composite

Abstract

The invention relates to a method of preparing a composite, a composite, and a polymeric valve for a heart. The composite comprises (a) pyrolyzed particles of lignocellulosic biomass with an average particle diameter up to about 10 µm; and (b) a polycarbonate urethane polymer. The amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the urethane polymer. The method comprises (i) pyrolyzing particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 3 hours to provide the (a) pyrolyzed particles of lignocellulosic biomass; and (ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite.

Description

[0001] COMPOSITE

[0002] Field of the invention

[0003] The present invention relates to a composite and a polymeric valve for a heart comprising the composite, and methods of making the same.

[0004] Background to the invention

[0005] Heart valves (HVs) are unique elements of the cardiovascular system with the function to provide unidirectional smooth blood flow through the heart chambers and the vasculature by regularly opening and closing throughout each cardiac cycle. Depending on their anatomical position and structural configuration, HVs are subjected to different dynamic workloads and mechanical conditions.

[0006] When a heart valve (HV) fails to maintain its normal physiologic function due to severe damage, heart valve replacement (HVR) is often required. As a HVR, polymeric heart valves (PHV) offer significant potential advantages over currently available bioprosthetic (porcine / bovine) heart valves (that show limited durability and risk of rejection), and Mechanical heart valves (that require permanent anti-coagulant treatments, and often reoperation).

[0007] Though valve replacement is also possible for the other HVs (tricuspid, pulmonary, mitral) we initially concentrate in the Aortic Valve Replacement (AVR). The current market size for AVR in UK has stably grown in the past years by approximately 30% of which about 60% were via traditional surgical implant and about 40% were via transcatheteral implantation.

[0008] According to data from 2016 to 2019, approximately 82.5% of the Aortic Valve (AV) implants were bioprosthetic while 17.3% were mechanical and the remaining 0.2% were replaced using tissues extracted from same patients (homograft / autograft implantations). Polymeric HVs are not widely used, challenged by their susceptibility to thrombogenicity and material degradation, which leads to leaflet stiffening and tearing under fatigue loading.

[0009] In addition, it is known that the biological tissues in a human AV is highly anisotropic, i.e. it shows very different mechanical properties in the circumferential (stiff) vs. radial direction (flexible). This mechanical property is difficult to achieve with a uniform polymer that is naturally isotropic. Accordingly, there is a need in the art to provide synthesis of suitable synthetic tissue to replace current bioprosthetic and mechanical implantations.

[0010] Conventional heart valve replacements typically have a lifetime of up to 10 years before needing to be replaced. This is not desirable for younger patients, who may require numerous replacements throughout their lifetime. Moreover, the escalating trend of aging populations worldwide underscores the growing significance of heart valve replacements. As longevity increases, the demand for durable heart valves that can withstand the test of time becomes more critical. Accordingly, there is also a need for heart valves replacements with extended durability and increased lifetimes.

[0011] Summary of the invention

[0012] In a first aspect there is provided a method of preparing a composite, wherein the composite comprises (a) pyrolyzed particles of lignocellulosic biomass (LCB) with an average particle diameter up to about 10 pm; and (b) a polycarbonate urethane polymer; wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the urethane polymer; wherein the method comprises:

[0013] (i) pyrolyzing particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 1 hour to provide the (a) pyrolyzed particles of lignocellulosic biomass; and

[0014] (ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite.

[0015] In a second aspect there is provided a method of preparing a polymeric valve comprising preparing a composite according to the first aspect, and forming the composite into the form of a polymeric valve.

[0016] In a third aspect there is provided a composite obtainable by the method of the first aspect or a polymeric valve obtainable by the method the second aspect.

[0017] In a fourth aspect there is provided a composite comprising:

[0018] (a) a polycarbonate urethane polymer, and

[0019] (b) pyrolyzed particles of lignocellulosic biomass having an average particle diameter of from about 1 pm to about 10pm, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 75 wt.% based on the weight of the polycarbonate urethane polymer, and wherein the pyrolyzed particles of lignocellulosic biomass are dispersed and intermixed throughout the (b) polycarbonate urethane polymer.

[0020] Brief Description of the Drawings

[0021] Figure 1 shows an SEM image of the morphology of an SpEC capsule (approximately 25x25 urn size) before pyrolysis.

[0022] Figure 2 shows composites prepared according to the invention with different proportions of LCB biochars, uniformly dispersed in the polymeric membrane.

[0023] Figure 3a shows the tensile stress and strain properties of composites prepared according to the invention compared with pure polymer, at various thicknesses, for a strain from 0 to 50%.

[0024] Figure 3b shows the tensile stress and strain properties of composites prepared according to the invention compared with pure polymer, at various thicknesses, for a strain from 0 to 900%.

[0025] Figure 4(A) and (B) shows monoaxial cyclic tensile tests performed on composite leaflets, with (A) showing the last cycle showing reduced tensile strains, and (B) showing increased Young’s moduli coupled to decreased hysteresis-related energy loss, calculated as a ratio between the work dissipated through hysteresis (WdjS) and the total work stored in samples in the loading phase (Wj).

[0026] Detailed Description

[0027] Process for preparing a composite

[0028] In a first aspect there is a method of preparing a composite, wherein the composite comprises (a) pyrolyzed particles of lignocellulosic biomass with an average particle diameter up to about 10 pm; and (b) a polycarbonate urethane polymer; wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the urethane polymer; wherein the method comprises:

[0029] (i) pyrolyzing particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 1 hour to provide the (a) pyrolyzed particles of lignocellulosic biomass; and

[0030] (ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite.

