Electrochemical synthesis system

Abstract

A system for electrochemical synthesis of a polymer, comprising: a. One or more reaction chambers comprising an inlet, an outlet, and a plurality of reaction sites comprising one or more individually addressable electrodes, b. A plurality of reservoirs, c. At least one flow control system for selecting a flow rate, comprising: i. At least one inlet, b. At least one outlet, and c. At least one flow control system for selecting a flow rate, wherein each reservoir is fluidly coupled upstream to a flow control system inlet, ii. At least one outlet, d. Microfluidic structures comprising: i. At least one inlet fluidly coupled downstream to a flow control system outlet, ii. At least one outlet for each reaction chamber, each microfluidic structure outlet fluidly coupled upstream to a reaction chamber inlet, and i. At least one outlet for each reaction chamber. E. An addressing system configured to individually address the electrodes, and f. A control unit configured to guide and control: i. The addressing system, and ii. The at least one flow control system.

Description

Technical Field

[0001] The present invention relates to the field of electrochemical synthesis system, and in particular to the field of memory devices based on the system. Background Art

[0002] New data is being generated at an exponential rate. Some is consumed as it is generated (e.g., Voice over IP), some needs to be readily available (e.g., everyday information sharing), and some needs to be securely stored for long or very long periods of time before being consulted.

[0003] Current technologies for data archiving typically have a lifespan of 10-20 years, consume electricity, and only allow for relatively low data densities.

[0004] On the other hand, biopolymers, such as DNA, have been optimized through evolution to store information for long periods of time in a very compact and energy-efficient manner. As a result, DNA has become a promising support for data encoding and storage.

[0005] EP3888783A1 discloses a system for addressing nanoelectrodes in a nanoelectrode array. The system allows for a high density of individually addressable electrodes, which is beneficial for realizing a high density electrochemical memory storage system. This system may allow for the selective synthesis of multiple different biopolymers in parallel on an electrode array.

[0006] This is only part of the puzzle, and existing technologies are still a long way from providing a fully working electrochemical synthesis system compatible with high-density information storage. For example, much progress needs to be made before polymers can be effectively used as memory storage media. In particular, the cost of synthesis remains high. This is partly due to the cost of the reagents and the speed at which they lose their effectiveness when they age or become contaminated. In addition, the speed at which one nucleotide can be added to a growing polynucleotide chain is currently about 5 to 10 minutes. This is too slow for most uses.

[0007] Therefore, there is a need in the art for new methods and systems that at least partially overcome one or more of these problems. Summary of the invention

[0008] It is an object of the present invention to provide a good system for the electrochemical synthesis of polymers.

[0009] The above objectives are achieved by the method and system according to the present invention.

[0010] In a first aspect, the present invention relates to a system (1) for electrochemical synthesis of polymers, comprising:

[0011] a. One or more reaction chambers (2), each reaction chamber (2) comprising:

[0012] i. Reaction chamber entrance (3),

[0013] ii. Reaction chamber outlet (4),

[0014] iii. a plurality of reaction sites, each reaction site comprising one or more individually addressable electrodes (5) for controlling a chemical reaction in that reaction site of the reaction chamber (2),

[0015] b. a plurality of pressurizable reservoirs (6) for containing liquids,

[0016] c. at least one flow control system (7) for selecting the flow rate at which liquid is to be delivered from one or more of the plurality of reservoirs (6), the at least one flow control system (7) comprising:

[0017] i. at least one flow control system inlet (8), wherein each reservoir (6) is fluidically coupled upstream to the flow control system inlet (8),

[0018] ii. at least one flow control system outlet (9),

[0019] d. Microfluidic structures, including:

[0020] i. at least one microfluidic structure inlet (10) coupled downstream fluidically to a flow control system outlet (9),

[0021] ii. at least one microfluidic structure outlet (11) per reaction chamber (2), each microfluidic structure outlet (11) being fluidically coupled upstream to a reaction chamber inlet (3),

[0022] e. an addressing system (13) configured to address the electrodes (5) individually, and

[0023] f. A control unit (14), which is configured to guide:

[0024] i. the addressing system (13), and

[0025] ii. The at least one flow control system (7).

[0026] In a second aspect, the present invention relates to a method for synthesizing an oligomer or a polymer in a reaction chamber (2) of a system (1) according to any embodiment of the first aspect, wherein:

[0027] the one or more individually addressable electrodes (5) of at least one of the reaction sites having attached to its surface a first protected monomer, oligomer or polymer, and

[0028] a plurality of reservoirs (6) comprising a first reservoir (6a) containing a washing solution, a second reservoir (6b) containing a deprotection solution, and a plurality of additional reservoirs (6d, 6e), each additional reservoir containing a different protected monomer solution,

[0029] The method comprises:

[0030] a. Deprotecting a protected monomer, oligomer or polymer by the following steps:

[0031] i. The control unit (14) controls the flow control system (7) so that:

[0032] - delivering a washing solution at a first flow rate from a first liquid reservoir (6a) to one or more reaction chambers (2), the first flow rate of the washing solution being lower than the second flow rate of the washing solution,

[0033] - delivering a deprotection solution at a second flow rate from the second liquid reservoir (6b) to the one or more reaction chambers (2), wherein the second flow rate of the deprotection solution is higher than the first flow rate of the deprotection solution,

[0034] ii. causing the control unit (14) to direct the addressing system (13) so that a potential is applied or a current is delivered to the one or more individually addressable electrodes (5) of at least one of the reaction sites, thereby deprotecting the first protected monomer, oligomer or polymer, wherein steps i and ii overlap,

[0035] iii. The control unit (14) controls the flow control system (7) so that:

[0036] - delivering a second flow rate of washing solution from the first reservoir (6a), and

[0037] - delivering a deprotection solution at a first flow rate from a second liquid reservoir (6b),

[0038] b. reacting the protected monomer with the deprotected monomer, oligomer or polymer by the following steps:

[0039] i. The control unit (14) controls the flow control system (7) so that:

[0040] - delivering a washing solution at a third flow rate from the first reservoir (6a), the third flow rate of the washing solution being lower than the fourth flow rate of the washing solution,

[0041] - delivering a second flow rate of the protected monomer solution from one of the additional reservoirs (6d, 6e), the second flow rate of the protected monomer solution being higher than the first flow rate of the protected monomer solution,

[0042] ii. Then the control unit (14) controls the flow control system (7) so that:

[0043] - delivering a washing solution at a fourth flow rate from the first reservoir (6a),

[0044] - delivering a first flow rate of the protected monomer solution from said one of the additional reservoirs (6d, 6e) of step bi, and

[0045] c. Optionally repeat steps a and b one or more times in sequence.

[0046] In a third aspect, the invention relates to a computer program comprising instructions for causing a control unit of a system of any embodiment of the first aspect to perform the steps of a method according to any embodiment of the second aspect.

[0047] In a fourth aspect, the invention relates to a computer readable medium having stored thereon a computer program according to any embodiment of the third aspect.

[0048] In a fifth aspect, the present invention relates to an electrode comprising graphene oxide on a surface thereof.

[0049] An advantage of the system according to an embodiment of the present invention is that it is compatible with the presence of very high density electrodes and therefore compatible with its use as a high density memory storage system. This compatibility also enables the system to be used as a reactor for producing vaccines.

[0050] An advantage of the system according to an embodiment of the present invention is that it is compatible with continuous flow of liquid from the reservoir for extended periods of time. This ensures that the system remains clean and the reactants used remain fresh, thereby improving monomer incorporation rates and accuracy, thereby increasing the quality of the data recorded.

[0051] An advantage of a system according to an embodiment of the present invention is that it is able to achieve a high synthesis throughput, thereby enabling high-speed recording of data.

[0052] An advantage of the system according to an embodiment of the present invention is that it is able to use low reagent volumes. It is therefore economical.

[0053] An advantage of the system according to an embodiment of the present invention is that it wastes almost no reagent when flushing the dead volume. Therefore, it is economical.

[0054] An advantage of a system according to an embodiment of the present invention is that it is compatible with parallel processing reagents. This increases synthesis throughput and therefore the speed at which data can be recorded.

[0055] An advantage of a system according to an embodiment of the present invention is that it can be automated, thereby increasing synthesis throughput and reducing data storage costs.

[0056] Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not just as explicitly set out in a claim.

[0057] While devices in the art are constantly improving, changing, and evolving, it is believed that the present inventive concepts represent a substantially new and original advancement involving a departure from prior practice, thereby providing a more efficient, stable, and reliable device of this nature.

[0058] The above and other characteristics, features and advantages of the present invention will become apparent from the following detailed description in conjunction with the accompanying drawings, which illustrate the principles of the present invention by way of example. This description is given for illustrative purposes only and does not limit the scope of the present invention. The reference figures cited below refer to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 is a schematic representation of a system according to an embodiment of the present invention.

[0060] Figure 2 is a perspective view of a microfluidic structure used in an embodiment of the present invention.

[0061] The same reference numbers in different drawings refer to the same or similar elements. DETAILED DESCRIPTION

[0062] The present invention will be described with respect to specific embodiments and with reference to certain drawings, but the invention is not limited thereto but only by the claims. The drawings described are schematic and non-limiting only. In the drawings, for illustrative purposes, the dimensions of some of the elements may be exaggerated and not drawn to scale. The dimensions and relative dimensions do not correspond to actual reductions to the implementation of the invention.

[0063] In addition, the terms first, second, third, etc. in the specification and claims are used to distinguish similar elements and are not necessarily used to describe a sequence in time, space, arrangement or any other manner. It should be understood that the terms so used are interchangeable where appropriate, and that the embodiments of the invention described herein can be operated in a different order than described or illustrated herein.

[0064] It should be noted that the term "comprising" used in the claims should not be interpreted as being limited to the devices listed thereafter; it does not exclude other elements or steps. Therefore, the term should be interpreted as specifying the presence of the stated features, integers, steps or components as mentioned, but does not exclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Therefore, the term "comprising" covers the situation where only the features are present (therefore, in order to limit the scope to the features, it can always be replaced by "consisting of...") as well as the situation where these features and one or more other features are present. The wording "comprising" according to the present invention therefore also includes an embodiment as an absence of other components. Therefore, the scope of the expression "a device comprising devices A and B" should not be interpreted as being limited to a device consisting only of components A and B. This means that for the present invention, the only relevant components of the device are A and B.

