/or pll and also provide temperature and/or pH responsive drug release; a substrate that may be incorporated into wound dressings; a substrate that may be incorporated into bandages; a substrate that has intrinsic anti-bacterial properties; a substrate that may be used to detect physiological changes; a substrate that may be used to improve wound management; a substrate that may be used to improve wound treatment; a substrate that may be used as a diagnosis tool; a substrate that may be used to deliver therapeutic agents in a controlled fashion; a substrate that may be used as a theranostic; a substrate that may be used an optical sensor; a substrate that may be used to absorb an agent with little loss of activity of the agent; to address one or more problems in the art; to provide one or more advantages in the art; and/or to provide a useful commercial choice. Other advantages of certain embodiments are disclosed herein.

[0063] Certain embodiments of the present disclosure provide a substrate comprising a stimulus responsive polymer attached to a substrate. Certain embodiments of the present disclosure provide a substrate with an attached stimulus responsive polymer. The use of one or more stimulus responsive polymers may thereby impart to the substrate stimulus responsiveness.

[0064] In certain embodiments, the substrate comprises one or more of silicon, gold, silver, aluminium, a polymer and a glass. Other suitable substrates are contemplated. Methods for producing such substrates are known in art. [0065] In certain embodiments, the substrate comprises a silicon substrate. Methods for producing silicon substrates are known in the art.

[0066] Certain embodiments of the present disclosure provide a silicon substrate comprising a stimulus responsive polymer attached to the silicon substrate. Certain embodiments of the present disclosure provide a silicon substrate with an attached stimulus responsive polymer.

[0067] Certain embodiments of the present disclosure provide a polymer substrate comprising a stimulus responsive polymer attached to the substrate. Certain embodiments of the present disclosure provide a polymer substrate with an attached stimulus responsive polymer. In certain embodiments, the polymer comprises a photonic polymer.

[0068] Certain embodiments of the present disclosure provide a glass substrate comprising a stimulus responsive polymer attached to the glass substrate. Certain embodiments of the present disclosure provide a glass substrate with an attached stimulus responsive polymer.

[0069] Certain embodiments of the present disclosure provide the use of a substrate as described herein in a sensor, a dip sensor, an optical fibre, a cell culture vessel, a wound dressing, a dressing, a bandage, a device, an implantable article, an insertable article, and an embeddable article. Other uses are contemplated.

[0070] In certain embodiments, the substrate comprises one or more of a flat substrate, a film, a membrane and particles.

[0071] In certain embodiments, the substrate comprises a flat substrate. In certain embodiments, the substrate comprises a film. In certain embodiments, the substrate comprises a membrane. In certain embodiments, the substrate comprises particles.

[0072] In certain embodiments, the substrate comprises a silicon substrate. In certain embodiments, the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane and silicon particles. [0073] In certain embodiments, the substrate comprises a flat silicon substrate. Methods for producing flat silicon are known in the art.

[0074] In certain embodiments, the substrate comprises a silicon membrane. Methods for producing silicon membranes are known in the art. In certain embodiments, the substrate comprises a flat silicon substrate. Methods for producing flat silicon are known in the art. In certain embodiments, the substrate comprises a silicon film substrate. Methods for producing silicon films are known in the art. In certain embodiments, the substrate comprises silicon particles. Methods for producing silicon particles are known in the art.

[0075] In certain embodiments, the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane and silicon particles.

[0076] In certain embodiments, the substrate with attached stimulus responsive polymer is responsive to a non-biological property. Examples of non-biological properties mclude temperature, pH, light, pressure, humidity and moisture. Other types of properties are contemplated. In certain embodiments, the substrate with attached stimulus responsive polymer is response to a non-physiological property. In certain embodiments, the substrate with attached stimulus responsive polymer may used to measure and/or determine a parameter associated with such properties and thereby provide information on the state of a property.

[0077] In certain embodiments, the substrate with attached stimulus responsive polymer is responsive to a biological property. Examples of biological properties include temperature, pH, glucose levels, oxygen levels, osmolality, levels of hormones, levels of nutrients and levels of toxins. Other types of biological properties are contemplated. In certain embodiments, the substrate with attached stimulus responsive polymer is responsive to a physiological property. In certain embodiments, the substrate with attached stimulus responsive polymer may used to measure and/or determine a parameter associated with such properties and thereby provide information on the state of a property. [0078] In certain embodiments, the substrate with attached stimulus responsive polymer comprises a thermoresponsive property and/or a pH responsive property. In certain embodiments, the thermoresponsive property comprises a thermoresponsive property between 25"C and 50"C, or about this range. In certain embodiments, the substrate with attached stimulus responsive polymer may used to measure and/or determine temperature and/or pH.

[0079] In certain embodiments, the pH responsive property comprises a pH responsive property between pH 2.6 and pH 9.6, or about this range. In certain embodiments, the pH responsive property comprises a pH responsive property with a sensitivity of at least 2 pH units, at least 1.5 pll units, at least 1.0 pH units, at least 0.5 pli units, or at least 0.2 pH units. In certain embodiments, the pH responsive property comprises a pH responsive property with a sensitivity of at 2 pi I units or less, 1.5 pll units or less 1.0 pH units or less, 0.5 pH units or less, or 0.2 pH units or less.

[0080] In certain embodiments, the thermoresponsive property and/or the pH responsive property comprise a change in optical reflective characteristics. In certain embodiments, the optical reflective characteristics may used to measure and/or detemiine temperature and/or pH.

[0081] In certain embodiments, the stimulus responsive polymer is responsive to a non-biological property. Examples of non-biological properties are described herein. In certain embodiments, the stimulus responsive polymer is responsive to a non- physiological property.

[0082] In certain embodiments, the stimulus responsive polymer is responsive to a biological property. Examples of biological properties are described herein. In certain embodiments, the stimulus responsh'e polymer is responsive to a physiological property.

[0083] In certain embodiments, the stimulus responsive polymer comprises a thermoresponsive property and/or a pH responsive property. In certain embodiments, the stimulus responsive polymer comprises a thermoresponsive property between 25°C and 50°C, or about this range. In certain embodiments, the stimulus responsive polymer comprises a pll responsive property between pH 2.6 and pH 9.6, or about this range. In certain embodiments, stimulus responsive polymer comprises a pH responsive property with a sensitivity of at least 2 pll units, at least 1.5 pH units, at least 1.0 pH units, at least 0.5 pH units, or at least 0.2 pH units. In certain embodiments, stimulus responsive polymer comprises a pH responsive property with a sensitivity of 2 pH units or less, 1.5 pH units or less, 1.0 pH units or less, 0.5 pH units or less, or 0.2 pH units or less. In certain embodiments, the stimulus responsive polymer comprises a property which comprises a change in optical reflective characteristics.

[0084] In certain embodiments, the stimulus responsive polymer comprises a single polymer. In certain embodiments, the stimulus responsive polymer comprises one or more polymers. In certain embodiments, the stimulus responsive polymer comprises a co-polymer.

[0085] In certain embodiments, the stimulus responsive polymer comprises a non- cross linked polymer. In certain embodiments, the stimulus responsive polymer comprises a cross-linked polymer. In certain embodiments, the stimulus responsive polymer comprises a cross-linked polymer and/or a non-cross linked polymer.

[0086] In certain embodiments, the stimulus responsive polymer comprises a polyacrylate polymer. Examples of polyacrylate polymers include poly(acrylic acid), poly(methacrylic acid), poly(propionic acid), poly(2-(dimethylamino)ethyl methacrylate) and poly(oligoethylene glycol methacrylates).

[0087] In certain embodiments, the polyacrylate polymer comprises a polymethylacrylate polymer.

[0088] In certain embodiments, the stimulus responsive polymer comprises a polyacrylamide polymer including poly(N-isopropylacrylamide) or Poly(N- ethylacrylamide).

[0089] In certain embodiments, the stimulus responsive polymer comprises a polyvinyl polymer including poly( vinyl methyl ether). [0090] In certain embodiments, the stimulus responsive polymer comprises one or more of a polyacrylate polymer, a polyacrylamide polymer and a polyvinyl polymer.

[0091] Methods for forming polymers on substrates are known. Methods for forming polymers on silicon are known in the art and are described, for example, in M. urkuri, M.R. Nussio, A. Deslandes, N.H. Voelcker. Thermoseiisitive Copolymer Coatings with Enhanced Wettability Switching. Langmuir, 24 (2008), 4238-4244 or S. Pace, R.B. Vasani, F. Cunin, N.H. Voelcker, Study of the Optical Properties of Thermoresponsive Polymer Grafted from Porous silicon Scaffolds, New Journal of Chemistry, 37 (2013), 228-235.

[0092] In certain embodiments, the stimulus responsive polymer is produced by a method comprising one or more of plasma polymerisation, atom transfer radical polymerisation, reversible addition- ragmentation chain transfer polymerisation, free radical polymerisation, spin coating, photo polymerisation or dip-coating. Other methods are contemplated. In certain embodiments, the stimulus responsive polymer is produced by a method comprising plasma polymerisation. In certain embodiments, the stimulus responsive polymer is produced by a method that does not involve atom transfer radical polymerisation.

[0093] In certain embodiments, the substrate comprises a stimulus response polymer with a thickness of 1 mm or less, 500 μιη or less, 400 μηι or less, 300 μηι or less, 200 μιη or less, or 100 μτη or less. Other thicknesses are contemplated and described herein.

[0094] In certain embodiments, the substrate comprises a stimulus response polymer with a thickness of 200 μητ or less. Other thicknesses are contemplated.

[0095] In certain embodiments, the substrate may further comprise a non-stimulus responsive polymer. In certain embodiments, the substrate may further comprise one or more non-stimulus responsive polymers. Examples of non-stimulus responsive polymers include poly(allyl amine) or poly( methyl methacrylale).

[0096] In certain embodiments, the substrate comprises a porous substrate. [0097] In certain embodiments, the substrate comprises a porous silicon substrate. Methods for producing porous silicon are known in the art and are as described herein.

[0098] In certain embodiments, the substrate comprises a porous aluminium substrate. Porous aluminium is known in the art. Methods for attaching polymers to porous aluminium are known in the art and are as described in, for example, A. Mutalib, D. Losic, J.G. Shapter, N.H Voelcker. Nanoporous anodic alumina membranes with layered surface chemistry. Chemical Communications, 21 (2009), 3062-3064.

[0099] In certain embodiments, the substrate comprises a flat gold substrate. Flat gold is known in the art. Methods for attaching polymers to this substrate are known in the art and as described in, for example, M. Cole, N.H. Voelcker, H. Thissen, R. Horn, H.J. Griesser, Colloid probe AFM study of thermal collapse and protein interactions of poly(N-isopropylacrylamide) coatings. Soft Matter, 6 (2010), 2657-2667.

[00100] In certain embodiments, the substrate comprises a porous silver substrate. Porous silicon substrates are known in the art and commercially available. Methods for attaching polymers to silicon substrates, including porous silicon, are known in the art.

[00101] In certain embodiments, the substrate comprises a porous photonic polymer. Methods for producing porous polymers are known in the art.