[0031] Particles of lignocellulosic biomass

[0032] LCB refers to plant dry matter. LCB comprises carbohydrate polymers, including cellulose and hemicellulose, and an aromatic polymer, lignin, which together form the cell walls of plants.

[0033] The particles of LCB useful in the invention may preferably be Sporopollenin exine capsules (SpEC), obtained from raw Lycopodium clavatum sporopollenin. Figure 1 shows an example of the micro-structure of the Sporopollenin exine capsules (SpEC), obtained from raw Lycopodium clavatum sporopollenin. SpEC can be obtained using methods known in the art.

[0034] One method of obtaining sporopolleninSpEC is by extraction from Lycopodium clavatum spores. Such extractions are known in the art, and carried out using for example acids, bases or organic solvents. The sporopollenin exine layer is isolated from the rest of the spore components like the cytoplasm and intine layer to provide just the SpEC material. Preferably, the extraction method uses 6% NaOH at 80°C for 24 hours to extract SpECs from L. clavatum spores, followed by washing and drying steps to obtain the final purified SpEC powder. Suitable methods of extraction are described in Industrial Crops & Products 154 (2020) 772774 which is incorporated by reference in its entirety, in particular see section 2.1.2.2. on page 3, which is also incorporated herein by reference. Further suitable methods of extraction are found in RSC Adv., 2016, 6, 16533, incorporated herein by reference.

[0035] Step (i): pyrolysis and optional physical activation

[0036] The method comprises pyrolyzing the particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 3 hours to provide the (a) pyrolyzed particles of lignocellulosic biomass (hereinafter sometimes referred to simply as “biochar particles” for brevity).

[0037] Heating may be performed in a ventilated pre-heated oven, optionally with periodic mixing of the particles.

[0038] Preferably, the method may comprise a pyrolysis step of heating to a temperature of from about 250 to about 600 °C, more preferably of from about 250 to about 350 °C in an inert atmosphere (e.g. N2 or Ar) for a period of from about 30 minutes to about 1 .5 hours, preferably of from about 45 minutes to 1 hour. For instance, the method may comprise a step of heating to a temperature of about 300 °C in an inert atmosphere for a period of about 1 hour. For instance, the heating step may be carried out with a ramp in temperature, e.g. starting at 250 °C and increasing at a rate of 10 °C min-1under a constant flow of inert gas (e.g. N2) for a set period of time.

[0039] Without wishing to be bound by theory, it is believed this pyrolysis step provides the particles of lignocellulosic biomass with increased surface area and pore volume (see Table 1).

[0040] The pyrolysis step may further comprise a second step of heating to a temperature of from about 700 to about 1000 °C, preferably about 900 °C in a mildly oxidising atmosphere, for a period of from about 30 minutes to about 4 hours.

[0041] Without wishing to be bound by theory, it is believed this second heating step physically activates the particles and provides a further increase of the surface area and porosity (see e.g. Table 1). This step may be carried out as with ramp in temperature from e.g. 700 °C increasing at a rate of 10 °C min-1up to 1000 °C under a constant flow of CO2 and inert gas, for a set period of time. Once the second step of heating is completed, the gas flow is preferably switched back to an inert gas (e.g. N2) before cooling.

[0042] It is particularly preferred that the first and second step may be performed sequentially, as part of a continuous ramp in temperature, with the gas flow switched from inert to mildly oxidising during the ramp. For example, the biomass may undergo carbonisation during a ramp in temperature from 300 to 900 °C at a heating rate of 10 °C min-1under a constant flow of N2. As soon as the temperature reaches 900 °C, the gas flow may be switched from N2 to CO2 to physically activate the particles, for a period of about 3 hours.

[0043] It will be appreciated that the temperature and period of heating can be individually adjusted within the above-mentioned ranges to adjust the surface area and porosity of the biomass particles, which in turn influences the mechanical properties of the resulting composite.

[0044] The pyrolyzed particles of lignocellulosic biomass of the invention have an average particle diameter of up to about 10 pm. This may be achieved by tip sonification in a deionised water solution, for example. The solids from tip sonification may then be dried, e.g. in a desiccator.

[0045] The method thus may comprise a step, after pyrolysis (and optional physical activation) of reducing the particle size via tip-sonication, preferably in a deionised water (0 °C) bath for about 2 hours. Tip sonification may be performed with a frequency of about 10-20 kHz and about 500 W power.

[0046] The pyrolyzed particles of lignocellulosic biomass may have an average particle diameter of from about 0.1 pm to about 10 pm, preferably from about 1 pm to about 10 pm, more preferably of from about 3 pm to about 5 pm.

[0047] Average particle diameter may be measured using laser diffraction spectroscopy, for example using a laser diffraction spectrometer such as Mastersizer 2000 from Malvern Instruments.

[0048] The pyrolyzed particles of lignocellulosic biomass, as a result of the pyrolysis step, may have a surface area of from about 800 to 1200 m2g-1, and / or a porosity of from about 0.2 to about 0.4 cm3g'1.

[0049] The step of pyrolysis provides the particles of lignocellulosic biomass with increased surface area and pore volume (see Example 1 and Table 1).

[0050] Without wishing to be bound by theory, the step of pyrolysis according to the invention is believed to provide a desired combination of porosity, morphology and surface chemistry to the biochar particles, thus allowing them to appropriately bond with the polymer.