[0065] Similarly, it should be noted that the term "coupled" used in the claims should not be interpreted as being limited to direct connections. The terms "coupled" and "connected" and their derivatives may be used. It should be understood that these terms are not intended to be synonymous with each other. Therefore, the scope of the phrase "device A is coupled to device B" should not be limited to devices or systems in which the output of device A is directly connected to the input of device B. This means that there is a path between the output of A and the input of B, which path may be a path that includes other devices or means. "Coupled" may mean that two or more elements are in direct physical or electrical contact, or that two or more elements are not in direct contact with each other, but still cooperate or interact with each other.

[0066] A is "fluidically coupled" to B means that there is a path for fluid to flow from A to B or from B to A, and A may be directly fluidically coupled to B without the need for intermediate elements, or A may be indirectly fluidically coupled to B through one or more intermediate elements.

[0067] A is "directly fluidically coupled" to B meaning that there is a path along which fluid can flow from A to B or from B to A, and A is directly fluidically coupled to B with no intervening elements.

[0068] A being "fluidly coupled downstream" to B means that during normal use of the system there exists a path along which fluid can flow from B to A in a typical flow direction.

[0069] A being "fluidly coupled upstream" to B means that during normal use of the system there exists a path along which fluid can flow from A to B in a typical flow direction.

[0070] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. Furthermore, in one or more embodiments, as will be apparent to one of ordinary skill in the art from this disclosure, the particular features, structures, or characteristics may be combined in any suitable manner.

[0071] Similarly, it should be understood that in the description of exemplary embodiments of the present invention, various features of the present invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and assisting in understanding one or more of the various inventive aspects. However, this disclosure method should not be interpreted as reflecting an intention that the claimed invention requires more features than those expressly recited in each claim. On the contrary, as reflected in the appended claims, inventive aspects reside in fewer features than all of the features of a single preceding disclosed embodiment. Therefore, the claims appended after the detailed description are hereby expressly incorporated into this detailed description, with each claim itself representing a separate embodiment of the present invention.

[0072] In addition, although some embodiments described herein include some features included in other embodiments but do not include other features included in other embodiments, as will be understood by those skilled in the art, the combination of features of different embodiments is intended to fall within the scope of the present invention and form different embodiments. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0073] In addition, some embodiments are described herein as methods or combinations of method elements that can be implemented by a processor of a computer system or by other means of performing the function. Therefore, a processor with the necessary instructions for performing such a method or method element forms a device for performing the method or method element. In addition, the elements of the device embodiments described herein are examples of devices for performing the functions performed by the element to implement the present invention.

[0074] In the description provided herein, numerous specific details are set forth. However, it should be understood that embodiments of the present invention may be implemented without these specific details. In other examples, well-known methods, structures, and techniques are not shown in detail to avoid confusing the understanding of this description.

[0075] As used herein, unless otherwise specified, the term "electrochemical synthesis" relates to a synthesis comprising at least one electrochemical step, i.e., at least one step in which electrical energy originating from a power source external to the reaction medium is used to effect or accelerate a chemical change. An example of such an electrochemical step is the removal of a protecting group from a monomer by electrochemically locally increasing the acidity of a liquid surrounding the protected monomer, said liquid comprising a deprotection solution which, when electrochemically activated, becomes acidic.

[0076] As used herein, unless otherwise specified, the term "downstream" characterizes the typical flow direction of liquid from multiple reservoirs to the flow control system to the microfluidic structure to one or more reaction chambers. Thus, for example, the microfluidic structure is located downstream of the reservoir, and the reservoir is located upstream of the flow control system.

[0077] Now refer to Figure 1 In a first aspect, the present invention relates to a system (1) for the electrochemical synthesis of polymers.

[0078] Although the system (1) according to the invention is applicable to the electrochemical synthesis of homopolymers and copolymers, it is particularly advantageous for the synthesis of copolymers. In addition, copolymers have the advantage that information can be stored in the sequence of the monomers that compose them.

[0079] In a preferred embodiment, the polymer is a copolymer and the system is a memory system for storing data. Preferred copolymers are biopolymers, such as polypeptides and polynucleotides. More preferred are polynucleotides, such as deoxyribonucleic acid (DNA) chains. For example, if the copolymer is a DNA chain, the nature of the data is determined by the base sequence in the DNA chain.

[0080] The system of the first aspect comprises one or more reaction chambers (2). They may also be referred to as supercells.

[0081] A single chamber or multiple chambers may be included in the system. In various embodiments, the chambers are arranged as a chamber array. For example, the system may include 10 or more chambers, such as 100 or more chambers, or 1000 or more chambers. Having multiple small reaction chambers rather than a single large reaction chamber is advantageous because the length scale is smaller (faster diffusion and lower dead volume).

[0082] In various embodiments, the length of each chamber may be 100 μm to 10 mm.

[0083] Each reaction chamber (2) comprises:

[0084] i. Reaction chamber entrance (3),

[0085] ii. Reaction chamber outlet (4),

[0086] iii. A plurality of reaction sites, each reaction site comprising one or more individually addressable electrodes (5) for controlling a chemical reaction in that reaction site of the reaction chamber (2).

[0087] Preferably, each reaction site (2) comprises a plurality of reaction chamber inlets (3). For example, each reaction chamber (2) may comprise at least as many reaction chamber inlets (3) as there are reservoirs (e.g. exactly as many). This is advantageous because it allows each reservoir to be connected to a reservoir fluid upstream via its own fluid system (including a flow control system and a microfluidic structure) without sharing with other reservoirs, thereby ensuring very low levels of contamination. As another example, each reaction chamber (2) may comprise at least as many reaction chamber inlets (3) as there are reservoirs minus the number of monomers (e.g. exactly as many reaction chamber inlets). For example, if there are four monomers and eleven reservoirs, the number of reaction chamber inlets (3) may be equal to at least seven (e.g. exactly seven). This would be a typical configuration in which the monomers are preferably mixed with an activator before entering the reaction chamber. In this configuration, the flow control system outlet (9) for the reservoir containing the activator and the flow control system outlet (9) for each reservoir containing a different monomer are fluidically coupled upstream to a common mixing channel that feeds the inlet of the microfluidic structure or is connected directly downstream from the inlet.

[0088] In various embodiments, the reaction chamber (2) may be configured such that the outlet (4) removes used fluid from the chamber (2). In various embodiments, the reaction chamber (2) may be configured such that the outlet (4) continuously removes used fluid from the chamber, i.e., the fluid flow out of the outlet remains non-zero as long as the system (1) is running.

[0089] In various embodiments, the reaction chamber can be configured so that an outlet for removing used fluid or another separate outlet can remove the synthesized polymer molecules from the chamber after the plurality of synthesized polymer molecules are separated from their electrodes. If each synthesized polymer molecule includes in its monomer sequence the signature of the reaction site at which it was synthesized, this removal allows subsequent reading of the memory contents by determining the monomer sequence.

[0090] In various embodiments, the reaction chamber can be configured so that an outlet or another separate outlet for removing the used fluid can remove these synthesized polymer molecules from the chamber after multiple identical synthesized polymer molecules are separated from one or more electrodes at the same reaction site. In fact, although different reaction sites usually synthesize different copolymer molecules, multiple identical copolymer molecules are usually synthesized on one or more electrodes present therein in each reaction site. In various embodiments, the chamber may include a driver for moving multiple synthesized copolymer molecules from the reaction site where they are synthesized to an outlet or another separate outlet for removing the used fluid. This helps to further process the synthesized copolymer molecules, such as separation, purification, replication and / or storage. The driver, for example, can be a dielectrophoresis structure, which is configured to move the synthesized copolymer from the electrode where it is synthesized to an outlet or another separate outlet for removing the used fluid.

[0091] In various embodiments, the chamber may include an outlet for removing used fluid or a retainer upstream of another separate outlet. The retainer may be suitable for concentrating the plurality of synthesized copolymer molecules after they are released from their reaction sites. For example, the retainer may be a dielectrophoresis structure.

[0092] In various embodiments, each chamber may include a heater for controlling the reaction temperature. In various embodiments, the control unit (14) may be configured to control the heater.

[0093] In various embodiments, the number of reaction sites in the chamber may be 30,000 or more reaction sites, preferably 100,000 or more, more preferably 1,000,000 or more reaction sites, still more preferably 10,000,000 or more, still more preferably 1,000,000,000 or more. EP 3888783 discloses techniques for achieving these numbers.

[0094] In various embodiments, the density of reaction sites may be 15,000 / cm 2 or greater, preferably 50000 / cm 2 or greater. For example, the density of reaction sites can be 200,000 / cm 2 or larger, 500000 / cm 2 or larger, 1000000 / cm 2 or larger, or 10000000 / cm 2 or greater, 100000000 / cm 2 or larger.

[0095] Each chamber includes a plurality of reaction sites. Typically, the reaction sites together form an array, i.e., they are typically arranged in a regular manner, such as a series of parallel rows and parallel columns with each row being perpendicular to each column. Other arrangements of the array (e.g., hexagonal packings) are also conceivable. The reaction sites may also be referred to as units.

[0096] In each reaction site, multiple (usually identical) copolymer molecules can be synthesized on one or more electrodes included in that reaction site. The chamber can be adapted so that the synthesis step occurring in one reaction site does not lead to the synthesis step at another reaction site. Therefore, the chamber can realize the spatially controlled synthesis of copolymers, and preferably realizes the spatially controlled synthesis of copolymers by sequentially adding monomers to the growing copolymer chain. In other words, the chamber can be adapted so that the reaction conditions for each reaction site are limited. When limitation is caused by the adaptation of the chamber, it is usually physical. Limitation can also be electrochemical. In this case, this is usually caused by the addressing system configuration.

[0097] For example, for reaction conditions to be limited by physical means, a reaction chamber may include a plurality of reaction sites on a substrate and a perforated cover layer above the plurality of reaction sites. The perforated cover layer may include a cavity covering and opening the reaction sites at its bottom. Thus, each cavity physically limits the reaction sites, wherein the walls defining the cavity hinder the diffusion of the reaction medium from one reaction site to the next reaction site, thereby locally limiting the reaction medium and thereby limiting the reaction conditions.

