Particulate porous materials

Abstract

Disclosed herein is a particulate porous material that comprises a crosslinked polymeric matrix including a first set of constitutional units formed from ethylene glycol dimethacrylate monomers, wherein the particulate porous material comprises a plurality of pores having a pore diameter of from about 16 nm to about 50 nm, and the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g. Also disclosed herein are a sorbent cartridge suitable for use in purification of a bodily fluid (e.g. a kidney dialysis treatment, such as a haemodialysis treatment, a peritoneal dialysis treatment or a hemoperfusion treatment), wherein the sorbent cartridge comprises the aforementioned particulate porous material, and a method of performing dialysis (e.g. haemodialysis, peritoneal dialysis or hemoperfusion), comprising a step of passing a dialysate through the aforementioned sorbent cartridge. Also disclosed herein are use of the aforementioned particulate porous material to adsorb beta-2 microglobulin, a method of removing beta-2 microglobulin from a fluid comprising providing a fluid comprising beta-2 microglobulin, and exposing said fluid to the aforementioned particulate porous material, and a method of preparing the aforementioned particulate porous material.

Description

[0001] PARTICULATE POROUS MATERIALS

[0002] FIELD OF INVENTION

[0003] The present invention generally relates to the removal of beta-2 microglobulin in biological fluids, and more particularly relates to particulate porous materials for efficient removal of beta-2 microglobulin in biological fluids.

[0004] BACKGROUND

[0005] The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0006] Beta-2 Microglobulin (B2M) is a small protein (99 amino acids, 1 1 .8 kDa) normally located on the surface of nucleated cells as part of the antigen complex MHC-II (major histocompatibility-ll complex). As it is present on many cellular surfaces, B2M is naturally shed into the bloodstream continuously. B2M is generated at a rate estimated at 0.159 mg / h per kg of body weight (approximately 200-300 mg per day) (Portales-Castillo, I., et al., Kidney360, 2020, 1, 1447-1455).

[0007] Under normal circumstances, 99.9% of B2M is removed by the kidneys through gloremular filtration and re-adsorbed by catabolism into amino acids. In cases of kidney failure, patients are reliant on dialysis for B2M removal. Due to the limitations of current dialysis membranes, B2M is inefficiently removed and it can accumulate to exceed the normal serum level 60-fold. An average patient of 70 kg is estimated to accumulate 73 g of B2M per year. The cumulative retention of 400-600 g B2M is associated with the onset of the disease Dialysis Related Amyloidosis (DRA). Conventional 4 h, 3.5x per week hemodialysis (HD) regimen removes only approximately 100-150 mg of B2M per day. At best, this only represents 50% removal, leading to DRA.

[0008] The pathogenicity of DRA involves the aggregation of B2M to form a polymer macrostructure, amyloid fibrils. The B2M fibrils are frequently found to deposit in critical areas of the body such as the kidneys and joints among other tissues, leading to severe abnormalities including kidney stones, bone cysts and carpal tunnel syndrome. Interpreted as foreign matter by the immune system, the fibrils incite macrophage recruitment and inflammation, causing serious damage to tissues and the central nervous system, as well as organ failure.

[0009] These complications are associated with serious symptoms including excruciating and debilitating pain, resulting in a reduced level of activity and quality of life. A study of 1704 hemodialysis patients found that predialysis serum B2M was a predictor for mortality, where each 10 mg / L increase in serum B2M corresponded with an 1 1% increase in mortality.

[0010] The main remedy available to the patient is not without its own challenges and risk, with the patient required to undergo invasive surgery to remove the fibrils and treat the damaged tissue.

[0011] Unfortunately, DRA is not an uncommon occurrence in dialysis patients. Studies in the US have found that over 95% of long-term dialysis patients (>15 years) suffered from DRA, while a European study of hemodialysis patients found that as many as 20% of short-term (2-4 years) and 100% of long-term (>13 years) patients were afflicted with the disease (Scarpioni, R., et al., Int. J. Nephrol. Renov. Dis., 2016, 9, 319-328).

[0012] Traditional high-flux membranes have been designed with a pore size distribution for effective removal of water and small solutes, while preventing removal of beneficial large protein solutes such as albumin. Unfortunately, this pore size distribution is ineffective in the removal of middle molecules like B2M (Zhang, Z., et al., Membranes, 2022, 12, 253).

[0013] Recently developed Medium Cut Off (MCO) dialyzers aim to overcome the limitations of high-flux membranes by shifting and narrowing the pore size distribution to increase the removal of middle molecules, while retaining larger proteins like albumin. Interestingly, a recent study comparing the efficacy of four MCO dialysers with a traditional high-flux membrane did not find a significant difference in B2M removal. The main improvement observed in MCO membranes was in removal of higher molecular weight middle molecules (17-45 kDa), at a cost of higher albumin losses (2-3 times higher) (Maduell, F., et al., Clin. Kidney J., 2022, 15, 2292-2299). Additionally, only patients undergoing HD are able to benefit from this technology. This type of invention is of limited applicability to peritoneal dialysis patients, who also suffer from DRA.

[0014] Further, hemoperfusion columns have been administered as standalone extracorporeal devices or in conjunction with hemodialysis therapy. Although the addition of hemoperfusion column improved B2M removal by 1 .5-2x, the device volume is very large (150-500 mL). A large extracorporeal volume leads to anemia, hypotension, etc. Additionally, some reduction in albumin, leucocytes and platelets were reported.

[0015] Protein adsorption and recognition is considered to be a challenging feat in the Molecular Imprinted Polymers (MIPs) discipline, since that would require the imprinting and removal of a macromolecular template, a time consuming and difficult endeavour. Moreover, in the MIP approach to protein recognition, only aqueous systems are considered since the crosslinker, functional monomer and template need to be soluble in the same medium. A recent review was not able to identify any MIPs targeting adsorption of B2M or other middle-molecules (Ma, Y., et al., Microporous Mesoporous Mater., 2021 , 319, 1 11035).

[0016] Therefore, there exists a need for new materials for efficient removal of B2M in biological fluids, which can overcome at least one of the aforementioned problems.

[0017] SUMMARY OF INVENTION

[0018] Disclosed herein is a material which surprisingly has high selectivity and adsorption capacity for B2M. In addition, the present invention can be produced cheaply, and has high chemical and physical stability.

[0019] Aspects and embodiments of the invention are provided in the following numbered clauses.

[0020] 1 . A particulate porous material that comprises a crosslinked polymeric matrix including a first set of constitutional units formed from ethylene glycol dimethacrylate monomers wherein: the particulate porous material comprises a plurality of pores having a pore diameter of from about 1 .6 nm to about 50 nm; and the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g.

[0021] 2. The particulate porous material according to Clause 1 , wherein:

[0022] (a) the particulate porous material has a Brunauer-Emmett-Teller adsorption average pore size of from 3 to 15 nm, such as from 3.5 to 10 nm (e.g. 3.6 to 9.4 nm); and / or

[0023] (b) the particulate porous material has a porosity of at least 6% (v / v) and a single point total pore volume of at least 0.3 cm3 / g.

[0024] 3. The particulate porous material according to Clause 1 or 2, wherein the crosslinked polymeric matrix further comprises up to 30 mol % of a second set of constitutional units formed from a hydrophilic monomer, optionally wherein:

[0025] (a) the hydrophilic monomer is selected from one or more of the group consisting of itaconic acid, 2-(trifluoromethyl)acrylic acid, and allylurea, and / or

[0026] (b) the second set of constitutional units are present in an amount of from 2 to 25 mol % of the crosslinked polymeric matrix.

[0027] 4. The particulate porous material according to Clause 1 or 2, wherein the crosslinked polymeric matrix is formed from a homopolymer consisting of constitutional units formed from ethylene glycol dimethacrylate monomers.

[0028] 5. The particulate porous material according to any one of the preceding clauses, having a porosity of from 8 to 30% (v / v), such as from 10 to 28% (v / v) (e.g. from 14 to 24% (v / v)).

[0029] 6. The particulate porous material according to any one of the preceding clauses, having a single point total pore volume of from 0.36 to 0.85 cm3 / g, such as from 0.4 to 0.8 cm3 / g (e.g. from 0.45 to 0.75 cm3 / g).

[0030] 7. The particulate porous material according to any one of the preceding clauses, having a porosity of from 8 to 30% (v / v) and a single point total pore volume of from 0.36 to 0.85 cm3 / g: optionally a porosity of from 10 to 28% (v / v) and a single point total pore volume of from 0.4 to 0.8 cm3 / g.

[0031] 8. The particulate porous material according to any one of the preceding clauses, wherein the particulate porous material comprises a plurality of pores having a pore diameter of from about 1 .6 nm to about 10 nm. 9. The particulate porous material according to any one of the preceding clauses, wherein the particulate porous material has a nitrogen adsorption isotherm that is Type II or Type IV.

[0032] 10. The particulate porous material according to any one of the preceding clauses, wherein the particulate porous material has a D50 of less than 200 pm.

[0033] 11 . The particulate porous material according to any one of the preceding clauses, wherein the particulate porous material has a total protein binding capacity that is less than 0.2g / g.

[0034] 12. A sorbent formulation comprising the particulate porous material of any one of clauses 1 to 1 1 and one or more of: cation exchange particles (e.g. zirconium phosphate); anion exchange particles (e.g. hydrous zirconium oxide); activated carbon ; a buffer; and a urease.

[0035] 13. The sorbent formulation of claim 12, wherein the sorbent formulation comprises:

[0036] (i) from 1 wt% to 6 wt% of the particulate porous material;

[0037] (ii) from 47 wt% to 57 wt% of cation exchange particles;

[0038] (ill) from 37 wt% to 47 wt% of anion exchange particles; and

[0039] (iv) from 0.5 wt% to 2.5 wt% of a buffer.

[0040] 14. The sorbent formulation of claim 12, wherein the sorbent formulation comprises:

[0041] (i) from 1 wt% to 10 wt% of the particulate porous material; and

[0042] (II) from 90 wt% to 99 wt% of activated carbon.

[0043] 15. A sorbent cartridge suitable for use in purification of a bodily fluid (e.g. a kidney dialysis treatment, such as a haemodialysis treatment, a peritoneal dialysis treatment or a hemoperfusion treatment), wherein the sorbent cartridge contains the particulate porous material according to any one of the preceding clauses.

[0044] 16. The sorbent cartridge according to Clause 15, wherein the sorbent cartridge contains the sorbent formulation of any one of clauses 12 to 14.

[0045] 17. A method of performing dialysis (e.g. haemodialysis, peritoneal dialysis or hemoperfusion), comprising a step of passing a dialysate through a sorbent formulation as defined in of any one of clauses 12 to 14 or through a sorbent cartridge as defined in Clause 15 or 16. 18. Use of a particulate porous material as defined in any one of Clauses 1 to 11 , a sorbent formulation according to any one of clauses 12 to 14, or a sorbent cartridge according to Clause 15 or 16, to adsorb beta-2 microglobulin.