[0051] Polycarbonate urethane polymer

[0052] The composite of the present invention comprises a polycarbonate urethane polymer.

[0053] A “polycarbonate urethane polymer” is a reaction product of at least a polycarbonate glycol having terminal hydroxyl groups and a diisocyanate having terminal isocyanate groups. The polymeric backbone has recurring urethane and / or urea groups.

[0054] The polycarbonate urethane polymer may be a silicone polycarbonate urethane polymer, preferably a thermoplastic silicone polycarbonate urethane polymer.

[0055] The polycarbonate urethane polymer is suitably biocompatible. “Biocompatible” refers to the ability of a material to perform with an appropriate host response in a specific application. In the context of a composite material for use in implants, biocompatibility refers to the ability of the material to be accepted by the body without eliciting an adverse reaction, such as inflammation or rejection.

[0056] The polycarbonate urethane polymer may comprise terminal silicone groups. The polycarbonate urethane polymer may have a silicone content of from about 5 to about 25%, preferably about 20%.

[0057] The polycarbonate urethane polymer may preferably be a segmented block copolymer comprising: a) polycarbonate or polytetramethylene carbonate hard segment blocks made from an aromatic diisocyanate like 4,4’-methylenebis(phenyl isocyanate) and a polycarbonate or polytetramethylene carbonate diol; b) polysiloxane soft segment blocks comprising polydimethylsiloxane; c) the polymer having surface-modifying end groups selected from hydroxyl-terminated polydimethylsiloxane, amine-terminated polydimethylsiloxane, or methoxy-terminated polyethylene oxide.

[0058] The polycarbonate urethane segmented block copolymer may preferably further comprise: d) a weight ratio of hard segments to soft segments from 95:5 to 50:50; e) a number average molecular weight of the soft segments from about 1000 to about 20,000 g / mol; and f) a number average molecular weight of the hard segments of from about 300 to about 6000 g / mol.

[0059] The average molecular weight of polymers herein, unless otherwise expressly mentioned, is measured by gel permeation chromatography (GPC).

[0060] The polycarbonate urethane polymer suitably is processable by extrusion, injection molding, or solution casting methods.

[0061] The polycarbonate urethane polymer suitably has one or more of the following properties:

[0062] (a) a density of from about 1.00 to about 1.25 g.cm3;

[0063] (b) a tensile strength of from about 30 to about 50 MPa;

[0064] (c) an elongation of from about 300 to about 500%; and

[0065] (d) a melt flow rate of from about 10 to about 60 g / 10 min at 224°C; and

[0066] (e) a glass transition temperature (Tg) of from about -20 to about 20 °C.

[0067] An example of a preferred polycarbonate urethane polymer is CarboSil® Thermoplastic Silicone-Polycarbonate-urethane commercially available from DSM. The polycarbonate urethane polymer may be a block polymer combining siloxane and carbonate segments. The block polymer may comprise: a) polycarbonate hard segment blocks made from an aromatic diisocyanate (such as a 4,4- methylene diphenyl diisocyanate (4,4-MDI)) and a polycarbonate diol; and b) polysiloxane soft segment blocks comprising polydimethylsiloxane.

[0068] Most preferred is a triblock polyurethane polymer comprising the following structure: wherein n, x, y, and z are positive integers. For instance, n, x, y, and z may each independently be from 1 to 100, preferably each independently from 1 to 50.

[0069] Without wishing to be bound by theory, it is believed the polycarbonate urethane polymer according to the invention is suitable for cardiovascular applications for it is biologically stable, resistant to calcification and shows favourable mechanical and viscoelastic properties.

[0070] Step (ii): mixing

[0071] The method comprises (ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite.

[0072] The (a) pyrolyzed lignocellulosic biomass (biochar) particles and (b) polycarbonate urethane polymer may be mixed in any suitable manner, preferably so long as the pyrolyzed particles of lignocellulosic biomass are dispersed and intermixed throughout the (b) polycarbonate urethane polymer. For example, the biochar particles and urethane polymer may be mixed using a standard magnetic stirrer.

[0073] Preferably the polymer is first dissolved in a solvent, such as dimethylaceamide (DMAc), before mixing with the biochar particles, and the solvent is then removed later, e.g. by drying.

[0074] If forming a polymeric valve from the composite, then the composite may be placed in a mould before removing the solvent by drying, thereby providing the composite in the form of a polymeric valve.

[0075] In the composite, the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the polycarbonate urethane polymer, preferably of from about 1 wt.% to about 50 wt.%, about 1 wt.% to about 25 wt.%, or about 2 to about 10 wt.%, most preferably of from about 3 to about 6 wt.%.

[0076] The amount of pyrolyzed particles of lignocellulosic biomass may be from about 10 wt.% to about 75 wt.%, from about 10 wt.% to about 60 wt.%, or from about 10 wt.% to about 30 wt.% relative to the weight of the polycarbonate urethane polymer.

[0077] Without wishing to be bound by theory, the bio-compatibility of the composite is believed to be guaranteed by the polymer which completely coats the pyrolyzed particles.

[0078] The ability to vary the amount of pyrolyzed biomass in the final composite advantageously allows for the properties (such as strain %, tensile strength, etc.) of the resulting composite to be tuned according to the needs of the specific application.

[0079] Composite

[0080] In another aspect there is provided a composite obtainable by the method of the first aspect.