[00102] In certain embodiments, the substrate comprises a porosity of at least 50%. Methods for determining the porosity of are known in the art. Other porosities are contemplated.

[00103] In certain embodiments, the substrate comprises a pore size of 10 to 500 nm. Methods for determining pore size are known in the art. Other pore sizes are contemplated.

[00104] In certain embodiments, the pores of a porous substrate are coated with a non- stimulus responsive polymer. Tn certain embodiments, the pores of a porous sub.strate are coated with one or more non-stimulus responsive polymers. Examples of non- stimulus responsive polymers are as described herein. Methods of attaching polymers to porous substrates are known in the art. [00105] In certain embodiments, a porous substrate comprises a releasable agent. Porous substrates are as described herein.

[00106] In certain embodiments, the release of the releasable agent is stimulus responsive.

[00107] In certain embodiments, the release of the releasable agent is responsive to a non-biological property. Examples of non-biological properties are as described herein. In certain embodiments, the release of the releasable agent is responsive to a non- physiological property. In certain embodiments, the release of the releasable agent is responsive to a non-physiological property.

[00108] In certain embodiments, the release of the releasable agent is responsive to a biological property. Examples of biological properties are described herein. In certain embodiments, the release of the releasable agent is responsive to a physiological property.

[00109] In certain embodiments, the release of the releasable agent is thermoresponsive and/or a pH responsive. In certain embodiments, the release of the releasable agent comprises a thermoresponsive property between 25°C and 50°C, or about this range.

[00110] In certain embodiments, the release of the releasable agent comprises a thermoresponsive property between 30"C and 50°C, 35"C and 50^UC, 25°C and 40"C and 35°C and 40°C, or about these ranges.

[001 1 1 ] In certain embodiments, the release of the releasable agent comprises a pH responsive property between pll 2.6 and pll 9.6, or about this range. In certain embodiments, the release of the releasable agent comprises a pH responsive property with a sensitivity of at least 2.0 pH units, at least 1.5 pH units, at least 1.0 pH units or at least 0.5 pH units. In certain embodiments, the release of the releasable agent comprises a pH responsive property with a sensitivity of 2.0 pH units or less, 1 .5 pH units or less, 1.0 pll units or less, or 0.5 pll units or less. In certain embodiments, the release of the releasable agent comprises a pH responsive property with a sensitivity of at least 0.2 pH units. [00112] In certain embodiments, the release of the releasable agent comprises a pH responsive property between pH 3.0 and pH 9.0, pH 4.0 and pH 9.0, pH 5.0 and pH 9.0, pH 6.0 and pll 9.0, pH 7.0 and pll 9.0, pH 8.0 and pH 9.0, pH 4.0 and pH 8.0, pH 5.0 and pH 8.0, pH 6.0 and pH 8.0, and pH 7.0 and pH 8.0, or about these ranges.

[00113] In certain embodiments, the substrate with the attached polymer produces both stimulus responsive sensing of a parameter and stimulus responsive release of the releasable agent.

[00114] In certain embodiments, the releasable agent comprises a non-organic compound, an organic compound, an enzyme, a reactant, an oxidant, a reductant, an acid, and a base. Other types of agents are contemplated.

[001 15] In certain embodiments, the releasable agent comprises a therapeutic agent.

[00116] In certain embodiments, the therapeutic agent comprises one or more of a drug, a small molecule, a biologic, an antibody, an aptamer, a polypeptide, an oligonucleotide, a siRNA, an enzyme, a growth factor, a nucleic acid, a wound healing agent, an anti-inflammatory agent, an anti-bacterial agent, an antibiotic, an anti-viral agent, an antisense RNA, a toxin, a cytotoxic agent, a cytostatic agent, a cytotoxic antibiotic, an anti-cancer agent, an alkylating agent, an anti-metabolite, a DNA synthesis inhibitor, an apoptotic agent, a cell division inhibitor, an agent that reduces cell resistance to a drug, an agent thai promotes activity of a drug, and an agent that induces differentiation of a cell (a cell differentiating agent). Other types of therapeutic agent are contemplated. The term "therapeutic agent" refers to an agent that when delivered to a biological site is able to provide a desirable and/or beneficial effect.

[00117] Examples of anti-cancer agents include alkylating agents (such as cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide), anti-metabolites (such as azathioprine and mercaptopurine), plant alkaloids and terpenoids (such as vincristine, vinblastine, vinorelbine and vindesine), cell cycle inhibitors (such as podophyllotoxin), taxanes (such as paclitaxel), topoisomerase inhibitors (such as camptothecins, irinotecan and topotecan, amsacrine, etoposide, etoposide phosphate, and tenyposide), and cytotoxic antibiotics (such as actinomycin, doxorubicin, daunorubiein, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin. Other anti-cancer agents arc contemplated.

[00118] Examples of antibiotics include Aminoglycosides, Ansamycins, Carbacephem, Carbapenems, Cephalosporins, Glycopeptides, Lincosamidcs, Lipopeptides, Macrolides, Monobactams, Nitrofurans, Oxazolidonones, Penicillins, Polypeptides, Quinolones, Sulfonamides, and Tetracyclines. Other antibiotics are contemplated.

[00119] In certain embodiments, the therapeutic agent comprises one of more of an anti-inflammatory agent, a NSAID, acetylsalicylic acid (aspirin), ibuprofen, prednisone, levofloxacin, vancomycin, a growth factor, a wound healing agent such as allopurinol or Flightless antibody. Other agents are contemplated.

[00120] In certain embodiments, the therapeutic agent comprises a combination of agents as described herein.

[00121] Certain embodiments of the present disclosure provide a material comprising a substrate comprising a stimulus responsive polymer, as described herein, thereby imparting stimulus responsive properties to ail or part of the material.

[00122] In certain embodiments, the material comprises particles comprising the substrate comprising a stimulus responsive polymer, as described herein. In certain embodiments, the material comprises a membrane comprising a substrate comprising a stimulus responsive polymer, as described herein. In certain embodiments, the material comprises a flat substrate comprising the substrate comprising a stimulus responsive polymer, as described herein. In certain embodiments, the material comprises particles comprising the substrate comprising a stimulus responsive polymer, as described herein. Methods for incorporating substrates into materials are known in the art.

[00123] In certain embodiments, the material comprises a substrate comprising a stimulus responsive polymer and a relcasablc agent, as described herein. In certain embodiments, the material has the property of stimulus responsive release of the relcasablc agent. [00124] In certain embodiments, the material may be incorporated into a device or article. Such a device or article may be used to assess or measure a parameter and/or to release a releasable agent in response to changes in a parameter. Examples of devices or articles include an optical fibre, a sensor, a bandage, a wound dressing, a dressing, a sensor, a cell culture vessel, and a multi-well plate, such as a microtitre plate.

[00125] Certain embodiments of the present disclosure provide an optical fibre comprising a substrate comprising a stimulus responsive polymer, as described herein. Methods for incorporating substrates into, or in communication with, optical fibres are known in the art. For example, an optically reflective substrate as described herein may be used in conjunction with an optical fibre, thereby allowing changes in the reflective properties of the substrate to be measured at a site using the optical fibre. Tn this way, a parameter such as temperature and/or pi I parameter can be assessed or measured.

[00126] Certain embodiments of the present disclosure provide a cell culture vessel comprising a substrate comprising a stimulus responsive polymer, as described herein. For example, a substrate comprising a pH responsive polymer as described herein may be incorporated into one or more of the walls of a plastic tissue culture flask and thereby allow assessment of the pH of the culture medium in which cells are growing. A substrate as described herein may similarly be incorporated into all or part of the wells of a multi-well plate. In certain embodiments, the cell culture vessel comprises a flat substrate as described herein. In certain embodiments, the cell culture vessel comprises a film as described herein. In certain embodiments, the cell culture vessel comprises a membrane comprising a substrate as described herein. Methods for incorporating substrates into plastics are known in the art.

[00127] Certain embodiments of the present disclosure provide a wound dressing or bandage comprising a substrate as described herein. For example, a flexible membrane or particles comprising a substrate as described herein may be incorporated or embedded into a wound dressing or bandage. Wound dressings and bandages are as described herein.

[00128] For example, a substrate comprising a thermoresponsive polymer and/or a pH responsive polymer can be incorporated into a wound dressing or bandage and used to monitor whether the wound becomes infected, such as due to changes in temperature and'Or pH. For many infections, a change in temperature is associated with the infection. Incorporation of a stimulus responsive substrate as described herein that is responsive to temperature into a wound dressing or bandage may be used to monitor the temperature of a wound and thereby provide an early indication of possible infection of the wound.

[00129] In another example, a substrate comprising a thermoresponsive polymer and/or a pH responsive polymer can be incorporated into a wound dressing or bandage and used to release a therapeutic agent to the wound when the wound becomes infected, such as due to changes in temperature and/or pH of the wound. For many infections, a change in temperature is associated with the infection. Incorporation of a stimulus responsive substrate as described herein that is responsive to temperature into a wound dressing or bandage may be used to deliver a therapeutic agent (such as an anti-bacterial agent) to the wound and thereby provide early treatment of possible infection of the wound.

[00130] In another example, a substrate comprising a thermoresponsive polymer and/or a pH responsive polymer can be incorporated into a wound dressing or bandage and used to both monitor whether the wound becomes infected and also to release a therapeutic agent to the wound when the wound becomes infected in response to changes in temperature and/or changes in H.

[00131] Certain embodiments of the present disclosure provide an implantable article comprising a substrate comprising a stimulus responsive polymer, as described herein. Examples of implantable articles include biological scaffolds, mechanical or electrical devices, pumps, and drug delivery devices.

[00132] Certain embodiments of the present disclosure provide a sensor comprising a substrate comprising a stimulus responsive polymer, as described herein.

[00133] In certain embodiments, the sensor provides qualitative sensing. For example, the visual colour of the sensor may be indicative of the temperature and/or pH of a site and changes in the colour indicative of changes in these parameters. [00134] In certain embodiments, the sensor provides quantitative sensing. In certain embodiments, the sensor provides qualitative and/or quantitative sensing. In certain embodiments, the sensor provides qualitative and quantitative sensing. In certain embodiments, the sensor is a point of care sensor or a dip-type sensor. Other types of sensor are contemplated.

[00135] In certain embodiments, the sensor comprises particles comprising the substrate as described herein. In certain embodiments, the sensor comprises a membrane comprising the substrate as described herein. In certain embodiments, the sensor comprises a flat substrate comprising the substrate as described herein. In certain embodiments, the sensor comprises a film comprising the substrate as described herein. Methods for incorporating substrates into sensors are known in the art.

[00136] Certain embodiments of the present disclosure provide a method of sensing a parameter using a substrate comprising a stimulus responsive polymer, as described herein. Certain embodiments of the present disclosure provide a method of sensing a parameter using a sensor as described herein.

[00137] Certain embodiments of the present disclosure provide a method of sensing a parameter, the method comprising using a substrate comprising a stimulus responsive polymer attached to the substrate to sense the parameter.

[00138] Examples of parameters are as described herein and include one or more of temperature, pH. light, pressure, humidity and moisture, glucose levels, oxygen levels, osmolality, levels of hormones, levels of enzymes, levels of nutrients, and levels of toxins. Other types of parameters are contemplated.

