Methods and systems for reacting, separating and manipulating a sample comprising a plurality of components

Abstract

Methods and systems for producing and processing a product of a conversion are provided Methods comprise migrating the product of a conversion relative to the sample surface is so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface. Methods alternatively or additionally comprise (I) analysing the product on a capture site; and (II) selectively releasing the product from a capture site, recovering the product and removing the product from a sample surface, and analysing the recovered product.

Description

METHODS AND SYSTEMS FOR REACTING, SEPARATING AND MANIPULATING A SAMPLE COMPRISING A PLURALITY OF COMPONENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Application No.63 / 548, 695, titled SYSTEMS, APPARATUS AND METHODS FOR MULTIDIMENSIONAL MOVEMENT OF AT LEAST ONE COMPONENT, filed 01 February 2024, which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] This disclosure relates to methods and systems for producing and processing a product, in particular the conversion of a part of a sample to the product, and methods and systems of producing and analysing a product.BACKGROUND

[0003] Chip-based reactors have been used as platforms for conducting various reactions and conversions of components or species at a microscale level. These potential advantages in terms of reduced sample volumes, faster reaction times, and increased throughput compared to traditional methods. Due to their versatility they are used in numerous fields, including biological fields such as DNA sequencing, protein analysis, and cell-based assays. Similarly, in chemistry and materials research, chip-based solutions have been utilized for synthesis, catalysis studies, and characterization of novel compounds.

[0004] Despite the advantages offered by chip-based reactors, there are drawbacks. Existing platforms have limited functionality. For example, sample and product handling functionality is limited and often relies on manual processing by a technician. This can lead to inefficient processes, poor distribution of samples and reagents on the surfaces, low yields and contaminations. Furthermore, the analysis and detection of reaction products can be difficult, particularly given the low concentrations and sample sizes on a chip-scale.SUMMARY OF THE DISCLOSURE

[0005] According to a first aspect of the present disclosure, a method of producing and processing a product of a conversion is provided. The method comprises: providing a reactor device comprising a substrate at least partially defining a sample surface and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site; providing a sample to the sample surface and retaining at least a part of the sample on the reactor site; applying a stimulus to the at least a part of the sample on the reactor site using the modification element so as to cause a conversion of the at least a part of the sample to a product; and applying a force to the product so as to migrate the product from the reactor site relative to the sample surface, wherein migrating the product relative to the sample surface is so as to (I) separatethe product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0006] According to a second aspect of the disclosure, a method of analysing a product derived from a sample is provided. The method comprises: providing a reactor device comprising a substrate at least partially defining a sample surface and a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; providing a sample to the sample surface; and applying a stimulus to at least a part of the sample on the sample surface using the modification element as to cause a conversion of the at least a part of the sample to a product, wherein the reactor device further comprises at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture the product to retain the product on the capture site; wherein the method further comprises selectively binding the product to the capture site so as to retain the product thereon; and wherein the method further comprise at least one of: (I) analysing the product on the capture site; and (II) selectively releasing the product from the capture site, recovering the product and removing the product from the sample surface, and analysing the recovered product.

[0007] According to a third aspect of the disclosure, a system for producing and processing a product from a sample is provided, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site and wherein the system is configured to retain a part of sample on the reactor site; a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and a control unit configured to operate: the modification element so as to apply a stimulus to the at least a part of the sample on the reactor site and thereby to cause a conversion of the at least a part of a sample retained on the reactor site to a product; and the manipulation assembly so as to cause the sample to migrate within medium provided at the sample surface so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0008] According to a fourth aspect of the disclosure, a system for producing and analysing a product from a sample is provided, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; and at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture a product derived from a sample to retain the product on the capture site; and a control unit configured to operate the modification element so as to apply a stimulus to the at least a part of the sample on the sample surface and thereby to cause a conversion of the at least a part of a sample to a product; and an analytical device configured to analyse the product, wherein at least one of: the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing ofproduct from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The present disclosure will now be described in more detail with reference to the accompanying drawings, which are not intended to be limiting:

[0010] FIG. 1 illustrates a flowchart of a method according to the disclosure.

[0011] FIG. 2A depicts a block diagram of a system for separating and manipulating samples, according to aspects of the present disclosure; FIG. 2B depicts a top view of a reactor device used in a method according to the disclosure and FIG. 2C depicts schematic cross-sectional view of the reactor device in use through line A-A of FIG. 2B.

[0012] FIG. 3 illustrates a flowchart of another method according to the disclosure.

[0013] FIG. 4A depicts a block diagram of a system for separating and manipulating samples, according to aspects of the present disclosure; FIG. 4B depicts a top view of a reactor device used in a method according to the disclosure and FIG. 4C depicts schematic cross-sectional view of the reactor device in use through line A-A of FIG. 4B.

[0014] FIG. 5 illustrates a flowchart of another method according to the disclosure.

[0015] FIG. 6A depicts atop view of a reactor device used in systems and methods according to the disclosure; FIGS. 6B to 6D depict schematic cross-sectional views of the reactor device through line B-B of FIG. 6A.

[0016] FIG. 7 illustrates a flowchart of another method according to the disclosure.

[0017] FIG. 8 A depicts atop view of a reactor device used in systems and methods according to the disclosure; FIGS. 86B to 8D depict schematic cross-sectional views of the reactor device through line B-B of FIG. 8A.

[0018] FIG. 10A schematically depicts a part of a reactor device which can be used in systems and methods according to the disclosure.

[0019] FIG. 10B schematically depicts a part of a reactor device which can be used in systems and methods according to the disclosure.

[0020] FIG. 11 illustrates a flowchart of a method according to the disclosure.

[0021] FIG. 10 provides a top view of a reactor device which can be used in the methods and systems according to the disclosure.

[0022] FIG. 11 provides an expanded view of a part of the reactor device of FIG.10.

[0023] FIG. 12 provides a schematic cross-sectional views of the reactor device through line C-C of FIG. 10.DETAILED DESCRIPTION

[0024] Despite the advantages offered by chip-based reactors and processing methods, there are still drawbacks. Existing platforms and methods have limited functionality. For example, sample and product handling functionality is limited and often relies on manual processing by a technician. Furthermore, the analysis and detection of reaction products can be difficult, particularly given the low concentrations and sample sizes on a chip-scale.

[0025] According to a first aspect of the present disclosure, a method of producing and processing a product of a conversion is provided. The method comprises: providing a reactor device comprising a substrate at least partially defining a sample surface and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site; providing a sample to the sample surface and retaining at least a part of the sample on the reactor site; applying a stimulus to the at least a part of the sample on the reactor site using the modification element so as to cause a conversion of the at least a part of the sample to a product; and applying a force to the product so as to migrate the product from the reactor site relative to the sample surface, wherein migrating the product relative to the sample surface is so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0026] According to a second aspect of the present disclosure, a method of analysing a product derived from a sample is provided. The method comprises: providing a reactor device comprising a substrate at least partially defining a sample surface and a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; providing a sample to the sample surface; and applying a stimulus to at least a part of the sample on the sample surface using the modification element as to cause a conversion of the at least a part of the sample to a product, wherein the reactor device further comprises at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture the product to retain the product on the capture site; wherein the method further comprises selectively binding the product to the capture site so as to retain the product thereon; and wherein the method further comprise at least one of: (I) analysing the product on the capture site; and (II) selectively releasing the product from the capture site, recovering the product and removing the product from the sample surface, and analysing the recovered product.

[0027] According to a third aspect of the disclosure, a system for producing and processing a product from a sample is provided, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site and wherein the system is configured to retain a part of sample on the reactor site; a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and a control unit configured to operate: the modification element so as to apply a stimulus to the at least a part of the sample on the reactor site and thereby to cause a conversion of the at least a part of a sample retained on the reactor site to a product; and the manipulation assembly so asto cause the sample to migrate within medium provided at the sample surface so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0028] According to a fourth aspect of the disclosure, a system for producing and analysing a product from a sample is provided, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; and at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture a product derived from a sample to retain the product on the capture site; and a control unit configured to operate the modification element so as to apply a stimulus to the at least a part of the sample on the sample surface and thereby to cause a conversion of the at least a part of a sample to a product; and an analytical device configured to analyse the product, wherein at least one of: the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing of product from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.

[0029] The methods and systems in these first to fourth aspects provide improved means for processing and handling products of a conversion, such as a reaction or other transformation of a sample or a component thereof. The products are handled and can be processed within the same device and on the same surface on which the conversion is performed. This reduce the risks associated with loss or contamination of the sample and product(s) present in existing reactors devices and, in turn, increases the effectiveness of the recovery of the product(s) and more accurate analysis of the resultant products.

[0030] For example, the methods and systems may include separating the product from at least one other species on the surface by applying a force. This accordingly provides a means for separating and purifying the product without the need to transfer the mixture including the product onto a separate reactor device. These conventional separation techniques using separate devices rely heavily on manual operation (e.g. due to non-integrated steps and the need for manual interventions), provide limited control over the separation process and subsequent or prior manipulation and have limitations such as sample size, speed and cost. This can lead to issues with reproducibility and precision. The use of a force on the same surface on which the sample is provided can lead to easier manufacturing and processing with fewer operator interventions, higher yields and improved resolution of the separation.

[0031] The methods and systems may also include applying the force so as to collect the product in a product region on the sample surface - i.e. a region on another part of the sample surface to that on which the sample is or was retained. This also provides improved product handling and allows for recovery or transfer of the product to another part of the sample surface so that it can be further processed, such as analysed or removed from the surface for further analysis. Collection in a single region advantageously can be used to concentrate the product in a single part of the device, improvingyield and the result of subsequent steps. For example, where this is subsequently separated, resolution may be improved by concentrating the product on a particular point.

[0032] The method of the second aspect, and optionally also the first aspect, comprises selectively binding the product to the capture site so as to retain the product thereon. The control unit of the system of the fourth aspect is configured to carry out this, and the system of the third aspect may optionally be too. This allows for the product of the conversion of the reaction to be captured on the sample surface on which it was produced, also improving handling and recovery. Moreover, the selective nature of the binding is such that this can provides an inherent separation of the product from the other species on the sample surface. That is, it can used to capture the products only on the capture site (e.g. in a product region) which separates these out for subsequent analysis. Thus, each capture site isolates a product on the sample surface, collecting the product in a separation regions associated.

[0033] The methods and systems may analyse the product on the capture site. By directly analysing the product on the sample surface, this also reduces the risk of contamination or loss of sample. Coupled with the separation provided by the selective capture of the product(s), this provides for improved analysis. This is particularly useful for the types of reactions performed on reactor devices, such as chip-based reactors, where the amount of product produced is small. Often the product sizes recovered manually from the surface of a chip are too small for traditional analysis techniques such as mass spectrometry and direct analysis in situ can improve the likelihood that these can be analysed.

[0034] The methods and systems may selectively release the product from the capture site, recover the product and remove the product from the sample surface, before analysing the recovered product. This combined with the selective capture provides a further way of isolating the product (or each product) so that it can be further analysed and recovered independently to other species. For example, this can be considered a further separation step (which may optionally also be present in the method of the first aspect) in which the product, held on a capture site, can be selectively released from the respective capture site into a recovery solution or fluid which is free or substantially free of other species, such as the sample, other products (where present), reagents or other contaminants. The recovered product may be transferred to a mass spectrometer or other suitable analysis tool. In other words, the methods may comprise causing the capture site (whether one or plural) capturing a specific product species to release the product species at a particular time so that the product is released back onto he surface when the surface is clear of other contaminants. Where there are different products, these may each be selectively captures on different sites and released at a different point in time, for example sequentially, while the other products remain bound on the surface. This allows the products to be recovered in isolation. In other words, the reactor device may be configured to individually release a product retained on each capture site.

[0035] Finally, these methods and systems also integrate sample conversion, product manipulation and analysis within a single device. This may lead to easier manufacturing and processing with feweroperator interventions, minimizing sample loss and contamination risks, higher yields of the conversions, and improved separation and analysis resolution.Conversion

[0036] In the methods and systems, a sample or a part thereof is converted into at least one product. By “conversion”, this refers broadly to any process that transforms a component or group of components from one form to another, including but not limited to: (i) a chemical reaction wherein one compound is converted into another, for example via synthesis, rearrangement, polymerization, isomerization, or substitution; (ii) a destructive transformation wherein a species is broken down or separated into component parts, for instance by decomposition, fragmentation, or pyrolysis; or (iii) any other process facilitating a change in composition or structure. This may include single-step or multi-step conversions (or “transformations”). “Conversion” may therefore encompass a variety of mechanisms instigated by the ’’stimulus” applied by a modification element, which is described in more detail, below.

[0037] The conversion accordingly may be a modification or a degradation of a structure of a component or group of components. This can be, for example, a degradation of the structure of the sample or a component. For example, the methods may apply a stimulus (such as heat or cooling, voltage, current) to the sample or a component thereof to cause the transformation. This could be used to release components from the sample (for example, to cause cell lysis where the sample is a cell), brake components down into sub-components (for example, causing molecules or other components to degrade into by-products) or similar.

[0038] Exemplary conversions which can be used with the methods and systems include at least one of: wherein the sample comprises a plurality of cells and wherein the conversion comprises applying the stimulus to cause cell lysis of the cell; wherein the sample comprises at least one protein and wherein the conversion comprises applying the stimulus to convert the at least one protein into at least one peptide or release at least one carbohydrate; wherein the sample comprises at least one a nucleic acid wherein the conversion comprises applying the stimulus to convert the nucleic acid into at least one base; and wherein the sample comprises a polymer and wherein the conversion comprises applying the stimulus to convert the polymer into at least one monomer. As these relate to breaking a component down into constituent parts (or derivatives of those constituent parts), this can be considered a degradation conversion. Accordingly, the resultant cell, peptide, base and monomer are the product. It will be appreciated that each of the protein, nucleic acid and polymer comprise a plurality of the resultant products (i.e. the peptide, carbohydrate base and monomer, respectively), but it may be that the transformation only generates a single one of these products. It will be appreciated that product may be a singular species or may mean plural of that species, for example, plural biomolecules of one type or protein. In some embodiments, there may be a plurality of different peptides, carbohydrates, bases and monomers formed, respectively.

[0039] In one implementation, the conversion may comprise electroporation of a cell. For example, the conversion may comprises applying the stimulus to cause cell lysis or cell membrane permeabilization of the cell (such as an electrical stimulus or sonication (using ultrasonic waves)) and the method may further comprise further modifying the cell. This may include introduction of a species or material into the cell (“cell transfection”), for example for cell reprogramming. This may include cell reprogramming, induced pluripotent stem cells (iPSCs), adoptive cell therapy (ACT), and intracellular drug delivery technology.

[0040] The methods and systems disclosed herein advantageously provide an improved means of cell manipulation. The cells can be provided to the sample surface and manipulated with a stimulus from the modification element, for example to open pores in the membrane. For example, an electrical pulse can be applied to cell membrane, allowing DNA, RNA, proteins, viruses, or other species or molecules to enter the cytoplasm. This is readily achievable using structures of systems disclosed herein since a transmembrane breakdown potential for a cell is typically around IV such that an electrical field strength of ~0.3 x 105V / m can be used for electrical lysis of cell with a 20pm diameter. This transformation can result in the cell expressing new genetic information (e.g., by integrating a plasmid) or otherwise altering its phenotype (e.g., by acquiring resistance markers or secreting different proteins). In this context, “conversion” may refer to the change in cell properties, such as transition of the cell from a non -transgenic state to a transgenic state. The reactor site(s) can be used to perform this on individual cells and the method of the first aspect and system of the third aspect (and optionally the method of the second aspect and system of the fourth aspect) comprises retaining the cell on the reactor site for this process, in these embodiments. This helps to control the process without excessive handling of the cells, which may otherwise damage it. Further, this offers benefits over conventional chemical methods (such as using cationic lipids or polymers complexed with DNA to achieve transfection) in that there is greater control and fewer reagents required.

[0041] Further, the use of the methods and systems disclosed herein are advantageous in the context of cell lysis or other release of components from cells can be used to further capture and analyze the products of the conversion. For example, lysis of the cell may lead to release of a plurality of products, for example in the form of nucleic acids (e.g. DNA, RNA), lipids, proteins and / or carbohydrates, these products can be isolated, separated and / or captured on the same surface for further processing or analysis.

[0042] Accordingly, conversion may comprise providing a sample comprising a plurality of cells and applying the stimulus to cause cell lysis or cell membrane permeabilization of the cells; and wherein the method further comprises transfecting the cells with at least one species.

[0043] Conversion may also be used in oligosaccharide and / or glycoconjugate synthesis. For example, a sample may comprise a cell or protein from which there is release triggered by a stimulus (which may be combined with enzymatic release). The reagent for the release may be adhered to the reactor site,for example. Glycans can then be isolated and separated using the application of the force across the sample surface, for example based on size and charge.Provision / retention of the sample

[0044] In the method of the first aspect and system of the third aspect (and optionally in the others), the sample is provided to the sample surface and at least a part of the sample is retained on the reactor site. The ability to retain a part of the sample on the reactor site enables more precise control over individual sample components compared to general bulk processing methods. For example, the interaction with the stimulus and conversion will be more predictable, and the initial generation of the product(s) in a specific region of the sample surface, meaning that subsequent manipulation may be more straightforward. Further, this enables allows a denser array of components on the sample surface. Provision of the stimulus can be localised just to the reactor site, reducing the risk of side reactions with other components in the sample. Further concurrent reactions can occur across the site with greater control. In the second and fourth aspects, the sample surface and may, but need not, be retained on a reactor site. Instead, in these aspects, the stimulus may be applied anywhere on the surface of the reactor device, where “on the surface” may mean within a medium provided on the surface such that it will be affected by the stimulus (but not necessarily in physical contact with the surface).

[0045] Movement of the sample to the respective reactor site may be through diffusion. However, to reduce incubation time, the method may further comprise transporting the sample to each of the reactor sites. Where there are plural reactor sites, this may comprise applying a force to the sample (or parts thereof) to migrate the parts sample to each of the reactor sites. Different forces can be applied in different regions of the sample surface to achieve this. For example, the methods and systems may further comprise applying a force, such as an electric field or magnetic field, to the sample or a part there so as to cause movement of the sample or a part thereof relative to or towards the sample surface, such as towards the reaction site(s). Such a method and system can speed up measurement time by causing movement of the species in the sample to migrate to the capture sites at a movement speed which is greater than diffusion.