[0081] The term “composite” herein is a noun and refers to a composite material made by combining two or more materials with different properties to create an end material with enhanced overall performance and characteristics.

[0082] In another aspect there is provided a composite comprising:

[0083] (a) a polycarbonate urethane polymer, and

[0084] (b) pyrolyzed particles of lignocellulosic biomass having an average particle diameter of from about 1 m to about 10pm, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 75 wt.% based on the weight of the polycarbonate urethane polymer, and wherein the pyrolyzed particles of lignocellulosic biomass are dispersed and intermixed throughout the (b) polycarbonate urethane polymer.

[0085] The pyrolyzed particles of lignocellulosic biomass may have a surface area of from about 800 to about 1200 m2g'1and / or a porosity of from about 0.2 to about 0.4 cm3g'1. These are measured using the standard Brunauer-Emmett-Teller (BET) method widely used to measure both surface area and porosity. The (b) pyrolyzed particles of LCB have preferably been pyrolyzed according to the pyrolysis methods identified herein in relation to the first aspect, thereby increasing the surface area and pore volume of the particles. Without wishing to be bound by theory, it is believed that the ability to tune the surface area and / or porosity of the biochar particles as identified herein allows for superior bonding with the urethane polymer.

[0086] The particles of lignocellulosic biomass may have been pyrolyzed by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 3 hours, preferably by heating to a temperature of from about 250 to about 600 °C in an inert atmosphere for a period of from about 30 minutes to about 1.5 hours.

[0087] It will be appreciated that the features described in relation to the first aspect, in particular with respect to the pyrolyzed particles of lignocellulosic biomass and polycarbonate urethane polymer, are equally applicable to the composite.

[0088] Polymeric valve for a heart

[0089] In a second aspect there is a method of preparing a polymeric valve comprising preparing a composite according to the first aspect, and forming the composite into the form of a polymeric valve. Preferably, the composite may be formed into the form of leaflets for a polymeric valve.

[0090] Preferably, the valve may be a heart valve.

[0091] The valve may comprise a stent and a plurality of leaflets (e.g. three). The stent may be made of the composite material of the invention described herein, or be made of metal or plastic mesh, and it may provide the foundational scaffolding for the polymeric valve leaflets to attach to. The stent may also have a metal reinforcing frame embedded in it for added structural support and stiffness where needed.

[0092] The leaflets may be the movable flaps or cusps that open and close to regulate blood flow through the valve. The leaflets may rhythmically open and close their operative ends in relation to each other in response to blood flow and pressure changes. The valve may comprise two, three, or four leaflets, preferably three.

[0093] In another aspect there is a method of preparing a polymeric valve comprising a composite, wherein the method comprises preparing a composite according to the first aspect, and forming the composite into the form of at least part of a polymeric valve. Preferably, the composite is formed into the form of leaflets for a polymeric valve.

[0094] Forming the composite into the form of a polymeric valve may be carried out according to any suitable methods known in the art. The composite provided by the method may be deformable, e.g. due to addition of solvent.

[0095] Forming the composite into the form of a polymeric valve may comprise the steps of: a) placing the composite into a mould, wherein the mould is in the shape of a polymeric valve; b) curing the composite in the mould, thereby providing the composite in the form of a polymeric valve, wherein the composite is preferably cured by removal of solvent (e.g. by drying).

[0096] Alternatively, the polymeric valve may be formed by dip-coating.

[0097] Advantageously, preparing a polymeric valve by using the composite according the invention provides a polymeric valve that can be thinner, yet still achieve desirable mechanical performance.

[0098] Preferably, the thickness of the polymeric valve herein may be from about 0.12 mm to about 0.25 mm, preferably 0.17 mm. Preferably, the thickness of the leaflets of the polymeric valve herein may be from about 0.12 mm to about 0.25 mm.

[0099] Figures 3A and 3B show that even at these low thicknesses, the composites according to the invention show improved mechanical performance, with favourable stretch and tensile stress properties whilst at the same time allowing for a very thin heart valve leaflet.

[0100] It will be appreciated that the features described in relation to the method of the first aspect and to the composite, in particular with respect to the pyrolyzed particles of lignocellulosic biomass and polycarbonate urethane polymer, are equally applicable to the polymeric valve.

[0101] There is also provided a polymeric heart valve as described herein for use in a method of treating a heart valve disorder in a patient.

[0102] There is also provided a method for treating a heart valve disorder in a patient, comprising: a. removing the patient's defective or diseased heart valve; and b. implanting a polymeric valve as described herein. The heart valve disorder may be aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonic stenosis, pulmonic regurgitation, or rheumatic heart disease, preferably aortic regurgitation, mitral stenosis, aortic stenosis or mitral regurgitation.

[0103] The aspects provided herein are also described in the following clauses:

[0104] 1. A method of preparing a composite, wherein the composite comprises (a) pyrolyzed particles of lignocellulosic biomass with an average particle diameter up to about 10 pm; and (b) a polycarbonate urethane polymer; wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the urethane polymer; wherein the method comprises:

[0105] (i) pyrolyzing particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 3 hours to provide the (a) pyrolyzed particles of lignocellulosic biomass; and

[0106] (ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite. la. A method according to clause 1 , wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 50 wt.% relative to the weight of the urethane polymer. l b. A method according to clause 1 , wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 25 wt.%, or is from about 1 wt.% to about 15 wt.% relative to the weight of the urethane polymer. lc. A method according to clause 1 , wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 10 wt.% to about 75 wt.%, from about 10 wt.% to about 60 wt.%, or from about 10 wt.% to about 30 wt.% relative to the weight of the polycarbonate urethane polymer.