[0098] On the other hand, for the restriction that is realized electrochemically, a perforated cover is not required. However, physical and electrochemical restrictions can be combined. In fact, restrictions can be realized by making the electrodes included in the reaction sites around the reaction sites (that is, active reaction sites) of the polymer to be synthesized react to cause opposite reactions to occur in the reaction sites around these. For example, (for example, by oxidizing hydroquinone to benzoquinone) protons can be generated at the active reaction sites and can be consumed at the reaction sites around (for example, benzoquinone is reduced back to hydroquinone). Therefore, when the protons generated begin to diffuse out from the active reaction sites that the polymer is to be synthesized, they will be consumed at the reaction sites around. Therefore, even in the absence of physical boundaries, the reaction conditions are still limited to the required reaction sites.

[0099] In embodiments where the reaction sites are arranged in a series of parallel rows and columns with the rows perpendicular to the columns, inactive reaction sites directly above, below, to the left, and to the right of any active reaction site may be configured to be reactive, thereby limiting the reaction.

[0100] In various embodiments, each reaction site may include one or more electrode units, as described in EP3888783. Specifically, the plurality of reaction sites may be an array of reaction sites, the array comprising an array of electrode units, each electrode unit comprising (i) an access transistor having a gate resistively coupled to a word line, a source resistively coupled to a bit line, and a drain; and (ii) a storage circuit resistively coupled to the drain and comprising an individually addressable electrode. The reaction site may include a single electrode unit or a subarray of such electrode units.

[0101] In various embodiments, the electrode unit array may include one or more rows, with the electrode units in a row linked by a common word line, and / or may include one or more columns, with the electrode units in a column linked by a common bit line. In various embodiments, the electrode units may be arranged in a cubic arrangement, a hexagonal arrangement, or any other suitable arrangement.

[0102] In various embodiments, the memory circuitry may include individually addressable electrodes and electrical connections (eg, wires) that resistively couple the nanoelectrodes to the six levels.

[0103] In various embodiments, the storage circuit may further include a capacitor. In various embodiments, the capacitor may have a terminal that is resistively coupled to both the drain and the individually addressable electrode (i.e., the same terminal may be coupled to both). In some embodiments, the capacitor may be a separate (i.e., distinct) capacitor, i.e., the capacitor may be an electrical component dedicated to this role.

[0104] In other alternative or complementary embodiments, the electrical component can play the role of a capacitor and perform one or more additional functions. For example, a capacitor can be formed around an electrical connection that couples the drain to the individually addressable electrode so that the entire set of components simultaneously satisfies the role of both an electrical connection and a capacitor. For example, such a capacitor can be implemented by wrapping the electrical connection with a dielectric and then wrapping the electrode around the dielectric. In other alternative or complementary embodiments, the storage circuit and / or the electrical connection itself can be considered a capacitor by its inherent parasitic capacitance (e.g., line capacitance).

[0105] In various embodiments, the storage circuit may have a capacitance of at least 0.01 fF, preferably at least 1 fF, more preferably at least 10 fF, even more preferably at least 20 fF, such as at least 30, 50, 100, 200 or 500 fF.

[0106] In particular in combination with a suitable refresh rate (e.g., 64 ms or higher; see below), such a capacitance, in particular a capacitance of about 10 fF (e.g., about 30 fF) or higher, should generally allow sufficient charge to be stored to drive an electrochemical reaction for a sufficient time (e.g., until the next refresh) to, for example, enable or disable a synthesis reaction within a synthesis cell above the electrode. The refresh rate is the duration between the start times of subsequent repetitions of the following steps: Setting a selected potential by, for each electrode cell, disconnecting the access transistor by asserting the word line and charging the storage circuit to the selected electrode potential by appropriately biasing the bit line.

[0107] In various embodiments, the capacitance of the storage circuit may be partially or entirely due to parasitic capacitance (e.g., line capacitance) of the storage circuit. In various embodiments, the capacitor may have a capacitance of at least 0.01 fF, preferably at least 1 fF, more preferably at least 10 fF, even more preferably at least 25 fF, and most preferably at least 30 fF, such as at least 30, 50, 100, 200, or 500 fF. It is worth noting that there is also a practical upper limit to the capacitance, because when the capacitance of the storage circuit is higher, it takes longer to charge the storage circuit. Therefore, when using front-end-of-line (FEOL) access transistors, the capacitance may be in a favorable range of about 20 to about 500 fF, and when using back-end-of-line (BEOL; see below) transistors, it may be about 1 to 25 fF.

[0108] In various embodiments, the access transistor and the optional electrode unit as a whole can be formed on a semiconductor substrate (e.g., Si, Ge, SiGe or a semiconductor-on-insulator substrate). In various embodiments, the access transistor can be a planar transistor (e.g., a planar field effect transistor, a planar FET) or a vertical transistor (e.g., a vertical FET, a VFET). In various embodiments, the access transistor can be a back-end-of-line (BEOL) transistor; that is, a transistor formed during the BEOL stage of semiconductor processing. The access transistor can be, for example, a thin-film metal oxide semiconductor FET (MOSFET), such as based on indium gallium zinc oxide (IGZO), polycrystalline silicon, 2D materials (e.g., MoS2, MoSe2, MoTe2, WS2 or WSe2) thin films. The use of BEOL access transistors advantageously allows the front-end-of-line (FEOL) area below the electrode unit array to be dedicated to peripheral circuits (e.g., write drivers, refresh circuits and / or data transmission).

[0109] In various embodiments, the electrodes are nanoelectrodes, i.e. electrodes having at least one lateral dimension (e.g. diameter) of 100 nm or less, preferably 10 to 100 nm. Such small dimensions allow for a high density of electrodes, which is beneficial in terms of cost per incorporated monomer.

[0110] In an embodiment, the distance between two adjacent individually addressable electrodes may be from 10 to 95 nm. Such a small distance allows a high density of electrodes, which is beneficial in terms of cost per incorporated monomer.

[0111] In various embodiments, the nanoelectrodes (e.g., nanoelectrode arrays) may have a pitch (i.e., the center-to-center distance between adjacent nanoelectrodes) of 1 mm or less, preferably 500 nm or less, more preferably 250 nm or less, still more preferably 150 nm or less, such as 100 nm or less. For example, the most advanced DRAM nodes currently use a hexagonal layout (e.g., of capacitors) with a pitch of about 30 nm, indicating that the above dimensions are well within the capabilities of current technology.

[0112] In a preferred embodiment, the metal forming the electrodes may be Pt or Ru, but any conductive material is suitable.

[0113] In various embodiments, the individually addressable electrodes may include graphene oxide on their surface. The electrode having graphene oxide on its surface is the subject of the fifth aspect of the invention. Each individually addressable electrode of the first aspect may be as described in the fifth aspect of the invention.

[0114] In various embodiments, the individually addressable electrodes may include an ion-releasing layer on a surface thereof, the ion-releasing layer being configured to release ions that serve as reactants in, or provide catalysis to, polymer synthesis.

[0115] In various embodiments, the number of individually addressable electrodes may be equal to the number of reaction sites. In other embodiments, the number of individually addressable electrodes may be an integer multiple of the number of reaction sites.

[0116] The electrodes may be individually addressable by an addressing system. As used herein, addressing an electrode refers to making the electrode active.

[0117] In various embodiments, addressing an electrode may cause the electrode to be set to a different potential than when the electrode is not addressed. In various embodiments, addressing an electrode may operate the electrode potentiostatically, galvanostatically, or potentiodynamically.

[0118] Addressing electrodes generally means applying a potential or delivering current to the electrodes. In various embodiments, the addressing system has the ability to address electrodes individually or in groups simultaneously. In this embodiment, any subgroup of one or more individually addressable electrodes can be addressed simultaneously. This allows the same monomer to be added to all growing copolymers attached to the subgroup simultaneously. Simultaneously means that all electrodes in the subgroup can be addressed by the addressing system in a total time of less than 100ms. This total time is at least one order of magnitude shorter than the time required to complete the chemical reaction (usually seconds), and the addressing of the electrodes can be considered to be simultaneous.

[0119] In various embodiments, when each reaction site comprises an electrode unit as described in EP3888783, the control unit may be configured to cause the addressing system to select a potential for each electrode and to set the selected potential by disconnecting the access transistor for each electrode unit by asserting the word line and charging the storage circuit to the selected electrode potential by appropriately biasing the bit line.

[0120] In general, the control unit may be configured to cause the addressing system to set each individually addressable electrode to active, neutral, or reactive. Here, "active," "neutral," and "reactive" refer to the electrochemical activity of the nanoelectrodes: the active electrode has a suitable potential for initiating a specific electrochemical reaction, the reactive electrode has a suitable potential for initiating a different reaction (e.g., an opposite reaction, as long as the electrochemical reaction is reversible), and the inactive electrode has an intermediate potential that is insufficient to initiate neither the specific electrochemical reaction nor the opposite reaction. In various embodiments, the control unit may be configured to cause the addressing system to select a more negative potential for the nanoelectrodes that will be active, an intermediate potential for the nanoelectrodes that will be inactive, and / or a more positive potential for the nanoelectrodes that will be reactive. In other embodiments, the control unit may be configured to cause the addressing system to select a more positive potential for the nanoelectrodes that will be active, an intermediate potential for the nanoelectrodes that will be inactive, and / or a more negative potential for the nanoelectrodes that will be reactive. In the above, the potentials are expressed relative to each other, not in absolute terms. In practice, the particular potential value will generally depend on the reference point chosen (e.g., ground or a counter electrode in contact with the reaction medium). Thus, in some cases, a "more negative" potential may still be positive, etc. However, no matter which reference point is chosen, the appropriate potential for setting the individually addressable electrodes to be active, inactive, or reactive for a particular electrochemical reaction can generally be calculated (e.g., based on theory or modeling) or can be derived by relatively straightforward trial and error.

[0121] The control unit may be configured to cause the addressing system to electrochemically achieve confinement of the reaction.