[0046] The methods and systems may be used to sort cells prior to conversion, for example. This may be based on physical properties of the cell (density or size), or on cell affinity (magnetic / adhesive properties). This may include cell analysis in one dimension through hydrodynamic focussing, where the cells can be separated out for cell-by-cell interrogation using the systems and methods disclosed herein and, in particular, the forces. This can improve the monitoring of subsequent conversions involving the cells. Further, these systems and methods can be used to manipulate cells for single cell analysis and sequencing.

[0047] The methods may further comprise providing a mixture comprising the sample to the sample surface; and wherein providing the sample to the plurality of reactor sites comprises migrating the mixture relative to the sample surface so as to separate the sample from at least one other componentof the mixture. The systems may be configured so that application of the force, where present, provides this. This initial separation step can improve the efficiency of the conversion process and the overall purity of the product. For example, where this is a further component or species unrelated to the conversion, the part of the sample for which the conversion is to take place may be separated out prior to the conversion by migrating the sample relative to the surface. This may be achieved in the same manner as the other separations set out herein in more detail below.

[0048] In certain embodiments, the sample comprises a first component and a second component. This may be two separate parts of the sample for which a conversion is to be undertaken or it may be a first part for which a conversion is to be undertaken, a reagent or other component for use in the conversion or a further component or species unrelated to the conversion. The latter is particularly common in a complex samples - such as bodily fluids or other biological sources.

[0049] In some embodiments, providing the sample to the sample surface further comprises migrating the sample on the sample surface so as separate the sample into the first component and the second component. The separation may also be used to assist with performing concurrent conversions. For example, where the first and second components (or, plurality of components) are each different species and parts of the sample for which a (different) conversion is to take place, these may also be separated by this, for example so that each can be provided to a different reactor site. Each reactor site may be configured to perform a different conversion on each of the species or components present. The reactor sites may therefore be selective to a particular species or group, as set out in more detail below. Accordingly, in some embodiments, retaining a part of the sample on each of the reactor sites comprises retaining the first component on a first reactor site and retaining the second component on a second reactor site.

[0050] Therefore, in some embodiments, the method further comprises providing a mixture comprising the sample to the sample surface; and wherein providing the sample to the reactor site(s) comprises migrating the mixture relative to the sample surface so as to separate the sample from at least one other component of the mixture. The systems may accordingly be configured to provide this separation through migration.

[0051] It will be appreciated that there are many ways in which a part of a sample may be retained on a reactor site.

[0052] The reactor site may be provided with a capture agent configured to retain a part of the sample thereon. This may be a capture species configured to selectively bind to the sample or a part thereof. Retaining the sample on the reactor site may therefore comprises selectively binding a part of the sample to the capture species. The types of captures agents and species that can be used are set out in more detail, below. Where there are a plurality of reactor sites and plural components within the sample, each of the plural components being for a conversion, at least one reactor site may be configured to selectively bind each of the plural components (e.g. comprise a capture species configured to selectively bind each of the plural components). For example, the first reactor site may comprise a first capturespecies configured to selectively bind to the first component so as to retain it thereon and a second reactor site may comprise a second capture species configured to selective bind to the second component so as to retain it thereon. For example, the systems may use the manipulation assembly or may further comprise another manipulation assembly configured to apply a force to the sample located on the reactor site so as to retain it thereon.

[0053] Another method for retaining a sample thereon may comprise applying a force to the sample located on the reactor site so as to retain it thereon. For example, this may be a force perpendicular to the sample surface and, in particular, the reactor site. This may be a force in accordance with the force set out herein, discussed in more detail, below. One exemplary implementation of this is where the sample comprises cells, which cells are retaining on reactor site(s) so that a stimulus can be applied thereto. An electric field can be generated with a direction perpendicular to the reactor site so as to confine the cell within the field (e.g. between two opposing electrodes, one located above the sample surface and the other within or beneath the sample surface). Another embodiment where an electric field can be used to confine or retain a charged species therein, such as a cell, includes using an electrode array to trap an ion. For example, a set of four opposing electrodes can each generate a field which retains a positively charged particle surrounded by a cloud of similarly charged particles such that a particle received between the four electrodes can be trapped (i.e. retained).Reactor site(s)

[0054] The reactor sites are each a distinct region of the sample surface and each comprise a portion of the sample surface of the device. Each reactor site comprises a modification element configured to apply a stimulus a part of a sample. The reactor site(s) may be defined by the extent of the modification element and / or, where present, a sensing element of each capture site / reactor site on the sample surface. Where there are plural of these elements on each site, this may be defined by the outer extent defined by the elements present. This is relative to the extent across the sample surface at the reactor site (i.e. perpendicular to the reactor site at the sample surface). Where there is a capture agent on the site, this may be defined by the extent of the coverage of the capture agent on the sample surface.

[0055] The reactor device may comprise a plurality of reactor sites provided on the sample surface, wherein each reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site. This configuration allows for parallel processing of multiple samples aliquots (i.e. parts of the same sample components) or parallel processing of different components of the sample, providing increases in scalability. For example, This may be one sample split into parts where each part comprises the same components or species (i.e. there is a first species or first group of species provided to each reactor) or it may be that the sample comprises a plurality of different species or groups of species and each reactor unit is provided with a different species or group of species (e.g. a first species or first group provided to a first reactor site and a second different species or a second different group of species provided to a second reactor site). The former provides large scale processing of thesame species or groups of species, which may be under the same conditions or may be under different conditions, depending on factors such as the type and intensity of the stimulus applied and any further reagents provided. The latter - i.e. each reactor unit is provided with a different species or group of species - allows for different conversions to take place on the same site. This may be particularly useful where there are mixtures of components within a complex sample - such as bodily fluids or other biological sources - and various conversions can take place depending on the specific species or components present. Each reactor site may be configured to perform a different conversion on each of the species or components present. The reactor sites may therefore be selective to a particular species or group, as set out in more detail below.

[0056] Where there are plurality of reactor sites, these may be spaced apart from one another. This can assist with the application of a stimulus since the stimulus can be applied locally and is less likely to impact another site. This may be a spacing of at least 0.01 mm, such as at least 0.05 mm, at least 0.1 mm, at least 1 mm or at least 2mm. For example, from 0.01 mm to 10 cm, 0.01 mm to 5 cm or 0.05mm to 2cm. The substrate or a dielectric may be provided between a part of each of the reactor sites.

[0057] The reactor site may comprise a capture agent (e.g. a capture species) configured to bind to the part of the sample so as to retain it thereon. Where there are a plurality of reactor sites, each may comprise a corresponding capture agent (e.g. capture species). This may be the same capture agent, for example, where a part of the sample comprising the same component(s) is provided to each reactor site. Alternative, where different components of the sample are retained on different sites, there may be correspondingly different capture agents on each species. For example, a first reactor site may comprise a first capture agent (e.g. capture species) configured to selectively bind to a first component of the sample so as to retain it thereon and a second reactor site may comprise a second capture agent (e.g. capture species) configured to selective bind to a second component of the sample so as to retain it thereon. This provides an effective sample management system which can deal with complex mixtures of samples and selectively capture the desired components of the sample on different sites for processing.

[0058] It will be appreciated that each site may capture a plurality of this one type of species, for example plural species molecules. That is, each reactor site is not limited to a single molecule or compound, thus there may be a plurality of capture species (of one type) to capture the component. The device may further comprise plural reactor sites configured to capture the same type of component. It may be advantageous from an incubation time perspective to have plural reactor sites across the sample surface configured to capture the same component.Modification element and stimulus

[0059] The methods and systems disclosed herein use a modification element to apply a stimulus to the at least a part of the sample on the reactor site so as to cause a conversion of the at least a part of the sample to a product. This may be that this triggers the reaction between components or it may be thatthe stimulus causes the conversion directly. The stimulus make be a direct stimulus (e.g. an electrical or thermal stimulus) or indirect (such as modifying a property on the reactor site). Accordingly, the or each modification element may be operable (or operated) to cause a transformation of the sample or a part thereof. The stimulus may be, for example, heat or cooling, voltage, current applied to the part of the sample or medium surrounding the part of the sample to cause the conversion.

[0060] The modification element may be used to locally modify a property. That is, it may be configured to modify a property (also referred to herein as “environmental property” or “medium property”) of the medium or environment adjacent (i.e. next to or on) the modification element or only modify the sample within a region local to the modification element. Each capture site may be provided or comprise a separate modification element such that the debinding on each site can occur under the control of a capture site-specific modification element. As such, where the modification element modifies the local environment, this can be local to each capture site.

[0061] By modification of property in this context, it is meant that it to modifies a physical (e.g. material) or chemical property of the bound pair or the environment (e.g. the solution) around the bound pair sample, such as by applying electrical energy or an electric field directly to the sample to change the property or by providing another form of energy (e.g. thermal energy). In some embodiments, this may be a physical or chemical property of the solution. The property can include physical properties, such as thermal properties (e.g. temperature) and / or chemical properties such as the pH of the solution adjacent the modification element. This can create localised regions having a different property. The property may be modified directly, e.g. by direct application of heat to change the temperature, or indirectly for example by causing a chemical change which in turn changes the property, such as hydrolysis or electrolysis due to application of electrical energy which can change the pH. For example, the modification element can be configured to create an electrical field which can cause a localised change in a part of the medium.

[0062] The modification element many be selected from or comprise an electrode or a thermal device, such as a heater or a cooler. A thermal device can be used to heat the part of the sample to cause the conversion. This can be to provide the input for the reaction to progress or to cause degradation, for example. The methods and systems disclosed herein may therefore comprise operating the thermal device to heat the part of the sample on the reactor site. This may be a local heating, whereby the increase in temperature is confined to the reactor site (e.g. adjacent reactor sites have a temperature difference of less than 10% of that of the reactor site in question).

[0063] The modification element(s) may comprise an electrode (e.g. a modification electrode) or a plurality of electrodes operable to interact with at least a part of the sample (e.g. the solution on the sample surface). An electrode can be used to provide a chemical, thermal, or mechanical manipulation, depending on the nature of the sample and the specific requirements of the conversion. For example, it can be used to can alter properties such as pH, electrical conductivity, or temperature of mediumsurrounding the modification element(s), thereby affecting the behaviour of the components and facilitating their separation and analysis.

[0064] The modification element(s) is a part of the reactor site in the methods of the first aspect and system of the third aspect, and may further optionally be in the method of the second aspect and system of the fourth aspect. The modification element(s) may be provided on the substrate and form a part of the sample surface. This further allows for integration into a chip or integrated circuit. Further, providing this on or adjacent or at the surface of the reactor site enables the modification locally at each reactor site.

[0065] The modification element(s) may further be used for other purposes within the methods and systems or additional / separate modification element(s) may be provided. For example, the modification elements can be used to provide a more general temperature increase across the specific sites or even the entire sample surface. An increase in temperature can decrease incubation time with a capture agent (or a capture species) by increasing the rate of binding (Kon). For example, by raising the temperature (e.g. by at least 1 °C, or at least 5 °C), the entire process may be sped up, by increasing mobility, reaction times and / or binding. It has been found that a rate of binding at or close to 37 °C is higher than that at room temperature (e.g. 21 °C), even if limited to the region adjacent the sample surface only (i.e. without increasing the bulk temperature). Ionic strength and pH (which are linked) also modify the binding parameters. For example, modification of the pH can change the propensity of the capture species and a sample or part thereof to bind.Property Modification Unit

[0066] The systems and methods may comprise a property modification unit comprising a modification element, where the property modification unit is configured to modify a property of medium provided at the sample surface using the modification element. This may be the modification element used in provision of a stimulus (where the stimulus modifies a property of the medium or local environment), such as the stimulus used in the conversion or a debinding stimulus. This may alternatively or additionally be or comprise a separate modification element, for example as to influence the migration of at least a part of the sample migrating along a respective pathway. The property modification unit may comprise a control unit or controller (which may be the control unit of the system or a separate control unit or controller) configured to operate the modification element, for example. The method may accordingly further comprise modifying a property of the medium, which may be so as to impart variation in the medium property along at least a part of the pathway.

[0067] The property modification unit may be configured to modify (and the method comprising modifying) at least one of pH, electrical conductivity, a thermal property (e.g. temperature of), and / or ionic strength of the medium (e.g. by operating the modification element).Manipulation and Separation

[0068] The method in the first aspect, and optionally in the second aspect, comprises applying a force to the product so as to migrate the product from the reactor site relative to (i.e. across or towards / away from) the sample surface, wherein migrating the product relative to the sample surface is so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface. Similarly, the system of the third aspect is configured for this and optionally the system of the fourth may be configured for this. Further, forces may be applied to other components, such as the sample itself or parts thereof, to manipulate (i.e. move) them across and on the sample surface and further within the device and system. Use of such a force can advantageously quickly and efficiently transfer the various components and species without direct handling. Both large- scale and small-scale movements are possible within the system.

[0069] Separating the product from at least one additional species may be from any other species. For example, it may be another product of the conversion. This may be an intended product, including byproducts, unintended products (e.g. resulting from incomplete conversion) or waste generated by the conversion. It may be any sample or components thereof which have not undergone a transformation - this may be that some sample has not reacted or the components remaining were in addition to the component which underwent transformation - or any excess / or unreacted reagents. Or any other contaminant on the sample surface, for example. Accordingly, this provides a means of purifying or isolating the product so that it is separated from at least one additional species, for example the sample and any other products formed on the surface, or indeed any other species.

[0070] In some embodiments, the conversion of the at least a part of the sample is to form a plurality of products, and applying a force or a plurality of forces is to the plurality of products so as to migrate the plurality of products relative to the sample surface. This feature enables simultaneous processing, and optionally separation, of multiple products. This may be so as to separate the plurality of products from one another. In such embodiments, the at least one additional species is another product of the conversion. Where plural forces are applied to different products or components, the plurality forces may differ in direction and / or intensity, for example. The methods and systems may additionally or alternatively comprise applying a force to the plurality of products so as to migrate the plurality of products to a product region. This can be a product region where the plurality of products are mixed. This may be used prior to separation, for example, to enhance the resolution of subsequent separation since the products can be collected at a single point and separated from the same point. This can reduce the spread of bands or overlap of separated components. Alternatively, this may be instead of a separation step, where the products can be recovered and / or analysed from the product region.

[0071] In some embodiments, there may be a plurality of products and / or the at least one product may comprise or be formed of plural components. Where there are plural products, each reactor site may produce a plurality of products. This may be the same or different products on each site. Alternatively, as a result of the stimulus applied, the part of the sample on the reactor site, additional inputs (such as regents) or a combination of these, each of the plurality of reactor sites may result in a different product.

[0072] Where there are a plurality of different products, separating or purifying may comprise separating or purifying the plurality of products together (i.e. relative to anything other than these products) so that they are provided as a single mixture of product or it may be separately to one other such that each of the plural products is purified individually, or a combination (i.e. some may be purified together and at least one product purified separately) . For the latter, the methods and system may further comprise migrating the products relative to the sample surface so as to separate the products from other species on the sample surface. This may be achievable using any suitable separation technique. For example, where the products are sufficiently similar to one another in respect of at least one property and sufficiently different to other species on the surface, these may be separated on the basis of that property (e.g. size, charge, interaction with a particular medium or solid phase etc.). Alternatively, these may be distinguished in another way, such as by providing a tag. For the latter, the methods and system may further comprise migrating the products relative to the sample surface so as to separate each product from the other product(s) . This may be achievable using any suitable separation technique, for example on the basis of a property (e.g. size, charge, interaction with a particular medium or solid phase etc.).

[0073] Applying the force may additionally or alternatively be to collect the product in a product region on the sample surface. The product region may be a distinct region of the sample surface separate to any of the reactor surfaces. It may comprise a portion of the sample surface of the device and, as set out above, may comprise a capture site. Where the product region comprises a capture site or plural capture sites, it may be defined by the extent of the capture site(s). Accordingly, these may be spaced apart from the reactor sites. This may be a spacing of at least 0.1 mm, at least 1 mm or at least 2mm or at least 1 cm. For example, from 0.1 mm to 10 cm. The substrate or a dielectric may be provided between a part of the product region and the nearest reactor site.

[0074] In some embodiments, migrating the product relative to the sample surface so as to collect the product in a product region on the sample surface may further comprise moving the product off the sample surface. In other words, removing it from the sample surface. This may be to move through the substrate or off the sample surface onto another device or surface, such as a transfer membrane. In some embodiments!, the substrate may comprise at least one opening provided at the sample surface. The methods and systems may comprise applying the force so as to migrate the product through the opening. Accordingly, this may create a pathway extending into the opening which is arranged at an angle relative to the sample surface and which extends into and through the opening so that migration of the product is through the opening. A well, channel or through hole may accordingly form a part of the pathway or define a part of the pathway and define the opening. Where a closed recess is formed (e.g. a well or channel), the nadir or base of the recess may define the end of the pathway. This can be used to collect the product therein. There may be a plurality of openings, with a plurality of pathways extending into a respective opening. The openings may be openings of channels, wells or through holes formed in the substrate and optionally further layers provided below or adjacent the substrate.Accordingly, the substrate may comprise at least one channel, well or through hole. The presence of openings in the substrate or a portion thereof provides significant additional functionality. The openings enable transfer of products into an enclosed or separate region, where further analysis or storage can occur. For example, products could be collected in wells or channels formed in the substrate so as to concentrate them. This can be useful where there are numerous samples or parts of samples from which the same product can be extracted (as part of the conversion) from each and then recombined in a well or device positioned below a through hole.

[0075] In some embodiments, collecting the product in a product region on the sample surface is so as to concentrate the product on the sample surface in the product region. Collection in a single region advantageously can be used to concentrate the product in a single part of the device.

[0076] In the methods and systems disclosed herein, these may comprise applying a force. For example, the systems and methods can generate electric or magnetic fields that guide sample migration along predefined paths or affect a change in the environmental conditions which in turn create a force which causes movement of the along a pathway.