[0107] 2. A method according to clause 1 or 1a or 1 b or 1c, wherein the step of pyrolyzing particles of lignocellulosic biomass comprises heating to a temperature of from about 250 to about 600 °C in an inert atmosphere for a period of from about 30 minutes to about 3 hours, preferably 45 minutes to about 1.5 hours. 3. A method according to clause 2, wherein the step of pyrolyzing particles of lignocellulosic biomass comprises heating to a temperature of from about 250 to about 350 °C in an inert atmosphere for a period of from about 45 minutes to about 1.2 hours.

[0108] 4. A method according to clause 3, wherein the step of pyrolyzing particles of lignocellulosic biomass comprises heating to a temperature of from about 300 °C in an inert atmosphere for a period of about 1 hour.

[0109] 5. A method according to any one of clauses 1 to 4, wherein the inert atmosphere is N2 or Ar gas.

[0110] 6. A method according to clauses 2-5, wherein the step of pyrolyzing particles of lignocellulosic biomass comprises, after heating in an inert atmosphere, a further step of heating to a temperature of from about 700 to about 1000 °C in a mildly oxidizing atmosphere for a period of about 30 minutes to about 4 hours.

[0111] 6a. A method according to clause 6, wherein, after heating in an inert atmosphere, the further step of heating comprises heating to a temperature of from about 800 to about 950 °C for a period of about 2 hours to about 4 hours.

[0112] 7. A method according to clause 6 or 6a, wherein the mildly oxidizing atmosphere is composed of 10% to 100% v / v CO2, with the remaining being inert gas.

[0113] 8. A method according to any one of clauses 1 to 7, wherein the particles of lignocellulosic biomass are Sporopollenin exine particles.

[0114] 9. A method according to clause 8, wherein the Sporopollenin exine particles (SpEC) are obtained from raw Lycopodium clavatum sporopollenin.

[0115] 10. A method according to clause 9, wherein the Sporopollenin exine particles (SpEC) are obtained from raw Lycopodium clavatum sporopollenin by extraction with sodium hydroxide solution.

[0116] 11. A method according to any one of the preceding clauses, wherein the particles of lignocellulosic biomass have an average particle diameter of from about 0.5 pm to about 10 pm. 12. A method according to clause 11, wherein the particles of lignocellulosic biomass have an average particle diameter of from about 3 pm to about 5 pm.

[0117] 13. A method according to any one of the preceding clauses, wherein the average particle diameter is measured by laser diffraction spectroscopy.

[0118] 14. A method according to any one of the preceding clauses, wherein the method comprises a step of tip sonication of the pyrolyzed particles of lignocellulosic biomass to provide the required average particle diameter.

[0119] 15. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer is a silicone polycarbonate urethane polymer.

[0120] 16. A method according to clause 15, wherein the silicone polycarbonate urethane polymer is a thermoplastic silicone polycarbonate urethane polymer.

[0121] 17. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer comprises terminal silicone groups.

[0122] 18. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer has a silicone content of from about 5 to about 25% w / w.

[0123] 19. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer comprises polycarbonate urethane hard blocks and polydimethylsiloxane (PDMS) soft blocks.

[0124] 20. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer is a segmented block copolymer comprising: a) polycarbonate or polytetramethylene carbonate hard segment blocks made from an aromatic diisocyanate and a polycarbonate or polytetramethylene carbonate diol; b) polysiloxane soft segment blocks comprising polydimethylsiloxane; c) the polymer having surface-modifying end groups selected from hydroxyl terminated polydimethylsiloxane, amine-terminated polydimethylsiloxane, or methoxy-terminated polyethylene oxide.

[0125] 21. A method according to any one of the preceding clauses, wherein the segmented block copolymer comprises: d) a weight ratio of hard segments to soft segments from 95:5 to 50:50; e) a number average molecular weight of the soft segments from about 1000 to about 20,000 g / mol; and f) a number average molecular weight of the hard segments of from about 300 to about 6000 g / mol, wherein the number average molecular weight is measured by gel permeation chromatography (GPC).

[0126] 22. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer has one or more of the following properties:

[0127] (a) a density of from about 1 .00 to about 1.25 g / cm3;

[0128] (b) a tensile strength of from about 30 to about 50 MPa;

[0129] (c) an elongation of from about 300 to about 500%; and

[0130] (d) a melt flow rate of from about 10 to about 60 g / 10 min at 224°C; and

[0131] (e) a glass transition temperature (Tg) of from about -20 to about 20 °C.

[0132] 23. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer is biocompatible.

[0133] 23a. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer is a block polyurethane combining siloxane and carbonate segments.

[0134] 23b. A method according to any one of the preceding clauses, wherein the polycarbonate urethane polymer comprises the following structure: wherein n, x, y, and z are positive integers that may each independently be from 1 to 100.

[0135] 24. A method according to any one of the preceding clauses, wherein the method comprises step (ia) of dissolving the polycarbonate urethane polymer in a solvent before the mixing step (ii).

[0136] 25. A method according to any one of the preceding clauses, wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 15 wt.% relative to the weight of the polycarbonate urethane polymer. 26. A method according to any one of the preceding clauses, wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 2 wt.% to about 10 wt.% relative to the weight of the polycarbonate urethane polymer.