[0122] Each time one or more individually addressable electrodes are addressed, if suitable reagents are present, a reaction can occur at these electrodes, resulting in the growing copolymer adding a monomer to its growing chain. For example, this may include: (a) setting the potential of the one or more electrodes, and (b) contacting one or more reagents with the electrodes; thereby locally forming an electrochemical environment for mediating synthesis.

[0123] For example, one or more counter electrodes arranged into an electrode array are also generally present in each reaction chamber. These can, for example, be located above an individually addressable electrode (e.g., a nanoelectrode array). For example, if a perforated cover layer is present above a plurality of reaction sites, the one or more counter electrodes can be on top of the perforated cover layer and in physical contact with the perforated cover layer, or further above. Each individually addressable electrode is then generally associated with a counter electrode. However, it is also possible that a counter electrode can be associated with a plurality of individually addressable electrodes. This is easier to achieve than having as many counter electrodes as individually addressable electrodes.

[0124] The system further comprises a plurality of reservoirs (6) for containing liquid.

[0125] The system comprises at least two reservoirs. This allows to dedicate one reservoir to the washing solution and the other reservoir to the monomer. However, a single monomer only allows the formation of homopolymers. This is of limited use in many applications.

[0126] Preferably, the system comprises at least three reservoirs. This allows, in addition to the above reservoirs, to dedicate another reservoir to the second comonomer. This is advantageous because it allows the formation of copolymers which can store information in their monomer sequence.

[0127] More preferably, the system includes at least four reservoirs. In addition to the above reservoirs, this also allows one reservoir to be dedicated to the deprotection solution. In many synthesis schemes, the deprotection of protected monomers requires the presence of dedicated reagents. For example, this is the case with typical polynucleotide synthesis schemes.

[0128] Even more preferably, the system comprises at least five reservoirs. In addition to the above reservoirs, this also allows one reservoir to be dedicated to the activator solution. In a typical polynucleotide synthesis protocol, the activator solution is preferably delivered together with the protected monomer to achieve or accelerate deprotection.

[0129] Still even more preferably, the system comprises at least six reservoirs.Except for the above reservoirs, this also allows one reservoir to be dedicated to the oxidation solution.In typical polynucleotide synthesis schemes, the phosphite triester backbone of the added building block is oxidized to a more stable four-coordinated phosphodiester.

[0130] Still even more preferably, the system comprises at least seven reservoirs. In addition to the above reservoirs, this also allows a reservoir to be dedicated to the end-capping solution. In a typical polynucleotide synthesis protocol, the end-capping solution is delivered to permanently block unreacted hydroxyl groups that may remain in the case of incomplete coupling.

[0131] More preferably, the system comprises at least nine reservoirs. In addition to the above reservoirs, this also allows two additional reservoirs to be dedicated to two additional comonomers. In this way, four different comonomers can be achieved, which allows typical polynucleotide synthesis involving four different bases.

[0132] For example, more reservoirs can be added to allow for different capping solutions or to add additional comonomers.

[0133] Any size reservoir is suitable. Typically, each reservoir may have a volume ranging from 0.1 to 10 ml.

[0134] The system further comprises at least one flow control system (7) for selecting a flow rate at which liquid will be delivered from one or more of the plurality of reservoirs (6) to a flow control system outlet (9), the at least one flow control system (7) comprising:

[0135] i. at least one flow control system inlet (8), wherein each reservoir (6) is fluidically coupled upstream to the flow control system inlet (8),

[0136] ii. At least one flow control system outlet (9).

[0137] Preferably, the number of flow control systems corresponds to the number of reservoirs. In other words, each reservoir (6) can be coupled to a different flow control system (7) in the upstream fluid. This has the following advantages: it is possible to extend the use of the system without washing the flow control system. This avoids the waste of reagents that would otherwise occur during the flushing of reagent dead volumes before the introduction of different reagents. This has the following additional advantages: each reservoir can continuously deliver liquid to the flow control system. The continuous outflow of the reservoir ensures that the liquid delivered to the reaction chamber is always fresh. This also prevents a reagent from flowing back or back diffusing to another reagent. This accelerates the chemical reaction at the expense of higher reagent consumption. However, in general, it is beneficial to the cost of each stored data by achieving continuous high-fidelity data storage. An additional advantage is the realization of parallel disposal of reagents.

[0138] In various embodiments, the first flow rate may be 0.1 nL / s to 10 nL / s per reaction chamber. In various embodiments, the second flow rate may be 0.1 pL / s to 2 nL / s per reaction chamber, preferably 0.1 pL / s to 10 pL / s. Relatively low flow rates are advantageous because they limit reagent consumption.

[0139] In various embodiments, the at least one flow control system (7) may be adapted to select between delivering liquid to the flow control system outlet at a first flow rate and delivering liquid to the flow control system outlet at a second flow rate different from the first flow rate. In these embodiments, the at least one flow control system may include a three-way valve, the three-way valve including: a three-way valve inlet coupled to the flow control system inlet at a downstream fluid, a first three-way valve outlet coupled to the flow control system outlet at an upstream fluid, and a second three-way valve outlet coupled to the flow control system outlet at an upstream fluid, wherein the flow control system (7) is configured to deliver liquid to the flow control system outlet at a first flow rate when the first three-way valve outlet is open and the second three-way valve inlet is closed, and to deliver liquid to the flow control system outlet at a second flow rate when the first three-way valve outlet is closed and the second three-way valve inlet is open. Preferably, the second flow rate is non-zero. For example, the first flow rate is at least five times greater than the second flow rate, preferably at least 50 times, more preferably at least 250 times, and even more preferably 500 to 2000 times greater, and the second flow rate is non-zero. A non-zero second flow rate has the advantage of preventing backflow or back diffusion of one reagent into the other reagent.

[0140] In various embodiments, the three-way valve may be electrically controllable.

[0141] In various embodiments, the selection between delivering liquid to the flow control system outlet at a first flow rate and delivering liquid to the flow control system outlet at a second flow rate can be performed electrically, for example, via an electrically controlled three-way valve. The valve can be piloted by a control unit.

[0142] In various embodiments, at least one flow control system (7) may include first and second microfluidic channels (e.g., pipes), wherein the first microfluidic channel is adapted to present a lower hydraulic resistance than the second microfluidic channel. For example, the first microfluidic channel may have a larger diameter than the diameter of the second microfluidic channel, may have a shorter length than the length of the second microfluidic channel, or both.

[0143] In various embodiments, a first microfluidic channel has an inlet fluidically coupled downstream to a first three-way valve outlet, and a second microfluidic channel has an inlet fluidically coupled downstream to a second three-way valve outlet.

[0144] In various embodiments, the first three-way valve outlet may include a first microfluidic channel and the second three-way valve outlet may include a second microfluidic channel.

[0145] In various embodiments, outlets of both the first and second microfluidic channels are upstream fluidically coupled to an outlet of the flow control system.

[0146] In various embodiments, the at least one flow control system can be adapted to select between not delivering liquid to the flow control system outlet, delivering liquid at a first flow rate, or delivering liquid at a second flow rate. Although the device achieves its function when it is impossible not to deliver liquid, it is advantageous to allow no delivery of liquid at all when placing or removing the reaction chamber, or when the system is not in use, for example, to clean the reaction chamber. For example, this can be achieved by having at least one flow control system, the at least one flow control system comprising a two-way valve (15), the two-way valve comprising a two-way valve inlet coupled to the flow control system inlet at the downstream fluid and a two-way valve outlet coupled to the flow control system outlet at the upstream fluid, wherein the flow control system (7) is configured to not deliver liquid to the flow control system outlet when the two-way valve is closed, and to deliver liquid to the flow control system outlet when the two-way valve is opened. When present, each flow control system generally has one such two-way valve. In various embodiments, the two-way valve can be coupled to a three-way valve at the downstream fluid and coupled to the flow control system outlet at the upstream fluid. Alternatively, the two-way valve can be coupled to a three-way valve at the upstream fluid and coupled to the flow control system inlet at the downstream fluid.

[0147] Typically, there is one flow control system inlet for each flow control system and each reservoir.

[0148] Typically, each flow control system has a flow control outlet.

[0149] Typically, each flow control system has a flow control inlet.

[0150] The system further comprises a microfluidic structure (17, see e.g. Figure 2 ), the microfluidic structure comprising:

[0151] i. at least one microfluidic structure inlet (10) coupled downstream fluidically to a flow control system outlet (9),

[0152] ii. At least one microfluidic structure outlet (11) per reaction chamber (2), each microfluidic structure outlet (11) being fluidically coupled upstream to a reaction chamber inlet (3).

[0153] The use of microfluidic structures allows the system of the present invention to process very small reagent volumes.Another consequence of the use of microfluidic structures is that the dead volume can be very small.

[0154] The microfluidic structure preferably comprises at least one microfluidic channel, ie a channel having a width of 100 μm or less.

[0155] The microfluidic structure has at least one inlet. Preferably, each reservoir has one inlet.

[0156] The microfluidic structure has at least one outlet. In various embodiments, the microfluidic structure may have two outlets, one for the synthesized copolymer and one for waste.

[0157] In various embodiments, the microfluidic structure can be coupled to all flow control systems (7) in the downstream fluid, wherein at least one of the flow control systems is configured to deliver liquid to the microfluidic structure (17) at a relatively higher flow rate than the relatively lower flow rate of one or more liquids delivered by the remaining other flow control systems (7), and wherein the microfluidic structure (17) is configured to distribute the liquid delivered at the relatively higher flow rate between all reaction chambers in the one or more reaction chambers (2), and to divert other liquids delivered at relatively lower flow rates away from all reaction chambers (2). A higher flow rate generally means the maximum of two possible non-zero flow rates leaving the flow control system. For example, this is the second, fourth, sixth and eighth flow rates of the washing solution, the third flow rate of the deprotection solution, the fourth flow rate of the protected monomer solution, the fifth flow rate of the activator solution and the sixth flow rate of the capping solution. A lower flow rate generally means the minimum of two possible non-zero flow rates leaving the flow control system. For example, these are the first, third, fifth and seventh flow rates of the washing solution, the first flow rate of the deprotecting solution, the first flow rate of the protected monomer solution, the first flow rate of the activator solution and the first flow rate of the capping solution.