[0077] For example, this may comprise applying an electric field and / or a magnetic field to the sample, the product(s) or another species. The use of an electric field for movement of charged species on the sample surface (and, more generally, in the device) is an efficient and effective means by which to manipulate the components on the surface. It will be appreciated that various forces, such as those applies by electric and / or magnetic fields, can be used. In some cases, the product(s), the sample, a part thereof, or other component may be charged. This is also advantageous in that it can be combined with the other functionality disclosed herein. For example, using a modification element or a particular medium portion, the charge of a particular component can be modified at different points on the sample surface, enabling different responses of the component to an applied electric field.

[0078] Applying a force to the product so as to migrate the product from the reactor site relative to the sample surface may comprise causing the product(s) to move along a first pathway. Similarly movement of the sample or any other component may be along a pathway. A pathway refers to a defined route or channel through medium when provided at the sample surface of the system. It may be delimited by a manipulation assembly, for example by the extent of the force generated by the manipulation assembly within the medium (e.g. where provided by a field, by the field within the medium). This may be limited by the physical structure of a manipulation assembly, for example where there are electrodes for providing the force, the respective pathway may be delimited by the outermost electrodes of the manipulation assembly. Thus, the pathway may be determinable without medium being present, but is nevertheless formed within the medium when provided on the channel. The pathway is continuous, such that a force can be generated by the respective manipulation assembly across the length. The pathway may also be defined or delimited by structures within a medium, such as a separate medium region (e.g. of a different composition) or by channels or barriers within the medium. Accordingly, the pathway serves as conduit for the movement or separation of components ofa sample or the product(s) within the systems and method. The pathways may be, but need not be, a linear pathway extending in a single direction. For example, the pathway may extend in plural directions. In some embodiments, the pathways may be physical channels. These may have a linear shape or may be non-linear, such as curved (e.g. serpentine). Where there is a separation, this may be along a pathway.

[0079] Accordingly, the reactor device may comprise at least one manipulation assembly operable to cause the product(s), the sample or a part of sample to move on (e.g. along or towards) the sample surface. In other words, this may be operable to apply a force which causes the product(s), the sample or a part thereof to move towards a desired region of the device. Such a manipulation assembly may be operable to generate an electric field and / or a magnetic field to provide the respective force.

[0080] It will be appreciated that there are also numerous other ways in which forces (beyond those resulting from the direct application of electric or magnetic fields to species affected by these fields) can be applied and separation can be affected, including for example:

[0081] (i) Applying a force may comprise providing a medium in which a property of the medium varies along a pathway so as to provide a force which acts on at least a part of the sample so as to causes the sample or a part thereof to migrate through the medium. This can define the corresponding pathway. In other words, the application of force is through the creation of an environment which leads to osmotic pressure or which causes diffusion across the pathway. This may be a property of the medium or it may be imparted on the medium by a corresponding manipulation assembly (where present in the method). For example, the methods (and systems) may comprise applying a force (which acts on at least one component) by providing a concentration variation or gradient within the medium along the pathway of at least one species. This can be a property of the medium or can provided by creating these regions through manipulations of species in the medium. For example, charged species (e.g. dopants not forming a part of the sample) within a medium could be manipulated by an electric field to create a particular concentration or charge gradient).

[0082] (ii) Applying a force may comprise applying a force to cause sedimentation of a sample (i.e. the separation of at least one non-soluble component from a liquid and / or for separating a plurality of nonsoluble components from one another within a liquid). This may be application of a kinetic force to cause velocity sedimentation (measuring the speed at which a component settles) or isopycnic sedimentation (based on density of the components). The force acting on the particles may be gravity (i.e. the sample is provided at a first height in the medium such that gravity can move the samples to a plurality of different heights, thereby applying the force). The force may alternatively or additionally be a centrifugal or centripetal force device, such as applied by manipulation assembly (e.g. a centrifugal or centripetal force device (such as a zonal rotor)). One implementation of (ii) is separating cells.

[0083] (iii) Causing separation by a difference in at least one of adhesion, cohesion, and surface tension. This may be separating based on the difference in these features and interaction with the medium of thesubstrate surface or a feature provided on the substrate (such as a coating or functionalization). In some embodiments, these forces may also be used to apply the force so as to cause migration.

[0084] (iv) Applying a force may comprise applying a centrifugal or centripetal force to cause separation through the medium. This may be based on at least one of size of the components of the sample, shape of the components, density of the components, medium viscosity and rotor speed. For example, this can be used in combination with the separation of based on sedimentation (i.e. (ii)). At least one of (or a plurality or each) manipulation assembly may comprise a device configured to apply a centrifugal or centripetal force (such as a zonal rotor).

[0085] (v) applying a force may comprise applying a force using acoustic waves. For example, the respective manipulation assembly or assemblies may be configured to apply a force using sound-waves. These can also advantageously be used to apply a directional force on the sample or a component thereof. In one embodiment, the respective manipulation assembly or assemblies comprise an ultrasonic sound-wave generator, such as an ultrasonic transducer. By ultrasonic it is meant that the device generates high-frequency sound-waves which cause vibrations in a fluid, particularly in a liquid. For example, sound-waves with a frequency of greater than 18kHz, optionally 20-400 kHz and further optionally 40-80 kHz.

[0086] Combinations of any of the means for applying a force can be combined, including any of (i) to (v) with the use of an electrical field and / or magnetic field which acts directly on the sample. For example, the combination of (i) and an electric field can be used to move a sample or a part thereof through a gradient (which itself could be generated by a manipulation assembly) under the force of an electric field. Similarly, changing pH across a gradient (e.g. (i)) can be combined with an electric field to separate based on isoelectric point.

[0087] At least one of the first, second or third manipulation assemblies (or a plurality of, or each) may be configured to modify a property of the medium so as to provide a force which causes the sample or a part thereof to migrate through the medium. This may be in addition to alternatively to a field acting on the sample or a part thereof. For example, the second or third manipulation assemblies may modify a property of the medium along the pathway to create a gradient of the property across the pathway. The property (also referred to herein as “environmental property” or “medium property”) may be of the medium across the pathway or just the environment adjacent (i.e. next to or on) one part of the manipulation assembly (e.g. an electrode). By modification of property, it is meant that it to modifies a physical (e.g. material) or chemical property of the medium, the environment or the sample, such as by applying electrical energy or an electric field directly to the sample to change the property or by providing another form of energy (e.g. thermal energy). In some embodiments, this may be a physical or chemical property of the medium. The property can include physical properties, such as thermal properties (e.g. temperature) and / or viscosity, and / or chemical properties selected from at least one of the pH, electrical conductivity, thermal conductivity and / or ionic strength of the sample or a part thereof. The property may be modified directly, e.g. by direct application of heat to change thetemperature, or indirectly for example by causing a chemical change which in turn changes the property, such as hydrolysis or electrolysis due to application of electrical energy which can change the pH. For example, the manipulation elements can be configured to create an electrical field which can cause a localised change in a part of the medium.

[0088] Accordingly, at least one of (or a plurality of, or each) the first, second or third manipulation assemblies is configured to modify at least one of the concentration of at least one component of the medium

[0089] For example, certain molecules are only charged within small pH ranges and may not bind to the corresponding moiety if not charged. Modification of the pH can change the propensity of the capture species and target analyte to bind, which can provide additional information on binding and kinetics of binding. In some cases, this can lead to dissociation. Changes in pH and / or ionic strength can also be used where the sample comprises other non-analyte species, by modifying the solution to a point where e.g. non-selective binding is reduced or eliminated. Moreover, pH is a critical factor in many aspects of biological processes and, indeed, is heavily susceptible to variation in biological samples, for example due to biological processes (e.g. CO2 or lactate production by cells). The ability to control this in situ and without requiring buffers or acids / bases provides a significant improvement.

[0090] The methods may comprise providing different force profiles along the pathway using a local force. The methods may comprise forming an individually controllable region along the pathway and applying a force to the product or part of the sample so as to cause the respective product or part of the sample to migrate along the pathway by selectively applying a first local force to the individually controllable region so as to influence or cause migration of at least the product or a part of sample migrate along the respective pathway within the individually controllable region. In embodiments of the systems, the manipulation assembly may be configured so as to define at least one individually controllable region along a part of the pathway in which a first local force can be selectively applied within the individually controllable region so as to influence or cause migration of at least a product or part of sample along the respective pathway within the individually controllable region. The control unit may be configured to operate the manipulation assembly to provide this. This can provide improved resolution and control over the manipulation and separation processes compared to traditional single and multi-dimensional separation techniques. That is, the provision of at least one the individually controllable region in which a local force can be provided allows for the manipulation of samples or products thereof to a greater degree. This can be used to provide more complex separations and a more precise level of control. For example, incorporation of an individually controllable region allows for individual manipulation of the product or part of the sample before, during and / or after conversion and / or separation. This can be used to move these species to a particular region (e.g. a sensing element or for better alignment with a subsequent pathway), to collect the component at a particular point (for example, to concentrate the product in the product region) or to create a greater degree of separation (i.e. resolution) between separated species. Further, the individually controllableregion allows for the generation of more complex (i.e. non-uniform) and sophisticated force profdes across the respective pathway to create a greater degree of separation species. For example, with the individually controllable region capable of providing a different force to the remainder of the pathway. The fine control over the local force within this region may also allow for adaptive separation protocols, where force profiles are adjusted in real-time, for example based on detected sample or product properties or separation progress.

[0091] A first manipulation assembly may comprise a first electrode set arranged and operable to provide the respective force. Use of electrodes provides a precise control over the applied forces and allows for integration of the assemblies into a chip or integrated circuit for precise manufacture and miniaturisation. The methods and systems (e.g. control unit) disclosed herein may therefore further comprise operating a manipulation assembly to provide a force. For example, the systems and methods can use these electrodes to generate electric fields that guide sample or product migration along predefined paths. The first electrode set can comprise a pair of electrodes provided as an electrically connectable or connected pair of field-generating electrodes for generating a field for influencing the product(s), the sample or a part thereof (e.g. an electric field and / or a magnetic field). Each of the pair of electrodes can be provided at an opposing end of the pathway and to define the entire length of the pathway. In other words, these are spaced apart and medium is provided therebetween so that the region defined between them is the pathway. The pair of electrodes are electrically connectable or connected so that the field providing the force can be defined therebetween along the length of the pathway. Where a magnetic field is used, this can be applied using an electromagnetic manipulation assembly configured to apply a magnetic field across at least a portion of the respective pathway. The use of an electric field or magnetic field to provide the force is particularly advantageous with the structures and arrangements disclosed herein. For example, the application of an electric field or magnetic field can be achieved using electrodes, further allowing integration of this into a chip or integrated circuit structure and manufacture using traditional semiconductor manufacturing processes (e.g. CMOS manufacturing processes). In such an arrangement, the first manipulation assembly and / or second manipulation assembly may comprise at least one further electrode provided along the respective first pathway and second pathway which in part defines the individual controllable region. This may be operated or operable to, for example with another electrode, generate a smaller region of force across the pathway formed by the pair of electrodes. Alternatively or additionally, there may a further pair of electrodes (i.e. there may be a plurality of further electrodes which are electrically connectable or connected to one another). That is, there may be an additional pair of electrodes (defining a local electrode set) to the pair of the first electrode set. This additional pair can be positioned so as to generate a local field therebetween across a sub-region of the respective pathway. Both electrodes may, in some cases, be located so as to form a local field wholly within the pathway, and accordingly may be located between the pair of the first electrode set. The methods and systems disclosed herein may accordingly comprise operating the pair of electrodes to generate the local force.

[0092] The electrodes in the system and provided along or interacting with the pathway can further be used to interrogate the product(s), the sample or the components thereof. For example, an electrode or electrodes may be used to obtain a signal relating to a property of the product(s), the sample or a part thereof, including electrical proprieties, such as current, voltage, resistance, capacitance, impedance or conductance. For example, the electrode set(s) and / or the at least one further electrode may be further operable to provide a signal indicative of a property of the sample or a product. These may be located at a position along a respective pathway they are moved along. Where there are plural electrodes, each may be further operable to provide a signal indicative of a property of the product or sample. A control unit may be configured to address the electrode set(s) and / or the at least one further electrode to obtain the signal and may, further, be configured to determine a property of the component based on the signal. The methods and systems disclosed herein may include obtaining a signal indicative of a property of a component of the sample or the property, for example along a pathway or in the product region. This advantageously utilises the electrodes used for manipulation of the sample to further interrogate the sample, providing additional functionality without increasing the number of components which need to be provided. This can also speed up and improve the robustness of the analysis, since the data is provided in situ, rather than using a separate device and requires no transfer.

[0093] The manipulation assembly may be operable to generate an electric field and / or a magnetic field to provide the respective force. In the methods disclosed herein, applying a force may comprise applying an electric field and / or a magnetic field. The use of an electric field allows for movement of charged species relative to the sample surface and is an efficient and effective means by which separation or manipulation can occur. This is also advantageous in that it can be combined with the other functionality disclosed herein. For example, using the medium or a modification element, the charge of a particular component (i.e. a species) can be modified at different points along the pathway, enabling different responses of the species to the applied electric field. This can in turn provide better separation. Where a magnetic field is used, this can be applied using an electromagnetic manipulation assembly configured to apply a magnetic field across at least a portion of the respective pathway. The use of an electric field or magnetic field to provide the force is particularly advantageous with the structures and arrangements disclosed herein. For example, the application of an electric field or magnetic field can be achieved using electrodes, further allowing integration of this into a chip or integrated circuit structure and manufacture using traditional semiconductor manufacturing processes (e.g. CMOS manufacturing processes).

[0094] Variation of the force may be based on the strength or intensity (e.g. as measured by the input voltage (V / m or mV / m)) of the field applied, such as the electric field. The strength of the electric field may vary dependent on the species being moved. It will be appreciated that in any of the embodiments mentioned here, although the resultant force of the electric field acting on a particular species will depend on a number of factors, including the charge on the component, the magnitude of the force willbe determined by the magnitude of the electric field such that a higher V / m value will lead to a greater force acting on the species in the sample.

[0095] The methods may further comprise applying a field (e.g. an electric field) to the product(s), sample or a part thereof so as to cause movement of the respective product(s), sample or a part thereof towards the sample surface, such as to a reactor site or capture site. Such a method can speed up measurement time by causing movement of the species in the sample to migrate to the desired region at a movement speed which is greater than diffusion. This can reduce the time of or reduce the need for an incubation period.

[0096] In some embodiments, movement may be in multiple directions. For example, the method may comprises applying a force to the sample so as to cause at least one component to migrate along a first pathway relative to the surface (e.g. through a medium); and applying a force to at least a part of the component so as to cause the part of the component to migrate from the first pathway along a second pathway across the surface (e.g. through the medium), wherein the second pathway is adjacent to or intersects the first pathway. Similarly, the control unit of the systems may be configured to operate the manipulation assembly / assemblies for this purpose. Migration along at least one of the first pathway and the second pathway may be so as to separate any two components. For example, the product(s) from at least one additional species, the parts of a sample and / or or a mixture containing the sample. In further embodiments, the method may comprise applying a further force so as to cause at least a part of the component to migrate along a third pathway relative to the surface (e .g . through a medium), wherein the third pathway is adjacent to or intersects the second pathway. By “adjacent to” it is meant that the pathway may be next to and either spaced apart from or abut the other pathway. Accordingly, a component or a part thereof may move directly from one pathway to the other or there may be a spacing between these parts. The space may be through a portion of the medium such that the component(s) do not need to be removed from the medium. By “intersects”, it is meant that the pathway in question joins the other pathway such that they are connected and may overlap. Thus, movement along the pathway in question may in turn result in removal from the earlier pathway.

[0097] In addition to the force, the system may be provided with a separation component provided on the sample substrate which interacts with at least a part of the sample as it is separated. This may be a component provided within the medium (e.g. particles) or provided on the sample surface (such as a coating or functionalization). Examples include antibodies provided on the sample surface, beads (which can be functionalized) or surface profiling on the sample surface.

[0098] The systems and method disclosed herein are advantageous in separation of complex mixtures, such as bodily fluids or created during cell lysis. Such mixtures often require several rounds of sample preparation, whereas the current systems and methods may be used to achieve separation with minimal operator interaction. For example, bodily fluids (such as blood, urine, saliva) contain large numbers of proteins which may be of limited use. The present systems can separate these out along a pathway or plural pathways, if required, leaving only the desired targets. The desired targets may be furtherseparated as a clean sample, retained or held on a particular part of the device and / or moved separately for further analysis.Capture Sites

[0099] The method of the second aspect and system of the fourth aspect provides a reactor device comprising at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture the product to retain the product on the capture site, and the method further comprises selectively binding the product to the capture site so as to retain the product thereon. The control unit of the systems may be configured to carry out this. The method of the first aspect may also include such a capture site and selective binding step, as can the system of the third aspect be configured for this purpose. As set out above, selective capture enables selective product capture, allowing for separation from other components and for analysis. In certain embodiments, the reactor device further comprises at least one capture site provided in the product region and comprising a capture agent configured to retain the product thereon.

[0100] Further, although the use of the capture sites has been disclosed in the context of the product, in embodiments, a capture site may be configured to bind to another component or species (in addition to or, for the first aspect, alternatively to a capture site for a product). This may be the sample or a part thereof or may be another component, for example for capture of a particular contaminant or reagent.

[0101] The capture sites are each a distinct region of the sample surface and each comprise a portion of the sample surface of the device. Each capture site may accordingly be a region of the sample surface with an array or arrangement of one type of capture species. Each capture site is adapted so that it captures only one of the products (i.e. one specific compound). Where there are plural components to capture, such as a plurality of products, there may be plural different types of capture site so that the reactor device overall is capable of capturing or configured to capture multiple different species (i.e. a plurality of capture sites, each configured to selective capture a different component, such as one of a plurality of products). It will be appreciated that each site may capture a plurality of this one type of species, for example plural species molecules. That is, each site is not limited to a single molecule or compound, thus there may be a plurality of capture species (of one type) to capture the component. The device may further comprise plural capture sites configured to capture the same type of component. It may be advantageous from an incubation time perspective to have plural capture sites across the sample surface configured to capture the same component. Accordingly, in the second aspect (and optionally in the first aspect), selectively releasing may comprise selectively releasing one type of component from plural capture sites simultaneously.Capture Agent

[0102] Each capture site and, in some embodiments, the reactor site comprises a capture agent configured to bind to a component. Examples include capture species (i.e. a molecular species orfunctional group) (or “capture probe”), which are selective so as to selectively bind to the respective species, or may include non-selective (or non-specific) capture agents such as gels, matrices, or porous bodies. For example, the capture agent may encapsulate the component.