[0046] 19. A method of removing beta-2 microglobulin from a fluid, comprising: providing a fluid comprising beta-2 microglobulin; and exposing said fluid to a particulate porous material as defined in any one of Clauses 1 to 1 1 .

[0047] 20. A method of preparing a particulate porous material as defined in any one of Clauses 1 to 1 1 , the method comprising the steps:

[0048] (i) providing mixture comprising a first monomer that is ethylene glycol dimethacrylate, an initiator, a porogen and optionally a second monomer that is a hydrophilic monomer;

[0049] (ii) conducting a polymerisation reaction to form a bulk porous material; and

[0050] (ill) grinding or pulverising the bulk porous material to provide a particulate porous material.

[0051] 21 . The method according to Clause 20, further comprising washing the particulate porous material to remove the porogen.

[0052] 22. The method according to Clause 20 or 21 , wherein the porogen is an organic solvent selected from the group consisting of toluene, chloroform, acetone, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, and acetonitrile.

[0053] 23. The method according to Clause 20 or 21 , wherein the porogen is an organic solvent having a Hansen distance (Ra) of up to 10 MPa1 / 2, where Dpoiymer = 17.0, Ppoiymer = 9.7 and Hpoiymer = 4.9.

[0054] 24. The method according to any one of Clauses 20 to 21 , wherein step (ii) is performed at a temperature of from 50°C to 70°C.

[0055] DRAWINGS

[0056] FIG. 1 depicts the synthesis of porous Poly-EGDMA particles.

[0057] FIG. 2 depicts the nitrogen porosimetry results for Poly-EGDMA, Poly-DVB, Poly-TRIM, and AC.

[0058] FIG. 3 depicts the illustration of Poly-EGDMA particles.

[0059] FIG. 4 depicts the labelled scanning electron microscopy (SEM) image of Poly-EGDMA surface. Inset: overall view of a microparticle.

[0060] FIG. 5 depicts the labelled Barrett-Joyner-Halenda (BJH) pore size distribution plot.

[0061] FIG. 6 depicts the synthesis of porous Poly-EGDMA monolith. FIG. 7 depicts the SEM images of monolithic polymers: (I) 181 - Toluene: (ii) 210 - Chloroform; (ill) 221

[0062] - Acetone; (iv) 223 - Dimethylformamide (DMF); (v) 224 - Dimethylsulfoxide (DMSO); (vi) 225- Dioxane; (vii) 226 - Ethyl Acetate; and (viii) 229 - Acetonitrile (MeCN).

[0063] FIG. 8 depicts the SEM images of particulate polymers: (i) 212 - n-Hexane; (ii) 222 - Methanol; (iii) 227

[0064] - Iso-Propanol; and (iv) 228 - Ethanol.

[0065] FIG. 9 depicts the nitrogen porosimetry results for 2B Chloroform, 2C Hexane, 2F DMF, and 2L Acetonitrile.

[0066] FIG. 10 depicts the pore size distribution according to BJH model for 2B Chloroform, 2C Hexane, 2F DMF, and 2L MeCN.

[0067] FIG. 11 depicts the hydrophobic and hydrophilic monomers.

[0068] FIG. 12 depicts the equilibrium adsorption isotherm.

[0069] FIG. 13 depicts a schematic of the device test.

[0070] FIG. 14 depicts the particle size distribution data.

[0071] FIG. 15 depicts (A) and (B) the Hansen Solubility Sphere (experimental). •: bad solvents. ▲: good solvents.

[0072] FIG. 16 depicts the Hansen Solubility Sphere (predicted). •: bad solvents. ▲ : good solvents.

[0073] FIG. 17 depicts the polymerisation mechanism.

[0074] DESCRIPTION

[0075] It has been surprisingly found that a porous polymeric sorbent based on crosslinked poly-EGDMA has unexpectedly high adsorption capacity and selectivity for B2M.

[0076] Thus, in a first aspect of the invention, there is provided a particulate porous material that comprises a crosslinked polymeric matrix including a first set of constitutional units formed from ethylene glycol dimethacrylate monomers wherein: the particulate porous material comprises a plurality of pores having a pore diameter of from about 1 .6 nm to about 50 nm; and the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g.

[0077] In embodiments herein, the word “comprising’’ may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word “comprising” may also relate to the situation where only the components / features listed are intended to be present (e.g. the word “comprising” may be replaced by the phrases “consists of’ or “consists essentially of’). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word “comprising” and synonyms thereof may be replaced by the phrase “consisting of’ or the phrase “consists essentially of’ or synonyms thereof and vice versa.

[0078] The phrase, “consists essentially of’ and its pseudonyms may be interpreted herein to refer to a material where minor impurities may be present. For example, the material may be greater than or equal to 90% pure, such as greater than 95% pure, such as greater than 97% pure, such as greater than 99% pure, such as greater than 99.9% pure, such as greater than 99.99% pure, such as greater than 99.999% pure, such as 100% pure.

[0079] As used herein, the singular forms “a,” “an,” and “the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, and the like.

[0080] Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0081] The term “particulate porous material” refers to particles that each include pores.

[0082] The term “constitutional units” may refer to the polymerised repeating units (and crosslinks) obtained from the use of one or more monomeric materials and, if necessary separate crosslinking agents, to form the crosslinked polymeric matrix.

[0083] As will be appreciated, the crosslinked polymeric matrix may be formed only from a polymeric material obtained from the polymerisation of ethylene glycol dimethacrylate monomers. This is because one of the methacrylate functional groups in a monomer may partake in the formation of a polymeric chain (i.e. this functional group forms part of a carbon skeleton of the polymer), while the other methacrylate functional group that is pendant to the carbon skeleton may (or may not) form a bond with a further pendant methacrylate group on a separate polymeric chain, thereby crosslinking the two polymeric chains together. As will be appreciated, one or more of the pendant methactylate chains may form crosslinks.

[0084] As will be appreciated, the crosslinked polymeric matrix may be a homopolymer. In this case, only constitutional units formed from ethylene glycol dimethacrylate monomers may be present (with or without the use of a separate crosslinking agent).

[0085] The term “homopolymer” refers to a polymer consisting of identical monomer repeating units.

[0086] A “crosslinking agent” when referred to herein is a material that may form links between adjacent polymeric chains. This may be in any suitable form. For example, this may be in the form of forming covalent or ionic bonds between the polymer chains. A crosslinking agent may be a separate material that is added to form said crosslinks. As will be appreciated, ethylene glycol dimethacrylate can selfcrosslink, so the presence of a separate crosslinking agent is optional.

[0087] For the avoidance of doubt, it is explicitly contemplated that where a number of numerical ranges related to the same feature are cited herein, that the end points for each range are intended to be combined in any order to provide further contemplated (and implicitly disclosed) ranges.

[0088] As noted above, the particulate porous material may have a pore diameter of from about 1 .6 nm to about 50 nm. In more specific embodiments, that may be mentioned herein, the particulate porous material may have a pore diameter of from about 1 .6 nm to 10 nm.

[0089] The pore diameter of the particulate porous material may be derived, for example, from the 33-datapoint adsorption branch of the N2 isotherm. Miromeritics MicroActive software version 5.02 may be used to analyse the data according to the Barrett-Joyner-Halenda model with Halsey-Faas correction, in order to derive the pore size distribution and average pore diameter data (see Barrett, E. P., Joyner, L. G. & Halenda, P. P., J. Am. Chem. Soc. 1951 , 73, 373-380; and Rouquerol, J., etal., Adsorption by powders and porous solids: principles, methodology and applications. 2013: Academic press). Details on the calculations performed by Miromeritics MicroActive software version 5.02 may be found at https: / / www.micromeritics.com / Repository / Files / Calculations - 2020 ASAP Jan 2019 .pdf.

[0090] The term “porosity" as used herein refers to the ratio of the pore volume to the tapped density of a material. As will be appreciated, porosity may be calculated via the below equation:

[0091] Porosity (%) = Single point total pore volume (cm3 / g) * tapped density (g / cm3) x 100

[0092] Tapped density may be measured by mechanically tapping the dry polymer samples in a 5 ml_ measuring cylinder, and allowing the sample to settle to a final volume under its own weight. The tapped density may be calculated as follows:

[0093] Tapped density = Sample mass (g) / Final Volume (cm3)

[0094] Specific details are provided in Example 4 below.

[0095] When used herein, the single point total pore volume is taken to mean the total volume of liquid Ns adsorbed by the sample, at a datapoint near saturation pressure of the N2 isotherm (P / Po > 0.95).

[0096] In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a porosity of at least 3% (v / v), such as at least 6% (v / v). For example, the particulate porous material may have a porosity of from 3 to 30% (v / v), such as from 3 to 28% (v / v), such as from 3 to 24% (v / v), such as from 3 to 14% (v / v), such as from 3 to 10% (v / v), such as from 3 to 8% (v / v), such as from 3 to 6% (v / v), such as from 6 to 30% (v / v), such as from 6 to 28% (v / v), such as from 6 to 24% (v / v), such as from 6 to 14% (v / v), such as from 6 to 10% (v / v), such as from 6 to 8% (v / v), such as from 8 to 30% (v / v), such as from 8 to 28% (v / v), such as from 8 to 24% (v / v), such as from 8 to 14% (v / v), such as from 8 to 10% (v / v), such as from 10 to 30% (v / v), such as from 10 to 28% (v / v), such as from 10 to 24% (v / v), such as from 10 to 14% (v / v), such as from 14 to 30% (v / v), such as from 14 to 28% (v / v), such as from 14 to 24% (v / v), such as from 24 to 30% (v / v), such as from 24 to 28% (v / v), such as from 28 to 30% (v / v). The term “single point total pore volume” as used herein refers to the total volume of the pores in a material, as determined by the single point calculation method. Specific details are provided below and in the examples.

[0097] The term “Brunauer-Emmett-Teller adsorption average pore size” as used herein refers to average pore size as determined by the Brunauer, Emmett and Teller method. Specific details are provided below and in the examples.

[0098] The single point total pore volume, and Brunauer-Emmett-Teller adsorption average pore size may be determined, for example, by following the dinitrogen adsorption-desorption experimental methods disclosed in ISO 9277-2022, which is incorporated in its entirety by reference herein. Briefly, measurements can be performed at 77.3 K on a Micrometrics ASAP model 2020 porosimeter, and can be calculated using methods provided by Micromeritics MicroActive software version 5.02.

[0099] More specifically, the single point total pore volume may be calculated at a single point approaching saturation pressure p / p° > 0.95, which is an application of the Gurvich rule (Rouquerol, J., et al., Adsorption by powders and porous solids: principles, methodology and applications. 2013: Academic press). The Brunauer-Emmett-Teller (BET) adsorption average pore size may be calculated via the Gurvich rule and BET method:

[0100] D = 4V / S,

[0101] Where D = average pore diameter, V = single point total pore volume, and S = specific surface area determined by BET model.