[00139] In certain embodiments, the parameter comprises temperature and/or pH.

[00140] Certain embodiments of the present disclosure provide a method of sensing temperature and/or pH, the method comprising using a substrate comprising a stimulus responsive polymer, as described herein.

[00141 ] Examples of substrates are as described herein. In certain embodiments, the substrate comprises one or more of silicon, gold, silver, aluminium, a polymer and a glass. Other substrates are contemplated.

[00142] In certain embodiments, the substrate comprises a silicon substrate. In certain embodiments, the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane, a silicon film and silicon particles. In certain embodiments, the silicon substrate is a porous silicon substrate.

[00143] In certain embodiments, the substrate comprises a photonic polymer.

[00144] Stimulus responsive polymers are as described herein. In certain embodiments, the polymer comprises a thermoresponsive and/or a pH responsive polymer.

[00145] Certain embodiments of the present disclosure provide a method of sensing temperature and/or pH, the method comprising using a sensor comprising a substrate comprising a stimulus responsive polymer to sense the temperature and/or pH.

[00146] In certain embodiments, the method comprises sensing the parameter at a non- bioiogical site. Examples of non-biological sites include environmental sites, sites associated with machinery, and sites associated with industrial or manufacturing processes.

[00147] In certain embodiments, the method comprises sensing the parameter at a biological site. Examples of biological sites include wounds, ulcers, burns, sites of infection (eg bacterial, viral, fungal), sites susceptible to infection, tissues, organs and in vitro sites including one or more cells (such as in cell culture vessels and multi-well plates). Other types of biological sites are contemplated.

[00148] In certain embodiments, the biological site comprises a wound, or a site of potential or known bacterial infection.

[00149] In certain embodiments, the biological site comprises all or part of a subject, such as a human or animal subject. Examples of subjects are as described herein.

[00150] Certain embodiments of the present disclosure provide a method of delivering a releasable agent to a site. [00151] Certain embodiments of the present disclosure provide a method of delivering a releasable agent to a site, the method comprising: providing to a site a substrate comprising a releasable agent and a stimulus responsive polymer, as described herein, and releasing the releasable agent from the substrate in response to a stimulus, thereby delivering the releasable agent to the site.

[00152] Certain embodiments of the present disclosure provide a method of delivering a releasable agent to a site, the method comprising:

providing to the site a substrate comprising a stimulus responsive polymer attached to the substrate and a releasable agent; and

releasing the releasable agent from the substrate in response to a stimulus, thereby delivering the releasable agent to the site.

[00153] Examples of sites to which a releasable agent may be delivered are as described herein. In certain embodiments, the site comprises a non-biological site. In certain embodiments, the site comprises a biological site. In certain embodiments, the biological site comprises a wound, an ulcer, a burn, a site of infection, a tissue or an organ. In certain embodiments, the biological site comprises all or part of a subject.

[00154] Delivery refers to providing a releasable agent to a desired or selected site, and includes one or more of contacting, exposing and administering. Delivery may also include delivery to sites other than the desired or selected site. Examples of delivery include directly and/or indirectly bringing the substrate comprising the releasable agent into contact with a desired site, bringing the substrate comprising the releasable agent into the vicinity of a desired site, bringing the substrate comprising the releasable agent near or adjacent to a desired site, or delivering the releasable agent to the desired site by release of the agent from the substrate at a remote site (such as by administration).

[00155] Examples of releasable agents are as described herein. In certain embodiments, the releasable agent comprises a therapeutic agent. Examples of therapeutic agents are as described herein.

[00156] Examples of substrates are as described herein. In certain embodiments, the substrate is provided in a form comprising a wound dressing or bandage comprising the substrate.

[00157] Examples of stimulus responsive polymers are as described herein. In certain embodiments, the stimulus responsive polymer comprises a thermoresponsive and/or pH responsive polymer.

[00158] Examples of stimuli are as described herein. For example, the release of the releasable agent may occur in response to a change in temperature and/or pH. Other examples of stimuli include glucose levels, oxygen levels, osmolality, levels of hormones, levels of nutrients and levels of toxins, and/or a change in such stimuli.

[00159] Certain embodiments of the present disclosure provide a therapeutic composition comprising a substrate comprising a stimulus responsive polymer and a therapeutic agent, as described herein.

[00160] Such compositions can be used, for example, to provide release of a therapeutic agent in response to a stimulus.

[00161] In certain embodiments, the substrate comprises a porous substrate. Examples of porous substrates are as described herein.

[00162] Certain embodiments of the present disclosure provide a therapeutic composition comprising a porous substrate comprising:

(i) a stimulus responsive polymer attached to the porous substrate; and

(ii) a therapeutic agent loaded onto the porous substrate.

[00163] The attachment of polymers to substrates is as described herein.

[00164] In certain embodiments, the therapeutic agent is absorbed onto the porous substrate, directly and/or indirectly.

[00165] Certain embodiments of the present disclosure provide a method of therapy, the method comprising exposing a subject to an effective amount of a therapeutic composition, as described herein. [00166] Certain embodiments of the present disclosure provide use of a substrate comprising a stimulus responsive polymer as described herein in the preparation of a medicament^".

[00167] In certain embodiments, a therapeutic composition as described herein may be used to prevent and/or treat selected diseases, conditions or states. In certain embodiments, the condition or state comprises a wound, an ulcer, a burn, or an infection. In certain embodiments, the diseases, conditions or state

[00168] A therapeutic composition may comprise other active agents, excipients, dosage forms, stabilizers, and other agents suitable for use in connection with the therapeutic composition.

[00169] The formulation of therapeutic compositions is known and described in, for example. Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.

[00170] The term "effective amount" as used herein refers to that amount of an agent or composition that when exposed to a cell, biological system or a subject is sufficient to illicit the desired response or outcome. In certain embodiments, the effective amount is a therapeutically effective amount.

[00171 ] The term "prevent", and related terms such as "prevention" and "preventing", refer to obtaining a desired pharmacologic and/or physiologic effect in terms of arresting or suppressing the appearance of one or more symptoms in the subject.

[00172] The term "treat", and related terms such as "treating" and "treatment", refer to obtaining a desired pharmacologic and/or physiologic effect in terms of improving the condition of the subject, ameliorating, arresting, suppressing, relieving and/or slowing the progression of one or more symptoms in the subject, a partial or complete stabilisation of the subject, a regression of the one or more symptoms, or a cure of a disease, condition or stale in the subject.

[00173] The term "therapeutically effective amount" as used herein refers to that amount of an agent that is sufficient to effect prevention and/or treatment, when administered to a subject. The therapeutically effective amount will vary depending upon a number of factors, including for example the specific activity of the agent being used, the severity of the disease, condition or state in the subject, the age, physical condition, existence of other disease states, and nutritional status of the subject.

[00174] In certain embodiments, the subject as described herein is human subject. In certain embodiments, the subject is a mammalian subject, a livestock animal (such as a horse, a cow, a sheep, a goat, a pig), a domestic animal (such as a dog or a cat) and other types of animals such as monkeys, rabbits, mice and laboratory animals. Other types of animals arc contemplated. Veterinary applications of the present disclosure are contemplated.

[00175] In certain embodiments, the subject is suffering from a disease, condition or state as described herein. Examples include bacterial infections or a cancer.

[00176] The therapeutic composition as described herein may be administered to the subject in a suitable form. In this regard, the terms "administering" or "providing" includes routes of administration that are systemic (e.g., via injection such as intravenous injection, orally in a tablet, pill, capsule, or other dosage form useful for systemic administration), topical (e.g., creams, solutions, and the like, including solutions such as mouthwashes, for topical oral administration), nasal administration (e.g. nasal sprays) and administration via the lung (e.g. nebulisation)

[00177] In certain embodiments, the therapeutic composition as described herein is administered orally. In certain embodiments, the therapeutic composition as described herein is administered intravenously. In certain embodiments, therapeutic composition as described herein is administered via injection, such as intravenous injection. In certain embodiments, the therapeutic composition as described herein is administered by nebulized administration, by aerosolized administration or by being instilled into the lung.

[00178] The therapeutic composition as described herein may be administered alone or may be delivered in a mixture with other therapeutic agents and/or agents that enhance, stabilise or maintain the activity of the active agents or the substrate In certain embodiments, an administration vehicle (e.g., pill, tablet, implant, injectable solution, etc.) may contain both the therapeutic composition as described herein and additional agent(s).

[00179] When administered to a subject, the therapeutically effective dosage may vary depending upon the therapeutic composition utilized, the mode of administration, the condition, and severity thereof, as well as the various physical factors related to the subject being treated. The daily dosages are expected to vary with route of administration, and the nature of the therapeutic composition administered. In certain embodiments the methods comprise administering to the subject escalating doses of therapeutic composition and/or repeated doses. In certain embodiments, therapeutic composition is administered orally. In certain embodiments, therapeutic composition as described herein is administered via injection, such as intravenous injection. In certain embodiments, therapeutic composition as described herein is administered parenterally. In certain embodiments, the therapeutic composition as described herein is administered by direct introduction to the lungs, such as by aerosol administration, by nebulized administration, and by being instilled into the lung. In certain embodiments, the therapeutic composition is administered by implant. In certain embodiments, the therapeutic composition is administered by implanting, insertion, embedding, subcutaneous injection, intraarticularly, rectally, inlranasally, intraocularly, vaginally, or transdermaliy.

[00180] "Intravenous administration" is the administration of substances directly into a vein. "Oral administration" is a route of administration where a substance is taken through the mouth, and includes buccal, sublabial and sublingual administration, as well as enteral administration and that through the respiratory tract, unless made through e.g. tubing so the medication is not in direct contact with any of the oral mucosa. Typical forms for the oral administration of therapeutic agents includes the use of tablets or capsules.

[00181] In certain embodiments, the therapeutic composition as described herein is provided in a pharmaceutically acceptable carrier suitable for administering to a subject. The carriers may be chosen based on the route of administration as described herein, the location of the target issue, therapeutic composition being delivered, the time course of delivery of the drug, etc. The term "pharmaceutically acceptable carrier" refers to a substantially inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. An example of a pharmaceutically acceptable carrier is physiological saline. Other physiologically acceptable carriers and their formulations are known in the art.

[00182] In certain embodiments, the therapeutic compositions or medicaments comprise other agents and/or agents that enhance, stabilise or maintain the activity of the active.

[00183] Oral formulations containing therapeutic composition as described herein may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodccylsulfatc, magnesium aluminium silicate, and triethanolamine. Oral formulations may utilize standard delay or time-release formulations to alter the absorption of the peptides. The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed. [00184] In certain embodiments, the therapeutic composition as described herein may also be administered by injection. Forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[00185] In certain embodiments, the therapeutic composition as described herein may also be administered intravenously. Compositions tor intravenous administration may be formulated by a skilled person.

[00186] In certain embodiments, the therapeutic composition as described herein may also be administered transdermally. Transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[00187] Additional numerous various excipients, dosage forms, dispersing agents and the like that are suitable for use in connection with administration of the therapeutic composition and/or formulation into medicaments. Formulations are known and described in, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.