[0158] In various embodiments, the microfluidic structure (17) may be present above (i.e., at a higher height than) one or more reaction chambers (2). This saves floor space. In various embodiments, the microfluidic structure (17) may be integrated with one or more reaction chambers (2).

[0159] The system comprises a plurality of pressurizable reservoirs, ie reservoirs adapted to be pressurized.

[0160] The system may further include a pressurizing device (12) configured to pressurize the plurality of reservoirs (6).

[0161] Preferably, the pressurizing means is configured to allow the pressure to be adjusted individually in each reservoir. This is advantageous because it allows the flow rate of each reservoir to be adjusted. Preferably, the pressurizing means is configured so that the flow rate of all reservoirs would be the same assuming no flow control system. This simplifies the system.

[0162] For example, each reservoir may be pressurized by its own independent pressurizing device. It is also possible to fluidly couple a single pressurizing device to multiple reservoirs via corresponding multiple valves that allow the pressure to be adjusted.

[0163] It is also possible to fluidly couple a single pressurizing device directly to multiple reservoirs, ie without means for individually regulating the pressure in each reservoir.

[0164] Examples of pressurizing devices include devices that operate based on mechanical principles (e.g., external syringe pumps, pneumatic diaphragm pumps, vibrating diaphragm pumps, piezoelectric / ultrasonic pumps, etc.), and devices that operate based on electrical or magnetic principles (e.g., electric pumps, electric fluid dynamic pumps, magnetohydrodynamic pumps, etc.), etc.

[0165] Preferably, the pressurizing device allows direct control (ie, regulation) of the pressure. In the case of blockage in the system, a pressurizing device that only allows indirect control of the pressure via, for example, flow rate may lead to overpressure. For this reason, a syringe pump is less preferred.

[0166] The system further comprises an addressing system (13) configured to individually address the electrodes (5).

[0167] In various embodiments, an addressing system includes a multiplexer device and a source measurement unit.

[0168] The multiplexer device is configured to allow any set of individually addressable electrodes to be turned on or off at a selected time (e.g., before, during, or after synthesis, depending on the specific synthesis step (characterization, functionalization, detritylation, chain release, etc.)).

[0169] In various embodiments, the multiplexer device may be a separate device connected to the individually addressable electrodes via external wiring. In other embodiments, the multiplexer device may be incorporated into the microfluidic chip itself (eg, using CMOS technology).

[0170] In various embodiments, the source measure unit may be a potentiostat device, i.e., a device capable of applying a specific potential. In various embodiments, the source measure unit may be a galvanostat device, i.e., a device capable of delivering a set amount of current. In various embodiments, the source measure unit may be capable of switching operation between a potentiostat and a galvanostat.

[0171] In various embodiments, the source measure unit may be a separate device connected to the input signal of the multiplexer device via external wiring. In other embodiments, the source measure unit may be incorporated into the microfluidic chip itself (eg, using CMOS technology).

[0172] The system further comprises a control unit (14) configured to control:

[0173] i. the addressing system (13), and

[0174] ii. The at least one flow control system (7).

[0175] In embodiments where the measuring system (16) is present, the control unit may be further configured to control iii. the measuring system (16).

[0176] The control unit may be a manually operated switchboard, but more practically, typically and advantageously it is a computer.

[0177] In various embodiments, the control unit can be programmed to direct the addressing system and at least one flow control system in such a way that a copolymer having a predefined monomer sequence is independently synthesized at each reaction site. The programming can be in hardware or software.

[0178] In other words, the control unit can be programmed in hardware or software to accept a series of data as input and convert it into a set of DNA strands assigned to electrodes (e.g., a unique sequence for each electrode), and to formulate and execute a set of actions for the flow control system and addressing system to achieve the synthesis of these strands.

[0179] In various embodiments, the control unit may be adapted to direct the addressing system to switch on or off any group of individually addressable electrodes.

[0180] In various embodiments, the control unit may be adapted to pilot a multiplexer device, a source measurement unit, or both.

[0181] In various embodiments, the control unit may be adapted to select the flow rate at which liquid will be delivered from one or more of the plurality of reservoirs (6). For example, when the flow control system comprises a valve, the control unit may be configured to cause the valve to select the flow rate and optionally to completely interrupt the flow.

[0182] In various embodiments, the control unit may use input data from at least one reaction site of the reaction chamber to direct the addressing system and at least one flow control system. The input data may be collected, for example, by a sensor, such as an electronic sensor. Typically, one sensor per reaction chamber is sufficient, but more sensors per reaction chamber may be present.

[0183] In other words, in various embodiments, the system may further include a measurement system (16) configured to measure an electrical property in the reaction chamber (2) at at least one of the reaction sites. For example, the electrical property may be selected from voltage, Faraday current, impedance or capacitance. For example, the voltage or Faraday current may be associated with an electrochemical reaction occurring at the electrode. Preferably, the electrical property is capacitance.

[0184] In various embodiments, the control unit (14) is further configured to receive a measurement of an electrical characteristic or a signal dependent on the measurement from the measurement system (16) and to use the electrical characteristic or signal to control the addressing system (13) and / or at least one flow control system (7).

[0185] In various embodiments, the control unit ( 14 ) may be configured to automatically perform the method according to any embodiment of the second aspect.

[0186] Figure 1 A system according to an embodiment of the present invention is schematically depicted. It comprises:

[0187] a. One or more reaction chambers (2, two are depicted), each reaction chamber (2) comprising:

[0188] i. at least one reaction chamber inlet (3, two are depicted),

[0189] ii. Reaction chamber outlet (4),

[0190] iii. a plurality of reaction sites, each reaction site comprising one or more individually addressable electrodes (5) for controlling a chemical reaction in that reaction site of the reaction chamber (2),

[0191] b. a plurality (five are depicted) of pressurizable reservoirs (6) for containing liquids,

[0192] c. at least one flow control system (7, two are depicted, but there are as many flow control systems as there are reservoirs (6)) for selecting the flow rate at which liquid will be delivered from one or more of the plurality of reservoirs (6) to a flow control system outlet (9a, 9b), the at least one flow control system comprising:

[0193] i. at least one flow control system inlet (8), wherein each reservoir (6) is fluidically coupled upstream to the flow control system inlet (8),

[0194] ii. At least one flow control system outlet (9a, 9b).

[0195] Two examples of flow control systems are depicted. The flow control system on the left is adapted to select between delivering no liquid to a flow control system outlet (9), delivering liquid to a flow control system outlet (9) at a first flow rate, or delivering liquid to a flow control system outlet (9) at a second flow rate. The flow control system on the right is unable to deliver liquid to a flow control system outlet (9).

[0196] The system further comprises:

[0197] d. A microfluidic structure (17), comprising:

[0198] i. at least one microfluidic structure inlet (two are depicted, 10a, 10b) fluidically coupled downstream to two flow control system outlets (9a, 9b),

[0199] ii. at least one microfluidic structure outlet (11) per reaction chamber (2) (two are depicted per reaction chamber), each microfluidic structure outlet (11a, 11b) being fluidically coupled upstream to one or more reaction chamber inlets (3, here four such inlets),

[0200] e. an addressing system (13) configured to address the electrodes (5) individually, and

[0201] f. A control unit (14), which is configured to guide:

[0202] i. the addressing system (13), and

[0203] ii. The at least one flow control system (7).

[0204] Figure 2 Depicted is a perspective view of a microfluidic structure (17) used in various embodiments of the present invention. Figure 2 The microfluidic structure (17) includes a downstream fluid coupled to a corresponding number of flow control system outlets (9a, 9b, see Figure 1 ) of two microfluidic inlets (10a, 10b). Figure 2 , the outlets (11a, 11b) of the microfluidic structure (17) are depicted as being fluidically coupled upstream to a single reaction chamber (2) via two reaction chamber inlets (3a, 3b). The long white arrows depict the fluid path taken by the liquid delivered to the inlet (10a) at a higher flow rate. The short white arrows depict the fluid path taken by the liquid delivered to the other inlet (10b) at a flow rate lower than the first flow rate. It can be observed that the liquid delivered at a high flow rate enters the inlet (10a) and the side drain (19) at the same time. Via the inlet (10a), the high flow rate liquid enters the reaction chamber (2), completely fills it, and then is discharged from the top at multiple reaction chamber outlets (4) (one is sufficient) and the second reaction chamber inlet (3b), thereby preventing the low flow rate liquid from entering the reaction chamber. The liquid delivered at a low flow rate enters the microfluidic structure inlet (10b), but is prevented from entering the reaction chamber inlet (3b) due to the presence of the high flow rate liquid. Therefore, the low flow rate liquid is completely diverted to the side drain (19) together with the high flow rate liquid.

[0205] Figure 2The microfluidic structure depicted in FIG. 4 has two microfluidic structure inlets ( 10 a , 10 b ), but a similar microfluidic structure can be designed having as many pressurizable reservoirs ( 6 ) as microfluidic structure inlets ( 10 ).

[0206] Figure 2 The microfluidic structure depicted in is connected upstream from a single reaction chamber (2), but similar microfluidic structures can be connected upstream to all reaction chambers in one or more reaction chambers (2) of the system (1).