[0102] In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a single point total pore volume of at least 0.15 cm3 / g, such as at least 0.3 cm3 / g. For example, the particulate porous material may have a single point total pore volume of from 0.15 to 0.85 cm3 / g, such as from 0.15 to 0.8 cm3 / g, such as from 0.15 to 0.75 cm3 / g, such as from 0.15 to 0.45 cm3 / g, such as from 0.15 to 0.4 cm3 / g, such as from 0.15 to 0.36 cm3 / g, such as from 0.15 to 0.3 cm3 / g, such as from 0.3 to 0.85 cm3 / g, such as from 0.3 to 0.8 cm3 / g, such as from 0.3 to 0.75 cm3 / g, such as from 0.3 to 0.45 cm3 / g, such as from 0.3 to 0.4 cm3 / g, such as from 0.3 to 0.36 cm3 / g, such as from 0.36 to 0.85 cm3 / g, such as from 0.36 to 0.8 cm3 / g, 0.36 to 0.75 cm3 / g, such as from 0.36 to 0.45 cm3 / g, such as from 0.36 to 0.4 cm3 / g, such as from 0.4 to 0.85 cm3 / g, such as from 0.4 to 0.8 cm3 / g, such as from 0.4 to 0.75 cm3 / g, such as from 0.4 to 0.45 cm3 / g, such as from 0.45 to 0.85 cm3 / g, such as from 0.45 to 0.8 cm3 / g, such as from 0.45 to 0.75 cm3 / g, such as from 0.75 to 0.85 cm3 / g, such as from 0.75 to 0.8 cm3 / g, such as from 0.8 to 0.85 cm3 / g.

[0103] In particular embodiments of the invention that may be mentioned herein, the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g.

[0104] In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a Brunauer-Emmett-Teller adsorption average pore size of from 3 to 15 nm, such as from 3 to 10 nm, such as from 3 to 9.4 nm, such as from 3 to 3.6 nm, such as from 3 to 3.5 nm, such as from 3.5 to 15 nm, such as from 3.5 to 10 nm, such as from 3.5 to 9.4 nm, such as from 3.5 to 3.6 nm, such as from 3.6 to 15 nm, such as from 3.6 to 10 nm, such as from 3.6 to 9.4 nm, such as from 9.4 to 15 nm, such as from 9.4 to 10 nm, such as from 10 to 15 nm.

[0105] In some embodiments, the particulate porous material may have a Brunauer-Emmett-Teller adsorption average pore size of from 3 to 15 nm, such as from 3.5 to 10 nm (e.g. 3.6 to 9.4 nm). In some embodiments, the particulate porous material may have a porosity of at least 6% (v / v) and a single point total pore volume of at least 0.3 cm3 / g. In some alternative embodiments, the particulate porous material may have a Brunauer-Emmett-Teller adsorption average pore size of from 3 to 15 nm, such as from 3.5 to 10 nm (e.g. 3.6 to 9.4 nm), and the particulate porous material may have a porosity of at least 6% (v / v) and a single point total pore volume of at least 0.3 cm3 / g.

[0106] The particulate porous material described above may further comprise up to 30 mol % of a second set of constitutional units formed from a hydrophilic monomer. Examples of hydrophilic monomers include, but are not limited to, itaconic acid, 2-(trifluoromethyl)acrylic acid, and allylurea. In some embodiments, the hydrophilic monomer may be selected from one or more of the group consisting of itaconic acid, 2- (trifluoromethyl)acrylic acid, and allylurea. In some embodiments, the second set of constitutional units may be present in an amount of from 2 to 25 mol % of the crosslinked polymeric matrix. In some alternative embodiments, the hydrophilic monomer may be selected from one or more of the group consisting of itaconic acid, 2-(trifluoromethyl)acrylic acid, and allylurea, and the second set of constitutional units may be present in an amount of from 2 to 25 mol % of the crosslinked polymeric matrix.

[0107] In particular embodiments of the invention that may be mentioned herein, the particulate porous material may have a porosity of from 8 to 30% (v / v) and a single point total pore volume of from 0.36 to 0.85 cm3 / g. For example, the particulate porous material may have a porosity of from 10 to 28% (v / v) and a single point total pore volume of from 0.4 to 0.8 cm3 / g.

[0108] In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a nitrogen adsorption isotherm that is Type II or Type IV. Without wishing to be bound by theory, a type of Type II isotherms herein may refer to macroporous materials while a type of Type IV isotherms herein may refer to mesoporous materials (e.g. mesoporous molecular sieves). For these Type IV materials, the monolayer-multilayer formation is followed by pore condensation, which means that the gas condenses to a liquid-like state in a pore at a pressure less than the saturation pressure po of the bulk liquid. Type IV isotherms finally reach a saturation plateau. Type IV(a) isotherms with hysteresis can be distinguished from Type I V(b) isotherms without hysteresis. Hysteresis occurs when the pore width exceeds a certain critical width which is depending on the adsorptive and temperature. For nitrogen and argon at 77 and 87 K, respectively, hysteresis occurs for pores larger than = 4 nm. In contrast, adsorbents having smaller mesopores show a completely reversible adsorption behavior leading to a Type IV(b) isotherm.

[0109] In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a D50 of less than 200 pm. The term “D50” as used herein refers to a mean or average particle size of a material. In some embodiments of the invention that may be mentioned herein, the particulate porous material may have a total protein binding capacity that is less than 0.2g / g. The term “total protein” as used herein refers to a mixture of dialysate or serum proteins containing ~80% albumin.

[0110] Without wishing to be bound by theory, it is believed that the properties of some embodiments of the invention that may be mentioned herein may be particularly useful in providing the particulate porous material size selectivity and B2M sieving effect due to the availability of surface adsorption sites.

[0111] In certain embodiments, the particulate porous material of the present invention comprises a crosslinked polymeric matrix including a first set of constitutional units formed from ethylene glycol dimethacrylate monomers, wherein: the particulate porous material comprises a plurality of pores having a pore diameter of from 1 .6 nm to 50 nm; the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g; and wherein the crosslinked polymeric matrix is a homopolymer consisting of the first set of constitutional units or the crosslinked polymeric matrix is a copolymer consisting of the first set of constitutional units and up to 30 mol % of a second set of constitutional units formed from a hydrophilic monomer.

[0112] In a second aspect of the invention, there is provided a sorbent cartridge suitable for use in purification of a bodily fluid (e.g. a kidney dialysis treatment, such as a haemodialysis treatment, a peritoneal dialysis treatment or a hemoperfusion treatment), wherein the sorbent cartridge contains the particulate porous material as disclosed above.

[0113] As will be appreciated, the sorbent cartridge may further contain one or more of: cation exchange particles (e.g. zirconium phosphate (ZP)); anion exchange particles (e.g. hydrous zirconium oxide (HZO)); activated carbon ; a buffer (e.g. calcium carbonate); and a urease.

[0114] Any suitable amount of the components listed above may be used in the sorbent cartridge mentioned herein.

[0115] Thus, also provided herein is a sorbent formulation for use in a sorbent cartridge, said sorbent formulation comprising (or consisting of) one or more of: cation exchange particles (e.g. zirconium phosphate (ZP)); anion exchange particles (e.g. hydrous zirconium oxide (HZO)); activated carbon ; a buffer (e.g. calcium carbonate); and a urease.

[0116] In certain embodiments, the sorbent formulation of the present invention may comprise (or consist of) the particulate porous material of the present invention, cation exchange particles (e.g. zirconium phosphate (ZP)), anion exchange particles (e.g. hydrous zirconium oxide (HZO)), and a buffer (e.g. calcium carbonate). For example, the sorbent formulation may comprise: i. from about 1 wt% to about 6 wt% (e.g. about 3 wt%) of the particulate porous material of the present invention; ii. from about 47 wt% to about 57 wt% (e.g. about 52 wt%) of cation exchange particles (e.g. zirconium phosphate (ZP)); ill. from about 37 wt% to about 47 wt% (e.g. about 43 wt%) of anion exchange particles (e.g. hydrous zirconium oxide (HZO)); and iv. from about 0.5 wt% to about 2.5 wt% (e.g. about 2 wt%) of a buffer (e.g. calcium carbonate).

[0117] In certain other embodiments, the sorbent formulation may comprise (or consisting of) the particulate porous material of the present invention and activated carbon (e.g. activated carbon that can selectively adsorb uremic toxins such as creatinine). For example, the sorbent formulation may comprise: i. from about 1 wt% to about 10 wt% (e.g. about 4 wt%) of the particulate porous material of the present invention relative to the total amount of sorbent mixture; and ii. from about 90 wt% to about 99 wt% (e.g. about 96 wt%) of activated carbon.

[0118] It follows that the sorbent cartridge of the present invention may contain a sorbent formulation of the present invention, as defined above. For the avoidance of doubt, the term “wt%” used above with respect to the components of the sorbent formulation refers to the wt% of the relevant component relative to the total mass of the sorbent formulation.

[0119] The term "cation exchange particles" as used herein refers to particles capable of capturing or immobilizing cationic or positively charged species when contacted with such species, typically by passing a solution of the positively charged species over the surface of the particles. For example, the cation exchange particles may be zirconium phosphate. For example, zirconium phosphate in the sodium or hydrogen form serves as a cation exchanger and absorbs cations such as ammonium (NH4+), calcium (Ca2+), potassium (K+), and magnesium (Mg2+). In exchange for absorbing these cations, zirconium phosphate releases two other cations, sodium (Na+) and hydrogen (H+).

[0120] Zirconium phosphate may be prepared by mixing sodium zirconium carbonate with a phosphate buffer having a desired pH value and in an appropriate ratio, which can readily be determined by a skilled person.

[0121] The zirconium phosphate particles may have an average particle size in the range of from about 10 microns to about 1000 microns, about 100 microns to about 900 microns, about 200 microns to about 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700, 500 microns to about 600 microns, about 25 microns to about 200 microns or from about 25 microns to about 150 microns or from about 25 microns to about 80 microns or from about 25 microns to about 50 microns or from about 50 microns to about 100 microns or from about 125 microns to about 200 microns, or from about 150 microns to about 200 microns, or from about 100 microns to about 175 microns, or from about 100 microns to about 150 microns or from about 150 microns to about 500 microns, or from about 250 microns to about 1000 microns. The term "anion exchange particles" as used herein refers to particles capable of capturing or immobilizing anionic or negatively charged species when contacted with such species, typically by passing a solution of the negatively charged species over the surface of the particles. The anion exchange particles may comprise of an amorphous and partly hydrated, water-insoluble metal oxide in its hydroxide-, carbonate-, acetate-, and / or lactate- counter-ion form, wherein the metal may be selected from the group consisting of titanium, zirconium, hafnium and combinations thereof. For example, the anion exchange particles may be zirconium oxide particles.