[00188] Certain embodiments of the present disclosure provide a device or article with the ability for both delivering a therapeutic agent delivery and also for sensing a parameter. Examples of devices and articles arc as described herein.

[00189] Certain embodiments of the present disclosure provide a device or article for delivering a therapeutic agent and sensing a parameter, the device or article comprising a substrate comprising a stimulus responsive polymer attached to the substrate and a releasable therapeutic agent. [00190] In certain embodiments, the device or article comprises a silicon substrate comprising a stimulus responsive polymer, as described herein.

[00191] In certain embodiments, the device or article comprises a photonic polymer substrate comprising a stimulus responsive polymer, as described herein.

[00192] Certain embodiments of the present disclosure provide a device or article for delivering a therapeutic agent and sensing a parameter, the device or article comprising a substrate comprising a stimulus responsive polymer attached to the silicon substrate and a releasable therapeutic agent.

[00193] Certain embodiments of the present disclosure provide a device or article for delivering a therapeutic agent and sensing a parameter, the device or article comprising a silicon substrate comprising a stimulus responsive polymer attached to the silicon substrate and a releasable therapeutic agent.

[00194] Examples of therapeutic agents are as described herein. In certain embodiments, the therapeutic agent comprises a drug.

[00195] Certain embodiments of the present disclosure provide a drug delivery and sensing device, the device comprising a substrate comprising a stimulus responsive polymer attached to the substrate and a releasable drug. Examples of substrates are as described herein.

[00196] Certain embodiments of the present disclosure provide a drug delivery and sensing device, the device comprising a silicon substrate comprising a stimulus responsive polymer attached to the silicon substrate and a releasable drug.

[00197] Certain embodiments of the present disclosure provide a method of producing a stimulus responsive material, as described herein.

[00198] Certain embodiments of the present disclosure provide a method of producing a stimulus responsive material, the method comprising:

functionalising a surface of a substrate; and

forming a polymer on the functionalised surface, wherein the polymer comprises a stimulus responsive properly.

[00199] In certain embodiments, the stimulus responsive material is responsive to a non-biological property. Examples of non-biological properties are as described herein and include temperature, pH, light, pressure, humidity and moisture. In certain embodiments, the stimulus responsive material is responsive to a non-physiological property. In certain embodiments, the stimulus responsive material is responsive to a non-physiological property.

[00200] In certain embodiments, the stimulus responsive material is responsive to a biological property. Examples of biological properties are as described herein and include temperature, pH, glucose levels, oxygen levels, osmolality, levels of hormones, levels of enzymes, levels of nutrients and levels of toxins. Other types of biological properties are contemplated. In certain embodiments, the stimulus responsive material is responsive to a physiological property.

[00201] In certain embodiments, the stimulus responsive material comprises a thermoresponsive property and'or a pH responsive property. In certain embodiments, the thermoresponsive property comprises a thermoresponsive property between 25°C and 50"C. In certain embodiments, the thermoresponsive property comprises a thermoresponsive property between 30°C and 50°C, 35°C and 50°C, 25°C and 40°C and 35°C and 40"C, or about these ranges.

[00202] In certain embodiments, the pH responsive property comprises a pH responsive property between pH 2.6 and pH 9.6. In certain embodiments, the pH responsive property comprises a pH responsive property with a sensitivity of at least 2.0 pH units, at least 1.5 pH units, at least 1.0 pH units, or at least 0.5 pH units. In certain embodiments, the pH responsive property comprises a pH responsive property with a sensitivity of 2.0 pll units or less, 1.5 pH units or less, 1.0 pll units or less, or 0.5 pH units or less. In certain embodiments, the pH responsive property comprises a pH responsive property with a sensitivity of at least 0.2 pll units.

[00203] In certain embodiments, the pH responsive property comprises a pH responsive property between pH 3.0 and pH 9.0, pH 4.0 and pH 9.0, pH 5.0 and pH 9.0, pH 6.0 and ρΙΊ 9.0, H 7.0 and pll 9.0, pH 8.0 and pll 9.0, pll 4.0 and pH 8.0, pli 5.0 and pH 8.0, pH 6.0 and pH 8.0, and pH 7.0 and pH 8.0, or about any of these ranges.

[00204] Examples of substrates are as described herein. In certain embodiments, the substrate comprises one or more of silicon, gold, silver, aluminium, a polymer, and a glass. Other suitable substrates are contemplated. Methods for producing such substrates are known in art. Substrates are as described herein.

[00205] In certain embodiments, the substrate comprises a silicon substrate. Methods for producing silicon substrates are known in the art.

[00206] In certain embodiments, the substrate comprises a photonic polymer. Methods for producing photonic polymers are known in the art.

[00207] In certain embodiments, the substrate comprises one or more of a flat substrate, a film, a membrane and particles.

[00208] In certain embodiments, the substrate comprises a flat silicon substrate. Methods for producing flat silicon are known in the art. Methods for functionalising flat silicon and attaching polymers are known in the art and are as described, for example, in M. Kurkuri, M. . Nussio, A. Deslandes, N.H. Voelcker. Thermosensitive Copolymer Coatings with Enhanced Wettability Switching. Langmuir, 24 (2008), 4238-4244 or S. Pace, R.B. Vasani, F. Cimin, N.H. Voelcker , Study of the Optical Properties of Thermoresponsive Polymer Grafted from Porous silicon Scaffolds, New Journal of Chemistry, 37 (2013), 228-235.

[00209] In certain embodiments, the substrate comprises a silicon membrane. Methods for producing silicon membranes are known in the art. In certain embodiments, the substrate comprises a flat silicon substrate. Methods for producing flat silicon are known in the art. In certain embodiments, the substrate comprises silicon particles. Methods for producing silicon particles are known in the art.

[00210] In certain embodiments, the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane and silicon particles. [00211] In certain embodiments, the substrale comprises a porous substrate. Examples of porous substrates are as described herein.

[00212] In certain embodiments, the substrate comprises a porous silicon substrate. Methods tor producing porous silicon are known in the art and are as described herein.

[00213] In certain embodiments, the substrate comprises a porous aluminium substrate. Methods for producing porous aluminium are known in the art. Methods for attaching polymers to porous aluminium are known in the art and are as described, for example, in A. Mutalib, D. Losic, J.G. Shapter, N.H Voelcker. Nanoporous anodic alumina membranes with layered surface chemistry. Chemical Communications, 21 (2009), 3062-3064.

[00214] In certain embodiments, the substrate comprises a flat gold substrate. Flat gold is known in the art. Methods for attaching polymer to this substrate with a polymer are known in the art and are described, for example, in M. Cole, N.H. Voelcker, H. Thissen, R. Horn, H.J. Griesser, Colloid probe AFM study of thermal collapse and protein interactions of poly(N-isopropylacrylamide) coatings. Soft Matter, 6 (2010), 2657-2667.

[00215] In certain embodiments, the substrate comprises a porous silver substrate. Porous silver substrates are known in the art and commercially available. Methods for attaching a polymer to silver substrates are known in the art.

[00216] In certain embodiments, the substrate comprises a porous polymer substrate. Porous polymer substrates are known in the art and commercially available. Methods for attaching a polymer to a polymer substrate are known in the art.

[00217] The term "functionalising" and related terms refers to the addition of one or more chemical groups directly and/or indirectly to the surface of a substrate. Methods for functionalising substrates are known in the art.

[00218] In certain embodiments the substrate comprises a silicon substrate. In certain embodiments, the functionalising comprises hydrosilylation of the silicon substrate. In certain embodiments, the functionalising comprises oxidation of the silicon substrate. In certain embodiments, the functionalising comprises silanisation of the silicon substrate. In certain embodiments, the functionalising comprises hydrosilylation and/or silanisation of the silicon substrate.

[00219] In certain embodiments, the functionalising comprises dual hydrosilyation.

[00220] In certain embodiments, the functionalising comprises addition of a reactive linker to the substrate.

[00221] In certain embodiments, the polymer is responsive to a non-biological property. Examples of non-biological properties are described herein. In certain embodiments, the polymer is responsive to a non-physiological property. In certain embodiments, the polymer is responsive to a non-physiological property.

[00222] Polymers are as described herein. In certain embodiments, the polymer is responsive to a biological property. Examples of biological properties are described herein. In certain embodiments, the polymer is responsive to a physiological property.

[00223] In certain embodiments, the polymer comprises a thermoresponsive property and/or a pH responsive property. In certain embodiments, the polymer comprises a thermoresponsive property between 25"C and 50"C, or about this range. In certain embodiments, the polymer comprises a pH responsive property between pH 2.6 and pH 9.6, or about this range. In certain embodiments, the polymer comprises a pH responsive property with a sensitivity of at least 2.0 pH units, at least 1.5 pH units, at least 1.0 pH units, or at least 0.5 pH units. In certain embodiments, the polymer comprises a pH responsive property with a sensitivity of 2.0 pH units or less, 1 .5 pH units or less, pH units or less, or 0.5 pH units or less. In certain embodiments, the polymer comprises a pH responsive property with a sensitivity of at least 0.2 pH units. In certain embodiments, the thermoresponsive property and/or the pH responsive property comprises a change in optical reflective characteristics of the substrate.

[00224] In certain embodiments, the polymer comprises a single polymer. In certain embodiments, the polymer comprises one or more polymers. In certain embodiments, the polymer comprises a co-polymer.

[00225] In certain embodiments, the polymer comprises a non-cross linked polymer. In certain embodiments, the polymer comprises a cross-linked polymer. In certain embodiments, the polymer comprises a cross-linked polymer and'Or a non-cross linked polymer.

[00226] In certain embodiments, the polymer comprises a polyacrylate polymer. Examples of polyacrylate polymers are as described herein. In certain embodiments, the polyacrylate polymer comprises a polymethylacrylate polymer.

[00227] In certain embodiments, the polymer comprises a polyacrylamide polymer. Examples of polyacrylamide polymers are as described herein.

[00228] In certain embodiments, the polymer comprises a polyvinyl polymer. Examples of polyvinyl polymers are as described herein.

[00229] In certain embodiments, the polymer comprises one or more of a polyacrylate polymer, a polyacrylamide polymer and a polyvinyl polymer.

[00230] Methods for forming polymers on substrates are known.

[00231] In certain embodiments, the polymer is produced on the functionalised surface by a method comprising one or more of plasma polymerisation, atom transfer radical polymerisation, photo polymerisation, reversible addition-fragmentation chain transfer polymerisation, free radical polymerisation, spin coating or dip-coating. In certain embodiments, the polymer is produced by a method that does not involve atom transfer radical polymerisation.

[00232] In certain embodiments, the polymer is produced by a method comprising plasma polymerisation. In certain embodiments, the polymer is formed by a method comprising plasma polymerisation. In certam embodiments, the polymer is produced by a method that does not involve atom transfer radical polymerisation.

[00233] In certain embodiments, the polymer is produced by a method comprising photo polymerisation. [00234] In certain embodiments, the method comprises forming a polymer coating with a thickness of 1 mm or less, 500 μιη or less, 400 μηι or less, 300 μιτι or less, 200 μηι or less, or 100 μηα or less. Other coating thicknesses are contemplated and described herein.