[0207] In a second aspect, the present invention relates to a method for synthesizing an oligomer or a polymer in a reaction chamber (2) of a system (1) according to any embodiment of the first aspect, wherein:

[0208] the one or more individually addressable electrodes (5) of at least one of the reaction sites having attached to its surface a first protected monomer, oligomer or polymer, and

[0209] a plurality of reservoirs (6) comprising a first reservoir (6a) containing a washing solution, a second reservoir (6b) containing a deprotection solution, and a plurality of additional reservoirs (6d, 6e), each additional reservoir containing a different protected monomer solution,

[0210] The method comprises:

[0211] a. Deprotecting a protected monomer, oligomer or polymer by the following steps:

[0212] i. The control unit (14) controls the flow control system (7) so that:

[0213] delivering a washing solution at a first flow rate from a first liquid reservoir (6a) to one or more reaction chambers (2), wherein the first flow rate of the washing solution is lower than the second flow rate of the washing solution,

[0214] delivering a deprotection solution at a second flow rate from a second liquid reservoir (6b) to the one or more reaction chambers (2), wherein the second flow rate of the deprotection solution is higher than the first flow rate of the deprotection solution,

[0215] ii. causing the control unit (14) to direct the addressing system (13) so that a potential is applied or a current is delivered to the one or more individually addressable electrodes (5) of at least one of the reaction sites, thereby deprotecting the first protected monomer, oligomer or polymer, wherein steps i and ii overlap,

[0216] iii. The control unit (14) controls the flow control system (7) so that:

[0217] delivering a washing solution at a second flow rate from the first reservoir (6a), and

[0218] delivering a deprotection solution at a first flow rate from a second liquid reservoir (6b),

[0219] b. reacting the protected monomer with the deprotected monomer, oligomer or polymer by the following steps:

[0220] i. The control unit (14) controls the flow control system (7) so that:

[0221] delivering a washing solution at a third flow rate from the first liquid reservoir (6a), the third flow rate of the washing solution being lower than the fourth flow rate of the washing solution,

[0222] delivering a second flow rate of the protected monomer solution from one of the additional reservoirs (6d, 6e), the second flow rate of the protected monomer solution being higher than the first flow rate of the protected monomer solution,

[0223] ii. Then the control unit (14) controls the flow control system (7) so that:

[0224] delivering a washing solution at a fourth flow rate from the first liquid reservoir (6a),

[0225] delivering a first flow rate of the protected monomer solution from said one of the additional reservoirs (6d, 6e) of step bi, and

[0226] c. Optionally repeat steps a and b one or more times in sequence.

[0227] The first protected monomer, oligomer or polymer is rendered unreactive by the presence of a protecting group that blocks the reactive group. Typically, the monomer, oligomer or polymer is a growing polynucleotide chain, the protecting group is a dimethoxytrityl group and the reactive group is a hydroxyl group.

[0228] The first protected monomer, oligomer or polymer is typically covalently attached to the surface of one or more individually addressable electrodes via a reactive group present on the surface. In the case of polynucleotide synthesis, the reactive group is typically a hydroxyl group.

[0229] Wash solutions are used between monomer addition steps to prevent contamination from one monomer addition stage to the next. In the case of polynucleotide synthesis, the wash solution is typically acetonitrile.

[0230] The deprotection solution is used to allow the removal of the protecting group. In various embodiments, the deprotection solution is selected in such a way that when the electrode is addressed in the presence of the deprotection solution, e.g., when a specific potential is set at the electrode, deprotection occurs only at the electrode. In the case of polynucleotide synthesis, when the protecting group is dimethoxytrityl, the deprotection solution can be a detritylation solution (e.g., hydroquinone / benzoquinone / lutidine in acetonitrile / MeOH).

[0231] In the case of polynucleotide synthesis, the different protected monomer solutions are at least two solutions, typically four solutions, each containing a specific nucleoside phosphoramidite.

[0232] In various embodiments, in addition to the first, second and additional reservoirs, a third reservoir (6c) may also be present, and the third reservoir may include an activator solution for achieving or accelerating the coupling of the protected monomer with the unprotected monomer, oligomer or polymer attached to the electrode surface. In these embodiments, in step bi, a second flow rate of the activator solution higher than the first flow rate of the activator solution may be delivered from the third reservoir (6c), and in step b.ii., a first flow rate of the activator solution may be delivered from the third reservoir (6c).

[0233] In the case of polynucleotide synthesis, the activator solution can be an acidic azole catalyst, such as 1H-tetrazole.

[0234] Steps ai and aii overlap. The overlap is typically such that step aii is active when the deprotection solution is in contact with the individually addressable electrode of at least one of said reaction sites.

[0235] In various embodiments, the system (1) for electrochemical synthesis of copolymers further comprises a measurement system (16) configured to measure an electrical property in the reaction chamber (2) at at least one of the reaction sites.

[0236] Step a comprises the following sub-steps: causing the control unit (14) to control the measurement system (16) so that the electrical characteristics in the reaction chamber (2) are measured at said at least one of said reaction sites, and wherein the presence or absence of the additional step a.iv. in the steps a.i. to a.iii. is cycled a plurality of times depends on the measured electrical characteristics, and if the additional step a.iv. is present, the number of cycles depends on the measured electrical characteristics, and / or

[0237] Step b comprises the following sub-step b.iii.: causing the control unit (14) to control the measurement system (16) so that the electrical characteristics in the reaction chamber (2) are measured at at least one of the reaction sites, and wherein the presence or absence of the additional step b.iii. in the steps b.i to b.ii. is cycled multiple times depends on the measured electrical characteristics, and if the additional step b.iii. is present, the number of cycles depends on the measured electrical characteristics.

[0238] In various embodiments, step bi may be performed such that a second flow rate of the protected monomer solution (and a second flow rate of the activator solution, if present) is delivered from one of the additional reservoirs (6d, 6e) (and respectively from the third reservoir (6c) in the case of an activator) until the electrode (5) is in physical contact with the solution, followed by slowing down the delivery of the solution (e.g. setting the solution delivery to its first flow rate) or stopping the delivery of the solution (or solutions, if an activator is used), thereby maintaining the electrode (5) in physical contact with the solution for 1 second to 600 seconds before performing step b.ii. In this embodiment, stopping or slowing down the delivery of the protected monomer solution (and the activator, if present) has the effect of reducing the consumption of the (or these) reagents. This step of refreshing the solution increases the reaction rate.

[0239] In various embodiments, step bi may be performed such that a second flow rate of protected monomer solution (and a second flow rate of activator solution, if present) is delivered from one of the additional reservoirs (6d, 6e) (and respectively from the third reservoir (6c), if an activator is used) until the chamber is filled.

[0240] In each embodiment, step b may include the following step i' between step i and step ii: causing the control unit (14) to direct the addressing system (13) to activate the one or more individually addressable electrodes (5) of at least one of the reaction sites in a manner such that the protected monomer is attracted thereto, thereby accelerating the reaction of the protected monomer with the deprotected monomer.

[0241] In various embodiments, the copolymer is a biopolymer, preferably a nucleic acid chain, more preferably a deoxyribonucleic acid chain.

[0242] In various embodiments, after step b (or c, if present), the method may further include d. capping the unreacted deprotected monomer, oligomer or polymer by the following steps: i. causing the control unit (14) to direct the flow control system (7) so that:

[0243] delivering a washing solution at a fifth flow rate from the first liquid reservoir (6a) to the one or more reaction chambers (2), wherein the fifth flow rate of the washing solution is lower than the sixth flow rate of the washing solution,

[0244] delivering a second flow rate of the capping solution from one of the additional reservoirs (6d, 6e) to the one or more reaction chambers (2), the second flow rate of the capping solution being higher than the first flow rate of the capping solution, and

[0245] ii. The control unit (14) controls the flow control system (7) so that:

[0246] delivering a washing solution at a sixth flow rate from the first liquid reservoir (6a) to the one or more reaction chambers (2),

[0247] A first flow rate of a capping solution is delivered from said one of the additional reservoirs (6d, 6e) to the one or more reaction chambers (2).

[0248] Preferably, step di is performed such that a second flow rate of the capping solution is delivered from one of the additional reservoirs (6d, 6e) until the electrode (5) is in physical contact with the solution, and then the delivery of the solution is slowed (e.g., reduced to the first flow rate) or stopped, thereby maintaining the electrode (5) in physical contact with the solution for 1 second to 600 seconds before performing step d.ii.

[0249] The capping solution can, for example, be adapted so that the capped polymer can be distinguished or separated from the uncapped polymer.

[0250] In various embodiments, after step b (or c, if present, or d, if present), the method may further comprise e. stabilizing the reaction product obtained in step b by the following steps:

[0251] -i. The control unit (14) controls the flow control system (7) so that:

[0252] delivering a seventh flow rate of a washing solution from one of the additional reservoirs (6d, 6e) to the one or more reaction chambers (2), the seventh flow rate of the washing solution being lower than the eighth flow rate of the washing solution,

[0253] delivering a second flow rate of a stabilizing solution from one of the additional reservoirs (6d, 6e) to the one or more reaction chambers (2), the second flow rate of the stabilizing solution being higher than the first flow rate of the stabilizing solution, and

[0254] ii. The control unit (14) controls the flow control system (7) so that:

[0255] delivering a washing solution at an eighth flow rate from the first liquid reservoir (6a) to the one or more reaction chambers (2),

[0256] A first flow rate of a stable solution is delivered from said one of the additional reservoirs (6d, 6e) to the one or more reaction chambers (2).

[0257] When the polymer is a polynucleotide chain, the stabilizing solution is typically an oxidizing solution suitable for oxidizing the phosphite triester backbone of the reaction product obtained in step b.

[0258] Preferably, step di is performed such that a second flow rate of a stable solution is delivered from one of the additional reservoirs (6d, 6e) until the electrode (5) is in physical contact with the solution, and then the delivery of the solution is slowed down (e.g., reduced to the first flow rate) or stopped, thereby maintaining the electrode (5) in physical contact with the solution for 1 second to 600 seconds, preferably 1 second to 10 seconds, before performing step d.ii.

[0259] Typically, the first, third, fifth, and seventh flow rates of the washing solution are equal to or within 5% of each other. However, this is optional. This is advantageous because it simplifies the system. Typically, the second, fourth, sixth, and eighth flow rates of the washing solution are equal to or within 5% of each other. However, this is optional. This is advantageous because it simplifies the system. Typically, the first, third, fifth, and seventh flow rates of the washing solution, the first flow rate of the deprotection solution, the first flow rate of the protected monomer solution, the first flow rate of the activator solution, and the first flow rate of the capping solution are equal to or within 5% of each other. However, this is optional. This is advantageous because it simplifies the system. Typically, the second, fourth, sixth, and eighth flow rates of the washing solution, the second flow rate of the deprotection solution, the second flow rate of the protected monomer solution, the second flow rate of the activator solution, and the second flow rate of the capping solution are equal to or within 5% of each other. However, this is optional. This is advantageous because it simplifies the system.

[0260] Any features of the second aspect may be as correspondingly described in any embodiment of the first aspect.