[0122] The zirconium oxide may be provided in any suitable form, such as zirconium oxide particles. When in the form of particles, the zirconium oxide particles may have an average particle size in the range of from about 10 microns to about 1000 microns, about 100 microns to about 900 microns, about 200 microns to about 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700, 500 microns to about 600 microns, about 10 microns to about 200 microns or from about 10 microns to about 100 microns or from about 10 microns to about 30 microns or from about 10 microns to about 20 microns or from about 20 microns to about 50 microns or from about 25 microns to about 50 microns or from about 30 microns to about 50 microns or from about 40 microns to about 150 microns or from about 80 microns to about 120 microns or from about 160 microns to about 180 or from about 25 microns to about 250 or from about 250 microns to about 500 or from about 250 microns to about 1000.

[0123] The zirconium oxide may be a hydrous zirconium oxide. Hydrous zirconium oxide may be synthesised by conventional methods, for example by reaction of an aqueous mixture of sodium zirconium carbonate and sodium hydroxide as described in US Pat No 4,256,718. After synthesis of hydrous zirconium oxide, the product may be titrated to a pH of from 12 to 13. This can be done by making an aqueous slurry of the hydrous zirconium oxide and titrating it with 5M sodium hydroxide until the slurry is at a pH of 12 to 13. In some instances, the hydrous zirconium oxide may then be washed until the concentration of leachables in the filtrate was within acceptable levels, and air dried. Alternatively, the hydrous zirconium oxide may recovered directly from the slurry and not washed before being air dried.

[0124] When used herein, the term “buffer” refers to a buffer suitable for use in a sorbent cartridge in purification of a bodily fluid (e.g. a kidney dialysis treatment, such as a haemodialysis treatment, a peritoneal dialysis treatment or a hemoperfusion treatment). Any suitable buffer may be used herein. For example, the buffer may be calcium carbonate.

[0125] When used herein, the term “urease” is a synonym for the term “uremic toxin-treating enzyme” and both refer to an enzyme able to react with a uremic toxin as a substrate. For example, the uremic toxictreating enzyme may be an enzyme able to react with urea as a substrate, with uric acid as a substrate, or with creatinine as a substrate. Uremic enzymes can be determined to have this function in vitro, for example, by allowing the enzyme to react with a uremic toxin in solution and measuring a decrease in the concentration of the uremic toxin. Examples of uremic toxin-treating enzymes include, but are not limited to, ureases (which react with urea), uricases (which react with uric acid), or creatininases (which react with creatinine). In a third aspect of the invention, there is provided a method of performing dialysis (e.g. haemodialysis, peritoneal dialysis or hemoperfusion), comprising a step of passing a dialysate through a sorbent cartridge as defined above.

[0126] In a fourth aspect of the invention, there is provided a use of a particulate porous material as defined above, or a sorbent cartridge as defined above, to adsorb beta-2 microglobulin.

[0127] In a fifth aspect of the invention, there is provided a method of removing beta-2 microglobulin from a fluid, comprising: providing a fluid comprising beta-2 microglobulin; and exposing said fluid to a particulate porous material as defined above.

[0128] In a sixth aspect of the invention, there is provided a method of preparing a particulate porous material as defined above, the method comprising the steps:

[0129] (i) providing mixture comprising a first monomer that is ethylene glycol dimethacrylate, an initiator, a porogen and optionally a second monomer that is a hydrophilic monomer;

[0130] (ii) conducting a polymerisation reaction to form a bulk porous material; and

[0131] (iii) grinding or pulverising the bulk porous material to provide a particulate porous material.

[0132] The term “initiator” refers to a chemical species that reacts with a monomer to initiate a polymerisation reaction. Examples of initiators include, but are not limited to, 2’-azobis(2-methylpropionitrile) (AIBN), 4,4’-azobis(4-cyanovaleric acid) (ACVA), benzoyl peroxide, and 1 ,1 ’-azobis(cyclohexanecarbonitrile).

[0133] When used herein, the term “porogen” refers to a material additive that can influence the pore structures of the particulate porous material. Examples of porogens include, but are not limited to, toluene, chloroform, acetone, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, and acetonitrile.

[0134] In some embodiments of the sixth aspect of the invention that may be mentioned herein, the porogen may be an organic solvent selected from the group consisting of toluene, chloroform, acetone, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, and acetonitrile.

[0135] Grinding or pulverising of the bulk porous material may be carried out by one or more of the following procedures:

[0136] 1 . manual grinding with a mortar and a pestle;

[0137] 2. milling using an analytical or industrial mill; and

[0138] 3. cryomilling, which involves milling of a sample chilled to 77 K.

[0139] The method of preparing a particulate porous material as defined above may further comprise washing the particulate porous material to remove the porogen. For example, the particulate porous material may be washed by sonicating the particulate porous material in a solvent, centrifuging the particulate porous material in the solvent, and decanting the supernatant solvent, to remove the porogen. As will be appreciated, the solvent may be selected from one or more of methanol, acetic acid, ethanol, deionised (DI) water, acetone, and sulfuric acid. In some embodiments of the sixth aspect of the invention that may be mentioned herein, the porogen may be an organic solvent having a Hansen distance (Ra) of up to 10 MPa1'2, where Dpoiymer = 17.0, Ppolymer = 9.7 and Hpolymer = 4.9.

[0140] The Hansen distance (Ra) may be calculated by applying the following equation.

[0141] The values of Dpoiymer, Ppoiymer and Hpoiymer may be determined by conducting Solubility Sphere Analysis according to the Hansen method. Specific details are provided in the following examples.

[0142] In some embodiments of the sixth aspect of the invention that may be mentioned herein, step (ii) may be performed at a temperature of from 50°C to 70°C.

[0143] As will be appreciated, the present invention provides the following advantages.

[0144] • Simplified synthesis: the present invention is the only B2M sorbent that can be synthesised through bulk polymerisation in a single step, from only three reagents. This allows for efficient and scalable production. Moreover, it uses cost-effective raw materials, making it economically viable for large-scale production.

[0145] • Novel design: novel in terms of chemical structure and microstructure, using a combination of pore size, porosity and hydrophilic / hydrophobic interactions to trap and adsorb B2M. There is no need for inactive carrier material, the polymer matrix is the adsorbent. This leads to reduced wastage of material and enables manufacturing of smaller devices.

[0146] • Novel, tunable structure: synthesis of porous sorbents from pure EGDMA appears to be a novel approach. Additionally, in the present disclosure, we have demonstrated the tunability of porosity and pore size of this novel sorbent by varying porogen type and porogen ratio. Tunability of functionality was demonstrated by incorporation of various comonomers while maintaining B2M adsorption capability (see Example 8 below).

[0147] • Desirable handling properties: the present invention is essentially a polyester powder. It is stable at room temperature and is inert under physiological conditions.

[0148] • High capacity: the present invention demonstrates exceptional performance, exhibiting high binding capacity even at low B2M concentrations, for example in dialysis fluid. Notably, it maintains its selectivity for B2M even in the presence of high glucose and salt concentrations, and other proteins commonly found in biological fluids.

[0149] • Fast binding kinetics: the kinetic properties of the present invention are also favourable, achieving rapid adsorption of significant quantities of B2M in both static and dynamic flow environments.

[0150] Sterilisability: additionally, the present invention is sterilizable, ensuring its suitability for medical applications without compromising its adsorption capabilities. • The following examples provides evidence of its performance in terms of binding capacity, selectivity, and kinetic properties, highlighting its potential impact in improving peritoneal dialysis outcomes.

[0151] Accordingly, the present invention may find applications in the following.

[0152] • Hemoperfusion: the primary application of B2M sorbent materials is as an active ingredient in hemoperfusion sorbent cartridges. In this type of application, the blood is passed through the sorbent cartridge. The sorbent interacts directly with the blood and filters it by removing unwanted B2M proteins.

[0153] • Peritoneal dialysis: the sorbent material may be used in a sorbent cartridge for dialysate regeneration in sorbent peritoneal dialysis (PD). For example, Poly-EGDMA could partially replace AC in an existing sorbent design, saving space and reducing overall device weight. The cartridge would also be more selective, with less glucose adsorption caused by AC.

[0154] • Hemodialysis: similarly, the sorbent could be of benefit when used in sorbent hemodialysis, allowing the manufacture of an optimised HD sorbent cartridge.

[0155] • General: Poly-EGDMA can be used to selectively remove B2M from biological fluids in general. For example, Poly-EGDMA may be used for selective removal of B2M from a research sample or a blood sample.

[0156] Further aspects and embodiments of the invention will now be discussed by reference to the following non-limiting examples.

[0157] EXAMPLES

[0158] Materials

[0159] All reagents and solvents were purchased from Sigma-Aldrich or TCI and used as received.

[0160] Samples were coated with Pt and analysed using FESEM JEOL JSM-7800F PRIME.

[0161] Example 1. Crosslinker Evaluation

[0162] The main criteria for a suitable sorbent are:

[0163] • high adsorption capacity, >1 mg / mL for beads or >1 mg / g for powder (as per application);

[0164] • high selectivity, minimal albumin removal (<10%); and

[0165] • biocompatibility (minimal binding of platelets and leucocytes, minimal increase in inflammatory markers).

[0166] Selection of crosslinking monomers was evaluated in order to identify suitable polymer matrix with affinity for the B2M molecule in PD solution. In total, 5 crosslinkers with varying structure, molecular weight, and hydrophobicity were screened. Each crosslinker was polymerized under similar conditions via free-radical polymerization. Resultant polymers were characterized and analysed for B2M adsorption properties.

[0167] Results and discussion

[0168] Table 1 . Crosslinker evaluation.

[0169] Hydrophobicity (logP): DVB = EGDMA > TRIM > PEGDA > BA Molecular weight: PEGDA > TRIM > EGDMA > DVB > BA Crosslinkable groups: TRIM > DVB = EGDMA = BA = PEGDA

[0170] Example 2. Synthetic method for polymers

[0171] Each crosslinker discussed in Example 1 was polymerized under similar, free-radical bulk polymerization conditions (FIG. 1 ). Allowance was made for variation in crosslinker solubility by adjusting porogen and washing conditions. In a 20 ml_ glass vial, the crosslinking monomer and initiator (ACVA), 30 mg, 0.1 1 mmol) were added to a porogen (6 mL) and sonicated for 30 s. The vial was purged with N2 for 2 min and sealed with a rubber lined cap. The mixture was polymerized by placing the vial in an oven at 60 °C for 48 h.

[0172] The resultant polymeric solid was divided into ~1 cm pieces with a spatula and transferred to a mortar and pestle. The polymer pieces were processed in two steps: 1 ) the transferred pieces were initially pulverized into particles smaller than approximately 3 mm to allow for efficient grinding; and

[0173] 2) the polymer was ground at approximately 1 cycle per second for 60 s.

[0174] The polymer particles were then collected in a 50 mL falcon tube and subjected to sequential washing steps consisting of: a) sonication for 15 min in 30 mL of solvent; and b) centrifugation for 10 min at 5000 rpm and decantation of supernatant solvent.