[00235] In certain embodiments, the method comprises forming a polymer coating with a thickness of 200 μπι or less. Other coating thicknesses are as described herein.

[00236] In certain embodiments, the substrate further comprises a non-stimulus responsive polymer. In certain embodiments, the substrate further comprises one or more non-stimulus responsive polymers. Examples of non-stimulus responsive polymers are as described herein.

[00237] In certain embodiments, the substrate comprises a porous substrate. Examples of porous substrates are as described herein.

[00238] In certain embodiments, pores of the porous substrate are coated with a non- stimulus responsive polymer.

[00239] In certain embodiments, the porous substrate comprises a reieasable agent. Examples of reieasable agents are as described herein. In certain embodiments, the reieasable agent is loaded onto the porous substrate by absorption. In certain embodiments, the reieasable agent comprises a therapeutic agent. Examples of therapeutic agents are as described herein.

[00240] In certain embodiments, the release of the reieasable agent is stimulus responsive. Examples of stimulus responsive release are as described herein. In certain embodiments, the release of the reieasable agent is thermoresponsive and/or pH responsive.

[00241] In certain embodiments, the substrate comprises stimulus responsive sensing of a parameter and/or stimulus responsive release of a reieasable agent.

[00242] In certain embodiments, the substrate comprises stimulus responsive sensing of a parameter and stimulus responsive release of a reieasable agent. [00243] In certain embodiments, the method comprises linking a first molecule to the functionaliscd substrate. In certain embodiments, the method comprises forming the polymer linked to and/or involving the first linked molecule.

[00244] In certain embodiments, the method comprises etching the functionaliscd substrate linked to the first molecule. In certain embodiments, a second molecule is linked to the substrate so etched.

[00245] In certain embodiments, a second polymer is formed linked to and/or involving the second molecule. In certain embodiments, the second polymer is not stimulus responsive. Examples of non-stimulus responsive polymers are as described herein.

[00246] Certain embodiments of the present disclosure provide a stimulus responsive material produced according to a method as described herein.

[00247] The present disclosure is further described by the following examples. It is to be understood that the following description is for the purpose of describing particular embodiments only and is not intended to be limiting with respect to the above description.

EXAMPLE 1 - Porous silicon preparation:

[00248] Porous silicon films were prepared by the electrochemical etching of highly doped, ( 100)-oriented, boron doped p⁺ Si wafers (0.00055-0.001 Ωαη resistivity) (Siltronix, France) in a 1 : 1 (48%) aqueous hydrofluoric acid (HF)/ethanol solution (Fisher Scientific). The etching process was performed in a Teflon cell with a platinum electrode and a computer-controlled galvanostat (Keithley 2425). Prior to formation of the sensing porous silicon layer, the silicon wafer underwent a pre-treatment in order to inhibit the formation of a parasitic surface layer during the etch (Sciacca B., Secret E., Pace S., Gonzalez P., Geobaldo F., Quignarda F. and C. F., Journal of Materials Chemistry, 201 1.). The wafer with an exposed area of 1.76 cm² was first etched using a current density of 28.4 mA/cn for 30 s, and then exposed to a 0.1 M NaOII solution for two minutes. The chip was exposed to a HF thanol (1 : 1 volume ratio) solution and then rinsed three times with ethanol and dried under a stream of nitrogen. The pre- treated silicon wafer was then etched at different constant current densities and times. The porous silicon samples were rinsed 3 times with ethanol and dried under a stream of nitrogen gas.

[00249] Thermal oxidation: Thermal oxidation was carried out by incubating the porous silicon substrates in a Labec tube furnace (Laboratory Equipment Pty. Ltd.) at 600 °C for 1 h. These substrates were subsequently coated with plasma polymerised films.

[00250] Plasma polymerisation: Plasma polymerisation was performed in a custom- built radio-frequency plasma reactor as previously described (Daw et ai, Biomaterials, 19 (1 98) 1717- 1725). During a typical coating process, the substrates are placed at or near the centre of the chamber. The chamber is then pumped down to a pressure of 2 x I 0^"3 Ton-. The monomer, at flow rate of 0.2 standard cubic centimetres per minute (seem) for DEAEMA or 0.75 seem for acrylic acid, is then bled into the chamber and the plasma is ignited at about 10W before being reduced to 2VV. The deposition is allowed to proceed until the desired film thickness is obtained. The plasma is then switched off and the chamber is pumped to base pressure before the samples are removed.

[00251] Chemical functionalisation: Three different surface functionalisations to introduce pNI PAM within nanostructurcd porous silicon were used (Figure 1 ). Path A: after etching, thermal oxidation was performed in a Labec tube furnace (Laboratory Equipment Pty. Ltd.), at 600 °C for 1 hour, generating SiO bonds at the surface (V. Petrova Koch, T. Muschik, A. Kux, B.K. Meyer, F. Koch and V. Lehmann, Appl. Phys. Lett., 1992, 61, 943-945). Silanisation reaction were carried out in a 4 % solution of 3- (2-bromoisobutyramido)propyl(triethoxy)silane (BIBAPTES) in freshly distilled toluene for 1 h, to immobilise the initiator. The BIBAPTES was synthesised following a published procedure (R. B. Vasani, S. .1. P. Mclnnes, M. A. Cole, A. M. M. Jani, A. V. Ellis and N. II. Voelcker, Langmuir, 201 1 , 27, 7843-7853). After the silanisation reaction, the samp les were rinsed with ethanol and dried under a stream of nitrogen gas. Surface initiated atom transfer radical polymerisation (SI-ATRP) of N- isopropylacrylamide (MP AM) (recrystallised, Aldrich) was carried out by immersing the silanised porous silicon sample in a monomer solution consisting of 10 % w/v NIP AM, 0.5 % w/v CuBr (Sigma), 0.1 % w/v CuBr2 (Sigma) and 1.5 % w/v PMDETA (99 %, Aldrich) in Milli-Q water ( 18.2 MQcm, Labconco). Nitrogen was continuously bubbled through the reaction solution to expel oxygen. Polymerisation was performed in a scintillation vial fitted with a modified screw-on cap for the introduction and escape of nitrogen gas. The reaction was performed at 25 °C for 10 min. Once the reaction was complete, the porous silicon samples were rinsed thoroughly with Milli-Q water and dried under a stream of nitrogen gas. Path B: after etching, the samples were oxidised by ozone for 30 min in order to generate silanol groups on the surface of the sample (E. J. Anglin, L. Y. Cheng, W. R. Freeman and M. J. Sailor, Advanced Drug Delivery Reviews, 2008, 60, 1266-1277). Siianisation and the polymerisation were carried out as described for path A.

[00252] Path C: after etching, the samples were thermally hydrosilylated with undecylenic alcohol at 120 °C for 3 h under argon, to introduce hydroxyl groups on the surface. Then the samples were reacted with 5 % w/v 2-bromoisobutyl bromide, 5 % w v triethylamine, in tetrahydrofuran (THF) for 1 h at room temperature to introduce the polymerisation initiator. The samples were rinsed with THF and ethanol and dried under a stream of nitrogen before performing polymerisation of NIP AM, DEAEMA or MDETA by SI-ATRP as described previously. Once the reaction was complete, the porous silicon samples were rinsed thoroughly with Milli-Q water and dried under a stream of nitrogen gas.

[00253 J A dual hydro silylation approach was also employed in order to form a polymer cap on the porous silicon films. After the first etching step and NaOH treatment (for the removal of the parasitic layer) the surface was dipped into 1 : 1 HF:ethanol for 5 min and then rinsed with ethanol, dried with nitrogen gas and thermally hydrosilylated with iindecylenyl alcohol for 3 h at 120°C under argon gas to introduce hydroxyl groups on the surface. Following this, the wafer was transferred back to the Teflon cell and a second etch was performed using different constant current densities and times. The etched surface was then rinsed with ethanol and thermally hydrosilylated with octene for 3 h at 110 °C under an argon atmosphere. Following the hydrosilylation reaction the samples were rinsed with ethanol and dried under a stream of nitrogen before performing polymerisation of NIP AM, acrylic acid or DEAEMA by Sl-ATRP as described previously. [00254] Alternatively, microwave hydrosilylation was also employed in the first hydrosilylation step. After the parasitic layer removal etch and NaOH treatment, the surface was placed in pre-purged (argon gas, 5 min) undecylenyl alcohol in a glass vial and then transferred microwaved at 360 W for 4 min. Following hydrosilylation, the surface was removed from the undecylenyl alcohol solution, washed with ethanol and dried. The following etching and functionalisation steps were performed as described above.

EXAMPLE 2 - Scanning electron microscopy (SEM):

[00255] SEM images were obtained on a FET QuantaTM 450 Field Emission Gun Environmental Scanning Electron Microscope. The porous silicon samples were coated with a thin (3 nm) layer of platinum to prevent charging. A spot size of 3.0 mm and an accelerating voltage of 15.0 kV were used to obtain the images in high vacuum mode.

EXAMPLE 3 - Fourier transform infrared (FT1R) spectroscopy:

[00256] FTIR spectroscopy was performed with a Nicolet iNIO microscope (Thermo scientific) coupled to the liquid nitrogen cooled Mercury-cadmium-telluride (MCT) detector, in attenuated total reflectance ( ATR) mode. Background spectra were taken in air and all spectra were recorded with an aperture size of 3 mm, over the range of 650 - 3800 cm^"1 , at a resolution of 4 cm^"1 averaging 64 scans.

EXAMPLE 4 - Nitrogen adsorption-desorption experiments:

[00257] Nitrogen adsorption-desorption isotherms of the porous silicon films were recorded at 77 using a Micromeritics ASAP 2020 volumetric apparatus. Prior to the adsorption experiment, the samples were outgassed overnight in situ at 298 . The surface area of the sample was measured by the BET (Bninauer -Emmett -Teller) method, which yields the amount of adsorbate corresponding to a molecular monolayer (P. H. E. Stephen Brunauer, Edward Teller, J. Am. Chem. Soc, 1 38, 60, 309-319; S. .1. Gregg and K. S. W. Sing, Adsorption, Surface Area and Porosity, Academic Press Inc., London, 1982). The pore dimensions were determined by using the BdB (Broekhof-de Boer) method irom the nitrogen adsorption curve (D. J. II. Broekhoff J.C.P., Journal of Catalysis, 1968, 10, 377-390). The mesoporous volume was measured as the adsorbed volume at the top of the capillary condensation step of the isotherm. The specific surface area of ihe porous matrix and the porous volume were expressed per geometrical unit area of the porous silicon sample.