[0261] In a third aspect, the invention relates to a computer program comprising instructions for causing a control unit of a system of any embodiment of the first aspect to perform the steps of a method according to any embodiment of the second aspect.

[0262] Any features of the third aspect may be as described for the first aspect or the second aspect respectively.

[0263] In a fourth aspect, the invention relates to a computer readable medium having stored thereon a computer program according to any embodiment of the third aspect.

[0264] In a fifth aspect, the present invention relates to an electrode comprising graphene oxide on a surface thereof.

[0265] Solid-phase DNA / RNA synthesis relies on the attachment of the first deoxynucleoside triphosphate (dNTP) to the hydroxyl moiety (-OH) of a solid support (e.g., controlled porosity glass (CPG), polystyrene beads), where the density of OH groups present on the surface influences the density of the resulting oligonucleotide sequence. The same principle applies to electro-controlled oligonucleotide synthesis, where dNTP addition occurs at the electrode surface. Natural oxides of metal electrodes (e.g., platinum, ruthenium, palladium, etc.) can support the synthesis. However, these oxides can be unstable during electrode operation. Semiconductor electrode materials, such as polycrystalline silicon or ceramics such as indium tin oxide (ITO), also present a high density of -OH functional groups, but are difficult to process, do not readily support faradaic electrochemical reactions, and have higher impedance than their metallic counterparts. Hydroxyl groups can be introduced by wet chemistry, deposition of functional adlayers (e.g., CPG / polymer composites, sucrose polymers), or covalent modification of the electrode with an organic monolayer (e.g., self-assembled monolayers of silanes or alkanethiols, electrochemically grafted diazo). These chemical modifications are performed in liquid and require lengthy incubation and washing steps, making the manufacturing process cumbersome and difficult to scale up. In addition, these wet modification steps need to be carefully optimized and tightly controlled to avoid electrode clogging (e.g., thickness, density, porosity), which could prevent oligonucleotide synthesis. A key step in oligonucleotide synthesis is the deprotection of the growing oligonucleotide chain using acidic conditions. This can be achieved by electrochemically oxidizing compounds that release protons upon oxidation (e.g., quinones, biphenyls, NAD / H, FAD / H, etc.). The efficiency of the deprotection step depends largely on the diffusion of the compound into the electrode and is hindered by any organic layer present on its surface. However, wet-based surface modification of nanoelectrodes can be limited because SAMs or grafted diazonium salts preferentially attach to metal grain boundaries. The particle size can be tens of nanometers, and only a small part of the nanoelectrode surface will carry -OH groups, so solid-phase DNA / RNA synthesis depends on the connection of the first deoxynucleoside triphosphate (dNTP) to the hydroxyl portion (-OH) of the solid support (such as controlled porosity glass (CPG), polystyrene beads), wherein the density of the OH groups present on the surface will affect the density of the resulting oligonucleotide sequence. Therefore, a scalable method is needed to conveniently introduce high-density hydroxyls on the electrode surface, with limited impact on electrode performance and support electrochemical synthesis of oligonucleotide sequences. The graphene oxide on the electrode surface proposed in the fifth aspect of the present invention is advantageous in copolymer electrochemical synthesis applications because the graphene oxide contains -OH groups, which helps monomers (such as nucleotides) to be covalently attached thereto. In particular, polynucleotide synthesis greatly benefits from the presence of OH groups on the electrode to initiate the attachment of the first nucleoside triphosphate. The presence of this first monomer on the graphene oxide surface promotes the subsequent sequential attachment of other monomers, thereby forming a monomer sequence. Providing -OH groups on the electrode usually leads to harmful electrical isolation of the electrode.This is usually the case for most coatings that are intended to provide such -OH groups on electrodes. However, the graphene oxide provided in the fifth aspect greatly limits electrode insulation. In addition, it provides a high density of -OH groups. In addition, unlike wet-based chemistry, it is compatible with nanoelectrode array modification. In addition, the graphene oxide provided in the fifth aspect can be easily scaled up, and the -OH density it provides is independent of the electrode grain size. The density of -OH groups on graphene oxide is about 1015 / cm2. 2 , that is, compared with using diazonium salt (about 1010 / cm 2 ) is 100,000 times higher, and is independent of the underlying metal grain size and is therefore not affected by the electrode size. In addition, the graphene oxide provided in the fifth aspect can support electrochemical reactions on its surface. Typically, graphene oxide is provided on the electrode by first growing graphene on the electrode and then oxidizing the formed graphene to graphene oxide, thereby introducing -OH groups. The graphene growth process is scalable, ensuring that graphene is only deposited on the electrode surface, can be achieved at the wafer level, and does not require any wet chemicals. Preferably, the metal forming the electrode is Pt or Ru. This is advantageous because graphene can be selectively grown as a single layer or multiple layers on these metals.

[0266] Example: Formation of graphene oxide on electrodes:

[0267] Graphene was grown on a Pt electrode in a CH4 (10 sccm) / H2 (10 scc m) / Ar (960 sccm) environment at 620 °C and 25 mbar for 2.5 min.

[0268] The grown graphene layer was then oxidized as follows. UVO Model 144AX was used for UV / ozone treatment. The process conditions included an oxygen flow rate of 300 l / h, no additional heating of the sample, a reaction chamber at room temperature and atmospheric pressure, a mercury lamp as a UV source (power setting: 100-120 V, 60 Hz), generating UV rays of 189.4 nm and 253.7 nm. The total treatment included a process step in which the mercury lamp was activated to generate ozone, and a fixed exhaust time of 6 minutes to remove all ozone in the reaction chamber. An electrode having a graphene oxide layer thereon was obtained.

[0269] Example: Use of the system according to the invention in biosynthesis

[0270] The system such as described in any embodiment of the first aspect for example can be used for the synthesis of (synthetic) polynucleotides (such as DNA chains) or another (bio) molecule. The method for amplifying one or more protected polynucleotide chains can for example start from the surface of attaching the first protected polynucleotide monomer, oligomer or polymer to one or more individually addressable electrodes. The first protected polynucleotide monomer, oligomer or polymer can be the same in each reaction site, or different in some reaction sites and the same in other reaction sites. Next, one or more reagents for deprotecting polynucleotide chains (such as proton generators for acid group deprotection, such as hydroquinone) can be provided in the reaction medium.

[0271] Multiple electrodes to which specific nucleotides are to be added can then be selected and addressed accordingly (e.g., the corresponding electrodes can be activated, and optionally, the surrounding electrodes can be set to be reactive). For example, one or more electrodes can electrochemically oxidize hydroquinone to benzoquinone, thereby producing protons and locally reducing the pH value. However, the migration of protons and other reaction products outside the reaction sites where they are formed is hindered by the wall of the perforated cover layer and / or by setting the surrounding electrodes to be reactive, so that protons remain confined to these reaction sites. Therefore, no change in pH value is observed in the reaction sites that do not include the selected one or more electrodes. By doing so, the deprotection reaction is locally enabled, and the selected polynucleotide chain can be specifically deprotected while protecting other polynucleotide chains. This allows the reaction conditions (e.g., pH) in each reaction site to be individually controlled by setting electrodes, so that the multiple reaction sites across the system manage where the reaction is enabled and where it is disabled. Then, a derivative of nucleotide (e.g., a nucleotide derivative with another protecting group) can be brought into the reaction medium and reacted with the deprotected chain to produce a selectively expanded chain, which again carries a protecting group. After washing away the nucleotide derivatives, the procedure can be restarted, for example, to add another nucleotide to the polynucleotide chain, and can be repeated any number of times to produce a DNA chain with any sequence. It is particularly important to note that since the chain to be amplified can be selected in each instance of the procedure, the sequence of the polynucleotide chain does not have to be the same. In fact, the polynucleotide chain in each reaction site may have a unique sequence. Therefore, the system can be used for polynucleotide data storage.

[0272] The following describes a process for adding a specific polynucleotide phosphite (e.g., one of A, C, G, and T in the case of DNA) to a growing polynucleotide chain. The process can be repeated multiple times with the same or different polynucleotide phosphites until the desired sequence is obtained.

[0273] 1. Perform a detritylation step (DET) in which the protecting dimethoxytrityl (DMT) group is selectively removed from those polymer chains to which the next building block must be attached (e.g., in phosphoramidite synthesis, removal of the DMT group generates a free -OH group to which the activated phosphoramidite can be coupled).

[0274] This happens through the following steps:

[0275] 1.1. Set the flow rate of the wash solution to low, and

[0276] 1.2. Set the flow rate of the detritylation solution (e.g., hydroquinone / benzoquinone / lutidine in acetonitrile / MeOH) to high to fill the supercell with the solution (FDS), and

[0277] 1.3. Enable the correct electrode group (MUX), then

[0278] 1.4. Apply a potential or current to these electrodes (SMU) to electrochemically alter local (i.e., near the enabled electrodes) conditions (e.g., increase acidity) for a sufficient time to achieve >99% DMT removal. The manner in which locality is achieved (e.g., continuous voltage / current) depends on the conditions within the reaction chamber (e.g., continuous or stopped flow, chamber height) and the electrode configuration (e.g., working electrode in well, counter electrode away from or surrounding each electrode). Thereafter:

[0279] 1.5. Wash with a solvent (such as acetonitrile) to remove any DET solution from the supercell by setting the flow rate of the DET solution to low and the flow rate of the wash solution to high.