[0103] In some embodiments, the capture agent may comprise a capture species (i.e. a molecular species or functional group) (or “capture probe”) adhered to the respective reactor or capture site, each capture species configured to selectively bind to the respective species. This can form a bound pair and retain the corresponding species on the reactor / capture site. The capture species may be configured to bind to the product to immobilise it on the reactor / capture site through covalent-like interactions (e.g., chemisorption of anchor species onto the surface through chemical bond formation) and / or non- covalent-like interactions (e.g., physisorption of capture species onto the surface through weaker, often van der Waals, interactions) depending on the identity of the capture species. The capture species may be selected from or comprise a protein, a peptide (e.g. an enzyme), a carbohydrate, a nucleic acid, an aptamer or a combination thereof. Some examples include a single or double stranded DNA chain. An aptamer may be defined as an oligonucleotide, polynucleotide or peptide configured to selectively bind to the species. In some cases, there may be a plurality of capture species (i.e. plural of the same capture species). Capture species may be plural, such that in some cases, there may be a plurality of capture species (i.e. plural of the same capture species) on each reactor / capture site.

[0104] The capture species may be covalently or non -covalently bonded to the capture site . The capture species (for example, a plurality of individual capture species) can be located adjacent to (i.e. next to or abutting) or on the sample surface, a modification element, a sensing element or any other component provided on the substrate (where these may also define at least a part of the sample surface) and interact with species provided on the sample surface. In some examples, the capture species is provided on (e.g. adhered to or bound to) the sample surface, a modification element, a sensing element or any other component provided on the substrate. In some examples, the sample surface is functionalized with the capture species. Such functionalization can be achieved in any suitable manner, such as by covalently or non-covalently immobilizing the capture species to the surface.

[0105] The capture species can be provided to the sites either by forming the capture species in situ (i.e. on a reactor surface) or these can be produced separately and applied to the capture sites.

[0106] As set out below, selective release from the sample surface may also comprise release of a part of the corresponding capture site. For example, a capture species configured to bind to a product may be detachable from the reminder of capture site (and the sample surface) so as to selectively release the product. In such cases, the capture species may be bound to the remainder of the capture site (e.g. the surface) by a cleavable group, such as a linker which can be cleaved. This may be cleavable by the application of a stimulus, such as heat or a change in environment (e.g. pH), which can be applied by the modification element, for example. In some embodiments, the or each capture site may comprise an individually actuatable modification element configured to cause the selectively releasing of the species bound to the capture site. This may be to provide the stimulus.

[0107] The structure of the reactor device lends itself to semiconductor manufacturing processes. As such, the number of reactor / capture sites which can be provided on a substrate can be much larger than conventional separation systems. In some embodiments, the number of reactor and / or capture sites on the reactor device is at least 16, such as at least 96 or at least 300.Other bound speciesIn some embodiments, the reactor sites may include a reaction species bound, adhered or otherwise held to the respective reactor site. This may be a species used in the conversion of the sample to the product, for example a catalyst or reagent. For example, this may be an enzyme configured to denature a sample or digest a sample to subunits (e.g. protein to peptides). Such a reaction species may be covalently or non-covalently bonded to the reactor site. In one exemplary, a species may be held on the respective reactor site in a matrix and may be configured to interact with the sample when sample is provided to the reactor site. This may a releasable species, for example held in a matrix which holds the species until a stimulus is provided or an environmental change occurs (e.g. the provision of a liquid). Selective release

[0108] The methods and systems may comprise selectively releasing the product from the capture site, recovering the product and removing the product from the sample surface, and analysing the recovered product. Where there is an analysis of the product on the capture site, this may occur after analysing the structure of the product bound on the capture site(s). The selective release (and recovery) may be so as to purify the product - i.e. remove the product from a mixture with at least one other species, but optionally it may be to isolate the product from any other species (such as other products, reagents, parts of the sample). Where there is a plurality of products, the methods and systems may further comprise selectively releasing each of the other products from the sample surfaces, recovering each of the other products separately and analysing each of the products separately.

[0109] By selective release, it is meant that one product (whether this is a single molecule or plural) is / are released from the capture surface. This may be that one product is / are released from the corresponding capture site(s) to which it is / they are bound, while the sample surface is free of other species (other than the medium). For example, this may be while the other product(s) are retained on their respective capture sites. In this way, the device can separate the products for further use. It will be appreciated that where product (i.e. one type of molecule) is retained across plural capture sites, the product may be selectively released from the plural capture sites on which it is retained, for example simultaneously. It will also be appreciated that release from the sample surface may also comprise release of a part of the corresponding capture site. For example, where the capture site comprises a capture species configured to bind to the product, it may be that the capture species is detached from the reminder of capture site (and the sample surface) so as to selectively release the product. Selective release may be triggered by an external input, such as an external stimulus, or may be caused by the device (e.g. by a modification element provided as a part of the reactor site)

[0110] Selectively releasing the product from the corresponding capture site may comprise applying a debinding stimulus to the bound pair of the capture species and the product to debind the product from the capture species. The debinding stimulus is an input which either directly or indirectly causes the product to debind or detach from the capture site, or more specifically the capture species (where present). The debinding stimulus may accordingly be an input which directly acts on the bonds or interaction between the bound pair, such as an electrical input (e.g. current or voltage), light energy, thermal energy. Alternatively or additionally, it may be indirect, for example the stimulus may cause a change in the environmental conditions directly on and adjacent the site (such as a change in temperature or change in pH), which in turn causes the debinding (or “dissociation”).

[0111] The debinding stimulus may be provided by the device. For example, this may be provided by a modification element which may be configured to provide an electrical input (e.g. current or voltage), light energy, thermal energy to a specific site. Alternatively or in addition, it may be a force generated by the device (such as an electric field) which can cause debinding.

[0112] Selective release on different sites may be achieved using different debinding stimuli. For example, a first type of debinding stimuli may be used for a first set comprising at least one capture site and a second, different type of debinding stimuli may be used for a second set comprising at least one capture site. This may allow for more selective release from capture sites. For example, the first debinding stimulus may be one of an application of heat locally, change in pH using the device, using an electric field generated by the device and the second debinding stimulus may be one of the other of an application of heat locally, change in pH using the reactor device, using an electric field generated by the device.

[0113] Prior to applying the debinding stimulus to the bound pair, the method and system may comprise applying a first stimulus to the capture site, the first stimulus having a lower intensity than the debinding stimulus such that it can cause debinding of any non-selectively bound species present on the capture site. It will be appreciated that there can under certain circumstances be non-specific binding between a capture site and another species, or in some cases imperfect binding between a capture species and another species. This binding will be non-specific and results in a weaker interaction between the two components in question. The first stimulus can be selected to remove non-specifically bound components which are then removed before selective release and / or analysis of the specifically bound product. Where the type of stimulus used as the first and as the debinding stimulus is the same, the first stimulus may therefore be less than the debinding stimulus. For example, if the stimulus is application of heat, the first stimulus may raise the temperature to a lower temperature than the debinding stimulus. This may take the form of a continuous increase in the stimulus applied to the capture site(s) in question, for example ramping up from or through the first stimulus and to the debinding stimulus but separately (or only) collecting the species portion released at the debinding stimulus. By “lower intensity” it is meant that the force is lower. Variation of the force may be based on the strength or intensity (e.g. asmeasured by the input voltage (V / m or mV / m)) of the field applied to generate the force, such as the electric field. The strength of the electric field may vary dependent on the species being moved.

[0114] Where an electrical field is used, the species interacting with the field may be a charged species or a species to which a charge can be attached (e.g. temporarily through a change in conditions or with the addition of a tag). Similarly, for the use of a magnetic field, where the species must be moveable in a magnetic field or be provided with a tag or label which can moved within a magnetic field.

[0115] Each capture site may comprise an individually actuatable modification element configured to cause the selectively releasing of the product bound to the capture site. Accordingly, the modification element may be operable to or configured to apply the debinding stimulus and may further be operable or configured to apply the debinding stimulus. The modification element accordingly may be operable (or operated) to cause a debinding of the bound pair. For example, it can be used to apply a stimulus (such as heat or cooling, voltage, current) to the bound pair to cause the debinding.

[0116] Alternatively or additionally, selective release may be selective release of the specific product and the capture species from the sample surface (i.e. the remainder of the capture site).

[0117] The methods and systems may further comprise monitoring the binding and / or selective release. For example, fluorescent or other indicators can be included in the system to detect binding and release events.Recovering

[0118] The methods and systems may recover the product after selective release. Recovering means obtaining the specific product separately to at least one additional component (e.g. product, sample, reagent); in other words, in isolation. Recovering may therefore comprise removing a single, isolated product (single molecule or plural) from the sample surface . This may be so as to purify the product - i.e. remove the product from a mixture with at least one other species, but optionally it may be to isolate the product from any other species (such as other products, reagents, parts of the sample). Where there are plural products, for example, this may be while the other products are either still retained on the sample surface on their respective capture sites or have already been removed from the sample surface. As such, the recovery step may comprise removing the specific product from the sample surface and recovering the product selectively released in a separate solution or vessel, for example.

[0119] Recovering the product may comprise releasing the product into a recovery fluid and removing the recovery fluid and isolated product from the sample surface. For example, this may comprise providing (e.g. flowing) a recovery solution over the sample surface (i.e. the capture site) as the specific product is selectively released or after it is selectively released to remove the specific product from the sample surface. Alternatively or additionally, where there are plural products, recovering the product separately to the other of the products may comprise releasing the product and applying a force to remove the product from the sample surface . For example, this may be achieved through the applicationof an electric field to the surface which can cause the specific product to migrate or move along the sample surface. This is discussed in more detail, below.

[0120] Where the methods and systems involve selectively releasing a product from the sample surface, prior to this there may be a step of removing any unbound species and / or non-selectively bound from the sample surface. Similarly, where the methods and systems involve analysis of a product bound to the site, prior to this step, there may be removal of any unbound species and / or non-selectively bound from the sample surface. Such a removal step removes any potential contaminants from the surface prior to either selective removal or analysis. The unbound species may be other components within the sample provided to the surface or may be products for which there is not a corresponding capture site. It will also be appreciated that, under certain circumstances, non-specific binding between a capture site and another species can occur. Non-specific binding results in a weaker interaction between the capture agent or species and a species the capture agent or species is not intended to bind to. Removal may include application of a first stimulus to remove unbound components and non-specifically bound components before selective release and / or analysis of the specifically bound product. Where the type of stimulus used as the first stimulus is the same as that for debinding, the first stimulus may therefore be less than the debinding stimulus. Accordingly, the methods and systems may comprise, prior to applying the debinding stimulus, applying a first stimulus to the capture site, the first stimulus having a lower intensity than the debinding stimulus such that it can cause debinding of any non-selectively bound species present on the capture site. For example, if the stimulus is application of heat, the first stimulus may raise the temperature to a lower temperature than the debinding stimulus. This may take the form of a continuous increase in the stimulus applied to the capture site(s) in question, for example ramping up from or through the first stimulus and to the debinding stimulus but separately (or only) collecting the product released at the debinding stimulus. The first stimulus may be an electric field.Analysis

[0121] The method of the second aspect and system of the fourth aspect include analysing the product, and this may optionally be present in the first aspect and third aspect. The analysis may be to determine a property of the product. For example, the property may be an intrinsic property of the product, such as the structure, melting point, etc. In particular, this may be analysis of the structure of the product, for example. In another embodiment, the property may be an extrinsic (or relational) property. In some embodiments, the property may be a concentration of the product on the capture site, or on the product surface. For example, this may be determination of a number of the individual product molecules or entities on the capture site.

[0122] This analysis may be a structural analysis for determining the structure of the product. The methods may therefore further comprise determining the structure of the product and the analytical instrument of the systems, where present, may be configured to determine the structure of the product. Exemplary techniques for determining the structure of the product include nuclear magnetic resonance(NMR) spectroscopy, mass spectrometry (MS) (e.g. electrospray ionization (ESI), matrix-assisted laser desorption / ionization (MALDI), or electron ionization (El)); infrared (IR) spectroscopy (e.g. Fourier transform infrared (FTIR) spectroscopy); chromatography (e.g. high-performance liquid chromatography (HPLC) or gas chromatography (GC), which can be carried out in combination with MS (e.g. HPLC-MS, HPLC-MS-MS or GC-MS); and X-ray crystallography. These techniques may be used individually or in combination to establish the structure.

[0123] The methods and systems may further comprise analysing the product bound on the capture sites. In other words, the methods can comprise analysing the product while the product is retained on the capture site. This allows for individual analysis directly on the sample surface. Further, by analysing on the surface without or before release, this reduces the potential losses of sample caused by transfer and, therefore, increases the amount of sample available for analysis. These analysis techniques may include solid-state or thin film analysis techniques, where any solution may be evaporated leaving behind bound product on the surface. Accordingly, in some embodiments, the capture site may be heated so as to evaporate any solvents present prior to analysis. This may be using the modification element, for example.

[0124] Exemplary techniques which can be used when the product are bound to a capture site include many of the abovementioned techniques but may specifically be a spectroscopy analysis. For example, MALDI-MS (this may optionally include time-of-flight (TOF) or tandem MS); secondary ion mass spectrometry (SIMS); infrared (IR) or Raman spectroscopy; and X-ray photoelectron spectroscopy (XPS) or energy-dispersive X-ray spectroscopy (EDX).

[0125] The methods may further comprise sensing a property to determine the presence of a product on at least one capture site. Alternatively or additionally, the methods may further comprise sensing a property to determine the presence of the part of a sample on the reactor site. This may be sensing a property of the respective capture / reactor site to determine the presence of the respective sample / product.

[0126] A sensing element can accordingly be used to monitor the capture site and / or the reactor site(s), for example in the systems. This may be one sensing element on each site, for example. The sensing element may be provided on or beneath the respective reactor / capture site within the substrate, for example. The sensing element may be an optical sensing element, thermal sensing element, pH sensing element, ion sensing element, conductivity sensing element, fluorescence sensing element or a sensing element configured to detect a chemical property. Electrochemical sensors such as amperometric, potentiometric or conductometric sensors may also be employed. This can then be used to provide information on a state of a reactor / capture site. The method may further comprise performing additional steps based on this determination, such as the selective release of the product from the capture site in question or the initiation of the stimulus. The control units of the systems may be configured for this purpose.

[0127] The sensing element (or “sensing device”) may provide a measurement signal indicative of the property and therefore may be addressable to provide the measurement signal. For example, the sensing element may comprise an electrode, which electrode may be addressable to provide the measurement signal. In some embodiments, there may be plural electrodes. Where there are plural electrodes, each may be individually addressable. A sensing layer (e.g. a dielectric layer) may also be provided on or adjacent the electrode to enhance or enable the response of the electrode to a particular component or analyte. In other embodiments, the sensing element may comprise a layer or structure through which current is passed (for example, where the sensing element comprises is a resistive layer or structure located between first and second electrodes). In some embodiments, a portion of the substrate defining the sample surface and / or a portion of the medium may define the sensing layer or structure between electrodes and the sensing element may comprise a pair of electrodes arranged to interrogate the portion of substrate and / or medium such that the product or part of the sample or a component in this particular region can be interrogated.

[0128] The method may further comprise retaining the product on the sample surface in the product region and analysing the product while retained on the sample surface.

[0129] The method may further comprise sensing at least one of: a property on the reactor site indicative of the progression of the conversion of the sample to the product; or a property of the product on the sample surface. The control unit of the systems may be configured to carry out this. This provides realtime monitoring of the conversion, which can allow for more precise control over reaction conditions and product formation. This may in turn improve efficiency and subsequent recovery. This property may depend on the conversion. For example, it may be monitoring the product directly (i.e. an increase in the presence / concentration of), the sample directly (i.e. a reduction in the presence / concentration of) or these indirectly (such as changes in conductivity, pH, temperature, for example).

[0130] Where there are a plurality of reactor sites, the method may comprise sensing a property on each reactor site indicative of the progression of the conversion of the sample to the product. For example, the reactor device may be operable to sense or analyse at least one of (i) each part of the sample on each reactor site during the application of the stimulus; and (ii) the product on the sample surface. Sensing the property of the at least one product on the sample surface may include analysing the product(s) during the application of the stimulus - i.e. during conversion. Alternatively or additionally, sensing the property of the at least one product may be after the application of the stimulus and the subsequent conversion. Accordingly, the methods may track the progression of the process by analysing the sample or analysing the product, or both. Where there are a plurality of reactor sites, the reactor device may be operable to analyse each part of the sample on each reactor site during the application of the stimulus. Accordingly, where there are a plurality of reactor sites, each reactor site may comprise a sensing element configured to sense or analyse at least one of (i) each part of the sample on each reactor site during the application of the stimulus; and (ii) the product on the sample surface.

[0131] In some embodiments, it will be appreciated that a single element may be operable to perform the same function of the sensing element and the modification element. For example, an electrode may be operable to provide the measurement signal and provide the stimulus. Accordingly, in some embodiments the modification element may be a sensing element.

[0132] The methods may comprise determining a concentration and / or a copy number of a component. The system may be configured to determine a concentration and / or a copy number of a component. This may be achieved by providing a plurality of different concentrations (e.g. dilutions) of at least a part of the sample, with each concentration being provided to a separate pathway (for example from other pathways); moving or causing the components to each move along their respective pathway to a sensing point (e.g. a sensing element) and determining the concentration and / or copy number.Substrate and Medium

[0133] The system and method comprise a substrate defining the sample surface. The substrate may be a planar surface or a non-planar surface. For example, the substrate may comprise multiple substrate portions, where the substrate portions are in different planes. For example, these may be angled with respect to each other or in opposing relationship (such that medium is provided therebetween). Each substrate portion may be planar. Where present, the substrate portions may abut one another or may be separated by joined by a liquid or gel medium.