EXAMPLE 5 - Interferometric reflectance spectral measurements (IRS):

[00258] White light from a tungsten lamp (Ocean Optics) was fed through one end of a bifurcated fiber-optic cable and focused through a lens onto the surface of the porous silicon film at normal incidence. The light source was then focused onto the centre of the sample surface with a spot size of approximately 1 mm in diameter. Light reflected from the film was collected through the same optics, and the distal end of the bifurcated fiber optic cable was connected to a CCD spectrometer (Ocean Optics S-2000). Reflectivity spectra were recorded in the wavelength range 400-1000 nm, with a spectral acquisition time of 0.1 s. Typically 50 spectral scans (5 s total integration time) were averaged. A fast Fourier Transform (FFT) using an algorithm from the Wave-metrics Inc. (www.wavemetrics.com) IGOR program library was applied to the resulting spectrum according to previously published procedure (S. Pace, B. Seantier, E. Belamie, N. Lautredou, M. J. Sailor, P.-E. Milhiet and F. Cunin, Langmuir, 2012).

[00259] Experiments were carried out in a custom-made aqueous flow cell at room temperature. In order to modulate the temperature of the solution, the samples were immersed in water of controlled temperature, and the temperature of the water was measured with a thermocouple. The water was introduced at a flow rate of 10 mL/min. The samples were monitored at 25 °C for 10 min, then the temperature was raised to 50°C for 10 min, followed by perfusion of 25 °C water through the flow cell for 10 min. Interference spectra were collected in 1 minute intervals. The data displayed are the average of six replicates for each condition. In order to modulate the pH of the solution, different solutions of 0.1 M phosphate-citrate buffer (pH 2.6 to pIT 7.0), sodium- phosphate (pH 5.0 to 8.0) or carbonate buffer (pH 9.6) were injected into the flow and allowed to incubate over the surface of the substrate under static (no flow) conditions. EXAMPLE 6 - Thickness and porosity calculations:

[00260] The optical parameters of porous silicon (thickness, porosity and refractive index) were obtained by performing a best-fit calculation of the reflectance spectrum, by means of a simulation program (SCOUT, obtained from M. Theiss Hard- and Software) that is based on the transfer matrix method (Born M. and W. E., 7th ed. Cambridge University Press: New York, 1999, 952.). The software generates the theoretical reflectance spectrum of the porous silicon film, calculating its effective refractive index using the dielectric function of bulk silicon and using a Bruggeman effective medium approximation (C. F. Bohren and D. R. Huffman, Adsorption and scattering of light by small particles, Wiley, New York, 1983). Porosity and thickness are the two free parameters of the model; their value is adjusted in a least-squares algorithm in order to obtain the best fit between the experimental and the calculated spectra.

EXAMPLE 7 - Pore filling calculation

[00261] The pore filling was calculated using the transfer matrix method from the program SCOUT, previously described. In order to obtain a best fit between the experimental reflectance spectrum and the theoretical reflectance spectra, the refractive index of the polymer, the pore filling and the thickness of the polymer layer were added to the previous parameters (thickness, porosity and refractive index of the porous layer). The experimental spectra were recorded in air. The model generates the theoretical reflectance spectrum of the porous silicon-polymer film, calculating its effective refractive index using the dielectric function of the bulk silicon, of the polymer and applying a Bruggeman effective medium approximation.

EXAMPLE 8 - Drug loading and release.

[00262] Levotloxacin loading was performed by placing the porous silicon-polymer composite surface into a glass vial fitted with a tap and then pumping the surface under vacuum tor 15 min in order to remove any air trapped inside the pores. Following this, a 16 mg/mL solution of levofloxacin in DMF was introduced into the chamber using a syringe and the vial was then quickly brought up to room temperature. The surface was then incubated in the drug solution for an hour at either room temperature or 40°C. Loaded surfaces were then taken out of the vial, rinsed with ethanol and dried under a stream of nitrogen gas. Aspirin loading was perform by placing the porous silicon- polymer composite films into glass vials containing a 40 mg/mL solution of aspirin in DMF in a vacuum dessicator and leaving the surfaces overnight under vacuum. Following this, the surfaces was removed from the vials and quickly rinsed with Milli-Q water (18 mQcm) and dried under nitrogen gas.

[00263] Drug release from porous silicon-polymer composites by fluorimetry. The release of levofloxacin from loaded samples was monitored by fluorimetry. The fluorimeter cuvette was filled with phosphate buffered saline (PBS) (pIT 7.4) and the drug-loaded sample was immersed into it and placed outside of the optical path. The release of the drug over time was measured using a Perkin Elmer Instruments LS55 Luminescence Spectrometer with an excitation wavelength of 292 nm and an emission wavelength of 454 nm and 5 nm slit widths. Loaded samples were cut into two pieces of similar dimensions. One piece was used for measuring the release at room temperature and the other tor measuring the release at 45 °C

[00264] The release of aspirin from the loaded samples was monitered using UV spectroscopy. The UV cuvette was filled with phosphate buffered saline (PBS) (pH 7.4) and the drug-loaded sample was immersed into it and placed outside of the optical path. The release of the drug over time was measured using a Hewlett-Packard 8452 diode array spectrophotometer and analysed using an Agilent Tecchnologies 8452 UV-Vis Chemstation, at a wavelength of 298 nm. Loaded samples were cut into two pieces of similar dimensions. One piece was used for measuring the release at room temperature and the other for measuring the release at 45°C.

EXAMPLE 10 - Change in colour associated with the switching of stimulus responsive polymer coated on a porous silicon substrate

[00265] Figure 2 shows a schematic representation of a porous silicon substrate coated with a stimulus responsive polymer (top) and a photograph of the porous silicon substrate before and after coating with the polymer (bottom). The change in the colour of the porous silicon substrate indicates the surface has been covered with the polymer (> 100 nm).

EXAMPLE 1 1 - Characterisation of a pDEAEMA coating

[00266] Figure 3 shows a typical X-ray pholoelectron spectroscopy (XPS) spectra of a porous silicon substrate coated with a 400 nm thick film of pDBAEMA by plasma polymerisation. The elements (oxygen, nitrogen, carbon) characteristic for the polymer are detected, whereas the underlying silicon substrate is not detected due to attenuation of the Si signal by the pDEAEMA film. This shows that the polymer was successfully coated onto the porous silicon substrate.

[00267] Figure 4 shows a side-on view of a porous silicon substrate coated with pDEAEMA by plasma polymerisation. The image was taken by scanning electron microscopy. The polymer thickness in this figure is 400 nm. It shows that the polymer is successfully coated over the porous silicon layer, which supports the XPS data,

EXAMPLE 12 - Measuring and quantifying changes in pH of the environment on porous silicon coated with pDEAEMA

[00268] Figure 5 shows a time-lapse graph showing the change in the EOT of porous silicon, coated with pDEAEMA, in response to changes in pH of 2.6 and 9.6. The pronounced and reproducible change in the EOT upon addition of low and high pH solutions clearly demonstrates the switchable nature of the sensor de vice.

[00269] Figure 6 shows time-lapse graph showing the change in the EOT of porous silicon, coated with pDEAEMA, in response to changes in pH from 6.0 to 2.6 as indicated in the graph. The results show the sensor has a detection limit as small as 0.2 pH units.

[00270] Figure 7 shows time-lapse EOT measurements of porous silicon functionalised with pDEAEMA under pH solutions. The results show a pronounced change in EOT between buffers of pH 7.0-5.0, pH 7.0-4.0 and pH 7.0-6.0. The magnitude of change in the EOT was dependant on the pH demonstrating that quantitative detection of pll changes is possible. [00271] Figure 8 shows the increase in EOT in response to change in pll from pH 7.0 to 4.0. or pH 7.0 to 5.0 or pH 7.0 to 6.0. Porous silicon samples were coated with pDEAEMA by plasma polymerisation at 2 W to a thickness of 100 or 400 nm in Panel A and at 2 W or 5 W to a thickness of 100 nm in Panel B. The results show that a range of plasma polymerisation conditions can be used for the preparation of the pH sensor for quantitative sensing.

[00272] Figure 9 shows the results of a pH sensing experiment on flat silicon. The sensor device in this experiment consists of flat silicon coated with pDEAEMA. The coating gives an interference pattern, which can be monitored interference reflectance spectroscopy. The graph shows that the wavelength of Ihe interference pattern rcproducibly increases or decreases as the pH of the solution is increased or decreased. This type of sensor can also be used to measure quantifiable changes in pH of the environment.

EXAMPLE 13 - pH sensor embedded in a wound dressing scaffold

[00273] Figure 10 shows a pH sensor embedded in a wound dressing scaffold. A photograph of a porous silicon substrate connected to a porous PCL scaffold, by thermally annealing the two materials together at 55°C, is shown at the top. The porous nature of the scaffold makes it possible to use the sensor to measure quantifiable changes in pH of the environment.

EXAMPLE 14 - pH sensor fabricated by coating porous silicon with plasma polymerised acrylic acid

[00274] Figure 11 shows the results of a pH sensing experiment on a porous silicon substrate coated with a plasma polymerised film of acrylic acid. The data shows that acrylic acid plasma polymer coatings on porous silicon can be used to measure quantifiable changes in pH and in a reproducible fashion (left graph - Buffer only) and the readout signal (i.e. increase or decrease in the EOT) is not affected by fouling proteins (fetal bovine serum, FBS) in the solution (right graph (Buffer + 10% (v/v/) FBS). This shows that a variety of polymers can be applied to make the sensor device enabling the fabrication of sensors with different sensitivities to pH; and that the sensors can be used in environments containing a complex mixture of organic materials and proteins such as wound fluid.

EXAMPLE 15 - Qualitative pH sensing on flat silicon coated with plasma polymerised pDEAE A

[00275] Figure 12 shows qualitative detection of pH changes on flat silicon coated with plasma polymerised pDEAEMA. Photographs of the pH sensor were taken in air and after subjecting the same sensor device to pH 7.0 and pH 4.0 solutions. The figure shows that obvious changes in colour can be detected on the sensor in response to changes in pH of the environment.

[00276] Figure 13 shows qualitative detection of H changes on flat silicon coated with plasma polymerised pDEAEMA. Photographs of the pH sensor were taken after spotting solutions of pH 4 and pH 7 over the sensor and after removing the excess solutions off the surface of the sensor device. This shows that the sensor can be used to map the pH of the environment (e.g. a wound bed) and can be used as a "dip-stick" or point-of-care sensor.

[00277] Figure 14 shows an example of a dip-stick type pH sensor fabricated by coating flat silicon with a plasma polymerised film of pDEAEMA. Solutions of pH 3.0 to 8.0, as indicated in the figure, were spotted onto the sensor device and were subsequently allowed to air dry. The figure shows that the intensity of the colour of the spots decreased as the pH was increased. This type of sensor could be used as a point of care device or for mapping the pH of the wound environment.

[00278] Figure 15 show the stimulus responsive polymers can be used to coat a wide range of materials such as a) polystyrene sheets for tissue culture or b) bandages for wound dressings. The porous silicon particles coated with the stimulus responsive polymers can be embedded into wound dressings such as polycaprolactone (PCL) scaffolds for sensing or drug delivery as shown in c) or d) porous silicon or flat silicon substrates can also be connected to (PCL) wound dressings for sensing/drug delivery. EXAMPLE 16 - Drug delivery

[00279] Figure 1 shows a schematic representation showing the fabrication process of the porous silicon drug delivery device, which can also be used concurrently for sensing pH or temperature, if desired.