[0280] 2. Coupling step (CPL), where a specific polymer building block is attached to a new DMT-free polymer. To do this, a polymer building block solution (e.g., a, C, T, or g) is flushed into the supercell along with an activator solution by the following steps:

[0281] 2.1. Set the flow rate of the wash solution to low, and

[0282] 2.2. Set the flow rates of the appropriate building block and activator solutions to high. The two solutions will then be mixed on the MFC before entering the supercell. Coupling can then occur for a given time (typically 1 second to 600 seconds), during which the flow is ideally reduced or stopped to reduce reagent consumption. Intermittent refreshing of the solutions may improve CPL yields. Subsequently:

[0283] 2.3. Wash with a solvent (e.g., acetonitrile) to remove any CPL solution from the supercell by setting the flow rate of the CPL solution to low and the flow rate of the wash solution to high

[0284] 3. Capping step (CAP), where any unreacted -OH groups are permanently blocked. This step is optional as it has no effect on the growth of the polymer itself. However, it is a way to reduce "missing" errors in the synthesized polymer, thereby improving the overall quality. This is accomplished by the following steps:

[0285] 3.1. Set the flow rate of the wash solution to low, and

[0286] 3.2. Set the flow rate of the CAP solution to high. Capping can then occur for a given time (usually 1 second to 10 seconds), during which time the flow is ideally reduced or stopped to reduce reagent consumption. Subsequently:

[0287] 3.3. Wash with a solvent (e.g., acetonitrile) to remove any CAP solution from the supercell by setting the flow rate of the CAP solution to low and the flow rate of the wash solution to high

[0288] 4. An oxidation step (OXI) in which the phosphite triester backbone of the added building block is oxidized to a more stable four-coordinated phosphite triester. This step is typical when the polymer to be synthesized is a polynucleotide. This is accomplished by the following steps:

[0289] 4.1. Set the flow rate of the wash solution to low, and

[0290] 4.2. Set the flow rate of the OXI solution to high. Oxidation can then occur for a given time (typically 1 second to 10 seconds), during which time the flow is ideally reduced or stopped to reduce reagent consumption. Subsequently:

[0291] 4.3. Wash with a solvent (e.g., acetonitrile) to remove any OXI solution from the supercell by setting the flow rate of the OXI solution to low and the flow rate of the wash solution to high

[0292] It should be understood that although the preferred embodiments, specific constructions and configurations and materials of the device according to the present invention are discussed herein, various changes or modifications may be made in form and detail without departing from the scope of the present invention. For example, steps may be added or deleted in the methods described within the scope of the present invention.

Claims

1. A system (1) for electrochemical synthesis of polymers, comprising: a. One or more reaction chambers (2), each reaction chamber (2) comprising: i. Reaction chamber entrance (3), ii. Reaction chamber outlet (4), iii. a plurality of reaction sites, each reaction site comprising one or more individually addressable electrodes (5) for controlling a chemical reaction in that reaction site of the reaction chamber (2), b. a plurality of pressurizable reservoirs (6) for containing liquids, c. at least one flow control system (7) for selecting the flow rate of liquid to be delivered from one or more of the plurality of reservoirs (6) to the flow control system outlet (9a, 9b), the at least one flow control system (7) comprising: i. at least one flow control system inlet (8), wherein each reservoir (6) is fluidically coupled upstream to the flow control system inlet (8), ii. at least one flow control system outlet (9a, 9b), d. A microfluidic structure (17), comprising: i. at least one microfluidic structure inlet (10a, 10b) coupled downstream fluidically to a flow control system outlet (9a, 9b), ii. at least one microfluidic structure outlet (11a, 11b) of each reaction chamber (2), each microfluidic structure outlet (11a, 11b) being fluidically coupled upstream to a reaction chamber inlet (3a, 3b), e. an addressing system (13) configured to address the electrodes (5) individually, and f. A control unit (14), configured to guide and control: i. the addressing system (13), and ii. The at least one flow control system (7).

2. A system (1) as described in claim 1, wherein the at least one flow control system (7) is adapted to select between delivering liquid to the flow control system outlet at a first flow rate and delivering liquid to the flow control system outlet at a second flow rate, wherein the second flow rate is different from the first flow rate, is non-zero, and is preferably at least five times smaller than the first flow rate.

3. The system (1) of claim 2, wherein the at least one flow control system (7) comprises a three-way valve (18), the three-way valve (18) comprising: A three-way valve inlet fluidically coupled to the flow control system inlet (8) at a downstream, a first three-way valve outlet fluidically coupled to the flow control system outlet (9) at an upstream, and a second three-way valve outlet fluidically coupled to the flow control system outlet (9) at an upstream, wherein the flow control system (7) is configured to deliver liquid to the flow control system outlet (9) at the first flow rate when the first three-way valve outlet is open and the second three-way valve inlet is closed, and to deliver liquid to the flow control system outlet at the second flow rate when the first three-way valve outlet is closed and the second three-way valve inlet is open.

4. A system (1) as described in claim 2 or claim 3, wherein the at least one flow control system (7) is adapted to select between not delivering liquid to the flow control system outlet (9), delivering liquid to the flow control system outlet (9) at the first flow rate, or delivering liquid to the flow control system outlet (9) at the second flow rate.

5. A system (1) as described in claim 4, wherein the at least one flow control system (7) includes a two-way valve (15), the two-way valve (15) including a two-way valve inlet coupled to the flow control system inlet (8) in the downstream fluid and a two-way valve outlet coupled to the flow control system outlet (9) in the upstream fluid, wherein the flow control system (7) is configured not to deliver liquid to the flow control system outlet (9) when the two-way valve (15) is closed, and to deliver liquid to the flow control system outlet (9) when the two-way valve (15) is opened.

6. The system (1) of claim 5, wherein each reservoir (6) is fluidically coupled upstream to a different flow control system (7).

7. A system (1) as described in any one of the preceding claims, wherein the microfluidic structure (17) is connected to all flow control systems (7) in a downstream fluid, wherein at least one of the flow control systems (7) is configured to deliver liquid to the microfluidic structure at a relatively higher flow rate than a relatively lower flow rate of one or more liquids delivered by the remaining other flow control systems (7), and wherein the microfluidic structure (17) is configured to distribute the liquid delivered at the relatively higher flow rate among all reaction chambers (2) of the one or more reaction chambers and to divert other liquids delivered at relatively lower flow rates away from all reaction chambers (2).

8. The system (1) according to any one of the preceding claims, further comprising: A measurement system (16) is configured to measure electrical characteristics in the reaction chamber (2) at at least one of the reaction sites.

9. A system (1) as claimed in claim 7, wherein the control unit (14) is further configured to receive a measurement of the electrical characteristic or a signal dependent on the measurement from the measurement system (16), and to use the electrical characteristic or signal to control the addressing system (13) and / or the at least one flow control system (7).

10. The system (1) according to any one of the preceding claims, wherein the individually addressable electrodes (5) comprise graphene oxide on their surface.

11. A method for synthesizing a polymer in a reaction chamber of a system according to any one of claims 1 to 9, wherein: The one or more individually addressable electrodes (5) of at least one of the reflection sites have a first protected monomer, oligomer or polymer attached to its surface, and The plurality of reservoirs (6) include a first reservoir (6a) containing a washing solution, a second reservoir (6b) containing a deprotection solution, and a plurality of additional reservoirs (6d, 6e), each of the additional reservoirs containing a different protected monomer solution, The method comprises: a. Deprotecting a protected monomer, oligomer or polymer by the following steps: i. causing the control unit (14) to control the at least one flow control system (7) so that: - delivering a washing solution at a first flow rate from the first liquid reservoir (6a) to the one or more reaction chambers (2), the first flow rate of the washing solution being lower than the second flow rate of the washing solution, - delivering a deprotection solution at a second flow rate from the second liquid reservoir (6b) to the one or more reaction chambers (2), wherein the second flow rate of the deprotection solution is higher than the first flow rate of the deprotection solution, ii. causing the control unit (14) to direct the addressing system (13) to apply a potential or deliver a current to the one or more individually addressable electrodes (5) of at least one of the reaction sites, thereby deprotecting the first protected monomer, oligomer or polymer, where steps i and ii overlap, iii. Then the control unit (14) controls the at least one flow control system (7) So that: - delivering a second flow rate of washing solution from said first reservoir (6a), and - delivering a deprotection solution at a first flow rate from the second liquid reservoir (6b), b. reacting the protected monomer with the deprotected monomer, oligomer or polymer by the following steps: i. causing the control unit (14) to control the at least one flow control system (7) so that: - delivering a washing solution at a third flow rate from the first liquid reservoir (6a) to the one or more reaction chambers (2), the third flow rate of the washing solution being lower than the fourth flow rate of the washing solution, - delivering a second flow rate of the protected monomer solution from one of the additional liquid reservoirs (6d, 6e) to the one or more reaction chambers (2), the second flow rate of the protected monomer solution being higher than the first flow rate of the protected monomer solution, ii. Then the control unit (14) controls the at least one flow control system (7) So that: - delivering a fourth flow rate of washing solution from said first reservoir (6a), and - delivering a first flow rate of protected monomer solution from said one of said additional reservoirs (6d, 6e) of step bi, and c. Optionally repeat steps a and b one or more times in sequence.

12. The method of claim 10, wherein the system (1) for electrochemical synthesis of polymers is according to claim 7, wherein: Step a comprises the following sub-steps: causing the control unit (14) to control the measurement system (16) so that the electrical characteristics in the reaction chamber (2) are measured at the at least one of the reaction sites, and wherein the presence or absence of the additional step a.iv. in the steps a.i. to a.iii. is cycled multiple times depends on the measured electrical characteristics, and if the additional step a.iv. is present, the number of cycles depends on the measured electrical characteristics, and / or Step b comprises the following sub-step b.iii.: causing the control unit (14) to control the measurement system (16) so that the electrical characteristics in the reaction chamber (2) are measured at at least one of the reaction sites, and wherein the presence or absence of the additional step b.iii. in the steps b.i to b.ii. is cycled multiple times depends on the measured electrical characteristics, and if the additional step b.iii. is present, the number of cycles depends on the measured electrical characteristics.

13. A method as claimed in claim 10 or claim 11, wherein step bi is performed so that a second flow rate of capping solution is delivered from one of the additional reservoirs (6d, 6e) until the electrode (5) is in physical contact with the solution, and then the delivery of the solution is slowed or stopped, thereby maintaining the electrode (5) in physical contact with the solution for 1 second to 600 seconds before performing step b.ii.

14. A method as described in any one of claims 10 to 12, wherein step b may include the following step i' between step i and step ii: causing the control unit (14) to control the addressing system (13) to activate the one or more individually addressable electrodes (5) of at least one of the reaction sites in a manner that attracts the protected monomer thereto, thereby accelerating the reaction of the protected monomer with the deprotected monomer.

15. The method of any one of claims 10 to 13, wherein the polymer is a biopolymer, preferably a deoxyribonucleic acid chain.

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