[0134] The substrate may be formed from or by a layer or, where there are plural substrate portions, may be formed of or by a plurality of layers or sections forming the surface, for example.

[0135] Medium may be provided onto or over the sample surface but may further extend into the substrate, in some embodiments, and / or beyond the sample surface. The substrate may be formed of or comprise any suitable material. For example, it may be a polymer layer, a glass layer, a glass-ceramic layer, a ceramic layer, a metal oxide layer, a metal nitride layer, a silicon -containing layer (e.g. silicon, silicon dioxide, or silicon nitride), a gallium -containing layer (e.g. gallium nitride or gallium arsenide) or combinations thereof.

[0136] The substrate may comprise at least one opening provided at the sample surface, wherein migration may be through the opening. As such, the method may further comprise providing a substrate defining the sample surface, the substrate comprising an opening provided therein at the sample surface, and migration of the product is so as to cause movement of the product through the opening. The opening may be provided by or communicate with a well, channel or through hole. Where a closed recess is formed (e.g. a well or channel), the product may be provided to the base of the recess. There may be a plurality of openings, with the force(s) being used to provide the product to each opening or different products to each opening. The openings may be openings of channels, wells or through holes formed in the substrate and optionally further layers provided below or adjacent the substrate. Accordingly, the substrate may comprise at least one channel, well or through hole. The presence of openings in the substrate or a portion thereof provides significant additional functionality. The openingsenable transfer of products into an enclosed or separate region, where further analysis or storage can occur. For example, products can be collected in wells or channels formed in the substrate so as to concentrate them. This can be useful where there are numerous samples or aliquots of samples from which the same product can be converted from each and then recombined in a well or a device positioned below a through hole.

[0137] Openings through a substrate, such as a well, channel or through hole, have been found to be particularly useful for sensing. Specifically, the system may further comprise sensing a property of a component of the sample within the well, channel or through hole. For example, a sensing element (as set out above) may be formed next to, around or within the well, channel or through hole. For example, there may be an electrode at least partially surrounding this or a pair of electrodes positions either side of the well, channel or through hole. Sensing elements using electrodes in this way have been found to provide a particularly useful tool for determining a property of a product, since the relative position of the analyte within or around the structures can have a significant effect on the properties and, hence, the signal from the sensing element. The measurement signal can be indicative of an impedimetric property (e.g. dielectric property (e.g. permittivity), resistance, capacitance, impedance, conductance, or a combination thereof) of the substrate and a component received between or within the well, channel or through hole modifies the impedimetric property. That is, it measures an impedimetric property, which in one embodiment is based on the permittivity of the sensing layer. This can function by the sensing layer having a first impedimetric property (e.g. permittivity) when in the presence of no sample (defined by the sensing layer and any fluid (e.g. a buffer or air) between the structures) and then receipt of the analyte between or within the structures can have significant impact on the impedimetric property (e.g. permittivity). Through holes are advantageous as these do not have a truncated structure and therefore the signal can be monitored as it passes through the through hole. Moreover, this can advantageously be used to provide an outlet for removal of products therethrough. Control of the interaction of products or components through the openings can lead to generation of a product or component-specific signal. Each product or component will interact differently with the surface and / or opening such that continuous measurement during the interaction and / or differential measurement can lead to a fingerprint signal specific to that product or component.

[0138] The openings may have a maximum diameter of from 1 nm to 500 pm. For sensing individual species (such as molecules), this may be from Inm to 2 pm such as from 1 nm to 1000 nm, or 10 nm to 100 nm. A through hole, well or channel defining the opening may also have a maximum diameter of from 1 nm to 2 pm, such as from 1 nm to 1000 nm, or 10 nm to 100 nm. The diameter of the opening may be the same as the corresponding through hole, channel or well. In other cases (including sensing) the dimensions may be larger, such as from 0.5 pm to 500 pm, or 5 pm to 200 pm, for example where the sample comprises cells.

[0139] In some embodiments, the depth of the well, channel or through hole may be less than or equal to 10 pm, for example less than or equal to 5 pm, for example less than or equal to 2pm, less than orequal to 800 nm, or less than or equal to 500 nm. In one embodiment, the wells, channels or through holes have a depth of from 10 nm to 10 pm. This may be 10 nm to 5 pm, such as 10 nm to 2 pm, 10 nm to 1000, 10 nm to 500 nm, 50 nm to 1000 nm, 50 nm to 800, 50 nm to 500 nm, 100 nm to 1000 nm, 100 nm to 800, or 100 nm to 500 nm. Exemplary combinations include a maximum diameter of 1 nm to 2 pm and a depth of 10 nm to 10 pm, such as 100 nm to 1000 nm maximum diameter and 10 nm to 2 pm depth. In one embodiment, the depth of the recesses or through holes is from 0.15 pm to 1 pm. The through holes or opening may be provided with or comprise a mesh or nanoporous structure, which can act as a further interrogator of the sample and / or a fdter where the through hole can be used to further separate the sample.

[0140] The system and method may further comprise a medium provided at (e.g. on) the sample surface. The medium may be or comprise any matter through which a sample can move. This may be a fluid medium, such as a gas (e.g. air), liquid or gel medium. Example gels include silica, alumina, cellulose, agarose or polyacrylamide gels. For example, an immoniline drystrip gel (“IPG gel”), an isoelectric focus gel (“IEF gel”), a polyacrylamide gel (polyacrylamide electrophoresis (“PAGE”)) and a silica gel. Other examples of media include size exclusion gels, affinity (modified) matrices, activated charcoal, native gels, and sample -dependent media. A liquid medium may be a liquid buffers or solvents. The medium may contain additives in some cases to enhance separation, such as detergents, denaturants, or specific binding molecules. In certain aspects, the medium may have a property gradient, such as a pH or ionic strength gradient, to facilitate separation based on properties such as isoelectric points or charge. It will be appreciated that the medium may be provided together with the sample.

[0141] The above mentioned conversions and manipulations take place on the surface and may be in a medium. Accordingly, application of the force may be so as to cause the species in question to move through medium, for example, along a pathway. Influencing the migration may be caused by a direct interaction with the sample, for example by creating an attractive force or slowing which slows down migration or by retaining the sample on the modification element, or it may be achieved by modifying the environment of the medium, which in turn may change how the sample or a part thereof moves through the medium. These modifications can have significant effects on the migration patterns of the sample components, allowing for more effective separation based on their physical and chemical properties. For example, it can modify how at least one component of the sample interacts with the medium or the force applied. For example, a change in pH may cause a change in charge of at least one of the components, and in turn this may modify how an electrical field interacts with the component, changing the way it migrates through the medium.

[0142] The medium may advantageously comprise different regions. For example, the medium may comprise a first medium portion having a first medium property and through which at least a portion of the first pathway extends; and a second medium portion having a second medium property and through which at least a portion of the second pathway extends, wherein the first and second medium properties are different. By different it is meant that the medium regions have a different properties which havedifferent interactions with a component or sample. For example, the medium may have regions with different physical states (e.g. at least one gel region and at least one liquid region or regions having different viscosities (whether gel or liquid)) or different compositions (base composition of the medium and / or different concentrations of specific functional components). This configuration allows for the creation of zones with different properties along the pathways, which can be used to separate components (such as products or parts of the sample) based on their responses to these properties. The medium regions may correspond to various other components disclosed herein. For example, the second medium region may correspond to an individually controllable region. Alternatively or additionally, a different medium region may be provided above a sensing element and / or one of the openings in the substrate, where present. In another example, this may include particles within the medium, such as beads, which influence migration and enhance separation. In another example, there may be nano or microstructured surfaces (e.g. this may be the sample surface) to interact with the sample and influence migration or the sample surface may be provided with a particular solid phase which interacts with the product or other component (e.g. part of the sample).

[0143] The medium and the product or sample may be immiscible. Where this is the case, the product or sample (and components thereof) may be manipulated using an electrowetting technique. Where the product or part of the sample is aqueous or provided within an aqueous matrix, the substrate may be hydrophobic such that the aqueous part can be manipulated through the medium on the surface. Such methods and systems may further use a modification element to control the immiscible product or part of the sample, such as modifying temperature and / or pH.Electrodes

[0144] Numerous embodiments of the systems and method disclosed herein employ electrodes of various types, including for generating fields and as modification elements. These electrodes may each be formed from or comprise gold, silver, copper, platinum, nickel, titanium, titanium nitride, ruthenium, a conducting polymer, a conductive carbon -based material (e.g. graphene) or combinations thereof. It will be appreciated that where an electrode is used, this may be a part of any suitable electrical circuit or system. For example, the electrode may be a working electrode and there may be a counter electrode provided in electrical connection with the working element, and there may further be a reference electrode (or pseudo reference electrode) provided as part of this electrical system. Where there are pairs of electrodes, these can act as working and counter electrodes.Method and System

[0145] The systems may be configured to perform any of the method steps disclosed herein. Moreover, any of the embodiments set out herein with respect to the methods apply equally to the systems, and any of the embodiments set out herein with respect to the systems apply equally to the methods.System

[0146] The system comprises a processing unit or control unit. The control unit may be or comprise a processor or controller. The control unit may be implemented in any suitable manner, with software and / or hardware, to perform the various functions required. One or all of the units may, for example, employ one or more microprocessors programmed using software (for example, microcode) to perform the required functions. It will be understood that the control unit may be or run on a single controller or processor or may be distributed over several computers and locations (e.g. connected via internet), such as a cloud -based computing infrastructure. Examples of processor components that may be employed in various embodiments include, but are not limited to, conventional microprocessors (e.g. a central processing unit (CPU), a digital signal processor (DSP)), application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs). The control unit may include, but is not limited to, PCs, workstations, laptops, PDAs, palm devices, servers, storages, and the like. Generally, in terms of hardware architecture, the control unit may include one or more processors, memory and one or more I / O devices that are communicatively coupled via an interface. In various implementations, the control unit may be associated with one or more non-transitory storage media such as volatile and non-volatile computer memory including any one or combination of volatile memory elements (e.g., random access memory (RAM), such as dynamic random access memory (DRAM), static random access memory (SRAM), etc.) and non-volatile memory elements (e.g., ROM, erasable programmable read only memory (EPROM), electronically erasable programmable read only memory (EEPROM), programmable read only memory (PROM), tape, compact disc read only memory (CD-ROM), disk, diskette, cartridge, cassette or the like, etc.). The memory can have a distributed architecture, where various components are situated remote from one another, but can be accessed by the control unit. The non-transitory storage media may be encoded with one or more programs that, when executed on one or more processors and / or controllers, perform the required functions. Various storage media may be fixed within a processor or controller or may be transportable, such that the one or more programs stored thereon can be loaded into the control unit.

[0147] In some non-limiting examples, the system includes a user interface, such as a display. Alternatively or additionally, the system may include a communications interface device, such as a wireless transmitter, configured to transmit data, such as the property determined by the property determination unit, to an external device, such as a personal computer, tablet, smartphone, remote server, etc.

[0148] Data between parts of the system (such as processors) or with external components may be via communications interfaces. The interfaces may communicate via a physical connection / transceiver.

[0149] Additionally, or alternatively, the communication interfaces may each comprise a wireless transmitter. Put another way, the communication interface and host controller may communicate via a non-physical connection. For example, this may be via a radio, RFID, NFC, Bluetooth, or Wi-Fi connection. Additionally, the transfer of data may be bi-directional, in that the wireless transmitted mayalso receive data from the host controller (e.g., the instruction as described above). Data transmitted between the system component and / or with external devices may be encrypted. The control unit may be configured to process the signals or data to generate an encrypted signal. The communication interface may then be configured to transmit the encrypted signal.

[0150] The control unit may be configured to analyse the signals and / or data using a machine learning algorithm trained to receive this data and output processed data based on the received data. For example, it may reive a measurement signal or the data derived therefrom. That is, the control unit provides the signal and / or data to a machine learning algorithm. The machine learning algorithm may be trained to process the signal to generate a value indicative of the property of the component being analysed.

[0151] The analysis of the signals and / or data may include a pattern recognition module configured to determine whether the signal and / or data (which may be processed data) corresponds to a predetermined or library signal or data. Accordingly, a signal and / or data can be matched with a known signal and / or data to identify a particular sample, component and / or sub-component.

[0152] Methods of training a machine -learning algorithm are well known. Typically, such methods comprise obtaining a training dataset, comprising training input data entries and corresponding training output data entries. An initialized machine -learning algorithm is applied to each input data entry to generate predicted output data entries. An error between the predicted output data entries and corresponding training output data entries is used to modify the machine -learning algorithm. This process can be repeated until the error converges, and the predicted output data entries are sufficiently similar (e.g. ±1%) to the training output data entries. This is commonly known as a supervised learning technique. Accordingly, the machine learning algorithm may be trained using a set of measurement signals and / or data. This training data may be specific to the type of component such that the machine learning algorithm is tuned to produce component data based on measurement signals and data for a specific sample, component or sub-component. Alternatively, the machine learning algorithm may be trained using training data for a variety of different samples, components or sub -component, such that the machine learning algorithm is capable of producing data for a variety of components.

[0153] In one aspect, there is provided a computer program comprising computer program code which is configured, when said computer program is run on one or more physical computing devices, to cause said one or more physical computing devices to implement the methods disclosed herein.

[0154] In one aspect, there is provided one or more non -transitory computer readable media having a computer program stored thereon, the computer program comprising computer program code which is configured, when said computer program is run on one or more physical computing devices, to cause said one or more physical computing devices to implement the methods disclosed herein.

[0155] In one embodiment, the system may further comprise a signal processing unit configured to process signals received relating to measurements, for example from the sensing elements and electrodes set out herein. A property determination unit may receive processed signals and determinedthe property based on the processed signals. The property determination unit may, in certain embodiments, be configured to determine the property based on (at least) the absolute change in measurement signal and / or the rate of change of the signals. The control unit may incorporate the property determination unit and / or the signal processing unit or may be in addition to one or both of these. The property unit and / or signal processing unit may each have the form of a processor or controller as set out above for the control unit.

[0156] It will be appreciated that the system as set out herein could in some embodiments be used as a stand-alone module. Alternatively or additionally, it can be integrated into another system, such as an analytical instrument. One example would be as a sample preparation module for HPLC prior to provision to the column, whereby the forces and selective release are used to provide the product to the HPLC.Specific implementations

[0157] Fig. 1 depicts a first method 100 of producing and processing a product 102 from a sample 101. Figs. 2A to 2C provides a schematic depiction of a system 104 and exemplary reactor device 150 for use in the method 100.

[0158] The method comprises providing 105 a system 104 which comprises a reactor device 150 (e.g. a chip) and a control unit 199. The reactor device 150 is for converting samples to products and processing the product(s). The control unit 199 is operatively connected to the reactor device 150 and is configured to operate the reactor device 150, including controlling the conversion and sample and product movement and manipulation.

[0159] The reactor device 150 comprises a substrate 155 on which the various components are arranged and which in part defines a sample surface 156 on which medium 157 is provided.

[0160] The reactor device 150 comprises a reactor site 164 provided on one side of the substrate 155 and forming a part of the sample surface 156. The reactor site 164 comprises and is defined by a modification element 160 provided in the substrate 155 and having an upper surface co-planar with the substrate 155, which in this embodiment can take the form of an electrode configured to provide an electrical stimulus to the reactor site 164 and, therefore, any sample 101 received thereon.

[0161] The system 104 further comprises a retention device for retaining a sample on the reactor site 164. The retention device comprises a set of electrodes comprising a first and a second field electrode 194A, 194B. The first field electrode 194A is located above the medium 157 and directly above the reactor site 164 and the second field electrode 194B is electrically connected to the first field electrode 194A and located below the substrate 155 directly below the reactor site 164. The first and second field electrode 194A, 194B can be used to generate an electric field therebetween which will cause charged species within a sample to migrate in the z-axis between the first and second field electrodes 194A, 195B. Given the location of the first and second field electrodes 194A, 195B, this can be used to drivea sample 101 or a part thereof to the reactor site 164 and can further be used to retain charged species within a sample 101 on the reactor site 164.

[0162] The reactor device 150 also comprises includes a first manipulation assembly comprising a plurality of field electrodes 191A-C located across the length ofthe substrate 155. A first field electrode 191A is located on one side of the substrate 155 (adjacent the outside edge of the reactor site 164) defining one end of a pathway and a third field electrode 191C is located on the other side of the substrate 155 and defines the other end of the first pathway. Each of the field electrodes 191A-C have a separate contact control point and can be connected in various combinations to operate with another one of the field electrodes 191A-C. For example, the first and third field electrodes 191 A, 191C can be used to generate an electric field across the first pathway so that a product 102 can be migrated across the length of the first pathway.

[0163] The intermediate (i.e. second) field electrode 19 IB is located between the first and third field electrodes 191 A, 191C to provide the first pathway with multiple individually controllable regions. That is, the second field electrode 19 IB can form an electric field with one ofthe first or third field electrodes 191 A, 191C thereby creating a smaller electric field which only extends across a part of the first pathway. These individually controllable regions accordingly allow for selective application of local electric field to influence or cause migration of the product within specific areas of the first pathway.

[0164] The reactor device 150 also comprises a recess 168 provided in the substrate 155 along the first pathway at the opposite end to the reactor device. The recess 168 extends from an opening in the sample surface 156 to a base. The recess 168 is arranged along the first pathway at a position where the product 102 can be migrated. Where a separation occurs, this may be a distance sufficient such that migration through the medium 157 separates the product 102 from at least one additional component. Depending on the specific implementation, medium 157 may extend into the recess 168 (this can be the same type of medium 157 as that provided on the sample surface 156 or there may be a different type, forming a second medium region) or there may be no medium in the recess 168. The use of the recess 168 is set out in more detail, below. In this embodiment, the recess 168 delimits a product region 167 in the medium above the opening.