[00280] Figure 17 shows the demonstration for the delivery of a biologically active horseradish peroxidase enzyme (left graph) and a glycosaminoglycan (right graph) from porous silicon and from porous silicon coated with a pH responsive plasma polymer film, enabling the sustained release of biomolecules. The plasma coating process does not damage/remove the sensitive enzyme when it is loaded into porous silicon. The drug delivery functionality can be directly incorporated into the sensor device without deterioration of the sensor's sensitivity. The hybrid drug delivery/sensor devices can be incorporated into wound bandage dressings.

EXAMPLE 17 - Porous silicon-polymer composite fabrication method: Silanisation Route

[00281] Figure 18 shows a porous silicon-polymer surface preparation using a silanisation approach and ATRP to graft the polymer from the surface.

[00282] The polymer can be grafted either with a crosslinker or without providing grafted polymer chains or a grafted hydrogel. The crosslinker depicted above is Ν,Ν'- methylenebisacrylamide, however, this can be changed to include diacrylates as well. The silanisation method can be used to immobilise initiators for ATRP, RAFT and also Free radical polymerisation onto the surface of the porous silicon film, membrane or particles.

EXAMPLE 18 - Characterisation of polymer switching using IRS

[00283] Figure 19 shows changes in effective optical thickness (EOT) of the pNIPAM grafted surface on temperature switching between 25 and 50 °C, as a function of crosslinker concentration. The polymer used here was pNIPAM and crosslinker was Ν,Ν'-methylenebisacrylamide and polymerisation was carried out using the silanisation route. The EOT changes indicate a switch in behaviour of the polymer from individual (EOT>0) chains to bulk hydrogel (EOT<0) as the crosslinker concentration increases.

EXAMPLE 19 - Aspirin release from porous silicon-pNIPAM films

[00284] Figure 20 shows aspirin release from A) a non-crosslinked and B) a crosslinked (1 % crosslinker) porous silicon-Ρ ΙΡΑΜ surface prepared using the silanisation approach and 10 min of ATRP polymerisation. From the data it can be inferred that the responsive release characteristics of the drug is dependent on the crosslinking density offering additional control over the release.

EXAMPLE 20 - Porous silicon-polymer cap composite fabrication: Dual hydrosilylati n method

[00285] Figure 21 shows a schematic showing fabrication of polymer cap on porous silicon using a dual hydrosilylation approach.

[00286] This method allows immobilisation of the polymerisation initiator onto only the outer surface of the porous layer. This allows for the formation of a polymer cap on the outer surface of the layer. As in the case of the silanisation route, this method can also be used to immobilise the initiators for ATRP, RAFT and free radical polymerisation.

EXAMPLE 21 - Levofloxacin release from porous silicon-pNIPAM composites prepared using the dual hydrosilylation route

[00287] Figure 22 shows Levofloxacin release from porous silicon-pNIPAM surface prepared using dual hydrosilylation; A) 30 and B) 60 mins of polymerisation (ATRP) with 1% crosslinker (N.N'-methylenebisacrylamide).

EXAMPLE 22 -Drug release from 1,7 - octadiene and acrylic acid modified pSi

[00288] Porous Silicon Preparation: Highly doped (0.00055 - 0.001 Ω cm resistivity; Siltronix) p-type wafers were etched at 28.29 mA/cm2 for 400 sec in 1 : 1 HF:Ethanol mixtures. Thermal Oxidation was carried out at 600 °C for 1 hr in air. [00289] Levofloxacin (LVX), a broad spectrum fluoroquinone antibiotic, was used as the model drug for these experiments. A 100 mg/mL solution of LVX in DM F was prepared and loading was performed by spin coating a drop of the stock onto the porous surface. Samples were rinsed in acetone for 30 seconds to remove the drug present outside the pores.

[00290] (i) Effect of the thickness of the plasma polymerised 1,7 - octadiene on levofloxacin release from p i

[00291 ] The porous silicon film was oxidised thermally at 600 ^CC for 1 hour and loaded with LVX using spin coating. The loaded film was then placed in a plasma reactor and coated with 4 different polymer layer thicknesses. The date is shown in Figure 23. We found that no significant change in the release kinetics was observed above a layer thickness of 100 ran. Hence, 256 ran layer thickness was employed for this purpose.

[00292] (ii) Effect of plasma power during 1,7 - octadiene deposition on LVX release from porous silicon

[00293] The porous silicon film was oxidised and loaded with LVX using spin coating and 256 nm of plasma polymerised octadiene was deposited onto the surface using 4 different plasma powers. The data is shown in Figure 24. We found that the plasma power had very little effect on the release kinetics.

[00294] (iv) Drug release controls

[00295] The porous silicon film was oxidised, loaded with levofloxacin and the release of the drug from the surfaces was measured in buffers at pH 3 and 7. The data is shown in Figure 25. No significant difference in the release kinetics was observed at the different pH and complete release of the payload occurred within 1 hour.

[00296] (v) Drug release from porous silicom modified with 500 nm of acrylic acid plasma polymer

[00297] A porous silicon surface was oxidised, loaded with LVX and placed in the plasma reactor where it was coated with an acrylic acid polymer layer of approximately 500 nm thickness. The data is shown in Figure 26. The release of the drug was found to be sustained at pH 3 however, a sudden burst release was observed at pll 7 (release everything in 30 min). This is due to the fact that acrylic acid layers do not bind well to pSi and delaminate on swelling at higher pll, thus opening the pores.

[00298] (vi) Drug release from pSi modified with 1,7 - octadiene followed by acrylic acid

[00299] Using a dual layer coating of 1 ,7 - octadiene followed by acrylic acid we managed to prevent the delamination of the acrylic acid layer while at the same lime use the thick octadiene layer to further regulate the drug release from the pores. The data is shown in Figure 27. We found that the release rate of LVX from the pores was approximately 4 times greater at pH 7 than at pH 3. Furthermore, the amount of drug released at pII3 is quite less and hence, this sort of release profile can be considered on- off.

EXAMPLE 23 - Delivery of functional heparin/FGF-2 from porous silicon stimulates cell proliferation

[00300] This study shows functional heparin can be released from the porous silicon- pH sensitive polymer substrate (i.e. porous silicon coated with 400 nm thick film of pDEAEMA). After loading porous silicon with heparin and heparin + FGF-2, the substrates were coated with a 400 nm thick film of pDEAEMA.

[00301] Cell based assays: 5000 cells were seeded in a 12-well plate in 500 μΐ of media. After incubation for 30 minutes, the wells were washed 3 times in PBS and counted (5 fields of view per well). A well insert with a mesh was added to hold the porous silicon samples 2 mm above the cells and a further 1 ml media was added. After incubation tor 12 h to allow release of the agents, the porous silicon samples were removed from the wells.

[00302] Cells were counted at 48 and 120 h of incubation and cell vitality was analysed with the resazurin assay at the 120 h incubation time period. The data is shown in Figure 28. Figure 28A shows cell count data, demonstrating that functional heparin and heparin + FGF-2 can be released from the porous silicon-pH sensitive polymer substrate (coated with 400 nm thick film of pDEAEMA) to stimulate cell proliferation after 120 h of incubation. Figure 28B shows the results of the resazurin assay, showing lhat the plasma delivery of heparin and heparin + FGF-2 can increase cell vitality in vitro.

EXAMPLE 24 - pH sensitive photonic polymers

[00303] Polymer was templated from colloidal crystal array of 200 nm diameter polystyrene spheres as shown in Figure 29 A.

[00304] 2.68 % (w v) polystyrene solution deposited on oxygen plasma cleaned glass. PDMS 'well' used to contain the solution. Liquid was evaporated at 45°C to facilitate formation of a colloidal crystal array.

[00305] Monomer mixture:

Methacrylic acid - 10 .L

Acrylic acid - 10 pL

2-hydroxyethyl methacrylate - 100 uL

Ethylenegiycol dimethacryiate - 3 pL

Photoinitiator (2,2-Dimet.hoxy-2-penylacetophenone)— 5 mg

H,0 - 50 pL

[00306] Photonic polymer formation is shown in Figure 29B, employing the following steps:

Infiltration of monomer mixture throughout interstitial space of colloidal crystal array

Photopolymerisation of monomer solution

Polystyrene removal in xylene, followed by washing in acetonitrile Polymer hydrated in H₂0 and transferred to Smith & Nephew transparent bandage

Polymer was transferred by fully hydrating the polymer at pH 2, which resulted in polymer delaminating from glass substrate

Excess water was removed and the polymer was then transferred to the adhesive side of a Smith & Nephew transparent bandage by bringing the bandage into contact with the polymer

A typical optical reflectance is shown in Figure 29C. A photograph of the photonic polymer at low pH Polymer was transferred by fully hydrating the polymer at pH 2, which resulted in po lymer delaminatirig from glass substrate

Excess water was removed and the polymer was then transferred to the adhesive side of a Smith & Nephew transparent bandage by bringing the bandage into contact with the polymer

[00307] Figure 31 A shows measurements of reflected photonic spectra at different pH from the photonic polymer incorporated into Smith & Nephew transparent bandage. Figure 3 IB shows the shift in photonic peak with changing pH.

[00308] Figures 32A and B show the photonic polymer integrated into wound dressing. In this case the polymer is sealed between two dressings to demonstrate the observable colour of the polymer. Figure 32C, D and E shows the photonic polymer integrated into wound dressing, applied to healthy skin (C) and two chronic wounds (D, E). In each case the polymer is displaying a red colour, indicating pli above 6.8. Data (not shown) demonstrates that the photonic polymer/wound dressing hybrids display a change in colour from green at low pH (4) to red at high pli (7.4).

EXAMPLE 25 - Dip Sensor

[00309] Photonic porous silicon preparation:

[00310] Porous silicon films were prepared from single-crystal p-type silicon (boron doped, 0.0005-0.001 1 O.cm resistivity, <100> orientation) at a modulated current density with a sine wave (between 11.36 and 28.4 mA. cm^"2, 19.9 s periodicity) for 415.5 s in a solution of 24 % of aqueous hydrofluoric acid (HF, 48%) diluted in absolute elhanol, to produce a rugate filter. This nanostruclure acts as a filter, reflecting the light at a precise wavelength that can be easily tuned.

[0031 1 ] For the formation of the porous silicon membrane, the resulting porous layer was then lifted off by electropolishing, in a solution of 5% of aqueous HF diluted in absolute ethanol for 60 s at a current density of 7 mA.cm^"2.

[00312] The porous silicon membrane was then modified with thermoresponsive polymer using the protocol described by S. Pace, R.B. Vasani, F. Cunin, N.II. Voelcker, Study of the Optical Properties of Thermoresponsive Polymer Grafted from Porous silicon Scaffolds, New Journal of Chemistry, 37 (2013), 228-235.

[00313] Combination of the optical fibre with a membrane of polymer-porous silicon and study of the response to pH or temperature:

[00314] The optical fibre was first cleaved in order to obtain a flat tip. Then the tip of optical fibre was immersed quickly on epoxy glue (Araldite® Rapid 24ml syringe), and let dry for 5 min, before being combine with the polymer-porous silicon membrane.