[0175] The resultant powders were oven dried at 40 °C until no weight change was detected, typically 48 h.

[0176] The washing step for each polymer is provided in the table below.

[0177] Table 2. Washing steps.

[0178] Specifically, polymer samples (1 A-1 C) were prepared with 3 different crosslinkers, under similar conditions:

[0179] 1 . crosslinker 9 mmol, ACVA 0.04 mmol, porogen 6 mL;

[0180] 2. polymerised at 60 °C for 48 h, pulverised < 3 mm and ground 60 s;

[0181] 3. washed as depicted in Table 2 above; and

[0182] 4. vacuum dried in a vacuum drying oven at 40 °C for 48 h.

[0183] Example 3. Static Adsorption Test

[0184] Samples 1 A-1 E prepared in Example 2 were taken for static adsorption test.

[0185] Static test method

[0186] 50 mg sample was incubated with 100 mL PD fluid (typically 1000-3000 pg B2M / L, total protein 0.5- 1 .0g / L. More specifically, 2108-2812 pg B2M / L, total protein 0.7-0.9 g / L), and incubated for 2 h at 23 °C, 150-250 rpm agitation rate. 50 mg AC tested for comparison.

[0187] B2M adsorption calculation:

[0188] Mass of B2M adsorbed per gram (mg / g) = (Cpre-CpOst) * VSamPie / MsamPiewhere Cpre= starting concentration of B2M in pg / L, CpOst = final concentration of B2M in pg / L, Vsampie = volume of PD fluid, and MsamPie= mass of polymer / AC sample in grams.

[0189] B2M assay

[0190] B2M assay was performed by SGH Clinical Pathology lab. |32-microglobulin was tested through Immuno-turbidimetry method performed on Roche Cobas c502 chemistry analyser (Brand / Part Number: Tina-quant p2-Microglobulin (B2MG) (08047430190). Assay kit manufacturer: Roche), according to the manufacturer’s protocol.

[0191] Protein Loss - Static Test Method

[0192] Test sample was prepared in same manner as in B2M assay.

[0193] Protein loss calculation:

[0194] Estimated protein loss (g / L) = Cpre- CpOst

[0195] Where Cpre= starting protein concentration in g / L, and Cpost = final protein concentration in g / L.

[0196] Protein estimation was determined by Bradford assay.

[0197] Bradford assay

[0198] In a 96-well plate, sample solutions (5 pL) were incubated with Bradford Reagent (250 pL; TCI Chemicals, Product No B5702) for 20 min, along with a blank solution (5 pL Milli-Q water) and standard solution (1 .Og / L Bovine Serum Albumin solution). The absorbance at 595 nm was measured using a UV-vis well plate reader. A blank correction was performed on the samples and standard by subtracting the absorbance attributed the blank solution. The absorbance value from the 1 g / L BSA solution was used to create a single point calibration curve (absorbance vs concentration). The calibration curve was used to determine the estimated protein content of samples based on their absorbance values.

[0199] Results and discussion

[0200] Table 3. Static adsorption test results.

[0201] Poly-EGDMA (1 A) exhibited unexpectedly strong, selective adsorption behaviour toward B2M in comparison to the other materials tested. This B2M selectivity is observed amongst a mixture of different proteins and solutes being present in PD fluid.

[0202] Example 4. Nitrogen Porosimetry

[0203] Samples 1 A, 1 B, 1 C and 1 F prepared in Example 2 were taken for nitrogen porosimetry study.

[0204] Surface area, pore volume and pore size distribution

[0205] Dinitrogen adsorption-desorption experiments were carried out by static manometric method (Standardization, I.O.f. , Determination of the specific surface area of solids by gas adsorption — BET method. 2022, ISO 9277:2022). Measurements were performed at 77.3 K on a Micrometrics ASAP model 2020 porosimeter. Equilibration time was set to 10 s and free space was measured by the instrument.

[0206] Samples (50-100 mg) were degassed at 40 °C under vacuum for 16 h prior to data collection.

[0207] Surface area, pore volume and pore size distribution were calculated using methods provided by Micromeritics MicroActive software version 5.02.

[0208] Multipoint surface area measurements utilized an 8-point adsorption isotherm collected over 0.05 to 0.20 p / p° and were analyzed using BET theory (Brunauer, S., Emmett, P. H. & Teller, E., J. Am. Chem. Soc., 1938, 60, 309-319).

[0209] The single point total pore volume was calculated and reported by Micromeritics MicroActive software. The single point total pore volume was calculated at a single point approaching saturation pressure p / p° >0.95, which was an application of the Gurvich rule (Rouquerol, J., et al., Adsorption by powders and porous solids: principles, methodology and applications. 2013: Academic press). BJH adsorption pore size distributions utilized a 33-point adsorption isotherm and were analyzed via the BJH method provided by Micromeritics software, using the Halsey-Faas correction option (Barrett, E. P., Joyner, L. G. & Halenda, P. P., J. Am. Chem. Soc., 1951 , 73, 373-380). Pore size ranges and isotherm types were classified according to IUPAC recommendations (Rouquerol, J., et a / ., Pure Appt. Chem., 1994, 66, 1739-1758: and Thommes, M., et a / ., Pure Appl. Chem., 2015, 87, 1051-1069).

[0210] The Brunauer-Emmett-Teller (BET) Adsorption Average Pore Size refers to an assumed cylindricalshaped pore width calculated via the Gurvich rule and BET method:

[0211] D = 4V / S

[0212] Where D = average pore diameter, V = single point total pore volume and S = specific surface area determined by BET model. The data were cited as calculated and reported by the MicroActive software.

[0213] Porosity was calculated via the below equation:

[0214] Porosity (%) = single point total pore volume (cm3 / g) * tapped density (g / cm3) x 100

[0215] Tapped density was measured by mechanically tapping the dry polymer samples in a 5 mL measuring cylinder, and allowing the sample to settle to a final volume under its own weight. The tapped density was calculated as follows:

[0216] Tapped density = Sample mass (g) / Final Volume (cm3)

[0217] The sample (1 g) was loaded into the measuring cylinder. The sample was then tapped for 60 s at 1 tap per second on the lab bench and volume measured. The sample was then tapped again for further rounds of 60 s until no further change was observed in the sample volume. This value was then taken as the final volume.

[0218] Results and discussion

[0219] FIG. 2 depicts the nitrogen porosimetry results.

[0220] Table 4. Nitrogen porosimetry results.

[0221] N2 adsorption-desorption experiments revealed that the synthesised polymers were mesoporous with average pore size in similar range of 2.9-4.5 nm according to BET model. 1 A had much higher affinity and capacity for B2M than the other synthesised mesoporous polymers 1 B and 1 C. This is in spite of the finding that 1 B had almost twice the porosity, surface area and total pore volume of 1 A. 1 C had a very low degree of porosity, therefore low B2M capacity was not surprising. AC had high degree of microporosity and surface area but this did not translate into significant B2M adsorption. Purely microporous materials appear unsuitable for B2M adsorption, which could be due to restrictive pore size vs B2M hydrodynamic radius (2.0 nm vs 1 .6 nm). In this case, molecular structure and functional properties dominated over surface properties as factors influencing B2M adsorption. This could imply that Poly-EGDMA exhibits chemical properties which are particularly suitable towards selective adsorption of B2M. Due to lack of porosity, gelatinous nature and low B2M binding, hydrophilic polymers 1 D and 1 E were not further characterised.

[0222] Poly-EGDMA is a novel porous adsorbent material developed for the highly selective and efficient removal of B2M from PD fluid (FIG. 3). Porous poly-EGDMA particles have an abundance of micro / mesopores (FIG. 3), are hydrophobic, and have simple synthesis. They are able to bind B2M in PD fluid in high efficiency, high selectivity, and high stability.

[0223] As such, a new B2M adsorbent material has been prepared from cross-linked Poly-EGDMA. EGDMA is a difunctional monomer which is commonly used as a crosslinker in free-radical polymerisation reactions. It is normally used in small amounts (1 -2% of total monomer content) and copolymerised with other monofunctional monomers like styrene and methyl methacrylate to form crosslinked polystyrene (PS) or polymethylmethacrylate (PMMA). EGDMA itself is polymerised to poly-EGDMA, a heavily crosslinked network polymer with high chemical and physical stability.

[0224] Example 5. Proposed Poly-EGDMA adsorption behaviour

[0225] Optimal structure and porosity

[0226] 1 . Poly-EGDMA: conglomerates of irregular shaped nodules

[0227] 2. Pores: free space between conglomerates

[0228] 3. Micropores and small mesopores - size selectivity and B2M sieving effect

[0229] 4. Macropores - efficient fluid transport channel into microparticle

[0230] IUPAC Classification

[0231] Macropore: >50nm Mesopore: 2-50 nm

[0232] Micropore: < 2nm

[0233] Pore diameter determination

[0234] The pore diameter data was derived from the 33-datapoint adsorption branch of the N2 isotherm. Miromeritics MicroActive software version 5.02 was used to analyse the data according to the Barrett- Joyner-Halenda model with Halsey-Faas correction, in order to derive the pore size distribution and average pore diameter data.

[0235] Results and discussion

[0236] B2M has a globular, compact structure, and a hydrodynamic radius of ~1 .6 nm, thus it can fit into large micropores and small mesopores.

[0237] FIG. 4 shows a SEM image of the poly-EGDMA microparticle. Poly-EGDMA has a high proportion of large micropores and small mesopores. The average pore diameter was 6.0 nm (FIG. 5).

[0238] Literature simulations (C. J. Dongmo Foumthuim etal., Mol. Biosyst. 2017, 13, 2625-2637) have shown that B2M binds quickly and irreversibly to hydrophobic surfaces via a 2-step process:

[0239] • initial adsorption by polar and charged groups; and

[0240] • partial unfolding occurs, maximizing adhesion of the protein to the hydrophobic surface (accentuated interaction of hydrophobic groups).

[0241] Poly-EGDMA is hydrophobic overall (EGDMA water / octanol partition coefficient —> logP = 2.8, lipophilic > 0). Ester groups may serve as polar groups for initial adsorption step.

[0242] Example 6. Effect of Porogen Type

[0243] Attempt was made to prepare Poly-EGDMA with different pore sizes, by varying porogen type. This was done in order to characterize the relationship between pore size and B2M sorption.

[0244] Synthesis of Poly-EGDMA (FIG. 6)

[0245] Four samples were polymerized under similar conditions to Sample 1 A in Example 2 except that the initiator used was AIBN and the porogen was varied.

[0246] Table 5. Synthetic method for 2A-2L.

[0247] This synthetic method is a free radical polymerisation process. It is a simple 1 -step synthesis + washing, sieving and drying. It gives high yield and is scalable. Hansen solubility parameter system (Chesnokov, S.A., et al., Macromol. Biosci., 2021, 21, 2000402.)