[0137] 27. A method according to any one of the preceding clauses, wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 3 wt.% to about 6 wt.% relative to the weight of the polycarbonate urethane polymer.

[0138] 28. A method of preparing a polymeric valve comprising a composite, the method comprising:

[0139] (i) preparing the composite according to any one of the preceding clauses, and

[0140] (ii) forming the composite into the form of a polymeric valve.

[0141] 29. A method of preparing a polymeric valve according to clause 28, wherein forming the composite comprises: iia) placing the composite into a mould, wherein the mould is in the shape of a polymeric valve; iib) curing the composite in the mould, thereby providing the composite in the form of a polymeric valve.

[0142] 29a. A method of preparing a polymeric valve according to clause 28, wherein forming the composite comprises: iia) providing the composite as a solution, iib) dip coating a mould into the composite solution, wherein the mould is in the shape of a polymeric valve; iic) curing the composite, thereby providing the composite in the form of a polymeric valve.

[0143] 30. A method of preparing a polymeric valve according to clause 29 or 29a, wherein the composite is cured by removal of a solvent.

[0144] 31. A method of preparing a polymeric valve according to any one of clauses 28-30, wherein a thickness of a plurality of leaflets of the polymeric valve is from about 0.12 mm to about 0.25 mm.

[0145] 31a. A method of preparing a polymeric valve according to any of clauses 28-31 , wherein the polymeric valve comprises a stent attached to a plurality of leaflets. 31b. A method of preparing a polymeric valve according to clause 31a, wherein the polymeric valve comprises three leaflets.

[0146] 31c. A method of preparing a polymeric valve according to clause 31a or 31b, wherein the stent is made of metal or plastic.

[0147] 31 d. A method of preparing a polymeric valve according to any of clauses 31 a-31 c, wherein the valve is a heart valve.

[0148] 32. A composite obtainable by the method of any of clauses 1-27 or a polymeric valve obtainable by the method of any of clauses 28-31 d.

[0149] 33. A composite comprising:

[0150] (a) a polycarbonate urethane polymer, and

[0151] (b) pyrolyzed particles of lignocellulosic biomass having an average particle diameter of from about 1 m to about 10pm, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 75 wt.% based on the weight of the polycarbonate urethane polymer, and wherein the pyrolyzed particles of lignocellulosic biomass are dispersed and intermixed throughout the (b) polycarbonate urethane polymer.

[0152] 33a. A composite according to clause 33, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 50 wt.% based on the weight of the polycarbonate urethane polymer.

[0153] 33b. A composite according to clause 33, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 25 wt.%, or from about 1 wt.% to about 15 wt.%, based on the weight of the polycarbonate urethane polymer.

[0154] 33c. A composite according to clause 33, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts is of from about 10 wt.% to about 75 wt.%, of from about 10 wt.% to about 60 wt.%, or of from about 10 wt.% to about 30 wt.%, based on the weight of the polycarbonate urethane polymer.

[0155] 34. A composite according to clause 33, or any one of 33a to 33c, wherein the pyrolyzed particles of lignocellulosic biomass have a surface area of from about 800 to about 1200 m2 / g. 35. A composite according to clause 33, or any one of 33a to 33c, or clause 34, wherein the pyrolyzed particles of lignocellulosic biomass have a porosity of from about 0.2 to about 0.4 cm3 / g.

[0156] 36. A composite according to any one of clauses 33-35, wherein the particles of lignocellulosic biomass are Sporopollenin exine particles.

[0157] 37. A composite according to any one of clauses 33-36, wherein the polycarbonate urethane polymer is a silicone polycarbonate urethane polymer.

[0158] 38. A composite according to any one of clauses 33-37, wherein the polycarbonate urethane polymer comprises terminal silicone groups.

[0159] 39. A composite according to any one of clauses 33-38, wherein polycarbonate urethane polymer has a silicone content of from 5 to 25%.

[0160] 40. A composite according to any one of clauses 33-39, wherein the polycarbonate urethane polymer comprises polycarbonate urethane hard blocks and polydimethylsiloxane (PDMS) soft blocks.

[0161] 41. A composite according to any one of clauses 33-40, wherein the polycarbonate urethane polymer comprises the following structure: wherein n, x, y, and z are positive integers that may each independently be from 1 to 100.

[0162] 42. A composite according to any one of clauses 33-41 , wherein the polycarbonate urethane polymer has one or more of the following properties:

[0163] (a) a density of from about 1.00 to about 1.25 g.cm3;

[0164] (b) a tensile strength of from about 30 to about 50 MPa;

[0165] (c) an elongation of from about 300 to about 500%; and

[0166] (d) a melt flow rate of from about 10 to about 60 g / 10 min at 224°C; and

[0167] (e) a glass transition temperature (Tg) of from about -20 to about 20 °C.

[0168] 43. A polymeric valve comprising the composite according to any of clauses 32-42. 44. A polymeric valve according to clause 44, wherein the polymeric valve comprises a stent attached to a plurality of leaflets.

[0169] 45. A polymeric valve according to any of clauses 43-44, wherein the polymeric valve comprises three leaflets.

[0170] 46. A polymeric valve according to any of clauses 43-45, wherein the stent is made of metal or plastic.

[0171] 47. A polymeric valve according to any of clauses 44-46, wherein a thickness of the plurality of leaflets of the polymeric valve is from about 0.12 mm to about 0.25 mm

[0172] 48. A polymeric valve according to any of clauses 43-47, wherein the valve is a heart valve.