[00 15] Figure 33 A shows a SEM image of an optical fibre coupled to a porous silicon membrane.

[00316] Once the polymer-porous silicon membrane was attached to the optical fibre, a simple setup was built to enable the remote analysis of the porous silicon- polymer system optical properties as shown in Figure 33B.

[00317] Figure 33B shows a schematic of the optical setup of the dip sensor for the analysis of interferometry of porous silicon. The schematic shows the typical setup employed in this work for biosensing, highlighting the interactions at the tip of the optical fibre. Right hand side cartoon shows the interaction between light and the porous silicon modified with the responsive polymer at the tip of the optical fibre.

[00318] White light was coupled into one side of the optical fibre, and the light reflected from the porous silicon-polymer system was split from the incoming light by a 50:50 beam splitter and focused into a patch cable to be fed into a spectrometer. The position of the reflectance peak was monitored during the immersion of the fibre-porous silicon-polymer system into buffer or wound fluid at different pH or temperature.

[00319] The response of the porous silicon membrane modified with the p(DEAEMA) coupled to the optical fibre upon exposure to citric buffer at different pH was tested. A porous silicon membrane functionalized with the initiator (BiBAPTES) was employed as a control At pH 7.4, a decrease in the variation of the wavelength was observed for the control, and which can be explained by a degradation of the sample; this phenomenon being even more pronounced in acidic conditions. The degradation of the sample causes a change of refractive index inside the porous matrix. A conspicuous shift (about 0.4 %) was consistently observed on the ftbre-pSi-p(DEAEMA) sample, when the pH changed from 7.4 to 3.4. The red shift observed when the pH decreased, is caused by the swelling of brushed polymer ai this pll. A larger response was observed when the samples were exposed to the human wound fluid at neutral pH and at acidic pH.

[00320] The same experiment was performed with the p(M(EO)2MA-co-OEOMA) modified porous silicon membrane, by varying the temperature of the environment (water or wound fluid) from 25 °C to 45°C. In the both cases a decrease of variation of the wavelength was observed. For the control, this variation in wavelength can be attributed to the small change of refractive index of water (about 0.16%) on heating between 25 °C to 45 °C. A conspicuous shift (about 0.24 %) was observed on the fibre - pSi-p(M(EO)2MA-co-OEOMA) sample, when the temperature changed from 25°C to 45 °C. The blue shift observed when the temperature increased, corresponding to a decrease of the effective refractive index inside the porous matrix, caused by a collapse of p(M(EO)2MA-co-OEOMA) at this temperature.

[00321] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Where a specific range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is included therein. All smaller sub ranges are also included. The upper and lower limits of these smaller ranges are also included therein, subject to any specifically excluded limit in the stated range.

[00322] The term "about" or "approximately" means an acceptable error for a particular value, which depends in part on how the value is measured or determined. In certain embodiments, "about" can mean 1 or more standard deviations. When the antecedent term "about" is applied to a recited range or value it denotes an approximation within the deviation in the range or value known or expected in the art from the measurements method. For removal of doubt, it shall be understood that any range stated herein that does not specifically recite the term "about" before the range or before any value within the stated range inherently includes such term to encompass the approximation within the deviation noted above. [00323] Throughout this specification, unless the context^" requires otherwise, the word "comprise^"', or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[00324] As used herein, the singular forms "a", "an" and "the" include plural aspects unless the context already dictates otherwise.

[00325] All methods described herein can be performed in any suitable order unless indicated otherwise herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the example embodiments and does not pose a limitation on the scope of the claimed invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential.

[00326] The description provided herein is in relation to several embodiments which may share common characteristics and features. It is to be understood that one or more features of one embodiment may be combinable with one or more features of the other embodiments. In addition, a single feature or combination of features of the embodiments may constitute additional embodiments.

[00327] The subject headings used herein are included only for the ease of reference of the reader and should not be used to limit the subject matter found throughout the disclosure or the claims. The subject headings should not be used in construing the scope of the claims or the claim limitations.

[00328] Future patent applications may be tiled on the basis of the present application, for example by claiming priority from the present application, by claiming a divisional status and/or by claiming a continuation status. It is to be understood that the following claims are provided by way of example only, and are not intended to limit the scope of what may be claimed in any such future application. Nor should the claims be considered to limit the understanding of (or exclude other understandings of) the present disclosure. Features may be added to or omitted from the example claims at a later date. [00329] Although the present disclosure has been described with reference to particular examples, it will be appreciated by those skilled in the art that the disclosure may be embodied in many other forms.

Claims

1. A substrate comprising a stimulus responsive polymer attached to the substrate.

2. The substrate according to claim 1 , wherein the substrate comprises one or more of silicon, gold, silver, aluminium, a polymer and a glass.

3. The substrate according to claims 1 or 2, wherein the substrate comprises a silicon substrate.

4. The substrate according to claim 3, wherein the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane and silicon particles.

5. The substrate according to claims 1 or 2, wherein the substrate comprises a photonic polymer.

6. The substrate according to any one of claims 1 to 5, wherein the substrate comprises a thermoresponsive property and'or a pH responsive property.

7. The substrate according to claim 6, wherein the thermoresponsive property comprises a thermoresponsive property between 25"C and 50"C,

8. The substrate according to claim 6, wherein the pH responsive property comprises a pH responsive property between pH 2.6 and pH 9.6.

9. The substrate according to any one of claims 6 or 8, wherein the pH responsive property comprises a pH responsive property with a sensitivity of at least 0.5 pH units.

10. The substrate according to any one of claims 6 to 9, wherein the thermoresponsive property and'or the pH responsive property comprise a change in optical reflective characteristics.

1 1 . The substrate according to any one of claims 1 to 10, wherein the stimulus responsive polymer comprises a co-polymer.

12. The substrate according to any one of claims 1 to 1 1 , wherein the stimulus responsive polymer comprises a cross-linked polymer and/or a non-cross linked polymer.

13. The substrate according to any one of claims 1 to 12, wherein the stimulus responsive polymer comprises one or more of a polvacrylate polymer, a polyacrylamide polymer and a polyvinyl polymer.

14. The substrate according to claim 13, wherein the polvacrylate polymer comprises a polymethylacrylate polymer.

15. The substrate according to any one of claims 1 to 14, wherein the stimulus responsive polymer is produced by a method comprising one or more of plasma polymerisation, atom transfer radical polymerisation, reversible addition-fragmentation chain transfer polymerisation, photo polymerisation, free radical polymerisation, spin coating or dip-coating.

16. The substrate according to any one of claims 1 to 15, wherein the stimulus responsive polymer is produced by a method comprising plasma and/or photo polymerisation.

17. The substrate according to any one of claims 1 to 16, wherein the substrate comprises a stimulus response polymer with a thickness of 1 mm or less.

18. The substrate according to any one of claims 1 to 17, wherein the substrate further comprises a non-stimulus responsive polymer.

19. The substrate according to any one of claims 1 to 19, wherein the substrate comprises a porous substrate.

20. The substrate according to claim 19, wherein pores of the porous substrate are coated with a non-stimulus responsive polymer.

21. The substrate according to claims 19 or 20, wherein the porous substrate comprises a releasable agent.

22. The substrate according to claim 21 , wherein release of the releasable agent is stimulus responsive.

23. The substrate according to claim 22, wherein the release of the releasable agent is thermoresponsive and/or pH responsive.

24. The substrate according to any one of claims 21 to 23, wherein the substrate comprises stimulus responsive sensing of a parameter and stimulus responsive release of the releasable agent.

25. The substrate according to any one of claims 21 to 24, wherein the releasable agent comprises a therapeutic agent.

26. The substrate according to claim 25, wherein the therapeutic agent comprises one or more of a drug, a small molecule, a biologic, an antibody, a polypeptide, an enzyme, a growth factor, a nucleic acid, a wound healing agent, and an anti-bacterial agent.

27. A material comprising a substrate according to any one of claims 1 to 22.

28. The material according to claim 27, wherein the material comprises particles comprising the substrate.

29. The material according to claim 27, wherein the material comprises a membrane comprising the substrate.

30. The material according to claim 27, wherein the material comprises a flat substrate or a film comprising the substrate.

31. A sensor comprising a substrate according to any one of claims 1 to 26.

32. A sensor according to claim 31 , wherein the sensor provides qualitative and/or quantitative sensing.

33. A cell culture vessel comprising a substrate according to any one of claims 1 to 26.

34. A wound dressing or bandage comprising a substrate according to any one of claims 1 to 26.

35. An implantable article comprising a substrate according to any one of claims 1 to 26.

36. A method of sensing temperature and/or pH, the method comprising using a substrate according to any ne of claims 1 to 26 to sense the temperature and/or pH.

37. A method of sensing a parameter, the method comprising using a substrate comprising a stimulus responsive polymer attached to the substrate to sense the parameter.

38. The method according to claim 37 wherein the substrate comprises one or more of silicon, gold, silver, aluminium, a polymer and a glass.

39. The method according to claims 37 or 38, wherein the substrate comprises a silicon substrate.

40. The method substrate according to claim 39, wherein the silicon substrate comprises one or more of a flat silicon substrate, a silicon membrane, a porous silicon substrate and silicon particles.

41. The method according to claims 37 or 38, wherein the substrate comprises a photonic polymer.

42. The method according to any one of claims 37 to 41, wherein the parameter comprises temperature and/or pH.

43. The method according to claim 42, wherein the polymer comprises a thermoresponsive and/or pH responsive polymer.

44. The method according to any one of claims 37 to 43, wherein the method comprises sensing the parameter at a non-biological site.

45. The method according to any one of claims 37 to 43, wherein the method comprises sensing the parameter at a biological site.

46. The method according to claim 45. wherein the biological site comprises a wound.

47. A method of delivering a releasabie agent to a site, the method comprising: providing a substrate comprising a releasabie agent according to any one of claims 21 to 26 to the site; and

releasing the releasabie agent from the substrate in response to a stimulus, thereby delivering the releasabie agent to the site.

48. A method of delivering a releasabie agent to a site, the method comprising: providing to the site a substrate comprising a stimulus responsive polymer attached to the substrate and a releasabie agent; and

releasing the releasabie agent from the substrate in response to a stimulus, thereby delivering the releasabie agent to the site.

49. A therapeutic composition comprising a porous substrate comprising:

(i) a stimulus responsive polymer attached to the porous substrate; and

(ii) a therapeutic agent loaded onto the porous substrate.

50. A method of therapy, the method comprising exposing a subject to the therapeutic composition according to claim 49.

51. Use of a substrate comprising a stimulus responsive polymer in the preparation of a medicament.

52. A method of producing a stimulus responsive material, the method comprising: functionalising a surface of a substrate; and

forming a polymer on the functionalised surface, wherein the polymer comprises a stimulus responsive property.

53. A stimulus responsive material produced according to the method of claim 52.

54. An article for delivering a therapeutic agent and sensing a parameter, the article comprising substrate comprising a stimulus responsive polymer attached to the substrate and a releasabie therapeutic agent.

55. A drug delivery and sensing device, the device comprising a substrate comprising a stimulus responsive polymer attached to the substrate and a releasabie drug.