[0248] There are number of different systems to classify solvents and their molecular properties (dielectric constant, polarity index, dipole moment, etc.). The Hansen solubility parameter system attempts to classify and rank solvents according their propensity to interact via dispersion, polar and H-bonding forces. Hansen solubility parameters, Hansen distance and sphere radius were calculated according to Hansen theory (Hansen, C. M., Hansen Solubility Parameters. 2007) by means of multiresponse optimization, utilizing the Excel Solver and DATAFIT functions (Diaz De Los Rios, M. & E. Hernandez Ramos, SN Applied Sciences, 2020, 2). By theory, the closer the Hansen parameters between a solvent and a given monomer, the better suited the solvent is to solublise that monomer and its polymeric derivatives (good vs bad solvent). The closer the solubility parameters between the polymer and the porogenic agent, the greater the thermodynamic affinity and lesser effect of phase separation during polymerisation. This affinity has a profound effect on polymer pore size. For example, literature studies found that the closer the value of solubility parameters are between EGDMA and its solvent, the smaller the resultant pore size in its polymer products.

[0249] Table 6. Hansen solubility parameters. The polymers prepared were imaged with SEM, taken for static adsorption test as described in Example 3, and taken for nitrogen porosimetry study as described in Example 4.

[0250] Results and discussion

[0251] For 2 A, 2B, 2D, 2F, 2G, 2H, 2! and 2L • Bulk monolith formed.

[0252] • Slow / reduced phase separation during polymerisation process.

[0253] • Good solvent-polymer affinity.

[0254] • Typically porous due to presence of porogen in polymer lattice. For2C, 2E, 2J and 2K

[0255] • Particulate product formed directly (without pulverisation).

[0256] • Indicative of fast, significant phase separation during polymerisation stage.

[0257] • Poor solvent-polymer affinity. • Typically non-porous due to early separation of porogen and polymer phases.

[0258] FIG. 7 depicts the SEM images of monolithic polymers. FIG. 8 depicts the SEM images of particulate polymers. The Nz adsorption-desorption isotherms are depicted in FIG. 9. Table 7. Static adsorption test of 2A-2L.

[0259] ’Selected for further analysis.

[0260] Monolithic Poly-EGDMA had much high B2M capacity than particulate Poly-EGDMA. Highest performing monolith (2B) was selected for analysis by N2 adsorption and compared with below average monoliths (2F, 2L) and particles (2C).

[0261] Table 8. Nitrogen porosimetry results of 2B, 20, 2F and 2L.

[0262] The pore size distribution according to BJH model is depicted in FIG. 10.

[0263] Table 9. Surface properties of 2B, 2C, 2F and 2L.

[0264] Porosity

[0265] From Samples 2C, 2E, 2J and 2K, it is clear that the presence of crosslinked EGDMA is not sufficient to guarantee B2M adsorption. Good porogen and sufficient porosity in the final polymer are required to allow adsorption process to occur.

[0266] Pore size

[0267] From Samples 2B, 2F and 2L, average pore size and pore size distribution may play influential role towards B2M adsorption. Other factors such as surface area are less important.

[0268] Comparing B2M adsorption and surface properties, it appears that mesopore dominant poly-EGDMA (i.e., 2B) with narrower pore size distribution is preferred. Poly-EGDMA with broad pore size distribution and macropore dominant characteristics (i.e., 2F and 2L) is less preferable. Porogen suitability

[0269] Good porogen -> porous monolith -> Chloroform, DMSO, Acetone, Dioxane, Ethyl Acetate, MeCN, DMF, toluene.

[0270] Poor porogen — » non-porous particles —> MeOH, hexane, IPA, ethanol.

[0271] Example 7. Effect of porogen affinity

[0272] We aimed to characterise the relationship between porogen affinity, polymer properties and B2M adsorption.

[0273] Example 6 revealed that porogen affinity has substantial effect on final polymer properties. Polymerisation was attempted in mixed porogen environment. According to Hansen solubility theory, a mixed porogen exhibits properties according to the weighted average of the parent porogens. This was done in order to characterize the relationship between pore size and B2M sorption, and to find optimal porosity.

[0274] Synthesis of Poly-EGDMA-co-AA (FIG. 1)

[0275] Poly-EGDMA-co-AA was prepared by following the protocol in Example 2 except an additional monomer is added in the first step (AA) and a mixture of two porogens is used instead of a single porogen. More specifically, EGDMA (75%) and acrylic acid (AA, 25%) were copolymerized in a mixture functional acrylic acid

[0276] Wheremonomer

[0277] Table 10. Synthetic method for 3A-3E.

[0278] The polymers prepared were taken for static adsorption test as described in Example 3.

[0279] Results and discussion Based on outcome of 3A and 3E, EGDMA-AA had similar porogen affinity to pure EGDMA. Both encountered early phase separation in poor porogen, and vice versa.

[0280] Table 11 . Static adsorption test of 3A-3E.

[0281] Based on result 3C-3E, there appears to be a minimum requirement of -30% good porogen to be present in order to produce an active polymer. From 3C, it appears that at least 8% porosity and 0.36 cm3 / g total pore volume may be required for substantial B2M adsorption to occur.

[0282] Example 8. Effect of copolymerisation

[0283] We attempted to characterise the relationship between polymer functionalisation, polymer properties and B2M adsorption, and to expand on available intermolecular interactions beyond those provided by EGDMA. The hydrophobic and hydrophilic monomers are depicted in FIG. 11 .

[0284] Table 12. Synthesis and static adsorption test.

[0285] *100% clearance.

[0286] EGDMA (9 mmol, 75% monomer content) was successfully copolymerised in the presence of functional monomers (3 mmol, 25% monomer content). This provided capability to introduce additional functionality for different applications. Copolymers retained B2M adsorption behaviour to varying extent, but did not exceed capacity of patent polymer. Carboxylate, amine / amide and alcohol containing copolymers retained B2M activity to a certain extent. Best performance was observed for IA, AU and TFMAA. Inclusion C12 and C18 alkyl chains reduced adsorption capacity significantly.

[0287] Example 9. Equilibrium adsorption isotherm

[0288] Poly-EGDMA was prepared as described in Example 2 (MeCN porogen), and taken for static adsorption test as described in Example 3. Specifically, samples (mass = 82, 103, 128, and 151 mg) were incubated with 100 mL PD fluid (2135 pg B2M / L) for 2 h at 23 °C, 250 rpm. B2M adsorption was calculated as in Example 3.

[0289] Freundlich and Langmuir parameters

[0290] Langmuir parameters qmax and b were obtained by linear regression, by plotting 1 / Qeqvs 1 / Ceq, to yield a straight line with y-intercept 1 / qmax and slope 1 / (b x qmax).

[0291] Freundlich parameters KF and 1 / n were obtained by linear regression, by plotting log Qeqvs log Ceqto yield a straight line with y-intercept log KF and slope 1 / n. Results and discussion

[0292] FIG. 12 depicts the equilibrium adsorption isotherm.

[0293] Table 13. Equilibrium adsorption isotherm results.

[0294] Table 14. Summary of physical properties and isotherm parameters.

[0295] Example 10. Device Test

[0296] The B2M clearance by Poly-EGDMA in dynamic flow environment was evaluated.

[0297] Synthesis

[0298] Poly-EGDMA was prepared in the same manner as Sample 1 A in Example 2 except at 60 g scale. Fine particles were removed by 3x sedimentation in EtOH (500 ml_).

[0299] Cartridge test

[0300] A series of sorbent cartridges containing Poly-EGDMA was prepared and the B2M adsorption was evaluated.

[0301] Pre and post B2M concentration were measured, along with volume cleared and pressure. B2M adsorption calculation:

[0302] Mass B2M adsorbed

[0303] Where Cpre = starting concentration of B2M in pg / L, Cpost = final concentration of B2M in pg / L, and = volume of collected PD fluid in L.

[0304] The device set up is shown in FIG. 13. As shown in FIG. 13, the device set up 1300 includes a pre sample 1301 , an ex -vivo PD fluid (37 °C) 1302, a peristaltic pump 1303 (e.g. WT600F Intelligent Dispensing Peristaltic Pump), a pressure sensor 1304, a sorbent cartridge 1305, and a post sample 1306. Below are experimental examples evaluated to show the broad applicability of Poly-EGDMA as a B2M-selective sorbent component in different types of sorbent cartridges for dialysate regeneration.

[0305] 1 ) Example 10A: Application of Poly-EGDMA in General Sorbent Dialysis cartridge A sorbent cartridge was prepared by packing a sorbent mixture comprising Poly-EGDMA (12g), ZP (187g), HZO (153g) and CaCOs (6g) into an empty flash chromatography column (Hawach Scientific Part No SLEP0330PF) with included screw-cap inlet. The sorbent mixture was fixed in place by fitting a filter paper on either end (Advantec Industrial Filter Paper No. 28, 60mm diameter). Spent PD fluid (6.5L, the entire spent fluid volume from one patient’s APD therapy) was heated to 37 °C and passed through the cartridge at 25mL / min with resultant fluidic pressure of 550-980mbar. 1 L samples were collected consecutively from the cartridge outlet. The results are shown in Table 15.

[0306] 2) Example 10B: Application of Poly-EGDMA in B2M and Creatinine Selective Sorbent Dialysis cartridge

[0307] In a similar procedure to Example 10A, a cartridge was prepared using Poly-EGDMA (3g, sieved within 100-200pm particle size) and a creatinine-selective Activated Carbon (70g, Haycarb RW1512). Spent PD fluid (16L, the combined and mixed volume of spent dialysate from two patients on APD therapy) was filtered through a Medica 0.6m2high-flux dialyzer to remove fibrin. The Spent Dialysate was heated to 37 °C and passed through the cartridge at 50mL / min and resultant fluidic pressure of 400mbar. A 14L cumulative sample was collected, followed by another timepoint sample at the 16L mark to check for any breakthrough. Dialysate biochemistry was analysed using an Ortho Clinical Diagnostics Vitros XT 3400 system and standard Vitros MicroSlide Assays. The results are shown in Table 16A.

[0308] 3) Example 10C: Application of Poly-EGDMA as standalone Sterile B2M Adsorbent cartridge

[0309] A sterile, Poly-EGDMA sorbent cartridge was prepared as follows. Poly-EGDMA (0.5g, sieved within 100-200pm) was pre-swelled by preparing a slurry in deionised water and allowing it to stand for 30min. The slurry was wet-packed into cartridge form by feeding the slurry into an empty 12g flash chromatography column (Hawach Scientific, Part No SLEP0012PF) fitted with included polyethylene frits (pore size 16-20pm) and screw-cap intlet. Excess DI water was drained through the oulets by allowing the cartridge to stand vertically for 10 mins. The cartridge outlets were closed loosely with male and female Luer caps, following which the cartridge was sealed in an autoclave bag and sterilised at 121 C, 15mins.