[0165] The reactor device 150 also includes a further, second manipulation assembly defining a second pathway (visible in FIG. 2C). This comprises a set of electrodes comprising a third and a fourth field electrode 194C, 194D. The third first field electrode 194C located above the medium 157 and directly above the recess 168 and the fourth field electrode 194D is electrically connected or connectable to the third field electrode 194C and is located below the substrate 155 directly below the recess 168. This defines the second pathway and generation of an electric field between the third and fourth field electrodes 194C-D of the second manipulation assembly causes charged product to migrate in the z- axis between the third and fourth field electrodes 194C-D. Given the location of the third and fourth field electrodes 194C-D and the recess 168, this can be used to drive a product (as shown by the arrow in FIG. 2C) along this particular second pathway from part of the medium 157 located above the recess168 into the recess 168 through the corresponding opening. Accordingly, the arrangement of the second pathway and the recess 168 enables multi-dimensional movement (and optionally separation) of a mixture to purify or isolate a product 102. The product 102 can also be collected within a specific product region 167.

[0166] The reactor device 150 also comprises a sensing element in the form of an electrode 163 located in the substrate 155 and which surrounds the base of the recess 168. Corresponding counter electrodes (not shown) and reference electrodes (not shown) may be present in the system 104. The electrode 163 can interrogate product 102 received in the recess 168 to provide a measurement signal. This can be used to determine when product 102 is present or a property of the product 102. It will be appreciated that other sensing elements or systems could be used.

[0167] The method 100 further comprises providing 110 a sample 101 to the sample surface 156 and retaining at least a part of the sample 101 on the reactor site 164. This is depicted in Fig. 2B, where sample 101 is provide on top of the reactor site 164. Retaining the sample 101 is achieved using the first and second field electrodes 194A, 194B (omitted from Fig. 2B for the sake of clarity) which hold the charged species of the sample 101 on the reactor site 164.

[0168] The method 100 further comprises applying a stimulus 115 to the at least a part of the sample on the reactor site 165 using the modification element 160 so as to cause a conversion of the at least a part of the sample 101 to a product 102. In the reactor device 150, this is achieved by applying an electrical stimulus using the modification element 160 to cause a conversion.

[0169] After or during the application of the stimulus 115, the method 100 further comprises applying a force 120 to the product 102 so as to migrate the product 102 from the reactor site 164 relative to the sample surface 156. In this embodiment, migrating the product 102 relative to the sample surface 156 is so as to collect the product 102 in the product region 167 on the sample surface 156. This allows the product 102 to be collected in this distinct region of the reactor device 150. The movement is achieved in this embodiment using the first manipulation assembly.

[0170] In this embodiments, this enables the product 102 to be moved off the sample surface 156 by collecting it in the recess 168 provided in the substrate 155. Alignment of the product 102 with the recess 168 may be controlled by the fine control provided by the individually controllable region between the second and third field electrodes 191B, 191C of the first manipulation assembly. Further, movement into the recess 168 is controlled by the third and fourth field electrodes 194C-D of the second manipulation assembly, as set out above. The use of the product region 167 and the recess 168 provides improved handling and analysis by providing a region in which the product 102 be collected. This can provide for improved direct analysis, since there is less likely to be interference when performing measurements in the recess 168 from other components, the medium 157 or the environment around the reactor device 150. Product 102 collected in the recess may be extracted from the system 104 for further processing or characterization. The product 102 can, for example, be concentrated by collection in the product region 167 and / or the recess 168.

[0171] Fig. 3 depicts another method 200 producing and processing a product 202 from a sample 201 . Figs. 4A to 4C provides a schematic depiction of a system 204 and exemplary reactor device 250 for use in the method 200.

[0172] The method comprises providing 205 a system 204 which comprises a reactor device 250 (e.g. a chip) and a control unit 299. The reactor device 250 is for converting samples to products and processing the product(s). The control unit 299 is operatively connected to the reactor device 250 and is configured to operate the reactor device 250, including controlling the conversion and sample and product movement and manipulation.

[0173] The reactor device 250 comprises a substrate 255 on which the various components are arranged and which in part defines a sample surface 256 on which medium 257 is provided.

[0174] As with the reactor device 150 of Figs. 2A-C, the reactor device 250 comprises a reactor site 264 provided on one side of the substrate 255 and forming a part of the sample surface 256. The reactor site 264 comprises and is defined by a modification element 260 provided in the substrate 255 and having an upper surface co-planar with the substrate 255, which in this embodiment can take the form of a thermal device configured to provide thermal stimulus to the reactor site 264 and, therefore, any sample 201 received thereon.

[0175] The reactor device 250 of this embodiment differs to the reactor device 150 of Figs. 2A-C in that it uses a different method for retaining the sample 201 on the reactor site 264. In this embodiment, the reactor site 264 comprises a capture species 261 functionalised on the surface of the modification element 260, where the capture species 261 is configured to specifically bind to the part of the sample 101 for which conversion is to be carried out. As such, provision of the sample 101 to the sample surface 156 will lead to specific binding of the sample 101 (or the desired part of the sample 101 ) to the reactor site 164. Any other species (e.g. in the sample 101) can be removed from the sample surface 156 (e.g. by washing).

[0176] The reactor device 250 also comprises includes a first manipulation assembly comprising a plurality of field electrodes 291A-D located across the length ofthe substrate 155. A first field electrode 291 A is located on one side of the substrate 255 (adjacent the outside edge of the rector site 264) defining one end of a pathway and a fourth field electrode 29 ID is located on the other side of the substrate 255 and defines the other end of the first pathway. Each of the field electrodes 291A-D have a separate contact control point and can be connected in various combinations to operate with another one of the field electrodes 291A-D. For example, the first and fourth field electrodes 291 A, 29 ID can be used to generate an electric field across a first pathway so that a product 202 can be migrated across the length of the first pathway.

[0177] The intermediate (i.e. second and third) field electrodes 291B, 291C located between the first and fourth field electrodes 291 A, 29 ID provide the first pathway with multiple individually controllable regions. Each of the second and third field electrodes 291B, 291C can either form an electric field with one ofthe first or fourth field electrodes 291 A, 29 IE or with the other intermediate (i.e. second or third)field electrode 291B, 291C thereby creating a smaller electric field which only extends across a part of the first pathway. These individually controllable regions accordingly allow for selective application of local electric field to influence or cause migration of sample portions within specific areas of the first pathway 2.

[0178] The reactor device 250 also comprises two sensing elements 263A, 263B arranged along the first pathway and provided within the substrate 255, with the surface of each of the sensing elements 263 A-B further defining the sample surface 256. Specifically, a first sensing element 263 A is provided between the second and third field electrodes 29 IB, 291C of the first manipulation assembly and the second sensing element 263B is provided the third and fourth field electrodes 291C, 291D of the first manipulation assembly. The sensing elements 262A-B are each an electrode configured to generate a measurement signal indicative of the amount (e.g. concentration) of a species on the electrode. Each sensing element 263A-B is individually addressable so that it can provide an individual signal to the control unit 299. In this way, properties of the product 202 or other species 203 can be detected as they move through the medium along the first pathway. The measurement signals generated by the sensing element 263 A-B are provided to the control unit 299 which can determine a property of the product 202 or other components 203. As set out above, this data can be used to monitor the progression of the separations / manipulations or to analyse the product 202 and / or other components 203. The location of the sensing elements 263A, 263B is such that separation of a mixture generated during a conversion can lead to the product 202 being provided on the second sensing element 263B and also a further component 203 of interest on the first sensing element 263 A (see Fig. 4C). This may be another product, for example. The sensing of the product 202 or the other component 203 may be used to determine when to stop applying the force using the first manipulation assembly. The region of medium 157 above the second sensing element 263B is a product region 267.

[0179] The method 200 further comprises providing 210 a sample 201 to the sample surface 256 and retaining at least a part of the sample 201 on the reactor site 264, which in this case is a part of the sample 201 which selectively binds to the capture species 261.

[0180] The method 200 further comprises applying a stimulus 215 to the at least a part of the sample on the reactor site 265 using the modification element 260 so as to cause a conversion of the at least a part of the sample 201 to a product 202. In the reactor device 250, this is achieved by applying heat using the modification element 260 to cause a conversion.

[0181] After or during the application of the stimulus 215, the method 200 further comprises applying a force 225 to the product 202 so as to migrate the product 2from the reactor site 264 relative to the sample surface 256, the migration of the product 202 relative to the sample surface 256 separating the product 202 from other components 203 on the reactor site 264. This allows the product 202 to be purified and collected in the product region 267 of the reactor device 250. The movement is achieved in this embodiment using the first manipulation assembly.

[0182] Fig. 5 depicts a method 300 of producing and analysing a product, which may be achieved using a system (not shown). Figs. 6A to 6D provide a schematic depiction of an exemplary reactor device 350 for use in the system and the method 300. Specifically, an exemplary reactor device 350 is depicted in Figs. 6A (schematic plan view) and 6B to 6E (schematic cross-sections through line A-A of Fig. 6A).

[0183] The method 300 comprises providing 330 a reactor device 350. The reactor device 350 depicted in Figs. 6A-6D comprises a substrate 355 and a plurality of capture sites 365A-C arranged in a grid - in this embodiment a 3 x 3 grid (where only the left hand column is labelled for clarity). Each capture site 365A-C comprises a circular sensing element 360A-C (in the form of an electrode) embedded in the substrate 355. Each of the sensing elements 360A-C is individually addressable so that a measurement signal can be obtained for each capture site 365A-C. Each sensing element 360A-C and is functionalised with a capture species 361A-C specific to a species which may be within the mixture on the sample surface, which in one embodiment may one of a plurality of products 302A-C which may form within the sample. For example, this may be used as a diagnostic tool or an identification tool for identifying which species is present in an unknown sample 302.

[0184] Accordingly, each of the sensing elements 360A-C and capture species 361A-C defines a capture site 365A-C for a corresponding product 302A-C. In particular and as schematically depicted in Fig. 6B, a first capture site 365A comprises a first capture species 361 A functionalised on the surface of a first sensing element 360A, the first capture species 361 A having a structure which is complimentary to (i.e. will specifically bind to) to the first product 302A. Similarly, a second capture site 365B comprises a second capture species 36 IB functionalised on a second sensing element 360B having a structure which is complimentary to (i.e. will specifically bind to) to the second one of the product 10 IB. A third capture site 165C comprises a third capture species 161C functionalised on a third sensing element 160C having sequence which is complimentary to (i.e. will specifically bind to) to the third product 101C.

[0185] In the embodiment, each capture site 365A-C further comprises a corresponding modification element 362A-C in the form of a heater formed in the substrate 355 and located directly beneath the corresponding sensing element 360A-C (visible in dashed lines in Fig. 6A and through the cross-section of Fig. 6B). Each of the modification elements 362A-C is individually actuatable. The modification elements 362A-C can be used to locally heat the region on and above each corresponding capture site 365A-C (e.g. the medium adjacent and on the corresponding capture site 365A-C). This can be used for a number of reasons, including first increasing the temperature of the solution around the capture sites 365A-C to promote binding of the specific product 302A-C. Binding kinetics can be improved when the temperature is raised above standard conditions (e.g. to a temperature of from 25 °C to 37 °C). It can also be further be used for selective release of any bound species, as set out below. Due to the individual actuation of the modification elements 362A-C and the local nature of each capture site 365A-C, the temperature on each capture site 365A-C can be different which can be particularly useful for selective release of the bound product 302A-C, as set out below.

[0186] Although not depicted, each of the sensing elements 360A-C and the plurality of modification elements 362A-C are electrically connected to a control unit (not shown) so that they can be operated under the control of the control unit.

[0187] The method 300 further comprises providing 335 a sample to the sample surface 356.

[0188] The method 300 further comprises applying a stimulus 340 to at least a part of the sample on the sample surface 356 as to cause a conversion of the at least a part of the sample to a product, in this embodiment, a plurality of products 302A-C. In this embodiment, this may be achieved by using the modification elements 362A-C of each capture site 365A-C, such that this provides heating (i.e. the stimulus) across the whole sample surface 356. Alternatively, there may be a further modification element (not shown) provided. The plurality of products 302A-C may be formed because they are derived from different species in the sample (i.e. different parts of the sample) or because the conversion leads to plural products 302A-C.

[0189] The method 300 further comprises selectively binding 345 the product 302A-C to the capture site 365 A-C so as to retain the product 302A-C thereon. In this case, it comprises binding each of the products 302A-C to a respective capture site 365A-C. This process is depicted in Figs. 6B and 6C, where Fig. 6C shows the products 302A-C and capture species 361A-C bound as a bound pair on each capture site 365 A-C. It will be appreciated that this will also have occurred for all of the other capture sites on the reactor device 350 (see Fig. 6A), where each of the other captures sites have captures species which correspond to the other products. As shown in Fig. 6C, before the subsequent steps, the solution over the sample surface 356 may be free of any other species so as to not contaminate any subsequent recovery. This may be achieved by any method, such as flowing a solution over the sample surface 356 to remove any unbound species or applying a force to the unbound species to remove them from the sample surface 356.

[0190] Accordingly, using the reactor device 350, the 302A-C can be separated from one another and from any other species and individually bound to different parts of the sample surface 356. This provides an effective method of capturing the products 302A-C in isolation, regardless of the complexity of the mixture. The method is accordingly efficient and straightforward and can be scaled up by simply adding more capture sites 365A-165C where more products are to be isolated.

[0191] The system further includes an analytical instrument (not show) which is configured to perform an analysis on a product 302A-C of the conversion.

[0192] The method further comprises selectively releasing 346 the product 302A-C - i.e. one of the 302A-C from the corresponding capture site 365A-C - and recovering 347 and removing the specific product 302-AC separately to the other of the plurality of products 302A-C. As depicted in Fig. 6D, this comprises releasing one of the products 302A-C - in Fig. 6D, the third product 302C - from the respective capture site 365 A-C - in Fig. 6D, the third capture site 365C - while still retaining the other products 302A-B on their respective capture sites 365A-B. This provides a solution above the sample surface 356 in which only the third product 302C is present and which can then be removed from thesample surface 356 in isolation to the other products 302A-B. In this embodiment, the selective release 320 is achieved using the modification element 362A-C forming a part of the corresponding capture site 365A-C. In particular, in the release of the third product 302C, the modification element 362C associated with the third capture site 365C can be actuated to provide a debinding stimulus which causes release of the third product 302C (such as melting or denaturing of the bound pair). The location of the modification element 362A-C on each capture site 365A-C and the spaced apart nature of the capture sites 365A-C means that the heating is local only such that this will only release the third product 302C and leave the remaining products 302A-B bound to the sample surface 356.

[0193] This process can then be repeated for the other products 302A-B, such that these products 302A- B are also selectively released 346 from their corresponding capture site 365A-B and recovered 347 separately to the other of the plurality of products 302A-C. A further selective release 346 and recovery 247 is depicted in Fig. 2E, which comprises releasing one of the products 302A-C - in Fig. 2E, the second product 302B - from the respective capture site 365A-C - in Fig. 2E, the second capture site 365B - while still retaining the other products 302A on their respective capture sites 365A. This provides a solution above the sample surface 356 in which only the second product 302B is present and which can then be removed from the sample surface 356 in isolation to the other products 302A.

[0194] The method further comprises analysing 348 the recovered product 302A-C separately and away from the sample surface 356 such that each product 302A-C can be in isolation. Where the release 346 process is repeated for all of the products 302A-C, this analysis 348 may be concurrently with the subsequent release 346 and recovery 347 of the other products 302A-B (after the third product 302C has been recovered) or it may be after all of the products 302A-C have been selectively released 346 and recovered 347. Accordingly, in this way, the selective release 346 maintains the separation of the products 302A-C but provides these in a form in which they can individually be analysed and further processed, if required, separately to the remainder of the other products 302A-C.

[0195] The analysis 348 step in this embodiment may be any analysis technique, as set out above, using the analytical instrument of the system. This may be operated by the control unit.

[0196] Fig. 7 depicts another method 400 of producing and analysing a product, which may be achieved using a system (not shown). Figs. 8 A to 8D provide a schematic depiction of an exemplary reactor device 450 for use in the system and the method 400, where Fig. 8A provides a schematic plan view and Figs. 8B-8D provides schematic cross-sections through line B-B of Fig. 8A.

[0197] The method 400 comprises providing 430 a reactor device 450. The reactor device 450 depicted therein comprises a substrate 455 and a plurality of electrodes 460A-C formed on and in the substrate 455. In this embodiment, the reactor device 450 includes eighteen circular electrodes 460A-C embedded in the substrate 455 and arranged in a grid. Each of the electrodes 460A-C is individually actuatable and is functionalised with a capture species 461A-C specific to one of a plurality of products 402A-C produced in a reaction from a sample. Accordingly, each of the electrodes 460A-C and capture species 461A-C defines a capture site 465A-C for a corresponding product 402A-C. In particular and asschematically depicted in Fig. 8B, a first capture site 465A comprises a first capture species 461 A functionalised on the surface of a first electrode 460A, the first capture species 461 A having a structure which is complimentary to (i.e. will specifically bind to) to a first one of the products 402A. Similarly, a second capture site 465B comprises a second capture species 46 IB functionalised on a second electrode 460B having a structure which is complimentary to (i.e. will specifically bind to) to a second product 402B. A third capture site 465 C comprises a third capture species 461C functionalised on a third electrode 460C having a structure which is complimentary to (i.e. will specifically bind to) to a third one of the products 402C. Although not depicted, each of the plurality of electrodes 460A-C are electrically connected to a control unit (optionally via a signal processing unit) so that the plurality of electrodes 460A-C can be individually actuated and addressed by the control unit. This can be used to provide stimuli, in this case a stimulus for a reaction and also optionally as a debinding stimulus, and also to address the electrodes 460A-C to obtain measurement signals which can indicate whether the products 402A-C are bound to the sample surface 456. Accordingly, the electrodes 402A-C can act as both a modification element and a sensing element. Although not depicted, each of the electrodes 460A- C are connected to a control unit (not shown) so that they can be operated under the control of the control unit.

[0198] The system further includes an analytical instrument (not show) which is configured to perform an analysis on a product 402A-C of the conversion.

[0199] The method 400 further comprises providing 435 a sample to the sample surface 456.