[0173] 49. A method for treating a heart valve disorder in a patient, comprising: a. removing the patient's defective or diseased heart valve; and b. implanting a polymeric valve according to clause 31 d or 48.

[0174] 50. A polymeric valve according to any of clauses 28-31 d, or clause 48 for use in a method of treating a heart valve disorder in a patient.

[0175] Examples

[0176] The present invention will now be described by way of reference to the following examples. These examples are not to be construed as being limiting on the invention.

[0177] Example 1a - pyrolysis of biomass

[0178] The pyrolyzed particles (biochar) are prepared as follows

[0179] 1 . Sporopollenin exine capsules (SpEC) from raw Lycopodium clavatum sporopollenin available commercially from different sources, extracted in 6% sodium hydroxide for 24 hours. The fully detailed methods for extraction of the capsules can be found in Industrial Crops & Products 154 (2020) 112714 (see section 2.1.2.2. of page 3).

[0180] 2. The extracted capsules are placed in a ventilated oven pre-heated to 300 °C and held at 300 °C for 1 hour and then cooled down naturally to room temperature.

[0181] 3. The carbonised SpEC are then collected and tip-sonicated in a deionised water solution, ratio of 0.1g of SpEC every 25ml of deionised water, cooled by an ice bath (0 °C) for 4 hours. 2 hours active sonication, 2 hours overall pause in between intervals with a pulse interval of 1 sec active sonication and 1 sec pause, at a frequency of 15 kHz.

[0182] 4. The prepared solids are then kept in a desiccator prior to mixing with the polymer.

[0183] The surface area and pore volume were measured before and after pyrolysis. The results are shown below in Table 1 , wherein it can be seen that the pyrolysis step provided the particles with significantly increased surface area and pore volume, compared with the untreated capsules.

[0184] Example 1b - physical activation of biomass

[0185] Example 1a was repeated except that, after the step of heating in an inert atmosphere, the particles were subjected to a further step of heating to higher temperatures (-900 °C) under a mildly oxidising atmosphere including CO2 and inert gas to physically activate the SpEC. This led to a further dramatic increase in surface area and porosity, evident from the results shown in Table 1. Table 1 : surface area and pore volume of SpEC before and after pyrolysis step

[0186] Without wishing to be bound by theory, it is believed that the increased surface area and pore volume contributes to the improvements in mechanical properties of the final composite.

[0187] Example 2 - preparing composites

[0188] The composites were prepared as follows:

[0189] 1. 4.25g of Dimethylacetamide (DMAc) is mixed with 0.75g of TSPCll (CarboSil™ 80A obtained from DSM Medical: Product name: FP70060 Carbosil 20 80A UR TSPCU) to provide a mixture.

[0190] 2. The pyrolyzed biomass from Example 1 is then added in varying amounts from 0.015 - 0.075g (corresponding to 2% - 10% by weight of the TSPCU polymer) and mixed to provide a homogenous mixture.

[0191] 3. The mixture is then cured in a flat glass dish at room temperature in a sealed container under 2 litres per minute (LPM) forced dry technical air for 24 hours, to provide a cured composite.

[0192] It will be appreciated that the composites are cured on a flat dish and thus obtain a flat shape in Example 2 (see Figure 2). However, various shapes, in particular for forming a valve leaflet for a polymeric heart valve, are obtainable in the same way by, e.g. curing the composite onto a shaped mould instead.

[0193] Example 3 - testing properties of the prepared composites

[0194] Composites containing 3 and 6 wt.% of pyrolyzed biomass (SpEC) and with thicknesses of 0.12mm, 0.16mm, 0.20mm, and 0.23mm were prepared according to the method of Example 2 and tested for their tensile stress (MPa) and strain % properties. The results were compared with control samples (“Polymer”) containing only polymer (i.e. without any biochar filler) with thicknesses of 0.06 mm and 0.08 mm. The results are shown in Figures 3A and 3B. It can be seen from Figures 3A and 3B that there is a clear correlation between an increasing amount of biochar (pyrolyzed particles of lignocellulosic biomass) content, and a decrease of the maximum stress and an increase of the maximum strain. An increase of the maximum strain is advantageous since a higher strain is correlated to higher durability, whilst a stress of 25 to 30 MPa is an order of magnitude higher that the expected stresses during a polymeric heart valve’s operation.

[0195] The shape of the stress-strain curve in Figures 3A and 3B for the samples comprising pyrolyzed biomass show a viscoelasticity suitable for use in a heart valve. In particular, the Young Modulus (slope of the curve) for strain between 0 and 30% are still within the range of an expected heart valve’s operation (with comparable results to the polymer only sample). Moreover, it has been shown that these results are achieved with samples having a low thickness. Decreased thickness significantly reduces the tissue bending stiffness (which is proportional to the cube of its thickness) and it is therefore desirable.

[0196] Advantageously, it can be seen from Figure 3B that the samples including pyrolyzed biomass have dramatically increased Strain %. There is a clear correlation between the amount of pyrolyzed biomass included in the sample and the Strain %. That is, the composites including pyrolyzed biomass show increased durability, which in turn, allows for a polymeric heart valve with an increased lifetime. As mentioned above, this may lead to a reduction in the number of heart valve replacements required throughout a patients lifetime.