[0310] Spent PD fluid (8L, the volume of spent dialysate from a single patient on APD therapy) was filtered through a Medica 0.6m2high-flux dialyzer to remove fibrin. The Spent Dialysate was heated to 37 °C and passed through the cartridge at 30mUmin with resultant fluidic pressure drop of 400-900mbar. Consecutive 2L samples were collected from the cartridge outlet. The results are shown in Table 16B.

[0311] Results and discussion

[0312] Table 15. Sample composition for Example 10A.

[0313] ‘amount of B2M in spent PD fluid before passing through the cartridge.

[0314] “amount of B2M in spent PD fluid after passing through the cartridge.

[0315] Based on the results shown in Table 15, the cartridge test passed as B2M was reduced to below the detection limit (200pg B2M / L) and pressure drop was maintained below < 1 bar. Clearance was maintained above 75% and at least 3839 pg B2M was adsorbed. This provided evidence that Poly- EGDMA could function as a synergistic sorbent component in combination with typical materials such as ZP and HZO, as well as additives like CaCOs. Table 16A. Sample composition for Example 10B.

[0316] ‘amount before the spent PD fluid passed through the cartridge; “amount after the spent PD fluid passed through the cartridge; n.d. = not determined.

[0317] Based on the 14L cumulative result in Table 16A, the combination of 3g Poly-EGMDA and 70g AC was able to reduce the creatinine and B2M concentrations to below the limit of detection. Other solutes remained almost constant, confirming the selectivity of the combination of poly-EGDMA and AC towards the targeted toxins. Data from an additional timepoint at the 16L mark showed that the cartridge had not yet been saturated and had additional capacity available. In addition to passing the toxin removal test, the cartridge was also able to pass fluidic pressure requirements by maintaining a pressure drop well below < 1 bar (observed: 200-400mbar).

[0318] Table 16B. Sample composition for Example 10C.

[0319] ’amount of B2M in spent PD fluid before passing through the cartridge; ’’amount of B2M in spent PD fluid after passing through the cartridge.

[0320] Results in Table 16B show that B2M was readily adsorbed onto Poly-EGDMA alone, even under dynamic conditions. Remarkably, a minute-sized cartridge containing just 0.5g of Poly-EGDMA was able to remove 7.3mg of B2M from solution, translating to a dynamic binding capacity 14.6mg B2M / g Poly-EGDMA, exceeding the measured static adsorption capacity by more than 3x. This result showed that selectivity for B2M was retained and that performance excelled under dynamic conditions. Fluidic pressure requirements of <1 bar were also met (observed: 400-900mbar).

[0321] Overall, the results showed that the efficacy of Poly-EGDMA as a B2M sorbent was maintained under dynamic flow conditions when tested as a single-component sorbent device, even after being subjected high-pressure and temperature conditions via autoclave sterilisation.

[0322] Example 11. Particle size

[0323] The effect of particle size on B2M adsorption in static environment was evaluated.

[0324] Synthesis

[0325] Poly-EGDMA was prepared in the same manner as Sample 1 B in Example 2 except at 60 g scale.

[0326] Particle size distribution analysis

[0327] The particle size distribution of pre-sieved material was analysed by laser diffraction using Horiba LA- 960 Laser Scattering Particle Size Distribution Analyser via wet measurement method. The method parameters are listed in Table 17 below. After pulverization, washing and drying, the powder was sieved into four fractions.

[0328] Table 17. Laser scattering particle size distribution analyser LA-960 parameters.

[0329] | Median size: | 162.06665 (pm) | Mean size: | 212.79991 (pm) |

[0330] Static adsorption test

[0331] B2M adsorption capacity was determined in a similar manner to Example 3. Pre-B2M concentration:

[0332] 2606 pg / L. 50 mg polymer / 100 mL PD fluid.

[0333] Results and discussion

[0334] FIG. 14 depicts the particle size distribution data.

[0335] Table 18. Parameter and particle size.

[0336] Table 19. Particle size and B2M adsorbed.

[0337] Based on the D10 and D90 values of the parent material 7A, it would be fair to assume that the undersize fraction 7B is mostly 27-106 pm while the oversize fraction 7E is mostly 212-475 pm. All fractions isolated had significant B2M adsorption capacity. Capacity increased dramatically as particle size range reduced from 7E to 7B. This makes sense as smaller particles have a higher amount of exposed surface area per unit mass, allowing for greater availability of surface adsorption sites.

[0338] Example 12. Hansen Solubility Parameter

[0339] We aimed to define what is a good porogen for Poly-EGDMA according to HSP theory and to calculate HSP range for good porogen.

[0340] Hansen Solubility Parameter (HSP) determination for good porogen Firstly, the HSP of Poly-EGDMA was approximated by conducting Solubility Sphere Analysis according to the Hansen method. In brief: a. each porogen was assigned a score (1 or 0) based on the experimental outcome of Example 6 (good porogen = 1 , bad porogen = 0); b. a 3D spherical function was fitted to encompass the 2xD, P and H values of all porogens with good score, while excluding porogens with bad score; c. the radius of the sphere was optimized to smallest possible value while maintaining a goodness of fit (Ai) of 1 ; and d. the HSP of Poly-EGDMA was estimated to be the origin of the sphere (according to Hansen method), with Dpoiymer = 17.0, Ppoiymer = 9.7 and Hpoiymer = 4.9. The radius of interaction for Poly-

[0341] EGDMA was also estimated, where Ro = 9.1 .

[0342] Secondly, HSP of good porogen was estimated to be all porogens within a Hansen Distance (Ra) less than or equal to Ro, where Ra 2 Ro, i.e., Ra 2 9.1 .

[0343] Results and discussion

[0344] Table 20. HSP values and fitted dataset.

[0345] D, P, H, Ro, Ra units = MPa1''2

[0346] FIG. 15 depicts the Hansen Solubility Sphere (experimental). FIG. 16 depicts the Hansen Solubility Sphere (predicted).

[0347] Table 21 . Predicted dataset.

[0348] Predicted dataset Porogen ranking

[0349] Porogen Abbrev Dispersion Polar H- RaRED Exp Pred bonding

[0350] Benzene BEN 18.4 0 2 10.5 1 .2 N / A 0

[0351] Diethyl ether EtzO 14.5 2.9 4.6 8.5 0.9 N / A 1

[0352] Tetrahydrofuran THF 16.8 5.7 8 5.1 0.6 N / A 1

[0353] Dichloromethane DCM 17 7.3 7.1 3.3 0.4 N / A 1 n-Butanol n-BuOH 16 5.7 15.8 11 .8 1 .3 N / A 0 n-Propanol n-PrOH 16 6.8 17.4 13.0 1 .4 N / A 0

[0354] Benzonitrile PhCN 17.4 9 3.3 1.9 0.2 N / A 1

[0355] 2-Butanone MEK 16 9 5.1 2.1 0.2 N / A 1

[0356] 2-Heptanone MAK 16.2 5.7 4.1 4.4 0.5 N / A 1

[0357] Cyclohexanone CH 17.8 6.3 5.1 3.8 0.4 N / A 1

[0358] Prediction of Good Porogen

[0359] The literature DPH value of untested porogen can be used to calculate Ra and relative energy difference (RED), where RED = Ro / Ra. For porogens with RED <1 , their DPH will lie within the solubility sphere and are thus likely to be good porogens. Conversely, porogen with RED > 1 are likely to be poor porogens.

[0360] Hansen Solubility Parameter

[0361] Hansen theory utilises the principle of “like dissolves like” to describe the interaction of compounds and solvents. Based on the experimental polymerization results, solvents were categorized as good or poor porogen for Poly-EGDMA. By fitting good porogens into and excluding poor porogens from a spherical function, the HSP of Poly-EGDMA was estimated to be D = 17.0, P = 9.7 and H = 4.9. This is somewhat different to the literature values published for the monomer (D = 16.4, P = 5.2, H = 8.6, T. Renkecz et al., Molecular Imprinting 2014, 2, 1 -17).

[0362] The radius of interaction for Poly-EGDMA was also estimated, where Ro = 9.1 . The HSP of good porogen was estimated to be all porogens with a Hansen Distance (Ra) less than or equal to Ro, where Ra < Ro, i.e. Ra9.1 . Alternatively, porogens with RED < 1 are likely to be good porogens, and porogen with RED > 1 are likely to be poor porogens, where RED = Ro / Ra. Table 22. Scope of the invention. Therefore, our sorbent is novel in terms of chemical structure and microstructure, using a combination of desired pore size, porosity and hydrophilic / hydrophobic interactions to trap and adsorb B2M.

[0363] Tailored pore size range: B2M adopts a globular structure in solution, with a reported hydrodynamic radius of 1 .6 nm.

[0364] Poly-EGDMA is a highly porous material. Through the bulk polymerisation process in presence of a porogen, the polymer precipitates in the form of irregular shaped nodules, which further crosslink and join up to form conglomerates. The porogen forms a separate phase in between conglomerates, leading to the formation of pores and eventual construction a highly porous network.

[0365] • Micropores & small mesopores - size selectivity and B2M sieving effect

[0366] • Macropores - efficient fluid transport channel into microparticle

[0367] The unique pore size distribution of our material may contribute to the high selectivity and adsorption capacity for B2M.

[0368] As such, in the present disclosure, we have surprisingly generated a material with high selectivity, without presence of template and functional monomer. This is advantageous as it would be very difficult to introduce B2M as a template molecule for a number of reasons.

[0369] 1 . Expensive cost of B2M.

[0370] 2. Insolubility and instability of B2M in organic porogens.

[0371] 3. Difficulty in removing B2M template to generate the cavities. The lack of necessity for a functional monomer simplifies and speeds up the entire synthetic process.

[0372] Comparative Example 1

[0373] Sorbent-based devices have been previously developed to aid the removal of additional B2M in hemodialysis. The devices are hemoperfusion cartridges, which are intended to be placed directly in the blood line of the HD circuit, either before or after the dialyser. Most concepts contain porous polymeric beads. Adsorption of B2M typically takes place by sieving / size-exclusion effect through a specific pore size, and through intermolecular forces such as hydrophobic interactions.

[0374] For example, Kaneka Corporation (Japan) has developed Lixelle (EP0647470 and Suzuki, K., Shimazaki, M. and Kutsuki, H., Ther. Apher. Dial., 2003, 104-107), an FDA approved hemosorbent product for the treatment of DRA. Cytosorbents have also developed a corresponding product (WO1999006098) which has undergone clinical trial, but not commercialised.

[0375] Although the addition of hemoperfusion column enhanced B2M removal by 1 .5-2x, numerous limitations affect the clinical acceptability and commercialisability of these solutions.

[0376] Cost: Lixelle is only available in Japan, reportedly due to high cost of the device. Cytosorb’s product is not available in the market, 20 years after research was published.

[0377] Biocompatibility: o Several adverse effects were reported during Lixelle clinical trials, including anemia and hypotension. These are associated with the large extracorporal volume of the device (150-350 ml_). o Leucocyte activation was also indicated in some users, associated with bioincompatibility. o There is limited data available on Betasorb / cytosorb device.