[0200] The method 400 further comprises applying a stimulus 440 to at least a part of the sample on the sample surface 456 as to cause a conversion of the at least a part of the sample to a product, in this embodiment, a plurality of products 402A-C. In this embodiment, this may be achieved by using the electrodes 460A-C of each capture site 465A-C, such that this provides stimulus across the whole sample surface 456. Alternatively, there may be a further modification element (not shown) provided. The plurality of products 402A-C may be formed because they are derived from different species in the sample (i.e. different parts of the sample) or because the conversion leads to plural products 402A-C.

[0201] The method 400 further comprises selectively binding 445 the product 402A-C to the capture site 465A-C so as to retain the product 402A-C thereon. In this case, it comprises binding each of the products 402A-C to a respective capture site 465A-C. This process is depicted in Figs. 8B and 8C, where Fig. 8C shows the products 402A-C and capture species 465 A-C bound as a bound pair on each capture site 465 A-C. It will be appreciated that this will also have occurred for all of the other capture sites on the reactor device 450 (see Fig. 8A), where each of the other captures sites have captures species which correspond to the other products. As shown in Fig. 4C, before the subsequent steps, the solution over the sample surface 456 may be free of any other species so as to not contaminate any subsequent analysis. This may be achieved by any method, such as flowing a solution over the sample surface 456 to remove any unbound species or applying a force to the unbound species to remove them from the sample surface 456.

[0202] The method 400 further comprises analysing at least one of the products 402A-C on the capture site 465A-C - in the embodiment, analysing each of the products 402A-C while they remain bound on their corresponding capture site 465A-C. Fig. 8D depicts the analysis of the first product 402A while it is retained on the first capture site 465A. In this example, an arrow 470 depicts an incident beam used in the analysis step and generated by the analytical instrument. This may be a laser beam as part of MALDI-MS analysis, for example, or could be an X-ray beam as part of an XPS analysis process. This analysis allows the structure of the product to be identified independently of the other products 402V-C. The reactor device 450 lends itself to this analysis because each of the products 402A-C is adhered to separated and distinct capture sites 465A-C and are provided as a layer on top of the surface (caused by the location of the capture species 461A-C on the substrate 455). This process can then be repeated for the other products 402B-C.

[0203] Although the methods 100, 200, 300, 400 of Figs. 1, 3, 5 and 7 are described as separate methods, it will be appreciated that the steps disclosed therein may be combined.

[0204] FIGS. 9A-9B depict specific parts of reactor devices which can be used in the systems and methods disclosed herein. FIG. 9A depicts a part of a reactor device in which cells 501, which have been separated out (e.g. using a first separation method, such as movement along a first pathway) are caused to migrate along a pathway (under the influence of a force). This may be by a manipulation element.

[0205] The reactor device also comprises a retention or modification element 562 comprising a pair of electrodes which are operable to apply an electric field which retains the cells 501 in a particular position as they pass. The pair of electrodes are shown as providing confinement in the z-direction (i.e. perpendicular to the pathway out of the substrate). Associated with each modification element 562 is an electrode 560 in the form of a planar electrode on the surface the cells 501 pass over. Cells 501 are held by the modification element 562 on the electrode 560. The electrodes 560 may be operated as a sensing element and, as such, a cells 501 can be captured on the electrode 560 and interrogated by the electrode 560. Compared to existing cell interrogation systems, such as those relying on hydrodynamic focusing, this provides continuous measurement, which can provide more reliable information about the cells, provide additional information using electrochemical measurement, is faster and puts less stress on cells. Alternatively or additionally, the electrode 560 could operate as a modification element and provide a voltage or current to cause lysis of the cell 501. The modification element 562 could also perform a similar function. Similarly, the pair of electrodes defining the modification element 562 could instead or additionally operate as a sensing element rather than modification element 562.

[0206] FIG. 9B depicts an arrangement for trapping ions or cells from a sample in a particular position which can utilise electrodes 591A-D having a structure (e.g. as endcaps) such as that of the electrode arrays depicted FIGS. 10 to 12. The electrodes 591A-D can each generate a field which retains a positively charged particle surrounded by a cloud of similarly charged particles such that a particle 501 A received between four electrodes 591A-D can be trapped (i.e. retained). These accordingly canact as a retention or modification element. The electric fields E which cause the trapping may be generated by a quadrupole of electrodes (positive) and a ring electrode. Fig. 9B left shows a first state during an AC cycle and Fig. 9B right shows a second state during an AC cycle.

[0207] Figs. 10 to 12 schematically depict a further reactor device 650 forming part of a system, which can be used in the methods disclosed herein. Fig. 10 provides a schematic plan view of the reactor device 650, Fig. 11 shows an expanded view of a part of the reactor device 650 and Fig. 12 provides a cross-section along line C-C in Fig. 10. Although not shown, the reactor device 650 comprises a control unit (not shown) which can be used in embodiments to perform the device -related steps of the methods.

[0208] The reactor device 650 comprises a substrate 655 in part defining an upper sample surface 656.

[0209] The reactor device 650 also comprises a plurality of capture sites 665 (only some of the electrode arrays 690 are labelled in FIG. 6 for the sake of clarity) arranged in a 4 x 4 grid in part also defining the upper sample surface 656 of the substrate 655 (although it will be appreciated that any number of the capture sites 665 may be provided in any configuration). The capture sites 665 have a similar form to the capture sites 365A-C of the reactor device 350 of Figs. 6A-6D. Each capture site 665 comprises a modification element 660 in the form of a heater embedded in the substrate 655. Each of the modification elements 660 is individually actuatable and is functionalised with a capture species 661 specific to a particular product generated in a conversion method. Accordingly, each of the modification elements 660 and capture species 661 defines a capture site 665 for a corresponding product.

[0210] Although not depicted, each of the plurality of modification elements 660 are electrically connected to a control unit so that the plurality of modification elements 660 can be actuated under the control of the control unit. The modification elements 660 can act as individual modification elements and can be used to locally heat the region on and above each corresponding capture site 665 (e.g. the solution adjacent and on the corresponding capture site 665). As set out above, this can be used to aid incubation (i.e. to promote binding of the product to the corresponding capture species 661). Due to the individual actuation of the modification elements 660 and the local nature of the modification element 660 (i.e. that each provides and is limited to a single capture site 665), the temperature on each capture site 665 can be different, which can be particularly useful for providing appropriate environments for each pair of product and capture species. It can also be further be used for selective release of the bound product, where this is present.

[0211] The functionality and use of the capture sites 665 is accordingly the same as for the other reactor devices 150, 250, 350, 450 disclosed herein. It will, therefore, be appreciated how such a device can be used with the methods disclosed herein.

[0212] The reactor device 650 further comprises a plurality of electrode arrays 690 arranged around each of the capture sites 665, where each electrode array 690 comprises four individual electrodes 691A-D (see Fig. 10) arranged so that each of the four electrodes 691A-D defines the edge of a square surrounding the capture site 665. Fig. 10 shows an expanded view of a part of the reactor device 650 in which the upper left electrode array 690 (as it is shown in Fig. 6 - i.e. the first electrode array 690 in the4 x 4 grid) is more clearly visible. Here it can be seen that this (and each) electrode array 690 comprises four elongated electrodes 691A-D defining the edges of a square shape. This provides two sets of opposing pairs of electrodes. Specifically, there is a first pair comprising a first electrode 691 A arranged spaced apart and opposing from a third electrode 691C (i.e. defining the opposite side of the square). The first electrode 691 A and third electrode 691C of the first electrode array 691 A are electrically connected or connectable to one another so that an electric field can be formed therebetween. There is also a second pair comprising a second electrode 69 IB (in this arrangement, this extends between the top ends of the first electrode 691 A and third electrode 691C). This opposes and is spaced apart from a fourth electrode 69 ID (i.e. defining the opposite side of the square), which is also arranged to extend across the bottom edge of the square between the bottom ends of the first electrode 691 A and third electrode 691C. The second electrode 69 IB and fourth electrode 69 ID of this electrode array 690 are electrically connected or connectable to one another so that an electric field can be formed therebetween. Each of the electrode arrays 690 of the reactor device 650 has a corresponding structure. Although we have noted that the opposing pairs of electrodes can be electrically connected, it should be noted that, in some configurations, all of the electrodes of the electrode arrays 690 may be connectable to or connected to all of the other electrodes of the electrode arrays 690 in a particular row or column of the grid to provide the ability to generate an electric field therebetween. This allows movement therebetween and sensing. In some configurations, all of the electrodes of the electrode arrays 690 may be connectable to or connected to all of the other electrodes of the electrode arrays 690.

[0213] These electrode arrays 690 of the reactor device 650 can serve multiple purposes and, accordingly, the control unit may be configured to operate these for a number of different reasons and operations during implementation of the methods disclosed herein.

[0214] First, these may be used to manipulate the product or parts of the sample (or, indeed, any other species) provided to the sample surface 656 so as to migrate these across the sample surface 656. That is, the electrodes 691A-D of each electrode array 690 may act as manipulation assemblies which can be used to apply a force to charged species. In particular, any combination of two electrodes 691A-D on the reactor device 650 can act as a manipulation assembly by providing an electric field therebetween. For example, a first manipulation assembly 693 could be considered to be formed across the top row defined by the first and third electrodes 691 A, 691C of each electrode array 690 extending across the width of the substrate 655. An electric field formed between the first and third electrodes 691 A, 691C of each electrode array 690 will cause charged species to move along the sample surface 656 between the corresponding first and third electrodes 691A, 691C (i.e. from right to left or left to right, as depicted in FIG. 6). Because of the provision of electrodes 691 A-D between each of the capture sites 665, this provides granular control of the movement of the product such that fine manipulation within individually controllable regions is possible across small regions of the sample surface 656.

[0215] These electrodes 691 A-D (and the manipulation assemblies they form) can be used to aid the specific steps of the methods disclosed herein. For example, this can be used to move product to aproduct region or to cause separation, as set out above, by defining a pathway through the medium through which the product can be caused to migrate and separate out from at least one other species. More generally, the electrodes 691A-D can be used to move species around the sample surface 656. For example, the sample may be provided to one part of the sample surface 656 and the electrodes 691A-D can be actuated to cause the sample to migrate across the sample surface 656 to the relevant reactor site (set out below). Similarly for products, it can be used to ensure that this is provided to the relevant product region and ensure that the capture sites 665 are exposed to the product. For example, a first electrode 691 A (e.g. the upper left most electrode) and a third electrode 691C (e.g. the upper right most electrode) along the same row of the grid could be used to generate an electric field therebetween causing product to migrate from one side of the reactor device 650 to the other side. It will be further be appreciated that the grid structure of the electrode arrays 690 is such that a species could be manipulated in more than one dimension - i.e. in two or more dimensions. For example, it is possible for a species to be migrated along a first dimension, followed by migration along a second dimension. At this point, the control unit may be further configured to cause another electrode pair to cause the species to be moved along another (third) dimension. Accordingly, the reactor device 650 provides a multi-dimensional manipulation system with a vast degree of flexibility to perform complex separations and manipulations.

[0216] Further, these can be used to remove any unbound species prior to selective release and / or analysis. This can also be used to strip off non-specifically bound species from the capture species 661 prior to selective release and / or analysis. The provision of the electrode arrays 690 surrounding each capture site 665 - and, accordingly, providing each capture site 665 with its own electrode array 690 - allows for different electric field strengths to be provided to different capture sites 665. This allows for greater control and for the electric field strength to be tailored to the capture species / bound species relationship (i.e. the strength of the bound pair). This allows for more accurate removal of non- specifically bound species, for example. Alternatively or additionally, this can be used as part of the selective release, where present. For example, by applying an electric field of an appropriate strength, this can be used to pull the bound product off the capture site 665. As noted above, the provision of the electrode arrays 690 surrounding each capture site 665 - and, accordingly, providing each capture site 665 with its own electrode array 690 - allows for different electric field strengths to be provided to different capture sites 665. This allows for greater control of the selective release stage. With respect to removal of a released product, the electrodes 691A-C can be used to apply a force and remove the product from the sample surface where it can be recovered. Because of the provision of electrodes 691A-D between each of the capture sites 665, this provides granular control of the movement of the released product such that fine manipulation is possible across small regions of the sample surface 656.

[0217] Each electrode array 690 could also be used to influence a part of the product with respect to the capture site 665. For example, at least two opposing electrodes 691 A-D of an electrode array 690 could be used to drive or concentrate the product to the appropriate capture site 665. It is possible thatmovement of the product will lead to diffusion of the product within the medium / solution and the electrodes 691A-C can be used (e.g. during the recovery step) to concentrate the product on a particular part of the sample surface 656, from which it can be recovered.

[0218] Second, the electrodes 691A-D can be used for sensing - i.e. as sensing elements - or modifications - i.e. as modification elements. For example, the configuration and location of the electrodes arrays 690 is such that these can be operated to (e.g. by the control unit) to serve as sensing elements or modification elements. For instance, the electrodes 691A-D can be used to interrogate species located between any of the two electrodes 691A-D. For example, it may be that the product bound to the capture site 665 will change the permittivity of the medium located therebetween and the electrodes 691A-D are calibrated or arranged so that the change in permittivity can be determined. Individual electrodes 691A-D could also be used to determine the location of species. Each electrode 691 A is individually addressable so that it can provide its own measurement signal. These could further be operated to act as a modification element, for example for applying a stimulus.

[0219] The reactor device 650 further comprises reactor sites 664 for use in a conversion. For example, the reactor sites 664 may comprise heaters on which the sample can be received (and optionally retained) and which can be used to instigate the conversion.

[0220] The apparatus comprises four additional manipulation assemblies arranged as four parallel rows from the top (as depicted in Fig. 10) to the bottom of the substrate 655. Each additional manipulation assembly has a similar structure comprises a pair of first and second field electrodes 693A, 693B extending across the width of the substrate 655. For each additional manipulation assembly, the first field electrode 693 A is provided on the outermost left hand side of the substrate 655, on one side of the reactor site 664 on this row, as depicted in Fig. 10 delimiting a pathway and a second field electrode 693B provided on the outermost right hand side of the substrate 655 delimiting the opposite end of the corresponding pathway. The pathway formed therebetween accordingly encompasses both the reactor site 664 of each row and the capture sites 665. An electric field formed between the first and second field electrodes 693A, B of each first manipulation assembly will cause charged species within the product to move along the corresponding pathway between the corresponding first and second field electrodes 693A, 693B (i.e. from right to left or left to right, as depicted in FIG. 10). Further, between the first and second field electrode 694A, B of each additional manipulation assembly are the electrodes of the electrode arrays 690, each of which can further interact with the first and second field electrodes 693A, B, defining additional individually controllable regions (beyond those formed by the electrode arrays 690 themselves).

[0221] The use of these electrodes and the arrays leads to a grid of multiple dimensions in which components can be separated and detected. For example, products can be produced on the reactor sites 664 and separated from other components or products in the horizontal direction. Where the same product(s) are produced on different reactor sites 664, these could be caused to align (e.g. by the separation or by further manipulation) with each other on a column, at which point the electrode arrays690 could be actuated so as to manipulate the product in question along a column (as it is depicted in Fig. 10). This could be used to concentrate the product on a particular part of the sample surface 565.

[0222] Although not depicted, it will be appreciated that the reactor device 650 of Figs. 10 to 12 may further include other components. For example, each of the capture sites 665 may comprise a corresponding electrode provided in the substrate 655. Each of the electrodes can be individually actuatable and can be functionalised with the capture species 661 specific to a product. Each of the plurality of electrodes can be electrically connected to a control unit (optionally via a signal processing unit) so that the plurality of electrodes can be individually actuated and addressed by the control unit. This can be used to provide stimuli, such as a debinding stimulus, and also to address the electrodes to obtain measurement signals which can indicate whether the product(s) are bound to the sample surface 656. Accordingly, the electrodes can act as both a modification element and a sensing element. These can be used in conjunction with the modification elements 660 such that both are present on the device. For example, the electrodes can be provided at the sample surface and be functionalized, with the heaters located beneath the electrodes within or beneath the substrate. Each capture site 665 in this arrangement will accordingly have a corresponding modification element 660 and electrode.

[0223] Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the disclosed systems and methods, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfil the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. If a computer program is discussed above, it may be stored / distributed on a suitable medium, such as an optical storage medium or a solid-state medium supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless telecommunication systems. If the term "adapted to" is used in the claims or description, it is noted the term "adapted to" is intended to be equivalent to the term "configured to". Any reference signs in the claims should not be construed as limiting the scope.

[0224] The flow diagrams and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the disclosed systems and methods. In this regard, each block in the flow diagrams orblock diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and / or flow diagrams and combinations of blocks in the block diagrams and / or flow diagrams, can be implemented by specialpurpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.

[0225] Further examples of the methods and systems disclosed herein are provided as clauses:

[0226] Clause 1. A method of producing and processing a product, the method comprising: providing a reactor device, the reactor device comprising: a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site; providing a sample to the sample surface and retaining at least a part of the sample on the reactor site; applying a stimulus to the at least a part of the sample on the reactor site using the modification element so as to cause a conversion of the at least a part of the sample to a product; and applying a force to the product so as to migrate the product from the reactor site relative to the sample surface, wherein migrating the product relative to the sample surface is so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0227] Clause 2. The method of clause 1, wherein conversion of the at least a part of the sample is to form a plurality of products; and wherein applying a force is to the plurality of products so as to migrate the plurality of products relative to the sample surface so as to separate the plurality of products.

[0228] Clause 3. The method of any preceding clause, wherein the reactor device comprises a plurality of reactor sites provided on the sample surface, wherein each reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site, wherein retaining comprises retaining at least a part of the sample on each reactor site; and applying a stimulus to the at least a part of the sample on the reactor site using the modification element so as to cause a conversion of the at least a part of the sample to at least one product.

[0229] 4. The method of clause 3, wherein the sample comprises a first component and a second component and wherein retaining a part of the sample on each of the reactor sites comprises retaining the first component on a first reactor site and retaining the second component on a second reactor site.