[0197] Example 4 - Monoaxial cyclic tensile tests (50 cycles) on composite leaflets

[0198] In this example, monoaxial cyclic tensile tests were performed on composites prepared according to Example 2. These tests involve subjecting the composites to testing conditions more similar to physiological loading.

[0199] The monoaxial cyclic tensile tests were preformed on composite leaflets for 50 cycles, up to 5 MPa maximum stress. The samples were 110-120 pm in thickness, containing from 0 to 25% w / w of the pyrolyzed biomass filler (relative to the weight of the urethane polymer). Figure 4 (A) shows the last cycle showing reduced tensile strains. Figure 4 (B) shows increased Young’s moduli coupled to decreased hysteresis-related energy loss, calculated as a ratio between the work dissipated through hysteresis (WdjS) and the total work stored in samples in the loading phase (Wj).

[0200] It can be seen from Figure 4 (A and B) that this test shows: 1) increasing Young’s moduli and lower maximum strains for higher concentrations of fillers (Figure 4 (A)); and

[0201] 2) decreasing hysteresis with increase of Young’s moduli above 10% w / w of filler (Figure 4 (B)).

[0202] These results show that the fillers improve the mechanical responses of the leaflets under physiological loading.

Claims

Claims1 . A method of preparing a composite, wherein the composite comprises (a) pyrolyzed particles of lignocellulosic biomass with an average particle diameter up to about 10 pm; and (b) a polycarbonate urethane polymer; wherein the amount of pyrolyzed particles of lignocellulosic biomass is from about 1 wt.% to about 75 wt.% relative to the weight of the urethane polymer; wherein the method comprises:(i) pyrolyzing particles of lignocellulosic biomass by heating to a temperature of from about 250 °C to about 1000 °C in an inert or mildly oxidizing atmosphere for a period of from about 30 minutes to about 3 hours to provide the (a) pyrolyzed particles of lignocellulosic biomass; and(ii) mixing together the (a) pyrolyzed particles of lignocellulosic biomass and (b) polycarbonate urethane polymer to provide the composite.

2. A method according to claim 1 , wherein the step (i) of pyrolyzing particles of lignocellulosic biomass comprises heating to a temperature of from about 250 to about 600 °C in an inert atmosphere for a period of from about 30 minutes to about 3 hours.

3. A method according to claim 2, wherein the step (i) of pyrolyzing particles of lignocellulosic biomass comprises, after heating in an inert atmosphere, a step of heating to a temperature of from about 700 to about 1000 °C in a mildly oxidizing atmosphere for a period of from about 30 minutes to about 4 hours.

4. A method according to any one of the preceding claims, wherein the particles of lignocellulosic biomass are Sporopollenin exine particles.

5. A method according to any one of the preceding claims, wherein the polycarbonate urethane polymer is a silicone polycarbonate urethane polymer.

6. A method according to any one of the preceding claims, wherein the polycarbonate urethane polymer comprises terminal silicone groups.

7. A method according to any one of the preceding claims, wherein the polycarbonate urethane polymer has a silicone content of from about 5 to about 25%.

8. A method according to any one of the preceding claims, wherein the polycarbonate urethane polymer comprises polycarbonate urethane hard blocks and polydimethylsiloxane (PDMS) soft blocks.

9. A method according to any one of the preceding claims, wherein the polycarbonate urethane polymer comprises the following structure:wherein n, x, y, and z are positive integers that may each independently be from 1 to 100.

10. A method of preparing a polymeric valve comprising a composite, the method comprising:(i) preparing the composite according to any one of the preceding claims, and(ii) forming the composite into the form of a polymeric valve.

11. A composite obtainable by the method of any of claims 1-9 or a polymeric valve obtainable by the method of claim 10.

12. A composite comprising:(a) a polycarbonate urethane polymer, and(b) pyrolyzed particles of lignocellulosic biomass having an average particle diameter of up to about 10pm, wherein the pyrolyzed particles of lignocellulosic biomass are present in amounts of from about 1 wt.% to about 75 wt.% based on the weight of the polycarbonate urethane polymer, and wherein the pyrolyzed particles of lignocellulosic biomass are dispersed and intermixed throughout the (b) polycarbonate urethane polymer.

13. A composite according to claim 12, wherein the particles of lignocellulosic biomass are Sporopollenin exine particles.

14. A composite according to any one of claims 12-13, wherein the polycarbonate urethane polymer is a silicone polycarbonate urethane polymer.

15. A composite according to any one of claims 12-14, wherein the polycarbonate urethane polymer comprises terminal silicone groups.

16. A composite according to any one of claims 12-15, wherein polycarbonate urethane polymer has a silicone content of from 5 to 25%.

17. A composite according to any one of claims 12-16, wherein the polycarbonate urethane polymer comprises polycarbonate urethane hard blocks and polydimethylsiloxane (PDMS) soft blocks.

18. A composite according to any one of claims 12-17, wherein the polycarbonate urethane polymer has following structure:wherein n, x, y, and z are positive integers that may each independently be from 1 to 100.

19. A composite according to any one of claims 12-18, wherein the polycarbonate urethane polymer has one or more of the following properties:(a) a density of from about 1.00 to about 1.25 g / cm3;(b) a tensile strength of from about 30 to about 50 MPa;(c) an elongation of from about 300 to about 500%; and(d) a melt flow rate of from about 10 to about 60 g / 10 min at 224°C; and(e) a glass transition temperature (Tg) of from about -20 to about 20 °C.

20. A polymeric valve comprising the composite according to any of claims 12-19.

Images