[0378] • Adsorption capacity: o Lixelle appears to have insufficient B2M capacity for present application, since extracorporeal volume is large enough to cause adverse effects. o There is limited data available on Cytosorb device. Davankov research paper (Davankov, V., etal., J. Chromatogr. B: Biomed. Sci. Appl., 2000, 739, 73-80) indicates similar adsorption capacity to Lixelle in serum.

[0379] • Applicability to Sorbent PD: o From Lixelle research paper (S. Furuyoshi et al., Ther. Apher. 1998, 2, 13-17), B2M capacity appears very low when B2M concentration is low. o This may cause complications in the use of this sorbent in sorbent PD, where B2M level in dialysate is 10-20x less than serum.

[0380] Sabie (WO2018211389A1 ) and Tharpa etal. (K. Tharpa etal., J. Artif. Organs 2020, 23, 47-53) disclose the preparation of a family urea-MIPs for dialysis purposes, by polymerisation of EGDMA and other crosslinkers, in the presence of hydrophilic monomers and urea. Thus, all of these products contain a comonomer, which suggest complicated synthetic processes.

[0381] In contrast, in our process, the bulk polymerisation takes place in a single step. The two main reagents (EGDMA and initiator) are used up in the polymerisation process, essentially reaching quantitative yield, after which only the porogen needs to be removed. The resultant polymer can be ground and sieved to any preferred size or particle size distribution.

[0382] In the case of Lixelle beads, their product first requires preparation of crosslinked cellulose beads with correct pore size distribution and particle size. Then, several chemical reaction steps are required for the linking of the hydrophobic ligand. With hexadecylamine for example, typically the cellulose surface would need to be activated with sodium hydroxide, followed by epoxidation and covalent coupling via amide bond.

[0383] In the case of cytosorbents (PCT / US1998 / 016118 and Davankov, V., etal., J. Chromatogr. B: Biomed. Sci. Appl., 2000, 739, 73-80), the invention involves formation of PS-DVB beads with hydrophilic coating. The synthesis of DVB beads is a comparatively lengthy process, requiring a more complex form of polymerisation such as emulsion or suspension polymerisation. These processes require addition of surfactant or stabilising agent, with many subsequent washing steps needed to remove the agent.

[0384] Comparative Example 2

[0385] Poly-EGDMA is a highly micro / mesoporous material, with a high proportion of large micropores and small mesopores, with an average pore size of 3.6-9.4 nm. These smaller pores are believed to provide size selectivity and B2M sieving effect. A small number of macropores present may allow for better fluid penetration into the interior of the particle, allowing for efficient mass transfer.

[0386] In contrast, other sorbents appear not to have not given priority to pore size (Lixelle, Kaneka Corporation (Japan)) or have focused on larger average pore size (Cytosorbents: 15-26 nm).

[0387] Comparative Example 3

[0388] Integrated binding sites within Polymer Matrix

[0389] B2M is a polypeptide is made up of 99 amino acid residues. B2M has both hydrophobic and hydrophilic residues on its surface. Literature simulations have shown that B2M binds quickly and irreversibly to hydrophobic surfaces via a 2-step process:

[0390] • initial adsorption by polar and charged groups; and

[0391] • partial unfolding occurs, maximizing adhesion of the protein to the hydrophobic surface (accentuated interaction of hydrophobic groups).

[0392] Poly-EGDMA is hydrophobic overall, based on EGDMA molecular properties (log P = 2.8, lipophilic > 0). Ester groups may serve as polar groups for initial adsorption step, while alkyl groups may provide hydrophobicity required for irreversible binding. The enhanced binding capacity of Poly-EGDMA may be due to utilisation of the entire polymer matrix for surface adsorption, whereby a larger surface area is available for B2M adsorption, allowing for more efficient and effective adsorption. The structure may allow for higher density of binding sites, compared to a design such as Lixelle, where only surface ligands are available for protein binding. This leads to increased binding affinity, as multiple interactions can occur simultaneously between B2M and the polymer matrix, enhancing overall binding strength.

[0393] Comparative Example 4

[0394] No inactive carrier material

[0395] In the case of Poly-EGDMA, the polymer matrix is the adsorbent. There is no need for an inactive solid support as in the cellulose beads used in Lixelle sorbent. This avoids wastage of space and enables manufacturing of smaller and lighter device.

[0396] Comparative Example 5

[0397] When considering the suitability of sorbent materials for a sorbent cartridge device in dynamic flow applications, the behavior and adsorption characteristics play a crucial role. Poly-EGDMA demonstrates rapid uptake and reaches saturation adsorption even at low B2M concentrations, indicating a strong affinity and efficient adsorption relationship with B2M. Therefore, Poly-EGDMA has high capacity and affinity for B2M.

[0398] In contrast, Lixelle beads exhibit a linear relationship between solute concentration and the quantity adsorbed, suggesting a weaker affinity or limited adsorption capacity even at high serum B2M concentrations. Further, large amount of beads are required to achieve significant binding and thus, they are likely to be ineffective for sorbent dialysis application where dialysate [B2M] is 1 / 60'hof serum level. Table 23. Comparative data.

[0399] Therefore, we have disclosed a porous polymeric sorbent based on crosslinked Poly-EGDMA, which unexpectedly has high adsorption capacity and selectivity for B2M, without templating. In comparison with the prior art, it can be produced cheaply, in addition to high chemical and physical stability.

[0400] Additionally, new functionalities such as hydrophilic moieties for improved biocompatibility can be easily incorporated into the synthesis and final product.

Claims

CLAIMS1 . A particulate porous material that comprises a crosslinked polymeric matrix including a first set of constitutional units formed from ethylene glycol dimethacrylate monomers wherein: the particulate porous material comprises a plurality of pores having a pore diameter of from about 1 .6 nm to about 50 nm: and the particulate porous material has a porosity of at least 3% (v / v) and a single point total pore volume of at least 0.15 cm3 / g.

2. The particulate porous material according to Claim 1 , wherein:(a) the particulate porous material has a Brunauer-Emmett-Teller adsorption average pore size of from 3 to 15 nm, such as from 3.5 to 10 nm (e.g. 3.6 to 9.4 nm); and / or(b) the particulate porous material has a porosity of at least 6% (v / v) and a single point total pore volume of at least 0.3 cm3 / g.

3. The particulate porous material according to Claim 1 , wherein the crosslinked polymeric matrix further comprises up to 30 mol % of a second set of constitutional units formed from a hydrophilic monomer, optionally wherein:(a) the hydrophilic monomer is selected from one or more of the group consisting of itaconic acid, 2-(trifluoromethyl)acrylic acid, and allylurea, and / or(b) the second set of constitutional units are present in an amount of from 2 to 25 mol % of the crosslinked polymeric matrix.

4. The particulate porous material according to Claim 1 , wherein the crosslinked polymeric matrix is formed from a homopolymer consisting of constitutional units formed from ethylene glycol dimethacrylate monomers.

5. The particulate porous material according to Claim 1 , having a porosity of from 8 to 30% (v / v), such as from 10 to 28% (v / v) (e.g. from 14 to 24% (v / v)).

6. The particulate porous material according to Claim 1 , having a single point total pore volume of from 0.36 to 0.85 cm3 / g, such as from 0.4 to 0.8 cm3 / g (e.g. from 0.45 to 0.75 cm3 / g).

7. The particulate porous material according to Claim 1 , having a porosity of from 8 to 30% (v / v) and a single point total pore volume of from 0.36 to 0.85 cm3 / g; optionally a porosity of from 10 to 28% (v / v) and a single point total pore volume of from 0.4 to 0.8 cm3 / g.

8. The particulate porous material according to Claim 1 , wherein the particulate porous material comprises a plurality of pores having a pore diameter of from about 1 .6 nm to about 10 nm.

9. The particulate porous material according to Claim 1 , wherein the particulate porous material has a nitrogen adsorption isotherm that is Type II or Type IV.

10. The particulate porous material according to Claim 1 , wherein the particulate porous material has a D50 of less than 200 pm.11 . The particulate porous material according to Claim 1 , wherein the particulate porous material has a total protein binding capacity that is less than 0.2g / g.

12. A sorbent formulation comprising the particulate porous material of Claim 1 and one or more of: cation exchange particles (e.g. zirconium phosphate); anion exchange particles(e.g. hydrous zirconium oxide); activated carbon ; a buffer; and a urease.

13. The sorbent formulation of claim 12, wherein the sorbent formulation comprises:(v) from 1 wt% to 6 wt% of the particulate porous material of Claim 1 ;(vi) from 47 wt% to 57 wt% of cation exchange particles;(vii) from 37 wt% to 47 wt% of anion exchange particles; and(viii) from 0.5 wt% to 2.5 wt% of a buffer.

14. The sorbent formulation of claim 12, wherein the sorbent formulation comprises:(iii) from 1 wt% to 10 wt% of the particulate porous material of Claim 1 ; and(iv) from 90 wt% to 99 wt% of activated carbon.

15. A sorbent cartridge suitable for use in purification of a bodily fluid (e.g. a kidney dialysis treatment, such as a haemodialysis treatment, a peritoneal dialysis treatment or a hemoperfusion treatment), wherein the sorbent cartridge contains the particulate porous material according to Claim 1 .

16. The sorbent cartridge according to Claim 15, wherein the sorbent cartridge contains the sorbent formulation of Claim 12.

17. A method of performing dialysis (e.g. haemodialysis, peritoneal dialysis or hemoperfusion), comprising a step of passing a dialysate through a sorbent formulation as defined in Claim 12 or a sorbent cartridge according to Claim 15.

18. Use of a particulate porous material as defined in Claim 1 , a sorbent formulation according to claim 12, or a sorbent cartridge according to Claim 15, to adsorb beta-2 microglobulin.

19. A method of removing beta-2 microglobulin from a fluid, comprising: providing a fluid comprising beta-2 microglobulin; and exposing said fluid to a particulate porous material as defined in Claim 1 .

20. A method of preparing a particulate porous material as defined in Claim 1 , the method comprising the steps:(i) providing mixture comprising a first monomer that is ethylene glycol dimethacrylate, an initiator, a porogen and optionally a second monomer that is a hydrophilic monomer;(ii) conducting a polymerisation reaction to form a bulk porous material; and(ill) grinding or pulverising the bulk porous material to provide a particulate porous material.21 . The method according to Claim 20, further comprising washing the particulate porous material to remove the porogen.

22. The method according to Claim 20, wherein one or both of the following apply:(a) the porogen is an organic solvent selected from the group consisting of toluene, chloroform, acetone, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, and acetonitrile; and(b) the porogen is an organic solvent having a Hansen distance (Ra) of up to 10 MPa1''2, where Dpoiymer23. The method according to Claim 20, wherein step (ii) is performed at a temperature of from 50°C to 70°C.

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