[0230] Clause 5. The method of clause 4, wherein the first reactor site comprises a first capture species configured to selectively bind to the first component so as to retain it thereon and the second reactor site comprises a second capture species configured to selective bind to the second component so as to retain it thereon.

[0231] Clause 6. The method of clause 4 or clause 5, wherein providing the sample to the sample surface further comprises migrating the sample on the sample surface so as separate the sample into the first component and the second component.

[0232] Clause 7. The method of any of clauses 4 to 6, wherein applying a stimulus to the first component is so as to convert the first component into at least a first product and wherein applying a stimulus to the second component is so as to convert the second component into at least a second product.

[0233] Clause 8. The method of any of clauses 4 to 7, wherein each modification element is individually actuatable.

[0234] Clause 9. The method of any preceding clause, wherein the method further comprises retaining the product on the sample surface in the product region and analysing the product while retained on the sample surface.

[0235] Clause 10. The method of any preceding clause, wherein the reactor device further comprises at least one capture site provided in the product region and comprising a capture agent configured to retain the product thereon.

[0236] Clause 11. The method of any preceding clause, wherein the reactor site comprises a capture agent configured to retain a part of the sample thereon.

[0237] Clause 12. The method of clause 11, wherein the capture agent is a capture species configured to selectively bind to the sample or a part thereof; and wherein retaining the sample on the reactor site comprises selectively binding a part of the sample to the capture species.

[0238] Clause 13. The method of any preceding clause, wherein the retaining the sample on the reactor site comprises applying a force to the sample located on the reactor site so as to retain it thereon.

[0239] Clause 14. The method of any preceding clause, wherein applying a force comprises applying at least one of an electric field or a magnetic field.

[0240] Clause 15. The method of any preceding clause, wherein applying the stimulus comprises applying thermal energy or electrical energy to the at least a part of sample using the modification element.

[0241] Clause 16. The method of any preceding clause, further comprising sensing at least one of: a property on the reactor site indicative of the progression of the conversion of the sample to the product; or a property of the product on the sample surface.

[0242] Clause 17. The method of clause 16, wherein the reactor site comprises a sensing element configured to sense at least one of the property on the reactor site indicative of the progression of the conversion of the sample to the product; or the property of the product on the sample surface.

[0243] Clause 18. The method of any preceding clause, further comprising providing at least one reagent to the reactor site and wherein the conversion is a reaction between the part of the sample and a reagent.

[0244] Clause 19. The method of any preceding clause, wherein at least one of: the sample comprises a plurality of cells and wherein the conversion comprises applying the stimulus to cause cell lysis of the cell; the sample comprises at least one protein and wherein the conversion comprises applying the stimulus to convert the at least one protein into at least one peptide or release at least one carbohydrate; the sample comprises at least one a nucleic acid wherein the conversion comprises applying the stimulus to convert the nucleic acid into at least one base; and the sample comprises apolymer and wherein the conversion comprises applying the stimulus to convert the polymer into at least one monomer.

[0245] Clause 20. The method of clause 19, wherein the conversion comprises providing a sample comprising a plurality of cells and applying the stimulus to cause cell lysis or cell membrane permeabilization of the cells; and wherein the method further comprises transfecting the cells with at least one species.

[0246] Clause 21. A method of producing and analysing a product, the method comprising: providing a reactor device, the reactor device comprising a substrate at least partially defining a sample surface; and a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; providing a sample to the sample surface; and applying a stimulus to at least a part of the sample on the sample surface using the modification element as to cause a conversion of the at least a part of the sample to a product, wherein the reactor device further comprises at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture the product to retain the product on the capture site; wherein the method further comprises selectively binding the product to the capture site so as to retain the product thereon; and wherein the method further comprise at least one of:(I) analysing the product on the capture site; and(II) selectively releasing the product from the capture site, recovering the product and removing the product from the sample surface, and analysing the recovered product.

[0247] Clause 22. The method of clause 21, wherein the method further comprises, prior to selectively releasing the product from the capture site and recovering the product, removing any unbound species from the sample surface.

[0248] Clause 23. The method of clause 21 or clause 22, wherein the capture site comprises a capture species adhered to the capture site, the capture species configured to selectively bind to the product so as to retain it on the capture site.

[0249] Clause 24. The method of any of clauses 21 to 23, wherein the applying a stimulus to at least a part of the sample on the sample surface to form the product comprises forming a plurality of products.

[0250] Clause 25. The method of clause 24, wherein the reactor device comprises a plurality of capture sites, each capture site configured to capture one of the plurality of products to retain the corresponding product thereon.

[0251] Clause 26. The method of clause 25, wherein selectively releasing a product from the corresponding capture site and recovering the product comprises selectively releasing one of theplurality of products from the corresponding capture site and recovering the product separately to the other of the plurality of products.

[0252] Clause 27. The method of clause 25 or clause 26, wherein each capture site comprises an individually actuatable modification element configured to cause the selectively releasing of the product retained on the capture site.

[0253] Clause 28. The method of any of clauses 21 to 27, wherein the method comprises applying a force to the product on the sample surface so as to migrate the product relative to the sample surface.

[0254] Clause 29. The method of clause 28, wherein migrating the product relative to the sample surface is so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0255] Clause 30. The method of any of clauses 21 to 29, wherein the sample comprises a first component and a second component; and wherein the stimulus is applied to at least one of the first component or the second component.

[0256] Clause 31. The method of clause 30, wherein providing the sample to the sample surface further comprises migrating the sample on the sample surface so as separate the sample into the first component and the second component.

[0257] Clause 32. The method of any of clauses 21 to 31, wherein the capture site comprises a sensing element operable to provide a measurement signal indicative of a property of a product on the capture site.

[0258] Clause 33. The method of any of clauses 21 to 32, wherein the capture site further comprises at least one modification element configured to provide a debinding stimulus; and wherein selectively releasing the product from the capture site comprises applying the debinding stimulus.

[0259] Clause 34. The method of any of clauses 21 to 33, further comprising providing at least one reagent to the sample surface and wherein the conversion is a reaction between the part of the sample and a reagent.

[0260] Clause 35. The method of any of clauses 21 to 34, wherein at least one of: the sample comprises a plurality of cells and wherein the conversion comprises applying the stimulus to cause cell lysis of the cell; the sample comprises at least one protein and wherein the conversion comprises applying the stimulus to convert the at least one protein into at least one peptide or release at least one carbohydrate; the sample comprises at least one a nucleic acid wherein the conversion comprises applying the stimulus to convert the nucleic acid into at least one base; and the sample comprises a polymer and wherein the conversion comprises applying the stimulus to convert the polymer into at least one monomer.

[0261] Clause 36. The method of clause 35, wherein the conversion comprises providing a sample comprising a plurality of cells and applying the stimulus to cause cell lysis or cell membrane permeabilization of the cells; and wherein the method further comprises transfecting the cells with at least one species.

[0262] Clause 37. A system for producing and processing a product from a sample, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site and wherein the system is configured to retain a part of sample on the reactor site; a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and a control unit configured to operate: the modification element so as to apply a stimulus to the at least a part of the sample on the reactor site and thereby to cause a conversion of the at least a part of a sample retained on the reactor site to a product; and the manipulation assembly so as to cause the sample to migrate within medium provided at the sample surface so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0263] Clause 38. The system of any clause 37, wherein the manipulation assembly is operable to generate an electric field and / or a magnetic field to provide the respective force.

[0264] Clause 39. The system of clause 37 or clause 38, wherein the manipulation assembly comprises a first electrode set arranged to provide the force and define a pathway along which the product is migrated.

[0265] Clause 40. The system of clause 39, wherein the manipulation assembly further comprises at least one further electrode provided along the pathway which in part defines an individual controllable region; and wherein the control unit is configured to operate the at least one further electrode to generate a first local force within the individual controllable region.

[0266] Clause 41. The system of clause 40, wherein the at least one further electrode is further operable to provide a signal indicative of a property of the product at a position along the pathway.

[0267] Clause 42. The system of any of clauses 37 to 41, wherein the reactor device comprises a plurality of reactor sites, each reactor site comprising a modification element configured to provide a stimulus to a sample present on the reactor site, wherein the system is configured to retain a part of the sample on each reactor site.

[0268] Clause 43. The system of any of clauses 37 to 42, wherein the modification element comprises an electrode configured to apply an electrical stimulus to the part of the sample or a thermal device configured to heat or cool the reactor site.

[0269] Clause 44. The system of any of clauses 37 to 43, wherein the reactor site comprises a capture agent configured to bind to the part of the sample so as to retain it thereon; and / or wherein the system further comprises a manipulation assembly configured to apply a force to the sample located on the reactor site so as to retain it thereon.

[0270] Clause 45. The system of any of clauses 37 to 44, where the reactor site further comprises a sensing element configured to provide a measurement signal indicative of the part of the sample retained thereon.

[0271] Clause 46. The system of any of clauses 37 to 45, wherein the reactor device further comprises a sensing element provided in the product region configured to provide a measurement signal indicative of the product in the product region.

[0272] Clause 47. The system of any of clauses 37 to 46, further comprising at least one capture site provided on the sample surface in the product region, wherein the capture site is configured to selectively capture the product to retain the product on the capture site.

[0273] Clause 48. The system of clause 47, further comprising an analytical device configured to analyse the product, wherein at least one of: the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing of product from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.

[0274] Clause 49. The system of any of clauses 37 to 47, further comprising a property modification unit comprising a further modification element, wherein the property modification unit is configured to modify a property of medium provided at the sample surface.

[0275] Clause 50. The system of clause 49, wherein the property modification unit is configured to modify at least one of pH, electrical conductivity, a thermal property or ionic strength of the medium

[0276] Clause 51. The system of any of clauses 37 to 50, further comprising a sensing element in the product region operable to provide a signal indicative of a property of the sample in the product region.

[0277] Clause 52. The system of any of clauses 37 to 51, further comprising a medium provided at the sample surface.

[0278] Clause 53. A system for producing and analysing a product from a sample, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; and at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture a product derived from a sample to retain the product on the capture site; and a control unit configured to operate the modification element so as to apply a stimulus to the at least a part of the sample on the sample surface and thereby to cause a conversion of the at least a part of a sample to a product; and an analytical device configured to analyse the product, wherein at least one of:the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing of product from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.

[0279] Clause 54. The system of clause 53, further comprising a reactor site provided on the sample surface, wherein the reactor site comprises the modification element.

[0280] Clause 55. The system of clause 54, wherein the system is configured to retain a part of sample on the reactor site.

[0281] Clause 56. The system of clause 54 or clause 55, wherein the reactor device comprises a plurality of reactor sites, each reactor site comprising a modification element configured to provide a stimulus to a sample present on the reactor site, optionally wherein the system is configured to retain a part of the sample on each reactor site.

[0282] Clause 57. The system of any of clauses 54 to 56, wherein the reactor site comprises a capture agent configured to bind to the part of the sample so as to retain it thereon; and / or wherein the system further comprises a manipulation assembly configured to apply a force to the sample located on the reactor site so as to retain it thereon.

[0283] Clause 58. The system of any of clauses 54 to 57, where the reactor site further comprises a sensing element configured to provide a measurement signal indicative of the part of the sample retained thereon.

[0284] Clause 59. The system of any of clauses 53 to 58, wherein the modification element comprises an electrode configured to apply an electrical stimulus to the part of the sample or a thermal device configured to heat or cool the sample surface.

[0285] Clause 60. The system of any of clauses 53 to 59, further comprising a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and wherein the control unit is configured to operate the manipulation assembly so as to cause the product to migrate within medium provided at the sample surface.

[0286] Clause 61. The system of clause 60, wherein the control unit is configured to operate the manipulation assembly so as to cause the product to migrate within medium provided at the sample surface so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

[0287] Clause 62. The system of clause 60 or clause 61, wherein the manipulation assembly is operable to generate an electric field and / or a magnetic field to provide the respective force.

[0288] Clause 63. The system of any of clauses 60 to 62, wherein the manipulation assembly comprises a first electrode set arranged to provide the force and define a pathway along which the product is migrated.

[0289] Clause 64. The system of clause 63, wherein the manipulation assembly further comprises at least one further electrode provided along the pathway which in part defines an individual controllable region; and wherein the control unit is configured to operate the at least one further electrode to generate a first local force within the individual controllable region.

[0290] Clause 65. The system of clause 64, wherein the at least one further electrode is further operable to provide a signal indicative of a property of the product at a position along the pathway.

[0291] Clause 66. The system of any of clauses 53 to 65, wherein the reactor device further comprises a sensing element provided configured to provide a measurement signal indicative of the product.

[0292] Clause 67. The system of clause 66, wherein each capture site comprises a sensing element configured to provide a measurement signal indicative of the product.

[0293] Clause 68. The system of any of clauses 53 to 67, further comprising a property modification unit comprising a further modification element, wherein the property modification unit is configured to modify a property of medium provided at the sample surface.

[0294] Clause 69. The system of clause 68, wherein the property modification unit is configured to modify at least one of pH, electrical conductivity, a thermal property or ionic strength of the medium.

[0295] Clause 70. The system of any of clauses 53 to 69, further comprising a medium provided at the sample surface.

Claims

CLAIMS1. A method of producing and processing a product, the method comprising: providing a reactor device, the reactor device comprising: a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site; providing a sample to the sample surface and retaining at least a part of the sample on the reactor site; applying a stimulus to the at least a part of the sample on the reactor site using the modification element so as to cause a conversion of the at least a part of the sample to a product; and applying a force to the product so as to migrate the product from the reactor site relative to the sample surface, wherein migrating the product relative to the sample surface is so as to(I) separate the product from at least one additional species; and / or(II) collect the product in a product region on the sample surface.

2. The method of claim 1, wherein conversion of the at least a part of the sample is to form a plurality of products; and wherein applying a force is to the plurality of products so as to migrate the plurality of products relative to the sample surface so as to separate the plurality of products.

3. The method of claim 1 or claim 2, wherein the method further comprises retaining the product on the sample surface in the product region and analysing the product while retained on the sample surface.

4. The method of any preceding claim, wherein the reactor site comprises a capture agent configured to retain a part of the sample thereon.

5. The method of any preceding claim, wherein the retaining the sample on the reactor site comprises applying a force to the sample located on the reactor site so as to retain it thereon.

6. The method of any preceding claim, wherein applying the stimulus comprises applying thermal energy or electrical energy to the at least a part of sample using the modification element.

7. The method of any preceding claims, wherein the conversion comprises providing a sample comprising a plurality of cells and applying the stimulus to cause cell lysis or cell membrane permeabilization of the cells; and wherein the method further comprises transfecting the cells with at least one species.

8. A method of producing and analysing a product, the method comprising:providing a reactor device, the reactor device comprising a substrate at least partially defining a sample surface; and a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; providing a sample to the sample surface; and applying a stimulus to at least a part of the sample on the sample surface using the modification element as to cause a conversion of the at least a part of the sample to a product, wherein the reactor device further comprises at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture the product to retain the product on the capture site; wherein the method further comprises selectively binding the product to the capture site so as to retain the product thereon; and wherein the method further comprise at least one of:(I) analysing the product on the capture site; and(II) selectively releasing the product from the capture site, recovering the product and removing the product from the sample surface, and analysing the recovered product.

9. The method of claim 8, wherein the method further comprises, prior to selectively releasing the product from the capture site and recovering the product, removing any unbound species from the sample surface.

10. The method of claim 8 or claim 9, wherein the capture site comprises a capture species adhered to the capture site, the capture species configured to selectively bind to the product so as to retain it on the capture site.

11. The method of any of claims 8 to 10, wherein the capture site further comprises at least one modification element configured to provide a debinding stimulus; and wherein selectively releasing the product from the capture site comprises applying the de binding stimulus.

12. The method of claim 11, wherein the conversion comprises providing a sample comprising a plurality of cells and applying the stimulus to cause cell lysis or cell membrane permeabilization of the cells; and wherein the method further comprises transfecting the cells with at least one species.

13. A system for producing and processing a product from a sample, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; and a reactor site provided on the sample surface, wherein the reactor site comprises a modification element configured to provide a stimulus to a sample present on the reactor site and wherein the system is configured to retain a part of sample on the reactor site;a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and a control unit configured to operate: the modification element so as to apply a stimulus to the at least a part of the sample on the reactor site and thereby to cause a conversion of the at least a part of a sample retained on the reactor site to a product; and the manipulation assembly so as to cause the sample to migrate within medium provided at the sample surface so as to (I) separate the product from at least one additional species; and / or (II) collect the product in a product region on the sample surface.

14. The system of claim 13, wherein the reactor device further comprises a sensing element provided in the product region configured to provide a measurement signal indicative of the product in the product region.

15. The system of claim 14 or claim 14, further comprising at least one capture site provided on the sample surface in the product region, wherein the capture site is configured to selectively capture the product to retain the product on the capture site.

16. The system of claim 15, further comprising an analytical device configured to analyse the product, wherein at least one of: the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing of product from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.

17. A system for producing and analysing a product from a sample, the system comprising: a reactor device comprising a substrate at least partially defining a sample surface; a modification element configured to provide a stimulus to at least a part of a sample present on the sample surface; and at least one capture site provided on the sample surface, wherein the capture site is configured to selectively capture a product derived from a sample to retain the product on the capture site; and a control unit configured to operate the modification element so as to apply a stimulus to the at least a part of the sample on the sample surface and thereby to cause a conversion of the at least a part of a sample to a product; and an analytical device configured to analyse the product,wherein at least one of: the analytical device is configured to analyse the product retained on the capture site and the control unit is configured to operate the analytical device to analyse the product on the capture site; and the control unit is further configured to cause selective releasing of product from the capture site so that it can be recovered and removed from the sample surface, and further to operate the analytical device to analyse the recovered product.

18. The system of claim 17, further comprising a reactor site provided on the sample surface, wherein the reactor site comprises the modification element.

19. The system of claim 17 or claim 18, wherein the reactor device further comprises a sensing element provided configured to provide a measurement signal indicative of the product.

20. The system of any of claims 17 to 19, further comprising a manipulation assembly operable to apply a force to a product to cause the product to migrate relative to the sample surface; and wherein the control unit is configured to operate the manipulation assembly so as to cause the product to migrate within medium provided at the sample surface.

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